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CD003785	[ "10622295", "10728741" ]	[ "Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group.", "Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group." ]	[ "Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.\n In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.\n At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.\n During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.", "To determine whether treatment with leflunomide (LEF), methotrexate (MTX), or sulfasalazine (SSZ) for 6-12 months retards progression of radiographic damage and to identify clinical variables that correlate with radiographic progression.\n Radiographs of the hands and feet were performed at baseline and at the end of study or early exit in 3 randomized controlled trials. Protocol US301 was a 12-month controlled trial of LEF or MTX treatment compared with placebo in 482 patients randomized in a 3:3:2 ratio. Protocol MN301 compared 6 months of LEF or SSZ treatment with placebo in 358 patients, randomized in a 3:3:2 ratio, with continued blinded treatment in the active control arms for 12 months. Protocol MN302 compared 12 months of LEF treatment with MTX in 999 patients. Radiographs were blinded for sequence and treatment and were scored for erosions and joint space narrowing. All analyses were by intent-to-treat. Sensitivity analyses were performed to account for missing data.\n LEF, MTX, and SSZ treatment resulted in statistically significantly less radiographic progression compared with placebo at 6 and 12 months: for protocol US301, LEF versus placebo P = 0.0007 and MTX versus placebo P = 0.0196; for protocol MN301, LEF versus placebo P = 0.0004 and SSZ versus placebo P = 0.0484. The effect of LEF treatment was similar to that of MTX and SSZ.\n These are the first 6- and 12-month randomized placebo- and active drug-controlled trials to demonstrate retardation of radiographic progression by a new disease-modifying antirheumatic drug (DMARD), LEF, as well as 2 commonly used DMARDs, MTX and SSZ." ]	Treatment with infliximab for 6 and 12 months significantly reduces RA disease activity and appeared to have an acceptable safety profile in these trials. Total radiographic scores improved, fewer patients showed radiographic progression, and more patients showed radiographic improvement with infliximab treatment at 12 months compared to controls. However, only 2 trials met the inclusion criteria, and these results are largely driven by the largest trial. The available efficacy and toxicity data is relatively short-term (6-12 months). In order to detect rare events that may be associated with infliximab, larger and longer term studies are required.
CD007290	[ "17534702" ]	[ "Evaluation of a short-form functional capacity evaluation: less may be best." ]	[ "Functional Capacity Evaluation (FCE) contributes to clinical decisions regarding fitness-for-work and may improve return-to-work outcomes. However, FCE is a burdensome clinical tool in terms of time and cost. We evaluated the effectiveness of a short-form FCE protocol.\n A cluster randomized controlled trial was conducted. Data were collected on all claimants undergoing FCE at Alberta's workers' compensation rehabilitation facility. Twenty-three clinicians who were trained and experienced with FCE were randomized to either an intervention or control group. The intervention group was trained to conduct short-form FCE and used this protocol through the trial's duration, while the control group continued standard FCE procedures. Data on subject characteristics, administrative outcomes (days to suspension of time loss benefits, days to claim closure, and future recurrence) and claimant satisfaction were extracted from the WCB-Alberta computer databases. Clinicians logged time taken to complete assessments. Analysis included examining differences between groups using independent samples t tests, Cox and logistic regression.\n Subjects included 372 claimants of whom 173 were tested with short-form FCE. Subjects were predominantly employed (64%) males (69%) with chronic musculoskeletal conditions (median duration 252 days). Administrative recovery outcomes were similar between groups as were claimant satisfaction ratings. No statistically significant or clinically relevant differences were observed on these outcomes between groups. A 43% reduction in functional assessment time was seen.\n A short-form FCE appears to reduce time of assessment while not affecting recovery outcomes when compared to standard FCE administration. Such a protocol may be an efficient option for therapists performing fitness-for-work assessments." ]	There is no evidence for or against the effectiveness of FCE compared to no intervention. A short version of FCE showed similar effectiveness to a long version in preventing re-injury. More RCTs are needed.
CD007248	[ "17485450" ]	[ "Propofol compared with the morphine, atropine, and suxamethonium regimen as induction agents for neonatal endotracheal intubation: a randomized, controlled trial." ]	[ "The purpose of this work was to compare the efficacy of propofol, a hypnotic agent, to the regimen of morphine, atropine, and suxamethonium as an induction agent for nonemergency neonatal endotracheal intubation. We hypothesized that propofol aids intubation by allowing the continuation of spontaneous breathing.\n We conducted a randomized, open-label, controlled trial of infants who required nonemergency endotracheal intubation. Primary outcome was successful intubation confirmed by chest auscultation and clinical examination of the infant.\n Infants randomly assigned to propofol (n = 33) and the morphine, atropine, and suxamethonium regimen (n = 30) were comparable in median gestational age (27 vs 28 weeks), birth weight (1020 vs 1095 g), weight at intubation (1068 vs 1275 g), and age at intubation (4 vs 3 days). Sleep or muscle relaxation were achieved within 60 seconds in both groups, but time to achieve successful intubation was more than twice as fast with propofol (120 vs 260 seconds). Blood pressure and heart rates were not different, but intraprocedural oxygen saturations were significantly lower in infants on the morphine, atropine, and suxamethonium regimen (trough arterial oxygen saturation: 60% vs 80%). Nasal/oral trauma was less common, and recovery time was shorter (780 vs 1425 seconds) in the propofol group. No significant adverse effects were seen in either group.\n Propofol is more effective than the morphine, atropine, and suxamethonium regimen as an induction agent to facilitate neonatal nasal endotracheal intubation. Importantly, hypoxemia was less severe, probably because of the maintenance of spontaneous breathing. A controlled environment may have promoted the ease of intubation, resulting in less trauma. The shorter duration of action would be advantageous in a compromised infant." ]	No practice recommendation can be made based on the available evidence regarding the use of propofol in neonates. Further research is needed on the pharmacokinetics of propofol in neonates and once a relatively safe dose is identified, randomised controlled trials assessing the safety and efficacy of propofol are needed.
CD006044	[ "10851374", "17662571", "18428211", "11502921", "17938371", "10506679", "9415509", "11160953", "17161535", "8232944", "17335465" ]	[ "A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy.", "Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain.", "Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3.", "Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study.", "Lamotrigine extended-release as adjunctive therapy for partial seizures.", "200 mg daily of lamotrigine has no analgesic effect in neuropathic pain: a randomised, double-blind, placebo controlled trial.", "Lamotrigine (lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial.", "Lamotrigine for central poststroke pain: a randomized controlled trial.", "Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.", "Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. U.S. Lamotrigine Protocol 0.5 Clinical Trial Group.", "Randomized double-blind study comparing the efficacy and safety of lamotrigine and amitriptyline in painful diabetic neuropathy." ]	[ "To investigate the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP).\n The pathogenesis of HIV-associated DSP is unknown and there is no effective treatment. A novel anticonvulsant, lamotrigine, blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. There have been anecdotal reports of efficacy of lamotrigine in the treatment of painful neuropathy and trigeminal neuralgia.\n In a multicenter, randomized, double-blind, placebo-controlled study, lamotrigine was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Study duration was 14 weeks. The primary outcome measure was change in pain on the modified Gracely scale with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief.\n Of 42 enrolled subjects, 13 did not complete the 14-week study endpoint. In five of these, rash was the cause for dropout. In the remaining 29 evaluable subjects, 20 patients received placebo and 9 received lamotrigine. The pain scores at baseline were not significantly different. The reduction in average pain from baseline to week 14 was greater (p = 0.03) in the lamotrigine group (-0.55) than in the placebo group (-0.18), adjusting for baseline levels of pain. There was no difference between the groups on the change in peak worst pain.\n In this small trial, lamotrigine showed promise in the treatment of pain associated with HIV-related DSP. The frequency of rash was greater than in lamotrigine studies in epilepsy. A larger controlled study of lamotrigine is warranted.", "This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.", "Lamotrigine, an antiepileptic agent, has been reported as being effective in reducing symptoms of neuropathy associated with various etiologies. Based on such data, a multicenter double-blind, placebo-controlled, randomized trial was conducted to evaluate the effect of lamotrigine on pain and other neuropathic symptoms due to chemotherapy-induced peripheral neuropathy (CIPN).\n Patients with symptomatic CIPN with symptom scores of either 1) >3 on a 0-10 Numerical Rating Scale (NRS) or 2) >1 on the 0-3 the Eastern Cooperative Oncology Group (ECOG) neuropathy scale (ENS) were eligible (higher numbers corresponding to greater severity of symptoms in both scales). Patients were randomly assigned to receive lamotrigine (target dose of 300 mg/day) or placebo for 10 weeks. Endpoints were measured biweekly.\n In all, 131 patients were enrolled. Both groups were well matched at baseline. Over the 10-week period of the trial, the average pain scores (NRS) for the lamotrigine and placebo arms declined in both arms, with no statistically significant difference noted between the changes in the 2 groups (0.3 and 0.5 unit reduction from baseline, respectively; P=.56). Similarly, decreases in the ENS with therapy were not statistically different (0.4 and 0.3, respectively; P=.3). Changes in other subjective symptom scales were also not found to be statistically different between the 2 groups. Toxicities were mild and similar in each group.\n The results suggest that lamotrigine is not effective for relieving neuropathic symptoms in patients because of CIPN.\n Copyright (c) 2008 American Cancer Society.", "To study the efficacy of lamotrigine in relieving the pain associated with diabetic neuropathy.\n The authors randomly assigned 59 patients to receive either lamotrigine (titrated from 25 to 400 mg/day) or placebo over a 6-week period. Primary outcome measure was self-recording of pain intensity twice daily with a 0 to 10 numerical pain scale (NPS). Secondary efficacy measures included daily consumption of rescue analgesics, the McGill Pain Questionnaire (MPQ), the Beck Depression Inventory (BDI), the Pain Disability Index (PDI), and global assessment of efficacy and tolerability.\n Twenty-four of 29 patients (83%) receiving lamotrigine and 22 of 30 (73%) patients receiving placebo completed the study. Daily NPS in the lamotrigine-treated group was reduced from 6.4 +/- 0.1 to 4.2 +/- 0.1 and in the control group from 6.5 +/- 0.1 to 5.3 +/- 0.1 (p < 0.001 for lamotrigine doses of 200, 300, and 400 mg). The results of the MPQ, PDI, and BDI remained unchanged in both groups. The global assessment of efficacy favored lamotrigine treatment over placebo, and the adverse events profile was similar in both groups.\n Lamotrigine is effective and safe in relieving the pain associated with diabetic neuropathy.", "To evaluate the efficacy and tolerability of once-daily adjunctive lamotrigine extended-release (XR) for partial seizures in epilepsy.\n Patients more than 12 years old diagnosed with epilepsy with partial seizures and taking one to two baseline antiepileptic drugs were randomized to adjunctive once-daily lamotrigine XR or placebo in a double-blind, parallel-group trial. The study comprised a baseline phase, a 7-week double-blind escalation phase, and a 12-week double-blind maintenance phase during which doses of study medication and concomitant antiepileptic drugs were maintained.\n Of the 243 randomized patients, 239 (118 lamotrigine XR, 121 placebo) entered the escalation phase and received study medication. Lamotrigine XR was more effective than placebo with respect to median percent reduction from baseline in weekly partial seizure frequency (primary endpoint-entire 19-week treatment phase: 46.6% vs 24.5%, p = 0.0001 [corrected] via Wilcoxon test; escalation phase: 29.8% vs 15.6%, p = 0.027; maintenance phase: 58.4% vs 26.8%, p [corrected] < 0.0001). The percentage of patients with >or=50% reduction in partial seizure frequency (44.0% vs 20.8%, p = 0.0002) [corrected] and time to >or=50% reduction in partial seizure frequency (p = 0.0001) [corrected] also favored lamotrigine XR over placebo. A similar pattern of results was observed for secondarily generalized seizures. The most common adverse events were headache (lamotrigine XR 16%, placebo 18%) [corrected] and dizziness (lamotrigine XR 19%, [corrected] placebo 5%). Differences between lamotrigine XR and placebo on health outcomes measures were not significant.\n Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced partial seizure frequency and was well tolerated in this double-blind study. Results support the clinical utility of this new once-daily formulation.", "Anticonvulsant drugs are commonly used in neuropathic pain. There is anecdotal evidence of an analgesic effect of the anticonvulsant lamotrigine in neuropathic pain, but this is verified by few randomised controlled trials. This randomised, double-blind, placebo controlled trial of examined the effect of lamotrigine in a dose increasing to 200 mg in 100 patients with neuropathic pain. Eight patients failed to attend for review, 18 withdrew early and 74 provided results. There was no statistical difference in age, sex or duration pre-treatment pain in the two groups. Total pain, the character of the pain, sensitivity, numbness, paraesthesia, sleep, mobility, mood, quality of life and analgesic consumption were measured. There was a correlation between burning and numbness (P<0. 01), shooting pain and total pain (P<0.01) and between analgesic consumption and mobility (P<0.05) throughout the study period. There were no correlation between any other measured variable. There was no significant change in any variable measured over the eight week period when lamotrigine was used. It is concluded that at the dose used and using the dose escalation regime described, lamotrigine had no effect on either pain, component pain symptoms or quality of life variables.", "Lamotrigine is a chemically novel antiepileptic drug which has not been adequately assessed for its antineuralgic properties. It was used in a double-blind placebo controlled crossover trial in 14 patients with refractory trigeminal neuralgia. Patients continued to take a steady dose of carbamazepine or phenytoin throughout the trial over a 31-day period. Each arm of the trial lasted 2 weeks with an intervening 3-day washout period. The maintenance dose of lamotrigine was 400 mg. Lamotrigine was superior to placebo (P = 0.011) based on analysis of a composite efficacy index which compared the numbers of patients assigned greater efficacy on lamotrigine with those assigned greater efficacy on placebo. Efficacy for one treatment over another was determined according to a hierarchy of: (i) use of escape medication; (ii) total pain scores; or (iii) global evaluations. Eleven of the 13 patients eligible for inclusion in the composite efficacy index showed better efficacy on lamotrigine compared with placebo. Global evaluations further suggested that patients did better on lamotrigine than placebo (P = 0.025). The adverse reactions with both lamotrigine and placebo were predominantly dose-dependent effects on the central nervous system. A 14th patient withdrew from the study due to severe pain during the placebo arm of the trial. It would appear that lamotrigine has antineuralgic properties.", "Central poststroke pain (CPSP) is usually difficult to treat. Amitriptyline, the only oral preparation shown to be effective in a randomized controlled trial, is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants. We investigated the effect of lamotrigine, a drug that reduces neuronal hyperexcitability, on poststroke pain.\n Thirty consecutive patients with CPSP (median age 59 years, range 37 to 77; median pain duration 2.0 years, range 0.3 to 12) from two centers participated in a randomized, double-blind, placebo-controlled cross-over study. The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out. The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine. Secondary endpoints were median pain scores while on lamotrigine 25 mg/d, 50 mg/d, and 100 mg/d; a global pain score; assessment of evoked pain; areas of spontaneous pain; and allodynia/dysesthesia.\n Lamotrigine 200 mg/d reduced the median pain score to 5, compared to 7 during placebo (p = 0.01) in the intent-to-treat population of 27 patients. No significant effect was obtained at lower doses. Twelve patients (44%) responded to the treatment. There was a uniform tendency to reduction of all secondary outcome measures, but lamotrigine only had significant effects on some of the secondary outcome measures. Lamotrigine was well tolerated with few and transient side effects. Two mild rashes occurred during lamotrigine treatment, one causing withdrawal from study.\n Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain. Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP.", "To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.", "We evaluated the efficacy and safety of lamotrigine (300 and 500 mg/day) as add-on therapy in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of 216 patients with refractory partial seizures. During 6 months of treatment, median seizure frequency decreased by 8% with placebo, 20% with 300 mg lamotrigine, and 36% with 500 mg lamotrigine. Seizure frequency decreased by > or = 50% in one-third of the 500-mg group and one-fifth of the 300-mg group. Reductions in seizure frequency and seizure days were statistically significant, compared with placebo, for the 500-mg group but not the 300-mg group. Most adverse events were minor and resolved over time. Nine percent of patients on lamotrigine withdrew because of adverse experiences. Lamotrigine plasma concentrations appeared to be a linear function of dose, and the drug did not affect plasma concentrations of concomitant antiepileptic drugs. Lamotrigine was safe, effective, and well tolerated as add-on therapy for refractory partial seizures.", "To compare the efficacy and safety of lamotrigine and amitriptyline in controlling chronic painful peripheral neuropathy in diabetic patients.\n A randomized, double-blind, crossover, active-control, clinical trial with variable dose titration was carried out (n = 53). Amitriptyline orally, at doses of 10, 25 and 50 mg at night-time, each dose for 2 weeks, and lamotrigine orally, at doses of 25, 50 and 100 mg twice daily, each dose for 2 weeks, by optional titration were used. There was a placebo washout period for 2 weeks between the two drugs. Assessment for pain relief, overall improvement and adverse events were carried out.\n Good, moderate and mild pain relief were noted in 19 (41%), six (13%) and seven (15%) patients on lamotrigine and 13 (28%), five (11%) and 15 (33%) patients on amitriptyline, respectively, by patient's global assessment of efficacy and safety. Patient and physicians global assessment, McGill pain questionnaire and Likert pain scale showed no significant difference between the treatments, although improvement with both treatments was seen from 2 weeks. Of the 44 adverse events reported, 33 (75%) were with amitriptyline, sedation being the commonest [in 19 (43%) patients]. Lamotrigine caused adverse events in 11 (25%), of which rash in three (7%) and elevations of creatinine in four (9%) were the most common. The preferred lamotrigine dose was 25 mg twice daily.\n As there are few differences between the two treatments in efficacy, lamotrigine 25 mg twice daily might be the first choice as it is associated with fewer adverse effects in our population." ]	The additional studies tripled participant numbers providing data for analysis, and new, more stringent criteria for outcomes and analysis were used; conclusions about lamotrigine's lack of efficacy in chronic pain did not change. Given availability of more effective treatments including antiepileptics and antidepressant medicines, lamotrigine does not have a significant place in therapy based on available evidence.
CD009097	[ "18295614", "16372905", "15098334", "17846069", "19118130", "9756581", "3288172", "16416356", "18534554", "10895994" ]	[ "Whole body vibration versus conventional physiotherapy to improve balance and gait in Parkinson's disease.", "The feasibility of Whole Body Vibration in institutionalised elderly persons and its influence on muscle performance, balance and mobility: a randomised controlled trial [ISRCTN62535013].", "[The effect of the complex rehabilitation on posture and gait in Parkinson disease].", "The effects of incremental speed-dependent treadmill training on postural instability and fear of falling in Parkinson's disease.", "Effects of constraint-induced therapy versus bilateral arm training on motor performance, daily functions, and quality of life in stroke survivors.", "A randomized, controlled pilot study of a home-based exercise program for individuals with mild and moderate stroke.", "Biofeedback and functional electric stimulation in stroke rehabilitation.", "Efficacy of a neuropsychological training programme for patients with multiple sclerosis -- a randomised controlled trial.", "The effect of exercise training in improving motor performance and corticomotor excitability in people with early Parkinson's disease.", "Treadmill training with body weight support: its effect on Parkinson's disease." ]	[ "To compare the effects of whole body vibration (WBV) and conventional physiotherapy (PT) on levodopa-resistant disturbances of balance and gait in idiopathic Parkinson's disease (PD).\n Randomized controlled rater-blinded trial comparing 2 active interventions, final follow-up assessment 4 weeks after termination of active intervention.\n Specialized referral center, hospitalized care.\n Patients with PD and dopa-resistant imbalance on stable dopamine replacement medication (N=27) were randomized (intent-to-treat population) to receive WBV (n=13) or conventional PT (controls, n=14). Twenty-one patients (per protocol population) completed follow-up (14 men, 7 women; mean age, 73.8 y; age range, 62-84 y; mean disease duration, 7.2 y; mean dopa-equivalent dose, 768 mg/d).\n Subjects were randomized to receive 30 sessions (two 15-min sessions a day, 5 days a week) of either WBV on an oscillating platform or conventional balance training including exercises on a tilt board. Twenty-one subjects (10 with WBV, 11 controls) were available for follow-up 4 weeks after treatment termination.\n The primary measure was Tinetti Balance Scale score. Secondary clinical ratings included stand-walk-sit test, walking velocity, Unified Parkinson's Disease Rating Scale (section III motor examination) score, performance in the pull test, and dynamic posturography.\n The Tinetti score improved from 9.3 to 12.8 points in the WBV group and from 8.3 to 11.7 in the controls. All secondary measures, except posturography, likewise improved at follow-up compared with baseline in both groups. Quantitative dynamic posturography only improved in patients with WBV (1937-1467 mm) whereas there was no significant change in controls (1832-2030 mm).\n Equilibrium and gait improved in patients with PD receiving conventional WBV or conventional PT in the setting of a comprehensive rehabilitation program. There was no conclusive evidence for superior efficacy of WBV compared with conventional balance training.", "Fatigue or lack of interest can reduce the feasibility of intensive physical exercise in nursing home residents. Low-volume exercise interventions with similar training effects might be an alternative. The aim of this randomised controlled trial was to investigate the feasibility of Whole Body Vibration (WBV) in institutionalised elderly, and its impact on functional capacity and muscle performance.\n Twenty-four nursing home residents (15 female, 9 male; mean age 77.5 +/- 11.0 years) were randomised (stratification for age, gender and ADL-category) to 6 weeks static WBV exercise (WBV+, N = 13) or control (only static exercise; N = 11). Outcome measures were exercise compliance, timed up-and-go, Tinetti-test, back scratch, chair sit-and-reach, handgrip strength and linear isokinetic leg extension.\n At baseline, WBV+ and control groups were similar for all outcome variables. Twenty-one participants completed the program and attended respectively 96% and 86% of the exercise sessions for the WBV+ and control groups. Training-induced changes in timed up-and-go and Tinetti-test were better for WBV+ compared to control (p = 0.029 for timed up-and-go, p = 0.001 and p = 0.002 for Tinetti body balance and total score respectively). In an alternative analysis (Worst Rank Score & Last Observation Carried Forward) the differences in change remained significant on the Tinetti body balance and total score. No other significant differences in change between both groups were observed.\n In nursing home residents with limited functional dependency, six weeks static WBV exercise is feasible, and is beneficial for balance and mobility. The supplementary benefit of WBV on muscle performance compared to classic exercise remains to be explored further.", "Rehabilitation plays an important role in treatment of Parkinson's disease (PD). The influence of rehabilitation on balance and gait in PD hasn't been widely investigated. There is general agreement about positive influence of rehabilitation on postural instability and prevention of falls, but therapeutic program prevention of falls hasn't been worked out. Ambiguous results of studies indicate necessity of further investigations.\n 61 patient were included (H&Y 1, 5-3) and randomly assigned to two groups with and without rehabilitation. The balance test battery included: Functional Reach Test, Balance Performance-Oriented Mobility Assessment (Tinetti), assessment on force platform of quiet standing and active standing with Rhythmic Weight Shifts Test and dynamic task (reaction time, number of hitted targets). Gait was assessed with: timed Up&Go test, 10 m walk, locomotion test and 360 degrees turn. Patients were assessed 3 times, at month intervals. Between 1 and 2 assessment, exercising group took part in 1 month complex rehabilitation, consist of the 28 therapeutic sessions.\n The group, which took part in rehabilitation significantly improved in quiet standing with closed eyes after rehabilitation in comparison with initial status. All of the rest variables significantly improved in exercising group after rehabilitation both in comparison between evaluations and in comparison with the nonexercising group.\n Rehabilitation significantly influences balance and gait of patients with PD.", "To detect the effectiveness of incremental speed-dependent treadmill training on postural instability, dynamic balance and fear of falling in patients with idiopathic Parkinson's disease.\n Randomized controlled trial.\n Ankara Education and Research Hospital, 2nd PM&R Clinic, Cardiopulmonary Rehabilitation Unit.\n Fifty-four patients with idiopathic Parkinson's disease in stage 2 or 3 of the Hoehn Yahr staging entered, and 31 patients (21 training, 10 control) had outcome data.\n Postural instability of patients with Parkinson's disease was assessed using the motor component of the Unified Parkinson's Disease Rating Scale (UPDRS), Berg Balance Test, Dynamic Gait Index and Falls Efficacy Scale. Twenty-one patients with Parkinson's disease participated in an eight-week exercise programme using incremental speed-dependent treadmill training. Before and after the training programme, balance, gait, fear of falling and walking distance and speed on treadmill were assessed in both Parkinson's disease groups.\n Walking distance and speed on treadmill, UPDRS, Berg Balance Test, Dynamic Gait Index and Falls Efficacy Scale.\n Initial total walking distance of the training group on treadmill was 266.45 +/- 82.14 m and this was progressively increased to 726.36 +/- 93.1 m after 16 training session (P < 0.001). Tolerated maximum speed of the training group on treadmill at baseline was 1.9 +/- 0.75 km/h and improved to 2.61 +/- 0.77 km/h (P < 0.001). Berg Balance Test, Dynamic Gait Index and Falls Efficacy Scale scores of the training group were improved significantly after the training programme (P < 0.01). There was no significant improvement in any of the outcome measurements in the control group (P > 0.05).\n Specific exercise programmes using incremental speed-dependent treadmill training may improve mobility, reduce postural instability and fear of falling in patients with Parkinson's disease.", "This study investigated the relative effects of distributed constraint-induced therapy (CIT) and bilateral arm training (BAT) on motor performance, daily function, functional use of the affected arm, and quality of life in patients with hemiparetic stroke.\n A total of 60 patients were randomized to distributed CIT, BAT, or a control intervention of less specific but active therapy. Each group received intensive training for 2 hours/day, 5 days/week, for 3 weeks. Pretreatment and posttreatment measures included the Fugl-Meyer Assessment (FMA), Functional Independence Measure (FIM), Motor Activity Log (MAL), and Stroke Impact Scale (SIS). The proximal and distal scores of FMA were used to examine separate upper limb (UL) elements of movement.\n The distributed CIT and BAT groups showed better performance in the overall and the distal part score of the FMA than the control group. The BAT group exhibited greater gains in the proximal part score of the FMA than the distributed CIT and control groups. Enhanced performance was found for the distributed CIT group in the MAL, the subtest of locomotion in the FIM, and certain domains of the SIS (eg, ADL/IADL).\n BAT may uniquely improve proximal UL motor impairment. In contrast, distributed CIT may produce greater functional gains for the affected UL in subjects with mild to moderate chronic hemiparesis.", "BACKGROUND and\n Many stroke survivors have minimal to moderate neurological deficits but are physically deconditioned and have a high prevalence of cardiovascular problems; all of these are potentially modifiable with exercise. The purposes of this randomized, controlled pilot study were (1) to develop a home-based balance, strength, and endurance program; (2) to evaluate the ability to recruit and retain stroke subjects; and (3) to assess the effects of the interventions used.\n Twenty minimally and moderately impaired stroke patients who had completed inpatient rehabilitation and who were 30 to 90 days after stroke onset were randomized to a control group or to an experimental group that received a therapist-supervised, 8-week, 3-times-per-week, home-based exercise program. The control group received usual care as prescribed by the patients' physicians. Baseline and postintervention assessments included the Fugl-Meyer Motor Assessment, the Barthel Index of Activities of Daily Living (ADL), the Lawton Scale of Instrumental ADL, and the Medical Outcomes Study-36 Health Status Measurement. Functional assessments of balance and gait included a 10-m walk, 6-Minute Walk, and the Berg Balance Scale. Upper extremity function was evaluated by the Jebsen Test of Hand Function.\n Of 22 patients who met study criteria, 20 completed the study and 2 refused to participate. The experimental group tended to improve more than the control group in motor function (Fugl-Meyer Upper Extremity: mean change in score, 8. 4 versus 2.2; Fugl-Meyer Lower Extremity: 4.7 versus -0.9; gait velocity: median change, 0.25 versus .09 m/s; 6-Minute Walk: 195 versus 114 ft; Berg Balance Score: 7.8 versus 5; and Medical Outcomes Study-36 Health Status Measurement of Physical Function: 15. 5 versus 9). There were no trends in differences in change scores by the Jebsen Test of Hand Function, Barthel Index, and Lawton Instrumental ADL Scale.\n This study demonstrated that a randomized, controlled clinical trial of a poststroke exercise program is feasible. Measures of neurological impairments and lower extremity function showed the most benefit. Effects of the intervention on upper extremity dexterity and functional health status were equivocal. The lasting effects of the intervention were not assessed.", "The study examined the efficacy of functional electric stimulation (FES) and biofeedback (BFB) treatment of gait dysfunction in patients with hemiplegia after stroke. These two therapeutic modalities were tested alone and in combination in a prospective, controlled, randomized trial. The authors hypothesized that in concurrent use, these two modalities would complement one another. Thirty-six hemiplegic patients undergoing rehabilitation after stroke were accepted for study and randomized into four groups to receive either control, FES, BFB, or combined therapies. Each patient received 30 minutes of treatment three times per week for six weeks, in addition to their general rehabilitation program. Quantitative gait analysis was performed biweekly on each subject during the experimental therapy and for four weeks afterward. Thirty-two subjects completed the study. Combined therapy with BFB and FES resulted in improvements in both knee and ankle minimum flexion angles during swing phase that were statistically significant with p = 0.05 and p = 0.02, respectively. Velocity of gait, cycle time, and symmetry of stance phases also improved. The length of time elapsed since the stroke did not prove to be a significant factor.", "One aim of this project was to investigate the efficacy of a specific training programme for MS patients which also contained compensation strategies and relaxation exercises relevant to everyday life. The other aim was to check the programme's relevance to everyday life.\n 19 patients, randomised into two groups, took part in the study. The participants in the treated group completed a specific neurological training programme which began immediately after the basic testing (visit 1) and lasted 4 weeks, with a total of 12 sessions. The monitoring test was done immediately after the training programme (at visit 2) and the follow-up was 3 months later (visit 3). Both study groups were fully comparable as regards clinical and socio-demographic data and baseline intelligence level.\n The results of the cognitive training programme were especially evident in the significant improvements in executive functions (CKV) and spatial-constructional abilities (HAWIE-R). Comparison between the treated and the control group showed no significant difference in the fatigue values (MFIS). However, when the treated group was examined over the three times of measurements, the symptoms of fatigue had diminished significantly. Regarding memory, comparison of the groups showed no changes; within the treated group; however, the verbal (VLT) and nonverbal learning and memory (NVLT) improved significantly. The results for sustained attention improved in both groups over time. It must be assumed that a learning effect had occurred here. The depression values (BDI) also improved in both study groups. The follow-up questionnaire showed that 60% (6) attributed an average to above-average benefit to the training.\n To summarise, it is apparent that MS patients with mild to moderate cognitive impairment are able to profit from even a fairly brief neuropsychological training programme and to integrate much of it into their everyday lives. In view of this, it would seem appropriate to offer such a programme as standard, associated with medication.", "To obtain preliminary data on the effects of high-intensity exercise on functional performance in people with Parkinson's disease (PD) relative to exercise at low and no intensity and to determine whether improved performance is accompanied by alterations in corticomotor excitability as measured through transcranial magnetic stimulation (TMS).\n Cohort (prospective), randomized controlled trial.\n University-based clinical and research facilities.\n Thirty people with PD, within 3 years of diagnosis with Hoehn and Yahr stage 1 or 2.\n Subjects were randomized to high-intensity exercise using body weight-supported treadmill training, low-intensity exercise, or a zero-intensity education group. Subjects in the 2 exercise groups completed 24 exercise sessions over 8 weeks. Subjects in the zero-intensity group completed 6 education classes over 8 weeks.\n Unified Parkinson's Disease Rating Scales (UPDRS), biomechanic analysis of self-selected and fast walking and sit-to-stand tasks; corticomotor excitability was assessed with cortical silent period (CSP) durations in response to single-pulse TMS.\n A small improvement in total and motor UPDRS was observed in all groups. High-intensity group subjects showed postexercise increases in gait speed, step and stride length, and hip and ankle joint excursion during self-selected and fast gait and improved weight distribution during sit-to-stand tasks. Improvements in gait and sit-to-stand measures were not consistently observed in low- and zero-intensity groups. The high-intensity group showed lengthening in CSP.\n The findings suggest the dose-dependent benefits of exercise and that high-intensity exercise can normalize corticomotor excitability in early PD.", "To test whether body weight-supported treadmill training (BWSTT) is effective in improving functional outcome of patients with Parkinson's disease.\n Prospective crossover trial. Patients were randomized to receive either a 4-week program of BWSTT with up to 20% of their body weight supported followed by 4 weeks of conventional physical therapy (PT), or the same treatments in the opposite order. Medications for parkinsonism were not modified throughout the study.\n Inpatient rehabilitation unit for neurologic diseases.\n Ten patients (5 men, 5 women) with Hoehn and Yahr stage 2.5 or 3 parkinsonism; mean age 67.6 years, mean duration of Parkinson's disease 4.2 years.\n The Unified Parkinson's Disease Rating Scale (UPDRS), ambulation endurance and speed (sec/10 m), and number of steps for 10-meter walk.\n The mean total UPDRS before/after BWSTT was 31.6/25.6, and before/after PT was 29.1/28.0. Analysis of covariance for improvement of UPDRS demonstrated a significant effect of type of therapy (F(1, 16) = 42.779, p < .0001) but not order of therapy (F(1, 16) = 0.157, p = .697 1). Patients also had significantly greater improvement with BWSTT than with PT in ambulation speed (BWSTT, before/after = 10.0/8.3; PT, 9.5/8.9), and number of steps (BWSTT, 22.3/19.6; PT, 21.5/20.8).\n In persons with Parkinson's disease, treadmill training with body weight support produces greater improvement in activities of daily living, motor performance, and ambulation than does physical therapy." ]	There is insufficient evidence of the effect of WBV training on functional performance of neurodegenerative disease patients. Also, there is insufficient evidence regarding its beneficial effects on signs and symptoms of the disease, body balance, gait, muscle strength and quality of life compared to other active physical therapy or passive interventions in Parkinson's disease or multiple sclerosis. More studies assessing other functional tests and accurately assessing safety are needed before a definitive recommendation is established.
CD003741	[ "11338290", "10981524" ]	[ "Prospective, controlled, multi-center study on the effect of an amino-acid-based formula in infants with cow's milk allergy/intolerance and atopic dermatitis.", "Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study." ]	[ "Cow's milk allergy/intolerance is treated by complete avoidance of cow's milk proteins. Because cow's milk is an important food for infants, its avoidance may lead to an increased risk of growth impairment. Whilst there is evidence for the beneficial effects of extensively hydrolyzed cow's milk formulate (eHF) in infants with cow's milk allergy/intolerance, little is known about the effects of amino-acid-based formulae (AA) in such infants. We therefore performed a prospective, controlled, multi-center trial to study the efficacy of AA in comparison with eHF, on the growth and clinical symptoms of 73 infants (median age 5.7 months) with cow's milk allergy/intolerance and atopic dermatitis. Cow's milk allergy/intolerance was proven in all infants by double-blind, placebo-controlled food-challenge. We observed a significant improvement in the SCORAD index in both groups, from a mean of 24.6, at entry, to a mean of 10.7 (p < 0.0001) after 6 months. In the AA group there was a significant increase in the length standard deviation score (p < 0.04), whilst there was no difference in the eHF group. The weight-for-length values were stable in both groups. The energy intake during the study was similar in both groups. Both an AA and eHF resulted in a significant clinical improvement in infants with an early onset of symptoms of cow's milk allergy/intolerance. Feeding an AA resulted in improved growth compared with feeding eHF, despite similar dietary intakes, and may therefore be considered as a beneficial alternative in infants with severe cow's milk allergy intolerance.", "The aim of this study was to compare the allergy-preventive effect of a partially hydrolyzed formula with two extensively hydrolyzed formulas, in infants with a high risk for development of allergic disease. High-risk infants from four Danish centres were included in the period from June 1994 to July 1995. Five-hundred and ninety-five high-risk infants were identified. High-risk infants were defined as having biparental atopy, or a single atopic first-degree relative combined with cord blood immunoglobulin E (IgE)> or =0.3 kU/l. At birth all infants were randomized to one of three different blinded formulas. All mothers had unrestricted diets during pregnancy and lactation and were encouraged to breast-feed exclusively. If breast-feeding was insufficient, one of the three formulas, according to randomization, was given during the first 4 months. It was recommended not to introduce cow's milk, cow's milk products. and solid foods until the age of 4 months. After the age of 4 months a normal unrestricted diet and conventional cow's milk-based formula were given when needed. All infants were followed-up prospectively with interview and physical examination at the age of 6, 12, and 18 months, and if any possible atopic symptoms were reported. If food allergy was suspected, controlled elimination/challenge procedures were performed in a hospital setting. Of 550 infants included in the study, 514 were seen at all visits and 36 were excluded owing to noncompliance. Of 478 infants who completed the study, 232 were exclusively breast-fed, 79 received an extensively hydrolyzed casein formula (Nutramigen), 82 an extensively hydrolyzed whey formula (Profylac), and 85 a partially hydrolyzed whey formula (Nan HA), during the first 4 months of life. These four groups were identical in regard to atopic predisposition, cord blood IgE, birthplace, and gender. Exclusively breast-fed children were exposed less to tobacco smoke and pets at home and belonged to higher social classes, whereas the three formula groups were identical concerning environmental factors. The frequency of breast-feeding was high; only eight (2%) children were not breast-fed at all. The three formula groups were identical in regard to duration of breast-feeding and age at introduction of formula and solid foods. No significant differences were found in the three groups of infants receiving formula milk regarding the cumulative incidence of atopic dermatitis or respiratory symptoms. The cumulative incidence of parental-reported cow's milk allergy was significantly higher in children fed partially hydrolyzed formula (Nan HA) compared with extensively hydrolyzed formula (Nutramigen or Profylac) at 12 and 18 months (NanHA, 7.1%; Nutramigen, 2.5%; Profylac, 0%; p=0.033). The cumulative incidence of confirmed cow's milk allergy was 1.3% (three of 232) in exclusively breast-fed infants, 0.6% (one of 161) in infants fed extensively hydrolyzed formula (Nutramigen or Profylac), and 4.7%(four of 85) in infants fed partially hydrolyzed formula (Nan HA). Partially hydrolyzed formula was found to be less effective than extensively hydrolyzed formula in preventing cow's milk allergy, 0.6% vs. 4.7% (p=0.05), but because of the small number of cases the results should be interpreted with caution. Compared with other similar studies the frequency ofatopic symptoms was low, even though the dietetic intervention did not include either maternal diet during lactation or dietary restrictions to the children after the age of 4 months." ]	Feeding with a soy formula cannot be recommended for prevention of allergy or food intolerance in infants at high risk of allergy or food intolerance. Further research may be warranted to determine the role of soy formulas for prevention of allergy or food intolerance in infants unable to be breast fed with a strong family history of allergy or cow's milk protein intolerance.
CD003361	[ "17055323", "12049374" ]	[ "Calcium channel blockers and beta-blockers in relation to Parkinson's disease.", "A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test." ]	[ "We investigated the risk of Parkinson's disease (PD) associated with calcium channel blockers (CCBs) and beta-blockers in a population-based case-control study of 206 men and women between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 controls without PD or other neurodegenerative disorders who were frequency matched on age, sex, duration of GHC enrollment and clinic. The adjusted odds ratio associated with ever use was 0.85 (95% confidence interval [CI]: 0.43, 1.66) for CCBs, and 1.20 (95% CI: 0.71, 2.03) for beta-blockers. We observed no association with PD risk for either class of medication in terms of duration, dose, number of prescriptions or pattern of use. The weakness of these associations and the absence of additional influence of dose or duration of use argue against any causal interpretation.", "The aim of this study was to assess the efficacy of lipophilic beta-blockers in preventing recurrent neurocardiogenic syncope and the value of head-up tilt test (HUT) in predicting response to therapy. The efficacy of beta-blockers in recurrent syncope is controversial. The value of HUT in predicting efficacy of therapy has not been investigated. Fifty-six patients (44+/-18 years, 36 women) with recurrent syncope (> 1 event in the last 6 months) of suspected neurocardiogenic origin were included in the study. Independent of the response to HUT, patients were randomized to receive metoprolol or propanolol at the maximal tolerated dose (28 patients, group A, 86+/-23 vs 98+/-29 mg/d) or no pharmacological therapy (28 patients, group B). The primary endpoint was the first recurrence of syncope. During the 1-year of follow-up, 20 patients of group A and 8 of group B had no recurrence. In group A, of 20 patients without recurrences 12 had a positive and 8 a negative HUT result while of 8 patients with recurrences 5 had a positive and 3 a negative response to HUT. In the group B, of 20 patients with recurrences 10 had a positive and 10 a negative HUT result while of 8 patients without recurrences 4 had a positive and 4 a negative response to HUT. In a multivariate Cox-regression analysis, medical therapy was the only independent factor for predicting recurrence of syncope (P = 0.004); HUT had no influence in this regard (P = 0.773). In conclusion, lipophilic beta-blockers appear efficacious in preventing recurrent syncope of suspected neurocardiogenic origin. The efficacy of therapy seems to be not predicted by HUT." ]	In view of this lack of evidence, it is impossible to determine whether beta-blocker therapy is effective and safe for the treatment of tremor in Parkinson's disease. The high frequency of bradycardia in one trial raises some concerns about the prescription of beta-blockers to normotensive elderly patients but the study was too small for the true degree of risk to be calculated.
CD003905	[ "12002496", "12107308", "9273452", "12931807", "8408148", "1430964", "7553006", "10884075", "12954254", "15010154", "8732400", "16777857", "16782569", "8543875", "15925158", "9330145", "11511016", "7995109", "15985575", "14694502", "17617802", "9222908", "12809659", "7574280", "11828556", "19196106", "17119800" ]	[ "Endoscopic versus open carpal tunnel release in bilateral carpal tunnel syndrome. A prospective, randomised, blinded assessment.", "Single-portal endoscopic carpal tunnel release compared with open release : a prospective, randomized trial.", "[Surgical treatment of carpal tunnel syndrome: endoscopic or classical (open)? A prospective randomized trial].", "Carpal tunnel release. A prospective, randomised study of endoscopic versus limited-open methods.", "Carpal tunnel release. A prospective, randomized assessment of open and endoscopic methods.", "Endoscopic release of the carpal tunnel: a randomized prospective multicenter study.", "The value of one-portal endoscopic carpal tunnel release: a prospective randomized study.", "Early recovery after endoscopic vs. short-incision open carpal tunnel release.", "Early outcome and cost-effectiveness of endoscopic versus open carpal tunnel release: a randomized prospective trial.", "A randomized controlled trial of knifelight and open carpal tunnel release.", "A prospective, randomized study with an independent observer comparing open carpal tunnel release with endoscopic carpal tunnel release.", "Outcomes of endoscopic surgery compared with open surgery for carpal tunnel syndrome among employed patients: randomised controlled trial.", "Intra-individual comparison between open and 2-portal endoscopic release in clinically matched bilateral carpal syndrome.", "Early results of conventional versus two-portal endoscopic carpal tunnel release. A prospective study.", "Mini-open blind procedure versus limited open technique for carpal tunnel release: a 30-month follow-up study.", "Ultrasonographically assisted carpal tunnel release.", "A randomized prospective study to assess the efficacy of two cold-therapy treatments following carpal tunnel release.", "[Carpal tunnel syndrome. Can it still be a controversial topic?].", "A randomized controlled trial of surgery vs steroid injection for carpal tunnel syndrome.", "Intracarpal steroid injection is safe and effective for short-term management of carpal tunnel syndrome.", "Postoperative splinting after open carpal tunnel release does not improve functional and neurological outcome.", "Local symptoms after open carpal tunnel release. A randomized prospective trial of two incisions.", "Evaluation of carpal tunnel release using the Knifelight instrument.", "Prospective, randomized trial of splinting after carpal tunnel release.", "Carpal tunnel release by limited palmar incision vs traditional open technique: randomized controlled trial.", "The effectiveness of conservative treatments of carpal tunnel syndrome: splinting, ultrasound, and low-level laser therapies.", "Wrist immobilization after carpal tunnel release: a prospective study." ]	[ "The advantages and disadvantages of endoscopic compared with open carpal tunnel release are controversial. We have performed a prospective, randomised, blinded assessment in a district general hospital in order to determine if there was any demonstrable advantage in undertaking either technique. Twenty-five patients with confirmed bilateral idiopathic carpal tunnel syndrome were randomised to undergo endoscopic release by the single portal Agee technique to one hand and open release to the other. Independent preoperative and postoperative assessment was undertaken by a hand therapist who was blinded to the type of treatment. Follow-up was for 12 months. The operating time was two minutes shorter for the open technique (p < 0.005). At all stages of postoperative assessment, the endoscopic technique had no significant advantages in terms of return of muscle strength and assessment of hand function, grip strength, manual dexterity or sensation. In comparison with open release, single-portal endoscopic carpal tunnel release has a similar incidence of complications and a similar return of hand function, but is a slightly slower technique to undertake.", "Carpal tunnel syndrome is a common condition causing hand pain and numbness. Endoscopic carpal tunnel release has been demonstrated to reduce recovery time, although previous studies have raised concerns about an increased rate of complications. The purpose of this prospective, randomized study was to compare open carpal tunnel release with single-portal endoscopic carpal tunnel release.\n A prospective, randomized, multicenter center study was performed on 192 hands in 147 patients. The open method was performed in ninety-five hands in seventy-two patients, and the endoscopic method was performed in ninety-seven hands in seventy-five patients. All of the patients had clinical signs or symptoms and electrodiagnostic findings consistent with carpal tunnel syndrome and had not responded to, or had refused, nonoperative management. Follow-up evaluations with use of validated outcome instruments and quantitative measurements of grip strength, pinch strength, and hand dexterity were performed at two, four, eight, twelve, twenty-six, and fifty-two weeks after the surgery. Complications were identified. The cost of the procedures and the time until return to work were recorded and compared between the groups.\n During the first three months after surgery, the patients treated with the endoscopic method had better Carpal Tunnel Syndrome Symptom Severity Scores, better Carpal Tunnel Syndrome Functional Status Scores, and better subjective satisfaction scores. During the first three months after surgery, they also had significantly (p < 0.05) greater grip strength, pinch strength, and hand dexterity. The open technique resulted in greater scar tenderness during the first three months after surgery as well as a longer time until the patients could return to work (median, thirty-eight days compared with eighteen days after the endoscopic release). No technical problems with respect to nerve, tendon, or artery injuries were noted in either group. There was no significant difference in the rate of complications or the cost of surgery between the two groups.\n Good clinical outcomes and patient satisfaction are achieved more quickly when the endoscopic method of carpal tunnel release is used. Single-portal endoscopic surgery is a safe and effective method of treating carpal tunnel syndrome.", "To compare the results of open with endoscopic release of the carpal tunnel in patients with the carpal tunnel syndrome.\n Randomised prospective study.\n General hospital Zeeuws-Vlaanderen, Oostburg and Terneuzen, the Netherlands.\n 178 patients were randomised for open or endoscopic release. The symptom severity score and functional status score were completed before and three months after the procedure. One week after the operation the patients' postoperative pain was measured on a 10-point visual analogue scale. Differences were analysed using the Chi-square test or the t-test.\n Randomisation failed in two patients; 85 patients had an endoscopic release and 91 patients had an open release. The postoperative pain was significantly less in the endoscopic group. Improvement in symptom severity score and functional status score was the same in both groups. There was no difference in absence from work. Two local complications occurred in the endoscopically treated group. Of the patients 25% were not or only slightly satisfied with the results.\n Endoscopic release of the carpal tunnel is as effective as the open release but it gives less postoperative pain. Because of the risk of complications and the additional costs, the endoscopic release is not the preferred method for treatment of the carpal tunnel syndrome, however.", "Endoscopic carpal tunnel release has the advantage over open release of reduced tissue trauma and postoperative morbidity. Limited open carpal tunnel release has also been shown to have comparable results, but is easier to perform and is safer. We have compared the results of both techniques in a prospective, randomised trial. Thirty patients with bilateral carpal tunnel syndrome had simultaneous bilateral release. The technique of release was randomly allocated to either two-portal endoscopic release (ECTR) or limited open release using the Strickland instrumentation (LOCTR). The results showed that the outcome was similar at follow-up of one year using both techniques. However, the LOCTR group had significantly less tenderness of the scar at the second and fourth postoperative week (p < 0.01). There was also less thenar and hypothenar (pillar) pain after LOCTR. Subjective evaluation showed a preference for LOCTR.", "To define the role of two-portal endoscopic carpal-tunnel release as a method for the treatment of compression of the median nerve at the wrist, a prospective, randomized, multicenter study was performed on 169 hands in 145 patients. Either open or endoscopic carpal-tunnel release was performed in all of the patients who had clinical signs and symptoms consistent with carpal tunnel syndrome, had not responded to or had refused non-operative management, and had had electrodiagnostic studies consistent with carpal tunnel syndrome. Follow-up evaluations were performed at twenty-one, forty-two, and eighty-four days. At the end of the follow-up period, both the open and endoscopic methods had resulted in high levels of achievement of the primary outcomes (relief of pain and paresthesias). The numbness and paresthesias were relieved in eighty (98 per cent) of eighty-two hands in the open-release group compared with seventy-seven (99 per cent) of seventy-eight hands in the endoscopic-release group. This parameter was not recorded for three hands in the open-release group or six hands in the endoscopic-release group. The satisfaction of the patients with the procedure, graded on a scale of 0 to 100 per cent, averaged 84 per cent in the open-release group compared with 89 per cent in the group that had had endoscopic release. We found no significant differences between the two groups with regard to the secondary quantitative-outcome measurements, including two-point discrimination, postoperative interstitial-pressure data for the carpal canal, Semmes-Weinstein monofilament testing, and motor strength. The open technique resulted in more tenderness of the scar than did the endoscopic method. Thirty-two (39 per cent) of eighty-two hands in the open-release group and fifty (64 per cent) of seventy-eight hands in the endoscopic-release group were not tender at eighty-four days. This parameter was not recorded for three hands in the open-release group and six hands in the endoscopic-release group. The open method also resulted in a longer interval until the patient could return to work (median, twenty-eight days, compared with fourteen days for the open-release and endoscopic-release groups). Four complications occurred in the endoscopic carpal-tunnel release group: one partial transection of the superficial palmar arch, one digital-nerve contusion, one ulnar-nerve neuropraxia, and one wound hematoma.(ABSTRACT TRUNCATED AT 400 WORDS)", "A 10-center randomized prospective multicenter study of endoscopic release of the carpal tunnel was carried out. Surgery was performed with a new device for transecting the transverse carpal ligament while control hands were treated with conventional open surgery. There were 122 patients in the study; 25 had carpal tunnel surgery on both hands and 97 had surgery on one hand. Of the surgical procedures, 65 were in the control group and 82 were in the device group. The endoscopic device was coupled to a fiberoptic light and a video camera. A trigger-activated blade was used to incise the transverse carpal ligament. After surgery, the best predictors of return to work and to activities of daily living were strength and tenderness variables. For patients in the device group with one affected hand, the median time for return to work was 21 1/2 days less than that for the control group. Two patients treated with the endoscopic device required reoperation by open surgical decompression; only one of these had incomplete release with the device. Two patients in the device group experienced transient ulnar neurapraxia.", "A randomized prospective study was carried out to compare one-portal endoscopic carpal tunnel release with an open procedure. There were 47 patients (mean age 52.6 years); 25 underwent an endoscopic and 22 an open release. The aim of the study was to evaluate the risks against the benefits for pain, grip, key-pinch strength and ability to return to work. The distribution of age, occupation, sex, neurographic findings and operated hand was similar in both groups. We detected no serious nerve complications. One \"open\" patient developed a hypertrophic scar, a second \"open\" patient a disabling reflex sympathetic dystrophy, one \"endo\" patient a transient neurapraxia. The remaining patients experienced complete relief of symptoms. Improvement of grip strength is significantly better after endoscopic release (P = 0.0001 at 3 months). In contrast, the key-pinch showed a similar pattern of improvement in both groups. The ability to use the operated hand as effectively as the contralateral one developed after 24 days for the endoscopic group versus 42 for the open approach (P = 0.0000). The carpal arch alteration was less important for the endoscopic group (P = 0.013), but without any correlation with the grip strength. Agee's one-portal technique only allows correct placement of a knife, not an inspection of the structures being operated upon. This is a major limitation, reducing the surgeon to a technician. Further development of this procedure demands a device that will enable a fruitful inspection of the carpal tunnel.", "Endoscopic carpal tunnel release has been claimed to offer improvement in recovery time and postoperative discomfort over open carpal tunnel release. Short-incision open carpal tunnel release has been claimed to offer recoveries comparable with endoscopic techniques. Patients receiving carpal tunnel surgery were randomized to short-incision open release or single-portal endoscopic release. Preoperative and postoperative evaluation included grip and pinch strength measurements and patient completion of a questionnaire regarding symptoms and function. Thirty-six operated hands completed evaluation, including 22 endoscopic and 14 open releases. Early grip and pinch strength after endoscopic carpal tunnel release were improved significantly over short-incision open release (p < 0.05). Subjective evaluation indicated a trend toward improved symptoms and function with endoscopic over short-incision open carpal tunnel release. Endoscopic carpal tunnel release provides faster recovery of strength than short-incision open carpal tunnel release and improves early postoperative comfort and function to a small degree.", "Proponents of endoscopic carpal tunnel release have been advocating the technique for more than 10 years but there is still debate about its efficacy, safety and cost-effectiveness. We have performed a randomized, prospective, blind trial to compare early outcome after single portal endoscopic or open carpal tunnel surgery and to assess the cost-effectiveness of the procedures. There were no significant differences in symptom and functional activity scores, grip strength or anterior carpal pain in the first 3 months. For those in employment, we found a statistically significant difference between the two treatment groups with the endoscopic group returning to work, on average, 8 (95% CI, 2-13 days) days sooner than the open group. This translates into a cost saving to industry. There were no major neurovascular complications in either group. On the basis of these findings, we recommend that endoscopic carpal tunnel release should be considered in the employed as a cost-effective procedure, but perhaps not in the general population as a whole.", "A randomized controlled trial was done to compare the results of carpal tunnel decompression using the standard open approach and the Knifelight technique. Twenty-six patients with bilateral carpal tunnel syndrome requiring operation were selected for the study and the operative technique was randomized for the first hand. Six weeks later, the second hand was operated upon using the alternate technique. There was little difference between the two techniques with regard to time taken to return to work, return of grip strength, symptom relief, complications, incidence of pillar pain and patient preference. However, the incidence of scar tenderness was significantly lower with the Knifelight technique.", "In order to define the role of two-portal endoscopic carpal tunnel release, a prospective randomised study with an independent observer was performed to compare endoscopic and open surgery. Thirty-two hands in 29 patients, with symptoms, clinical signs and EMG changes consistent with idiopathic carpal tunnel syndrome were randomised to either endoscopic carpal tunnel release or open release. No significant difference in sick leave between the two groups could be found, being a mean of 17 days (range 0-31 days) with endoscopic surgery, and 19 days (range 0-42 days) with open conventional surgery. No differences in surgical results were found, but three patients in the endoscopic group suffered transient numbness on the radial side of the ring finger.", "To compare endoscopic and open carpal tunnel release surgery among employed patients with carpal tunnel syndrome.\n Randomised controlled trial at a single orthopaedic department.\n 128 employed patients aged 25-60 years with clinically diagnosed and electrophysiologically confirmed idiopathic carpal tunnel syndrome.\n The primary outcome was severity of postoperative pain in the scar or proximal palm and the degree to which pain or tenderness limits activities, each rated on a 4 point scale, transformed into a combined score of 0 (none) to 100 (severe pain or tenderness causing severe activity limitation). The secondary outcomes were length of postoperative work absence, severity of symptoms of carpal tunnel syndrome and functional status scores, SF-12 quality of life score, and hand sensation and strength (blinded examiner); follow-up at three and six weeks and three and 12 months.\n 63 patients were allocated to endoscopic surgery and 65 patients to open surgery, with no withdrawals or dropouts. Pain in the scar or proximal palm was less prevalent or severe after endoscopic surgery than after open surgery but the differences were generally small. At three months, pain in the scar or palm was reported by 33 patients (52%) in the endoscopic group and 53 patients (82%) in the open group (number needed to treat 3.4, 95% confidence interval 2.3 to 7.7) and the mean score difference for severity of pain in scar or palm and limitation of activity was 13.3 (5.3 to 21.3). No differences between the groups were found in the other outcomes. The median length of work absence after surgery was 28 days in both groups. Quality of life measures improved substantially.\n In carpal tunnel syndrome, endoscopic surgery was associated with less postoperative pain than open surgery, but the small size of the benefit and similarity in other outcomes make its cost effectiveness uncertain.", "Based upon bilateral carpal tunnel syndrome (CTS) we undertook a prospective randomised intra-individual comparison between open (OR) and 2-portal endoscopic release (2-PER) to establish if there is any demonstrable advantage in undertaking either technique in a 1 year follow-up. Ten patients with bilateral CTS were enrolled in this study and underwent a 2-PER on the one and an OR with two minimised incisions on the contralateral hand. Both hands were examined pre- and postoperatively after 2, 4, 6 and 12 weeks and after 6 and 12 months, respectively. Preoperatively both hands revealed statistically no significant differences in all the parameters recorded. Comparing both techniques no significant differences could be detected in the follow-up period. Nevertheless, both techniques showed significant improvements in the severity of symptoms and pain, in sensory nerve testing and in electro-diagnostic parameters, when comparing pre- with postoperative data after 1 year. The endoscopic approach revealed no distinct advantages over the open technique not only in the late but also in the early postoperative follow-up period when performing intra-individual comparison. Considering the higher complication rate and costs when performing 2-PER the OR with two minimised incisions seems to be a good alternative in order to keep the recovery period as short as possible.", "The authors compare in a prospective, randomized study the early outcome of carpal tunnel release using either a conventional palmar open release (n = 40) or a two-portal endoscopic release (n = 56). Both groups were similar. No statistically significant differences were found regarding pain, disappearing of paraesthesiae or time to return to work. However, better recovery of grip strength was observed in the endoscopic group at 1 and 3 months. No surgical complications were observed in either group.", "To evaluate prospectively the safety and effectiveness of a mini-open blind technique for carpal tunnel release (group A) when compared with a limited open technique (group B).\n From November 1999 to May 2001 (mean follow-up period, 30 mo) we performed 222 carpal tunnel release procedures on 185 consecutive patients. All patients were affected by mild to moderate median nerve compression. Patients in group A (82 patients, 99 procedures) had a short transverse incision at the wrist (length, 2 cm). We used a manual surgical instrument that helps in blindly dividing the flexor retinaculum because it has an integrated light source. The light makes it possible to locate precisely the tool blade by transillumination. Patients in group B (103 patients, 123 procedures) had a limited longitudinal incision (length, 3-4 cm). The preoperative and postoperative patient statuses were evaluated with an Italian modified version of the Boston Carpal Tunnel questionnaire with a mean of 30 months' follow-up after surgery (range, 24-39 mo).\n Group A patients showed better results than group B patients in all of the sections of the Italian modified version of the Boston Carpal Tunnel questionnaire at a mean follow-up period of 19 months, whereas after a mean of 30 months of follow-up evaluation the differences between groups A and B tended to decrease. Disease recurred in 7 group B patients, whereas only 1 patient in group A experienced symptom recurrence at the latest office evaluation.\n The blind mini-invasive technique has been shown to be as safe as traditional techniques but the recovery period is significantly shortened. With the technique we described a low recurrence rate was observed. All patients in group A reported great reduction in preoperative pain and numbness.", "An operative technique of carpal tunnel release using intraoperative ultrasonography is described. In this technique, \"safe line\" is defined in the transverse carpal ligament and the adjacent deep forearm fascia midway between the ulnar margin of the median nerve and the radial margin of the ulnar artery. After ultrasonographic design of a 1.0 to 1.5-cm skin incision along the safe line at the distal carpal tunnel, the distal ligament is released under direct vision. Proximal release is performed along this line under ultrasonographic monitoring using a device that consists of a basket punch and an outer metal tube. In a prospective randomized study, the outcomes were compared for carpal tunnel release using either this technique in 50 hands of 50 patients or conventional open release in 53 hands of 53 patients. Follow-up assessment at 3, 6, 13, 26, 52, and 104 weeks showed no significant difference with respect to numbness and paresthesias, static two-point discrimination, findings on Semmes-Weinstein monofilament testing, findings on manual muscle testing of the abductor pollicis brevis, and electrophysiologic findings. The ultrasonographic-release group had better outcomes regarding pain, tenderness of the scar, and key-pinch strength at 3, 6, and 13 weeks, and grip strength at 3 and 6 weeks after surgery. The scar was more aesthetic in this group. There were no complications with either technique.", "A prospective randomized study was performed comparing the efficacy of controlled cold therapy (CCT) with the efficacy of ice therapy in the postoperative treatment of 72 patients with carpal tunnel syndrome. Immediately after surgery, patients applied either a temperature-controlled cooling blanket (CCT) or a standard ice pack over their surgical dressings. Pain was assessed by visual analog scale and swelling by wrist circumference preoperatively, immediately after surgery, and on postoperative day 3. Patients kept log books of daily treatment times. Narcotic use (of Vicodin ES) was determined by pill count at day 3 and by daily log book recordings. Patients who used CCT showed significantly greater reduction in pain, edema (wrist circumference), and narcotic use at postoperative day 3 than did those using ice therapy. This study indicates that after carpal tunnel surgery, the use of CCT, compared with traditional ice therapy, provides patients with greater comfort and lessens the need for narcotics.", "The authors studied two aspects of the carpal tunnel syndrome. As far as the diagnosis is concerned, clinical signs and provocative manoeuvres compared to the accepted standard of electrophysiological studies proved to be insufficient to settle a surgical indication in 85 carpal tunnel syndromes. When surgery is needed, post-operative course is frequently bothered by pillar pain and decreased strength postponing return to manual activities. The authors performed a prospective randomized study of 3 techniques in 251 carpal tunnel releases: classical technique, Agee endoscopic technique and anterior ligamentoplasty. Strength was only improved by the last technique. The only advantage for the endoscopic technique was greater post-operative comfort.", "Decompressive surgery and steroid injection are widely used forms of treatment for carpal tunnel syndrome (CTS) but there is no consensus on their effectiveness in comparison to each other. The authors evaluated the efficacy of surgery vs steroid injection in relieving symptoms in patients with CTS.\n The authors conducted a randomized, single blind, controlled trial. Fifty patients with electrophysiologically confirmed idiopathic CTS were randomized and assigned to open carpal tunnel release (25 patients) or to a single injection of steroid (25 patients). Patients were followed up at 6 and 20 weeks. The primary outcome was symptom relief in terms of the Global Symptom Score (GSS), which rates symptoms on a scale of 0 (no symptoms) to 50 (most severe). Nerve conduction studies and grip strength measurements were used as secondary outcome assessments.\n At 20 weeks after randomization, patients who underwent surgery had greater symptomatic improvement than those who were injected. The mean improvement in GSS after 20 weeks was 24.2 (SD 11.0) in the surgery group vs 8.7 (SD 13.0) in the injection group (p < 0.001); surgical decompression also resulted in greater improvement in median nerve distal motor latencies and sensory nerve conduction velocity. Mean grip strength in the surgical group was reduced by 1.7 kg (SD 5.1) compared with a gain of 2.4 kg (SD 5.5) in the injection group.\n Compared with steroid injection, open carpal tunnel release resulted in better symptomatic and neurophysiologic outcome but not grip strength in patients with idiopathic carpal tunnel syndrome over a 20-week period.", "A double-blinded placebo-controlled trial was performed to evaluate the use of steroid injections beneath the transverse carpal ligament in the treatment of carpal tunnel syndrome (CTS) refractory to nonsurgical therapy. Forty-three patients received 6 mg betamethasone and lidocaine and 38 patients received 1 ml saline placebo and lidocaine. The primary outcome measure was satisfaction with symptom relief. Thirty patients (70%) in the steroid-treated group were satisfied or highly satisfied compared with 13 (34%) of placebo-treated patients (P < 0.001). Patients receiving steroids also showed significant improvement in median nerve conduction parameters and scores on validated symptom/function questionnaires. Forty-six patients were treated with serial injections for recurrent CTS symptoms. After 18 months, 17 patients reported adequate symptom relief with steroid injection, and 18 patients with unsatisfactory symptom relief were referred for carpal tunnel release surgery. We conclude that although steroid injections are safe and effective for temporary relief of CTS, most patients will eventually require surgery for long-term control of their symptoms.", "Although surgical division of the transverse carpal ligament is the operative treatment of choice for carpal tunnel syndrome (CTS), controversy exists about the immediate postoperative treatment regimen. Splinting for up to 6 weeks after surgery is recommended by some investigators. We therefore evaluated effectiveness of splinting after open carpal tunnel surgery by a randomized, controlled trial. Fifty consecutive patients with clinically and electrophysiologically confirmed idiopathic CTS were assigned to open carpal tunnel release and randomized to receiving a light bandage (25 patients) or a bulky dressing with a volar splint (25 patients) for 2 days each. All patients were followed up at 3 months. Parameters retrieved were pain as measured using a visual analog scale, two-point discrimination, and grip strength, and nerve conduction studies. At follow-up, all patients reported definite improvement of symptoms, but there was no statistically significant difference between the two groups for any of our outcome measures. Thus, postoperative splinting after open carpal tunnel release does not yield any benefit to eventual outcome. In fact, it adds to the overall operating time and can safely be abandoned.", "We report a randomized trial of two skin incisions for carpal tunnel decompression, namely a standard incision and an ulnar L incision. We looked particularly at the resolution of local symptoms namely pillar pain and scar sensitivity. There were 47 patients in the trial. No difference was found in pillar pain between the two incisions, but one had a lower incidence of scar sensitivity. These results give a baseline for comparison of local postoperative symptoms following open release with those following endoscopic release.", "We have performed a prospective randomized controlled trial to compare the results of open carpal tunnel release with those of carpal tunnel release using a Knifelight (Stryker, Kalamazoo, MI). This is a new knife with its own battery-powered light source which enables the operation to be performed through a small incision in the palm of the hand. There were 43 patients in the open operation group and 39 in the Knifelight group. We found no difference in discomfort reported during surgery, in the operative time, in the grip strength measured at 2 and 6 weeks post-operatively or in the proportion of patients cured of their pre-operative symptoms. Patients in the Knifelight group had a statistically significant improvement in the time to return to work and in scar tenderness at 6 weeks post-operatively.", "To determine the possible beneficial effect of postoperative splint immobilization after open carpal tunnel release, we performed a prospective, randomized study comparing 2 weeks of postoperative wrist splinting versus a bulky dressing only. Forty patients with 43 carpal tunnel releases were evaluated. There were no statistically significant differences between the two groups using subjective parameters of patient satisfaction with their outcome and objective parameters of grip and lateral pinch strength, complication rates, and digital and wrist range of motion. No clinical evidence of bowstringing could be noted in either group of patients. We found no beneficial effect from postoperative splinting after open carpal tunnel release when compared to a bulky dressing alone.", "To compare a limited palmar incision for carpal tunnel release (CTR) with a traditional open technique, which is still considered the gold standard.\n Seventy-two patients with a carpal tunnel syndrome were individually randomized into the trial (limited incision CTR) (n=36) and control group (traditional technique CTR) (n=36). In the trial group, skin incision parallel to the thenar crease was made up to 2.5 cm in length, under an operating microscope and endoscopic transillumination. Skin incision in the control group began at the distal border of the carpal ligament, followed the longitudinal crease of the palm, and crossed the base of the palm in a zigzag fashion. Three months after surgery, the patients were asked about symptomatic relief and intervals between the operation and return to their daily activities and work, and examined for scar tenderness and esthetic outcome. Distal motor latency, conduction velocity, scar length, scar width, and operation time were measured.\n There were no differences between the two groups in symptomatic relief and electrophysiological parameters. Intervals between the operation and return to daily activities (median 5 days, range 2-15) were shorter in the trial group than in the control group (median 10 days, range 2-21; p<0.001), as well as the intervals between the operation and return to work (median 15 days, range 5-45 vs median 30 days, range 10-60; p<0.001). Scar/pillar tenderness, scar length and width, esthetic outcome, and operation time were significantly better in the trial group.\n Limited palmar incision CTR is as effective and safe as traditional CTR technique, but with better postoperative recovery and cosmetic results.", "The objective of this study was to investigate the effectiveness of splinting, ultrasound (US), and low-level laser (LLL) in the management of carpal tunnel syndrome (CTS).\n CTS is the entrapment mononeuropathy most frequently seen in clinical practice, caused by compression of the median nerve at the wrist. Although several treatment modalities are routinely in use, there is no consensus about the best way to manage CTS.\n In our study, patients were randomly allocated to three groups that received the following treatment protocols: splinting only, splinting plus US, and splinting plus LLL therapy. Patients were assessed with the Boston Questionnaire, patient satisfaction inquiry, visual analogue scale for pain, and electroneuromyography.\n The study was completed with a total of 100 hands of 50 women patients with bilateral CTS at 3 mo after treatment. At the end of the follow-up period, each of the groups had improvements to varying degrees. It appeared that the combinations of US or LLL therapy with splinting were more effective than splinting alone in treating CTS. However, LLL therapy plus splinting was more advantageous than US therapy plus splinting, especially for the outcomes of lessening of symptom severity, pain alleviation, and increased patient satisfaction.", "This prospective study evaluates the possible advantages of wrist immobilization after open carpal tunnel release comparing the results of two weeks immobilization and no immobilization. Fifty two patients with idiopathic carpal tunnel syndrome were randomly selected in two groups after open carpal tunnel release. In one group (A, n=26) the patients wore a neutral-position wrist splint continuously for two weeks. In the other group (B, n=26) no wrist immobilization was used. Clinical assessment was done pre-operatively and at 2 weeks follow-up and included the two-point discrimination test at the second finger and two questionnaires as an outcome measurement of symptoms severity and intensity. All the patients presented improvement in the postoperative evaluations in the three analyzed parameters. There was no significant difference between the two groups for any of the outcome measurements at the final follow-up. We conclude that wrist immobilization in the immediate post-operative period have no advantages when compared with no immobilization in the end result of carpal tunnel release." ]	There is no strong evidence supporting the need for replacement of standard open carpal tunnel release by existing alternative surgical procedures for the treatment of carpal tunnel syndrome. The decision to apply endoscopic carpal tunnel release instead of open carpal tunnel release seems to be guided by the surgeon's and patient's preferences.
CD002032	[ "8334888" ]	[ "A multicenter comparative trial of triphasic and monophasic, low-dose combined oral contraceptives." ]	[ "A comparative multicenter clinical trial of two combined oral contraceptives (OCs) was conducted at clinics located in the Sudan, Sri Lanka, Chile, the Dominican Republic and Ecuador. The trial was designed to determine if there were differences in efficacy, safety and acceptability between a triphasic and a low-dose monophasic OC. This report includes analysis of 1088 women. At each center, subjects were randomly allocated to one of the two OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. There were two accidental pregnancies attributed to user failure reported during the study period; one in the triphasic group and one in the monophasic group. Adverse experiences were mainly minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. Cycle control was good in both groups with women in the triphasic group reporting fewer complaints of intermenstrual bleeding. Both OCs were safe and effective." ]	Conclusions are limited by the identification of only one trial, the methodological shortcomings of that trial, and the absence of data on accidental pregnancies. However, the trial found no important differences in bleeding patterns between the biphasic and monophasic preparations studied. Since no clear rationale exists for biphasic pills and since extensive evidence is available for monophasic pills, the latter are preferred.
CD008714	[ "3533699" ]	[ "Randomized trial of chlorambucil for primary biliary cirrhosis." ]	[ "Twenty-four patients with primary biliary cirrhosis were entered into a prospective, randomized trial of chlorambucil therapy. Thirteen patients received chlorambucil (0.5-4 mg/day) and 11 patients received no therapy; all have been followed for 2-6 yr (mean, 4.1 yr). Two control but no treated patients died. Average serum bilirubin, serum aspartate aminotransferase activities, and albumin levels improved or remained unchanged in treated patients but worsened in controls. Serum alkaline phosphatase levels did not change in either group. Immunoglobulin M levels decreased and became normal in all treated patients but in only 3 control patients. Liver biopsy histology revealed an improvement in inflammatory cell infiltrate in treated patients in comparison with controls, but no significant change in degree of fibrosis or the histologic stage of disease. Side effects of therapy included bone marrow suppression necessitating discontinuation of the drug in 4 patients. These findings indicate that chlorambucil therapy may retard the progression of primary biliary cirrhosis. Whether such therapy will ultimately decrease morbidity and improve survival in this disease can only be demonstrated by large-scale, placebo-controlled trials." ]	There is not sufficient evidence to support or reject the use of chlorambucil for patients with primary biliary cirrhosis. Chlorambucil may show benefit in some unvalidated surrogate outcome measures (for example, serum bilirubin and immunoglobulin M levels). Chlorambucil is, however, connected with a number of adverse events. Bone marrow suppression should be noted in particular. Further randomised clinical trials are necessary to assess the benefits and harms of chlorambucil in this indication.
CD003645	[ "16014597", "11805748", "1575555", "17133185", "11157606", "3505606", "10618878", "14506534", "1533209", "7575835", "19830358", "16215365", "12837864", "17273449", "10693095", "2357093", "8419896", "2107286", "3341324", "3102211" ]	[ "Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial.", "Decreased activity and oxygen desaturation in prone ventilated preterm infants during the first postnatal week.", "Effect of positioning on the breathing pattern of preterm infants.", "High-frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation.", "4A randomized trial of prolonged prone positioning in children with acute respiratory failure.", "The effect of body position on the respiratory rate of infants with tachypnea.", "Effects of body position on blood gases and lung mechanics of infants with chronic lung disease during tube feeding.", "[Effect of preterm infant position on weaning from mechanical ventilation].", "Effect of position on the mechanical interaction between the rib cage and abdomen in preterm infants.", "Effect of body position on the blood gases and ventilation volume of infants with chronic lung disease before and after feeding.", "Prone position and reduced thoracoabdominal asynchrony in preterm newborns.", "Comparison of prone positioning and high-frequency oscillatory ventilation in patients with acute respiratory distress syndrome.", "Effect of posture on oxygenation, lung volume, and respiratory mechanics in premature infants studied before discharge.", "First-time mothers' selection of infant supine sleep positioning.", "Does supine positioning increase apnea, bradycardia, and desaturation in preterm infants?", "Transcutaneous oxygen saturation in sleeping infants: prone and supine.", "Pulmonary mechanics and gas exchange: effect of lateral positioning during recovery from respiratory distress syndrome.", "Effects of position changes on transcutaneous carbon dioxide tension in neonates with respiratory distress.", "Lateral positioning of the stable ventilated very-low-birth-weight infant. Effect on transcutaneous oxygen and carbon dioxide.", "Randomized controlled trial of very early continuous distending pressure in the management of preterm infants." ]	[ "In uncontrolled clinical studies, prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury. However, the effect of prone positioning on clinical outcomes in children is not known.\n To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning.\n Multicenter, randomized, controlled clinical trial conducted from August 28, 2001, to April 23, 2004, of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning. Randomization was concealed and group assignment was not blinded.\n Patients were randomized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria, with those patients in the prone group being positioned within 4 hours of randomization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days, after which they were positioned supine. Both groups were treated using lung protective ventilator and sedation protocols, extubation readiness testing, and hemodynamic, nutrition, and skin care guidelines.\n Ventilator-free days to day 28.\n The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule. There were no differences in the number of ventilator-free days between the 2 groups (mean [SD], 15.8 [8.5] supine vs 15.6 [8.6] prone; mean difference, -0.2 days; 95% CI, -3.6 to 3.2; P = .91). After controlling for age, Pediatric Risk of Mortality III score, direct vs indirect acute lung injury, and mode of mechanical ventilation at enrollment, the adjusted difference in ventilator-free days was 0.3 days (95% CI, -3.0 to 3.5; P = .87). There were no differences in the secondary end points, including proportion alive and ventilator-free on day 28 (P = .45), mortality from all causes (P>.99), the time to recovery of lung injury (P = .78), organ-failure-free days (P = .88), and cognitive impairment (P = .16) or overall functional health (P = .12) at hospital discharge or on day 28.\n Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury.", "To compare the effects of supine and prone positions on oxygen saturation (SpO(2)), desaturation episodes (SpO(2) < 90% and >or= 20 seconds), and motor activity in ventilated preterm infants during their first postnatal week.\n With use of a crossover design, we randomly assigned infants to a supine/prone or prone/supine position sequence. Infants were placed in each position for 2 hours. A stabilization period of 10 minutes before observation of each position was allowed. During the protocol, care procedures were kept minimal and ventilator settings remained unchanged.\n Neonatal intensive care units at 2 tertiary care centers in Taiwan.\n The sample consisted of 28 infants receiving mechanical ventilation who were 25 to 36 weeks' gestation, without known congenital abnormalities, within 7 postnatal days of birth, and were not receiving sedation.\n When prone, infants had higher SpO(2), fewer episodes of oxygen desaturation, and less motor activity than when supine. No significant differences in duration of SpO(2) less than 90%, 85%, and 80% were found between the 2 positions. Seventy-four percent of desaturation episodes were associated with vigorous motor activity and crying.\n The prone position results in less motor activity and may stabilize oxygenation for ventilated preterm infants. This may conserve energy and decrease complications of hypoxia for sick preterm infants.", "Respiration, as judged by gas exchange and pulmonary function, is improved in preterm infants kept in the prone rather than the supine position. The influence of position on the breathing pattern as documented by the pneumogram was studied in 14 stable preterm infants with recent clinical apnoea. Ten of the infants had oximetry and nasal flow studies simultaneously with the impedance pneumogram. Each infant had consecutive nocturnal pneumograms, one in the prone, one in the supine position. The infants were kept for more than six hours in the assigned position. A significant increase in apnoea density and in periodic breathing was found in the supine v the prone position (mean (SE) 4.5 (0.7)% v 2.5 (0.5)%, and 13.6 (3.2)% v 7.7 (2.2)%, respectively). There was no positional difference in the incidence of bradycardia and prolonged apnoea. The examination of obstructive apnoea, mixed apnoea, and cyanotic spells did not reveal a consistent disparity between the two positions. These findings indicate an increase in central apnoea in preterm infants kept predominantly in the supine position. Possible relations of positional changes to lung mechanics are discussed. When evaluating pneumograms, attention must be given to the position in which they were performed.", "The improvement in oxygenation with prone positioning is not persistent when patients with acute respiratory distress syndrome (ARDS) are turned supine. High-frequency oscillatory ventilation (HFOV) aims to maintain an open lung volume by the application of a constant mean airway pressure. The aim of this study was to show that HFOV is able to prevent the impairment in oxygenation when ARDS patients are turned back from the prone to the supine position.\n Prospective, comparative randomized study.\n A medical intensive care unit.\n Forty-three ARDS patients with a Pao2/Fio2 ratio <150 at positive end-expiratory pressure > or =5 cm H2O.\n After an optimization period, the patients were assigned to one of three groups: a) conventional lung-protective mechanical ventilation in the prone position (12 hrs) followed by a 12-hr period of conventional lung-protective mechanical ventilation in the supine position (CV(prone)-CV(supine)); b) conventional lung-protective mechanical ventilation in the supine position (12 hrs) followed by HFOV in the supine position (12 hrs) (CV(supine)-HFOV(supine)); or c) conventional lung-protective mechanical ventilation in the prone position (12 hrs) followed by HFOV in the supine position (CV(prone)-HFOV(supine) group).\n Pao2/Fio2 ratio was higher at the end of the study period in the CV(prone)-HFOV(supine) group than in the CV(prone)-CV(supine) group (p < .02). Venous admixture at the end of the study period was lower in the CV(prone)-HFOV(supine) group than in the two other groups.\n HFOV maintained the improvement in oxygenation related to prone positioning when ARDS patients were returned to the supine position.", "To compare the effect of the prone position (PP) vs supine position (SP) on oxygenation in children with acute respiratory failure (ARF).\n Prospective, randomized controlled trial.\n A 36-bed pediatric critical-care unit in a tertiary-care, university-based children's hospital.\n Ten children (mean [SD] age, 5 +/- 3.6 years) with ARF with a baseline oxygenation index (OI) of 22 +/- 8.5.\n Following a period of stabilization in the SP, baseline data were collected and patients were randomized to one of two groups in a two-crossover study design: group 1, supine/prone sequence; group 2, prone/supine sequence. Each position was maintained for 12 h. Lung mechanics and acute response to inhaled nitric oxide were examined in each position.\n OI was significantly better in the PP compared to the SP over the 12-h period (analysis of variance, p = 0.0016). When patients were prone, a significant improvement in OI was detected (7.9 +/- 5.3; p = 0.002); this improvement occurred early (within 2 h in 9 of 10 patients) and was sustained over the 12-h study period. Static respiratory system compliance and resistance were not significantly affected by the position change. Inhaled nitric oxide had no effect on oxygenation in either position. Urine output increased while prone, resulting in a significantly improved fluid balance (+ 6.6 +/- 15.2 mL/kg/12 h in PP vs + 18.9 +/- 13.6 mL/kg/12 h in SP; p = 0.041). No serious adverse effects were detected in the PP.\n In children with ARF, oxygenation is significantly superior in the PP than in the SP. This improvement occurs early, remains sustained for a 12-h period, and is independent of changes in lung mechanics.", "In neonatal disease states where lung compliance is reduced (e.g., inadequate resorption of fetal lung fluid or, surfactant deficiency) an infant's normally low functional residual capacity (FRC) decreases even further. Tachypnea is an efficient compensatory maneuver for the newborn. We evaluated the effect of different bed and body positions on the increased respiratory rate observed in infants with transient tachypnea of the newborn (TTN), infant respiratory distress syndrome (RDS), and bronchopulmonary dysplasia (BPD). Seventeen infants were studied (TTN, n = 6; RDS, n = 6; BPD, n = 5) in four different positions: supine flat, supine elevated, prone flat, and prone elevated. Respiratory rate and heart rate were evaluated in each position. Analysis of variance for the three patient groups showed a lower respiratory rate when the bed was elevated 20-30 degrees compared to flat (P = 0.0001), in the prone posture compared to supine (P = 0.031), and no significant difference in heart rate. The lowest mean respiratory rate occurred when patients were in the prone elevated position. The significant improvement in tachypnea seen in the prone and elevated positions was likely related to improved FRC resulting from reduced cephalad stress on the diaphragm from the abdomen. Positioning neonatal patients with respiratory insufficiency was a simple and safe therapeutic maneuver with prompt and demonstrable benefit.", "The effects of body position and feeding on lung mechanics and blood gases in very low birthweight infants with chronic lung disease (CLD) is not fully elucidated.\n Seven very low birthweight infants who were being mechanically ventilated because of CLD were examined. They were enrolled in this study when their feeding volume exceeded 100 mL/kg per day. Each patient was kept on the same position (either prone or supine) during feeding. Feeding was given by a nasogastric tube for over 1 h every 3 h. Blood gases and lung mechanics were evaluated before, 20 min and 40 min after the initiation of the feeding and at the end of the feeding.\n The prone position resulted in a significant increase in arterial oxygen saturation during feeding. The tidal volume in the prone position was significantly larger than in the supine position only before feeding. There were no significant differences in minute ventilation between these positions during the study. Pulmonary resistance was not different in either position, but the static compliance and the work of breathing of spontaneous breaths were improved significantly when the infants were in the prone position. In the supine position, work of breathing increased and static compliance decreased significantly with time, while in the prone position, those values did not change significantly.\n The improvement in lung mechanics may partly explain better oxygenation obtained in the prone position. The prone position could decrease energy expenditure for spontaneous breathing and may shorten the period of ventilatory support for very low birthweight infants with CLD.", "To determine the effects of prone positioning on cardiorespiratory stability and weaning outcome of preterm infants during weaning from mechanical ventilation.\n From January to December 1999, a sample of 42 preterm infants, with birthweight < 2,000 g, mechanically ventilated in the first week of life, were randomly divided, in the beginning of the weaning process, into two groups according to the position: supine position (n = 21) or prone position (n = 21). Heart rate, respiratory rate, transcutaneous oxygen saturation and ventilatory parameters were recorded every one hour. Length of the weaning process and complications were also assessed.\n In both groups the mean gestational age was 29 weeks, most of the patients presented very low birthweight and respiratory distress syndrome. The mean length of the weaning process was 2 days. There were no differences between the groups regarding respiratory rate, heart rate and transcutaneous oxygen saturation, however, oxygen desaturation episodes were more frequent in supine position (p = 0.009). Ventilatory parameters decreased faster and reintubation was less frequent in the prone group (4% versus 33%). No adverse effects of prone positioning were observed.\n These results suggest that prone position is a safe and beneficial procedure during weaning from mechanical ventilation and may contribute to weaning success in preterm infants.", "To determine the influence of body position on chest wall and pulmonary function, we studied the ventilatory, pulmonary mechanics, and thoracoabdominal motion profiles in 20 preterm infants recovering from respiratory disease who were positioned in both the supine and prone position. Thoracoabdominal motion was assessed from measurements of relative rib cage and abdominal movement and the calculated phase angle (an index of thoracoabdominal synchrony) of the rib and abdomen Lissajous figures. The ventilatory and pulmonary function profiles were assessed from simultaneous measurements of transpulmonary pressure, airflow, and tidal volume. The infants were studied in quiet sleep, and the order of positioning was randomized across patients. The results demonstrated no significant difference in ventilatory and pulmonary function measurements as a function of position. In contrast, there was a significant reduction (-49%) in the phase angle of the Lissajous figures and an increase (+66%) in rib cage motion in prone compared with the supine position. In addition, the degree of improvement in phase angle in the prone position was correlated to the severity of asynchrony in the supine position. We speculate that the improvement in thoracoabdominal synchrony in the prone position is related to alterations of chest wall mechanics and respiratory muscle tone mediated by a posturally related shift in the area of apposition of the diaphragm to the anterior inner rib cage wall and increase in passive tension of the muscles of the rib cage. This study suggests that the mechanical advantage associated with prone positioning may confer a useful alternative breathing pattern to the preterm infant in whom elevated respiratory work loads and respiratory musculoskeletal immaturity may predispose to respiratory failure.", "The effect of body position before and after tube feeding was evaluated in six extremely immature infants who were being mechanically ventilated because of chronic lung disease. Their mean birthweight and gestational age were 722.7 g (range, 540 to 994) and 24.9 weeks (range, 23.9 to 26.0), respectively. This study was performed at a mean postnatal age of 47.5 days (range, 21 to 85 days). The prone position resulted in a significant increase in arterial oxygen saturation before and after feeding, whereas the tidal volume demonstrated an increase only before feeding. Also the prone position showed a significant decrease in heart rate before and after feeding and a tendency to decrease transcutaneous carbon dioxide tension values before feeding. There were no significant differences in minute ventilation despite increased tidal volume in the prone position, most likely due to a decrement of the spontaneous respiratory rate in the prone positioning. We conclude that the prone position may offer an advantage over the supine position in the management of extremely immature infants with chronic lung disease before and after feeding.", "To assess the effect of prone and supine positions on breathing pattern variables, thoracoabdominal motion and peripheral oxygen saturation of hemoglobin of premature newborn infants recovering from respiratory distress syndrome, while breathing spontaneously and in rapid eye movement sleep.\n This was a quasi-experimental study. Twelve preterms weighing > 1,000 g at enrollment were studied in both positions, in random order. Respiratory inductive plethysmography was used to analyze breathing pattern (tidal volume, respiratory rate, minute ventilation, mean inspiratory flow) and thoracoabdominal motion (labored breathing index, phase relation in inspiration, phase relation in expiration, phase relation in total breath and phase angle). Pulse oximetry was used to evaluate peripheral oxygen saturation. Student's t test for paired samples or the Wilcoxon test were used for statistical analysis. Significance was set at p < 0.05.\n A total of 9,167 respiratory cycles were analyzed. The prone position was associated with significant reductions in labored breathing index (-0.84+/-0.69; p = 0.001; 95%CI -1.29 to -0.40), phase relation in inspiration (-27.36+/-17.55; p = 0.000; 95%CI -38.51 to -16.20), phase relation in expiration (-32.36+/-16.20; p = 0.000; 95%CI -42.65 to -22.06) and phase relation in total breath (-30.20+/-14.76; p = 0.000; 95%CI -39.59 to -20.82). There were no significant differences between the two positions in any of the other variables analyzed.\n The prone position resulted in a significant reduction in thoracoabdominal asynchrony, without affecting breathing pattern or peripheral oxygen saturation.", "Both prone position and high-frequency oscillatory ventilation (HFOV) have the potential to facilitate lung recruitment, and their combined use could thus be synergetic on gas exchange. Keeping the lung open could also potentially be lung protective. The aim of this study was to compare physiologic and proinflammatory effects of HFOV, prone positioning, or their combination in severe acute respiratory distress syndrome (ARDS).\n : Prospective, comparative randomized study.\n A medical intensive care unit.\n Thirty-nine ARDS patients with a Pao2/Fio2 ratio <150 mm Hg at positive end-expiratory pressure > or =5 cm H2O.\n After 12 hrs on conventional lung-protective mechanical ventilation (tidal volume 6 mL/kg of ideal body weight, plateau pressure not exceeding the upper inflection point, and a maximum of 35 cm H2O; supine-CV), 39 patients were randomized to receive one of the following 12-hr periods: conventional lung-protective mechanical ventilation in prone position (prone-CV), HFOV in supine position (supine-HFOV), or HFOV in prone position (prone-HFOV).\n Prone-CV (from 138 +/- 58 mm Hg to 217 +/- 110 mm Hg, p < .0001) and prone-HFOV (from 126 +/- 40 mm Hg to 227 +/- 64 mm Hg, p < 0.0001) improved the Pao2/Fio2 ratio whereas supine-HFOV did not alter the Pao2/Fio2 ratio (from 134 +/- 57 mm Hg to 138 +/- 48 mm Hg). The oxygenation index ({mean airway pressure x Fio2 x 100}/Pao2) decreased in the prone-CV and prone-HFOV groups and was lower than in the supine-HFOV group. Interleukin-8 increased significantly in the bronchoalveolar lavage fluid (BALF) in supine-HFOV and prone-HFOV groups compared with prone-CV and supine-CV. Neutrophil counts were higher in the supine-HFOV group than in the prone-CV group.\n Although HFOV in the supine position does not improve oxygenation or lung inflammation, the prone position increases oxygenation and reduces lung inflammation in ARDS patients. Prone-HFOV produced similar improvement in oxygenation like prone-CV but was associated with higher BALF indexes of inflammation. In contrast, supine-HFOV did not improve gas exchange and was associated with enhanced lung inflammation.", "To determine if the prone versus the supine posture was associated with higher oxygenation levels in prematurely born infants before discharge, whether any such effect was explained by alterations in lung volume or respiratory mechanics, and if the changes were greater in oxygen-dependent infants.\n Twenty infants (10 oxygen-dependent), median gestational age 30 (range: 27-32) weeks, were studied at a median postconceptional age of 35 weeks (range: 32-38 weeks).\n On 2 successive days, infants were studied both supine and prone; each posture was maintained for 3 hours. Oxygen saturation was continuously monitored and at the end of each 3-hour period; compliance and resistance of the respiratory system and functional residual capacity (FRC) were measured.\n Overall, the median oxygen saturation and FRC were significantly higher in the prone position; compliance of the respiratory system and resistance of the respiratory system were not significantly affected by posture. Differences in oxygen saturation and FRC were significantly higher in the prone posture in the oxygen-dependent, but not the nonoxygen-dependent infants.\n Superior oxygenation in the prone posture in oxygen-dependent premature infants studied before discharge could be explained by higher lung volumes.", "The incidence of Sudden Infant Death Syndrome (SIDS) has decreased dramatically since the inception of the \"Back to Sleep\" campaign initiated by the American Academy of Pediatrics in 1992. However, that decrease has leveled off and many new parents cease to follow the recommendation to place their infants in the supine position for sleep between 1 and 3 months of age, the peak age for the incidence of SIDS. Shortened hospital stays for new mothers and the overwhelming amount of required patient teaching dictate the need to find the best method of instruction. The purpose of this study was to determine if a one-on-one teaching intervention improved the effectiveness of patient education and led to an increase in the desired behavior of placing the infant to sleep in the supine position. A quantitative experimental approach was used to examine the difference in compliance of supine infant positioning. Participants were drawn from a convenience sample of 61 primiparous women between the ages of 18 and 35 years with random assignment to either the experimental or control group. Compared to mothers in the control group, mothers in the experimental group demonstrated greater compliance in selecting supine sleep position in the first week home from the hospital and on the day of follow-up 6 weeks later. However, no difference in \"usual position\" was reported at 6 weeks and for the night previous to follow-up.", "The purpose of this study was to determine the effects of prone and supine positioning on the cardiorespiratory stability of preterm infants with apnea and bradycardia.\n A total of 22 preterm infants with symptomatic apnea and bradycardia (gestational age of 26.9 +/- 1.8 weeks and birth weight of 865 +/- 235 gm) were monitored for 24 hours (in four sequential 6-hour blocks) for apnea, bradycardia, and oxygen desaturation in alternating positions (prone or supine) following randomization. Postconceptional age at the time of study was 31.9 +/- 3.0 weeks. Respiratory rate, heart rate, and transcutaneous oxygen saturation were continuously monitored. All episodes of apnea (> or = 10 seconds), bradycardia (< 100 beats per minute), and oxygen desaturation (< 90%) were recorded on an event monitor. Episodes of apnea, bradycardia, and oxygen desaturation were defined as clinically significant if the following criteria were met: apnea, > or = 15 seconds; bradycardia, < 90 beats per minute; and oxygen desaturation, < 80%. All other recorded episodes were considered mild. The episodes were analyzed for statistical significance using the paired t-test.\n No significant differences (p > 0.05) in the incidence of clinically significant apnea, bradycardia, or desaturation between supine and prone positions were seen in these preterm infants.\n Our results suggest that the cardiorespiratory stability of preterm infants is not significantly compromised by supine positioning.", "Pulse oximetry was used to measure transcutaneous arterial oxygen saturation in infants aged 2 to 11 months prone and supine in quiet sleep. Groups of healthy infants (n = 34), infants with upper respiratory tract infections (n = 13), and infants with generalised moderately severe lower respiratory tract infections (n = 17) were studied. No clinically important differences were demonstrated in any of these groups, although there was a small advantage in the prone position in the group with lower respiratory tract infection. The effect of posture on infants with more severe lower respiratory tract infection and during active sleep has yet to be determined.", "Sixteen stable intubated premature infants without a clinically significant patent ductus arteriosus were studied during recovery from respiratory distress syndrome in order to determine the effects of left and right lateral, as compared to supine, positioning. Pulmonary mechanics were measured for spontaneous breaths 5 and 15 minutes after positioning, and arterial blood gases 15 minutes after positioning. Infants were randomized to 1 of 2 position sequences: (1) supine, left, supine, right or (2) supine, right, supine, left. No significant differences were detected between positions for dynamic compliance, tidal volume/kg, and total, inspiratory and expiratory pulmonary resistance. Likewise, no significant differences in PaO2 or PaCO2 were detected between the positions. The sequence of positions did not affect the pulmonary mechanics of spontaneous breaths or arterial blood gases. This suggest that short-term lateral positioning as well as supine positioning can be utilized without deleterious effects on pulmonary mechanics and gas exchange in neonates recovering from respiratory distress syndrome.", "Routine neonatal care includes frequent position changes. Recent research has concluded that positions other than supine may result in beneficial physiologic responses. Specifically, several studies suggest that neonates may ventilate more effectively in a prone rather than in a supine position. This study tested the hypothesis that transcutaneous carbon dioxide tension (TcPCO2) would be lower in the prone than in the supine position in neonates with respiratory distress. Fourteen ventilated infants were studied. TcPCO2 was measured and recorded in prone, supine, and right-side-lying positions for each subject. There were no statistically significant differences in mean TcPCO2 values between the three positions (F = .45; df 2,39; P = .64). The relationship between TcPCO2 and PaCO2 values was stable (r = .88) during the studies. The results indicate that changing a neonate's position does not significantly alter transcutaneous carbon dioxide tension.", "Eighteen stable very-low-birth-weight (VLBW) mechanically ventilated infants with chronic lung disease were studied to examine the effects of right and left lateral positioning in contrast to supine positioning on transcutaneous (tc) oxygen (tcPO2) and carbon dioxide measurements (tcPCO2). The neonates were studied at a median postnatal age of 31 days (range, 17 to 57 days) and had median birth weights and gestational ages of 975 g (range, 570 to 1360 g) and 27.5 weeks (range, 24 to 30 weeks), respectively. Median fraction of inspiratory oxygen was 0.32 (range, 0.23 to 0.40). The sequence of study positions was randomly determined. Sleep state as well as tcPO2 and tcPCO2 were recorded every 30 s for five minutes. A significant difference in mean tcPO2 or tcPCO2 was not detected for any of the positions. Lateral positioning may facilitate the development of midline behavior in VLBW infants. Care givers are often reluctant to position infants in side lying, however, because of concerns that ventilation or oxygenation might be compromised. We conclude that placing the stable VLBW mechanically ventilated infant in a side-lying position has no deleterious effects on oxygenation and ventilation, as measured by tcPO2 and tcPCO2, and therefore should be encouraged.", "Application of continuous distending pressure at birth (very early CDP) should stabilize the immature airways and reduce the severity of respiratory distress syndrome (RDS) in preterm infants. Eighty-two preterm infants of less than 32 weeks gestation were randomly assigned at birth to early treatment group (TG), in which CDP of 6 cm water pressure was applied at birth by the nasopharyngeal route (NP-CDP), or to control group (CG), in which CDP was applied when indicated for established criteria (pO2 less than 50 mmHg in FiO2 greater than 0.5). Characteristics of the infants in the two groups were comparable. No statistically significant difference between the two groups was found in the incidence of RDS. The course of RDS, and oxygen and ventilatory requirements also did not appear to be changed. In blood gas parameters of most of the time frames, no significant difference was found between the two groups when the results were analyzed according to the assigned group. When the results were analyzed separately for the infants who developed RDS, infants in TG appear to have fared worse from the therapy in terms of oxygenation, as indicated by significantly higher FiO2 (P less than 0.01) and lower a/A (P less than 0.01) values on the third day of the course of RDS, as compared to infants in CG. The incidence of complications was comparable in the two groups. Four infants from TG (9.3%) and one from CG (2.6%) died (P = NS). We conclude that VECDP by nasopharyngeal route does not reduce the incidence of RDS and does not appear to improve the outcome and may worsen the severity of RDS when compared to application of CDP for established criteria." ]	The prone position was significantly superior to the supine position in terms of oxygenation. However, as most participants were ventilated preterm infants, the benefits of prone positioning may be most relevant to these infants. In addition, although placing infants and children in the prone position may improve respiratory function, the association of SIDS with prone positioning means that infants should only be placed in this position while under continuous cardiorespiratory monitoring.
CD001774	[ "8638536", "10202165", "7844607", "8081045", "10202166", "2196107", "1914084", "15238405", "17996926", "17112001", "16077990", "7918123", "10764435", "12691318" ]	[ "The role of neoadjuvant intraarterial infusion chemotherapy with cisplatin and bleomycin for locally advanced cervical cancer.", "Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer.", "Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advanced cervical cancer. Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association.", "[Neoadjuvant chemotherapy of stage IIb or III cancers of the uterine cervix. Long-term results of a multicenter randomized trial of 151 patients].", "Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma.", "A randomized study comparing two regimens of neoadjuvant and adjuvant chemotherapy in multimodal therapy for locally advanced head and neck cancer.", "Phase II trial of carboplatin or iproplatin in cervical cancer.", "Adding concurrent low dose continuous infusion of cisplatin to radiotherapy in locally advanced cervical carcinoma: a prospective randomized pilot study.", "Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study.", "Topotecan in combination with cisplatin for the treatment of stage IVB, recurrent, or persistent cervical cancer.", "A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck.", "A randomized phase II study comparing sequential versus simultaneous chemo-radiotherapy in patients with unresectable locally advanced squamous cell cancer of the head and neck.", "Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer.", "The role of neoadjuvant chemotherapy for squamous cell cervical cancer (Ib-IIIb): a long-term randomized trial." ]	[ "To clarify the effect of neoadjuvant intraarterial infusion chemotherapy on the cure rate in advanced cervical cancer with bulky tumor, a total of 50 patients were examined prospectively. The clinical stage according to the International Federation of Gynecology and Obstetrics (FIGO) classification included 23 IIb, 6 IIIa, and 21 IIIb. These patients were randomly divided into the neoadjuvant intraarterial infusion chemotherapy group and the control group. There were no significant differences in mean age, FIGO clinical stage, and tumor histology between groups. Twenty-five patients in the former group were given 25 mg/m2 of cisplatin and 15 mg/m2 of bleomycin via each internal iliac artery. If the results of the evaluation indicated that surgery was feasible, radical surgery was performed. The patients whose tumors were inoperable received radiation therapy consisting of external irradiation and intracavitary irradiation. Twenty-five patients in the control group also underwent the same radiation therapy. The overall response rate was 80.0%. Eighteen of 20 responders underwent surgery. The 3-year survival rate was 85.7% for operated patients, 42.9% for patients receiving neoadjuvant intraarterial infusion chemotherapy followed by irradiation, and 49.5% for the control group. In the present study, neoadjuvant intraarterial infusion chemotherapy did not improve the prognosis of patients with advanced cervical cancer compared to radiation therapy alone, and only responders who underwent surgery obtained an advantage in survival.", "On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens -- cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone -- in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 micromol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3).\n The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively.\n Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.", "Pelvic radiation is standard treatment for women with stage IIb to IVa cervical cancer, but treatment results are disappointing, particularly for women with bulky tumors. We investigated the role of primary chemotherapy followed by pelvic radiotherapy in a randomized trial.\n Two hundred sixty patients with stage IIb and IVa cervical cancer received either standard pelvic radiotherapy or primary chemotherapy with cisplatin 60 mg/m2 and epirubicin 110 mg/m2 administered at 3-week intervals for three cycles, followed by pelvic radiotherapy.\n Ninety-nine patients have relapsed with a median follow-up duration of 1.3 years; in 62 patients, the first site of progressive disease was the pelvis. Patients who received primary chemotherapy had a significantly higher pelvic failure rate than those who received radiotherapy alone (P < .003). Seventy-six patients have died, and those who received primary chemotherapy had significantly inferior survival compared with those who received radiotherapy alone (P = .02). Tumor response following chemotherapy was observed in 63%. After radiotherapy, tumor response occurred in 72% of those who received combined modality treatment, compared with 92% of those who received radiotherapy alone.\n Primary chemotherapy with epirubicin and cisplatin, although resulting in tumor response in a significant proportion of patients, is accompanied by an inferior local control rate and survival compared with standard pelvic radiotherapy alone.", "Present chemotherapy, with cisplatin combinations, currently offers the possibility of seeking adjuvant therapy in locally advanced and bulky carcinomas of the cervix, which have an unfavorable prognosis (nodal involvement). This initial adjuvant chemotherapy may improve the results of classical pelvic irradiation. From 1982 to 1987, a randomized phase III trial was performed in order to determine the long term effect of induction chemotherapy before irradiation in stage IIb-N1, III, M0 squamous cell carcinomas of the cervix. Radiotherapy (R) for all patients consisted in 50 Gy in the pelvis with a boost by external irradiation of the brachytherapy (cumulative dose of 68 Gy). The chemotherapy regimen (C + R group) was an association of methotrexate, chlorambucil, vincristine and cisplatin, given every 3 weeks, at least two courses were to be given before assessing efficacy and two more courses were given to patients who responded. After a follow up of 5-10 years, 76 patients were fully evaluable in the R arm and 75 in the C + R arm. The response rate (> 50%) to chemotherapy was 42.5% and after completion of treatment, remission rate was 93% in the R arm and 96% in the C + R arm. The disease-free survival was 40% in the C + R group and 35% in the R group, and the median survival was 42 and 45 months respectively (NS). The survival of patients with a complete response at the end of radiotherapy was significantly better in the C + R group when they are responding to chemotherapy, than in R group (P < 0.05). Radiotherapy was not modified whether patients had an initial chemotherapy or not; tolerance was not significantly different between the two groups. Efficacy of induction chemotherapy is an available test for long term results. This approach has the potential for improving the outlook in patients with high-risk primary cancer: earlier use and higher dose intensity of chemotherapy may be associated with a better cytoreduction, and probably a better survival. Further controlled investigations are warranted to confirm the value of adjuvant chemotherapy in cervical cancer.", "Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer.\n Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later.\n The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent).\n Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.", "Two regimens of neoadjuvant chemotherapy for previously untreated patients with locally advanced head and neck cancer were compared with the goal of identifying a regimen with a greater than 50% complete response (CR) rate. Patients with a performance status of 0 to 2 and normal end-organ function were randomized to receive either four cycles of neoadjuvant methotrexate, cisplatin, and continuous infusion 5-fluorouracil (5-FU) (MPF) (arm A), or four cycles of bleomycin, cisplatin, and methotrexate (PBM) alternating with cisplatin and 5-FU (PF) (arm B). Patients with a performance status of greater than 2 or a carbon monoxide diffusion capacity of less than 50% of the predicted value were assigned to the arm A regimen but were analyzed separately (arm C). Local therapy consisted of surgery (for patients with resectable disease) or radiation therapy followed by two cycles of adjuvant chemotherapy with the regimen that was administered initially. Of the 42 patients who were evaluated, 16 were randomized to arm A, 13 to arm B, and 13 to arm C. The clinical CR rate was 19% on arm A (95% confidence interval, 0% to 38%), 39% on arm B (95% confidence interval, 12% to 66%) (P = 0.41), and 54% on arm C (95% confidence interval, 27% to 81%). At a median follow-up time of 35 months, the 2-year actuarial survival rate was 61% on arm A, 69% on arm B (the P value was not significant), and 38% on arm C. The 2-year survival rate for all 42 patients who were treated was 57% and the median survival time was 31 months. Toxicities of neoadjuvant chemotherapy on all arms consisted of mild to moderate myelosuppression and renal toxicity. The incidence of moderate to severe mucositis was significantly higher on arm A than arm B (P = 0.02). Two cycles of adjuvant chemotherapy were administered to only 11 of 42 patients due to patient refusal or cumulative toxicity. In conclusion, both neoadjuvant chemotherapy regimens resulted in similar response and survival rates, but mucositis was more severe with arm A. However, since neither regimen was likely to cause a CR rate of greater than 50%, this study was closed to further patient accrual.", "From July 1984 to November 1987, 89 patients with recurrent measurable squamous-cell cancer of the uterine cervix were randomized in a single institution to receive treatment with either carboplatin (CBDCA) or iproplatin (CHIP). Objective response rates were similar: 2 complete regressions (CRs) and 10 partial regressions (PRs) were recorded both in the 46 evaluable patients treated with CBDCA (response rate, 26.1%; 95% confidence interval, 15-41%) and in the 40 evaluable patients treated with CHIP (response rate, 30%; 95% confidence interval, 17-47%). The median duration of response was 5.5 months for CBDCA and 6 months for CHIP; the median survival was 7.5 and 7.6 months, respectively. Both drugs were given in an outpatient setting and myelosuppression (thrombocytopenia) was the predominant toxicity. Analysis of all toxic events yielded additional interesting observations: the occurrence of moderate to severe platelet nadirs beyond cycle 1 was confined to CHIP, a higher incidence of gastrointestinal toxicity during treatment with CHIP, and five moderate to severe complaints of asthenia (recorded as neurologic events) during CHIP therapy versus only one during treatment with CBDCA. Because of its antitumor activity and its toxicologic advantage, a future role for CBDCA in the treatment of cervical cancer appears likely.", "The tolerability and efficacy of the continuous infusion of cisplatin during radiotherapy was studied by tumour response, survival and pelvic control, in carcinoma of the cervix. 44 patients with stage IIB-IIIB cervical carcinoma were prospectively randomized into two groups: radiation alone (control group) versus radiation plus cisplatin (study group). While there was no significant difference in diarrhoea and urinary complication scores, emesis and appetite changes were significantly greater in the study group. Tumour responses were no different at the end of the treatment and 3 months after completion of treatment. After 40 months median follow-up, 40/44 patients were assessed (one had a second primary tumour and three were lost to follow-up). Persistent disease was found in 3 patients: one in the study arm and two in the control arm. Recurrence was seen in 10 patients in the first 2 years. 5-year pelvic control rates were; 69.4% and 63.9% (p=0.7), survival rates were 52.0% and 48.9% (p=0.7) and disease-free survival rates were 67.5% and 58.7% (p=0.3) for the control and the study groups, respectively. Although the continuous infusion of cisplatin during radiotherapy was well tolerated, this additional treatment did not appear to show an improvement in pelvic control, survival, or disease-free survival.", "To establish an optimal adjuvant therapy for intermediate- and high-risk endometrial cancer patients, we conducted a multi-center randomized phase III trial of adjuvant pelvic radiation therapy (PRT) versus cyclophosphamide-doxorubicin-cisplatin (CAP) chemotherapy in women with endometrioid adenocarcinoma with deeper than 50% myometrial invasion.\n Among 385 evaluated patients, 193 patients received PRT and 192 received CAP. The PRT group received at least 40 Gy. The CAP group received cyclophosphamide (333 mg/m2), doxorubicin (40 mg/m2) and cisplatin (50 mg/m2) every 4 weeks for 3 or more courses.\n No statistically significant differences in progression-free survival (PFS) and overall survival (OS) were observed. The 5-year PFS rates in the PRT and CAP groups were 83.5% and 81.8% respectively, while the 5-year OS rates were 85.3% and 86.7% respectively. These rates were also not significantly different in a low- to intermediate-risk group defined as stage IC patients under 70 years old with G1/2 endometrioid adenocarcinoma. However, among 120 patients in a high- to intermediate-risk group defined as (1) stage IC in patients over 70 years old or with G3 endometrioid adenocarcinoma or (2) stage II or IIIA (positive cytology), the CAP group had a significantly higher PFS rate (83.8% vs. 66.2%, log-rank test P=0.024, hazard ratio 0.44) and higher OS rate (89.7% vs. 73.6%, log-rank test P=0.006, hazard ratio 0.24). Adverse effects were not significantly increased in the CAP group versus the PRT group.\n Adjuvant chemotherapy may be a useful alternative to radiotherapy for intermediate-risk endometrial cancer.", "Topotecan, a camptothecin analog previously approved for the treatment of ovarian cancer and small-cell lung cancer, was granted regular approval by the US Food and Drug Administration (FDA) on June 14, 2006, for use in combination with cisplatin to treat women with stage IVB, recurrent, or persistent carcinoma of the cervix not amenable to curative treatment with surgery and/or radiation therapy. The purpose of this summary is to review the database supporting this approval.\n In a randomized multicenter study enrolling 293 eligible patients, topotecan plus cisplatin (TC) was compared with cisplatin monotherapy. The TC regimen consisted of cisplatin 50 mg/m2 IV over 1 hour on day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1, 2, and 3 every 21 days.\n There was a clinically relevant and statistically significant improvement in overall survival in the TC treatment arm. Median overall survival was 9.4 months (95% confidence interval [CI]:7.9-11.9) in the TC arm, compared to 6.5 months (95% CI:5.8-8.8) with cisplatin alone. The unadjusted hazard ratio for overall survival between treatment arms was 0.76 (95% CI: 0.59-0.98, P = .033) favoring the combination arm. The most common toxicities with TC included myelosuppression, nausea and vomiting, mucositis, rash, and hepatotoxicity.\n This report describes the FDA's review supporting this first approval of a chemotherapeutic drug for advanced cervical cancer based on demonstration of a survival benefit.", "We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.", "Single-modality radiotherapy is still considered standard treatment for patients with locally advanced unresectable cancer of the head and neck. As treatment outcome is poor, attempts to integrate chemotherapy into the overall management of these patients are ongoing.\n A randomized study was undertaken to compare a sequential with a simultaneous chemoradiotherapy program. Between February 1986 and February 1991, 93 eligible patients with locally advanced unresectable cancer of the head and neck were stratified by WHO PS, T and N class and primary site and then randomized to receive either three courses of neoadjuvant chemotherapy with cisplatin (100 mg/m2 i.v. d 1) and 5-fluorouracil 1000 mg/m2/days 1-5 by continuous i.v. infusion every 3 weeks prior to definitive conventional radiotherapy of 65-70 Gy (sequential treatment), or cisplatin 100 mg/m2 on days 1, 22, 43 given simultaneously for the duration of the same conventional radiotherapy (simultaneous treatment).\n At the end of the entire treatment 18 complete responses (47%) in the sequential-treatment arm and 18 (41%) in the simultaneous treatment arm were obtained. No statistically significant differences in the 5-yr progression-free survival, in the median time to loco-regional and distant progression and in the 5-yr overall survival were observed. Leukopenia was more frequent in the simultaneous than in the sequential arm (p = 0.03), whereas alopecia (p = 0.008) and phlebitis (p < 0.0001) were more frequent in the sequential-treatment arm. A better compliance was associated with the concomitant treatment, with 87% of the patients completing the entire radiotherapy program versus 63% of those in the sequential arm (p = 0.01).\n In the present study, the two treatment arms showed similar activity (complete response, progression-free and overall survival rates). Compliance to treatment was better in the concomitant arm. These data suggest that concomitant chemo-radiation therapy might be considered an option in unresectable locally advanced cancer of the head and neck. Phase III studies are needed in order to establish the superiority of this combination of cisplatin and radiotherapy versus radiotherapy alone.", "To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer.\n Women with previously untreated bulky (primary tumor >/= 4 cm) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2) and vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days for three cycles followed by radical hysterectomy (NAC arm) or receive primary pelvic radiotherapy only (R/T arm). The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative.\n Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival.\n NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.", "to verify whether a regimen of preventive chemotherapy in the treatment of cervical carcinoma allows surgical treatment in a larger number of patients and whether cases treated with this combined neoadjuvant polychemotherapy/surgery regimen improves overall and disease-free survival rates. Design: prospective randomized clinical study. Setting: Department of Gynaecology and Obstetrics, University of Rome \"La Sapienza\".\n 192 patients suffering from squamous cell carcinoma of the uterine cervix in Stages Ib-IIb were randomized to one of the following treatments: three courses of neoadjuvant chemotherapy with cisplatin, vincristine, bleomycin (NACT arm; n = 106); conventional surgery or radiotherapy alone (CO arm; n = 86). One hundred and fifty-six patients in Stage Ib-IIb (n = 86, NACT arm and n = 70, CO arm) and 16 patients in Stage III (NACT arm) who proved to be sensitive to the neoadjuvant chemotherapy, underwent radical hysterectomy. Four Stage III patients not sensitive to chemotherapy and 16 patients, Stage III, of the CO arm underwent radiotherapy.\n the 5-year overall survival rates for the NACT and CO arm, respectively, were 78.6% and 73.2% in Stages Ib-IIa (p = NS), 68.7% and 64.3% in Stage IIb (p = NS). A 5-year disease-free survival rate for the NACT arm and CO arm, respectively, of 77.1% and 64.3% in Stages Ib-IIa (p < .05), 56.2% and 57.1% in Stage IIb (p = NS) was found.\n the responsiveness of cervical cancer to neoadjuvant chemotherapy allows surgical treatment in a larger number of patients and results in longer overall and disease-free survival." ]	The timing and dose intensity of cisplatin-based neoadjuvant chemotherapy appears to have an important impact on whether or not it benefits women with locally advanced cervical cancer and warrants further exploration. Obtaining additional IPD may improve the strength of these conclusions.
CD008296	[ "20555312", "19959339", "20473057", "20389255", "19941696", "21092748" ]	[ "A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia.", "Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study.", "A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia.", "Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study.", "Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study.", "A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia." ]	[ "Paliperidone palmitate is a long-acting injectable antipsychotic agent. This 13-week, multicenter, randomized (1 : 1 : 1 : 1), double-blind, parallel-group study evaluated the efficacy, safety, and tolerability of fixed 25, 50, and 100 milligram equivalent (mg equiv.) doses of paliperidone palmitate vs placebo administered as gluteal injections on days 1 and 8, then every 4 weeks (days 36 and 64) in 518 adult patients with schizophrenia. The intent-to-treat analysis set (N=514) was 67% men and 67% White, with a mean age of 41 years. All paliperidone palmitate dose groups showed significant improvement vs placebo in the Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure; 25 and 50 mg equiv., p=0.02; 100 mg equiv., p<0.001), as well as Clinical Global Impression Severity scores (p< or =0.006) and PANSS negative and positive symptom Marder factor scores (p< or =0.04). The Personal and Social Performance scale showed no significant difference between treatment groups. The overall incidence of treatment-emergent adverse events was similar between groups. Parkinsonism, the most frequently reported extrapyramidal symptom, was reported at similar rates for placebo (5%) and paliperidone palmitate (5-6% across doses). The mean body mass index and mean weight showed relatively small dose-related increases during paliperidone palmitate treatment. Investigator-evaluated injection-site pain, swelling, redness, and induration were similar across treatment groups; scores for patient-evaluated injection-site pain (visual analog scale) were similar across groups and diminished with time. All doses of once-monthly paliperidone palmitate were efficacious and generally tolerated, both locally and systemically. Paliperidone palmitate offers the potential to improve outcomes in adults with symptomatic schizophrenia.", "We assessed efficacy and tolerability of the injectable atypical antipsychotic paliperidone palmitate in delaying time-to-relapse in adults with schizophrenia.\n Eligible patients (Positive and Negative Syndrome Scale [PANSS] total score < 120) were transitioned from previous antipsychotics to paliperidone palmitate during a 9-week, open-label phase. Patients received the first 2 intramuscular injections of paliperidone palmitate (50mg eq) one-week apart, then subsequent injections (25, 50, or 100mg eq, flexibly-dosed), once-monthly. Stable patients (PANSS total score < or = 75) continued into the 24-week maintenance phase. At maintenance phase endpoint, stabilized patients were randomized (1:1 ratio) to either continue paliperidone palmitate (at stabilized dose) or begin placebo in the variable-duration, double-blind phase.\n The preplanned interim analysis (conducted after 68 relapse events) included 312 patients: mean age = 40 years, 55% men, 66% white, and mean transition baseline PANSS total score (SD): placebo, 69.5 (16.89); paliperidone palmitate, 69.3 (17.39). Time-to-relapse (primary endpoint) favored paliperidone palmitate (p<0.0001, log-rank test) at interim and final analysis (n=408). The hazard ratio (placebo/paliperidone palmitate) at the final analysis was 3.60 (95% CI: 2.45, 5.28). Treatment-emergent adverse event rates (final analysis set) were: 67% for transition and maintenance phases, and 45% (placebo) and 44% (paliperidone palmitate) for the double-blind phase. Across phases, the incidence of glucose-related adverse events was low (< or = 4%), while mean weight increased by 1.9 kg for paliperidone palmitate and remained unchanged for placebo patients. Injection site tolerability was comparable between groups.\n Paliperidone palmitate significantly delayed time-to-relapse compared with placebo and presented no new safety signals.\n 2009 Elsevier B.V. All rights reserved.", "This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P < or = 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (> or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.", "This 13-week, double-blind study evaluated the efficacy and safety of the atypical antipsychotic paliperidone palmitate (recently approved in the United States) versus placebo administered as monthly gluteal injections (after two initial doses given 1 week apart) in acutely symptomatic patients with schizophrenia. Patients (N=388) were randomly assigned (1 : 1 : 1 : 1) to paliperidone palmitate 50, 100, or 150 mg eq. or placebo. As the 150 mg eq. dose was administered to fewer patients (n=30) than planned, meaningful and definitive conclusions cannot be drawn from the results of this group. The change from baseline in Positive and Negative Syndrome Scale total score at endpoint showed improvement in both paliperidone palmitate 50 and 100 mg eq. groups but was significant only in the 100 mg eq. group (P=0.019). The paliperidone palmitate 50 (P=0.004) and 100 mg eq. (P<0.001) groups showed significant improvement in the Personal and Social Performance score from baseline to endpoint versus placebo. Common adverse events (in >or=2% of patients in any group) more frequent with paliperidone palmitate 50 or 100 mg eq. than placebo (>or=5% difference) were headache, vomiting, extremity pain, and injection site pain. Treatment with paliperidone palmitate (100 mg eq.) was efficacious and all doses tested were tolerable.", "We evaluated the efficacy and safety of the investigational long-acting injectable antipsychotic agent paliperidone palmitate (PP) in the treatment of schizophrenia. Patients were randomized to receive gluteal injections of placebo or PP (50 or 100 mg eq., fixed doses), without oral supplementation, on days 1, 8, and 36 (9-wk, double-blind phase) in this phase 2b study. Patients (n=197, intent-to-treat analysis set) were 62% men, mean (s.d.) age 39 (10) yr, with a baseline mean (s.d.) Positive and Negative Syndrome Scale (PANSS) total score of 87.0 (12.5). Mean (s.d.) PANSS total scores showed significant improvement at endpoint (primary measure) for both the PP 50 mg eq. [-5.2 (21.5)] and PP 100 mg eq. [-7.8 (19.4)] groups, vs. placebo [6.2 (18.3)] (p0.001, each dose vs. placebo). This improvement was detected by day 8 and maintained to endpoint (p0.011) for both doses. In the safety analysis set (n=247), fewer PP-treated patients (2%) discontinued for treatment-emergent adverse events vs. placebo-treated (10%). Rates of treatment-emergent extrapyramidal syndrome-related adverse events were comparable between active treatment and placebo, with the exception of parkinsonism-related disorders (50 mg eq. 5%, 100 mg eq. 8%, placebo 1%). Results of other safety measures suggest PP to be generally well-tolerated. Throughout the study, investigators rated injection-site pain as absent (56-71%), mild (24-39%), moderate (2-12%), or severe (0-2%). PP (50 and 100 mg eq. doses) administered as a gluteal intramuscular injection was efficacious and generally tolerated in these patients with acute symptomatic schizophrenia.", "This 13-week double-blind study was designed to assess noninferiority of the recently approved (in the U.S.) injectable atypical antipsychotic paliperidone palmitate (PP) versus risperidone long-acting injectable (RIS-LAI) in adult patients with schizophrenia. Patients (N=1220) were randomized (1:1) to either a) PP: deltoid injections on day 1 (150 mg eq.), day 8 (100 mg eq.), and once-monthly flexible dosing as deltoid or gluteal injections on day 36 (50 mg eq. or 100 mg eq.) and day 64 (50 mg eq. or 100 mg eq. or 150 mg eq.) or b) RIS-LAI: gluteal injections days 8 and 22 (25mg), days 36, 50 (25 or 37.5mg) and days 64, 78 (25, 37.5 or 50mg). RIS-LAI-treated patients received oral supplementation with RIS 1-6 mg/day (days 1 to 28), and PP-treated patients received oral placebo. The safety analysis set (n=1214) included 58% men, 78% white, with mean (SD) baseline PANSS total score: PP, 84.1 (12.09); and RIS-LAI, 83.6 (11.28). Mean (SD) change from baseline to endpoint in PANSS total score decreased similarly in both groups; PP (-18.6 [15.45]) and RIS-LAI (-17.9 [14.24]). PP treatment was noninferior to RIS-LAI (point estimate [95% CI]: 0.4 [-1.62;2.38], per-protocol analysis set [primary analysis]). The tolerability and safety of PP was generally similar to RIS-LAI with no new safety or tolerability findings.\n Copyright © 2010 Elsevier Inc. All rights reserved." ]	In short-term studies, paliperidone palmitate is an antipsychotic drug that is more efficacious than placebo. We found its adverse effects to be similar to those of its related compounds, paliperidone and risperidone, with extrapyramidal movement disorders, weight gain, and tachycardia all more common with paliperidone palmitate than placebo. While no difference was found in the incidence of reported adverse sexual outcomes, paliperidone palmitate is associated with substantial increases in serum prolactin. When flexibly dosed with a mean doses of approximately 70 to 110 mg every four weeks, paliperidone palmitate appears comparable in efficacy and tolerability to risperidone long-acting injection flexibly dosed with mean doses of approximately 35 mg every two weeks.
CD002151	[ "9291905", "14640494", "19017387", "1616392", "9311648", "11229858", "20858280", "1909469", "15941413" ]	[ "Effect of paracetamol on parasite clearance time in Plasmodium falciparum malaria.", "Antipyretic, parasitologic, and immunologic effects of combining sulfadoxine/pyrimethamine with chloroquine or paracetamol for treating uncomplicated Plasmodium falciparum malaria.", "A randomized trial to monitor the efficacy and effectiveness by QT-NASBA of artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment and transmission control of uncomplicated Plasmodium falciparum malaria in western Kenya.", "Evaluation of the relative efficacy of various antimalarial drugs in Nigerian children under five years of age suffering from acute uncomplicated falciparum malaria.", "A comparative clinical trial of sequential treatments of severe malaria with artesunate suppository followed by mefloquine in Thailand.", "Effect of antipyretic drugs in children with malaria.", "Impact of repeated four-monthly anthelmintic treatment on Plasmodium infection in preschool children: a double-blind placebo-controlled randomized trial.", "A randomized trial comparing a pentavalent antimonial drug and recombinant interferon-gamma in the local treatment of cutaneous leishmaniasis.", "A randomized, placebo-controlled, double-blind trial on sulfadoxine-pyrimethamine alone or combined with artesunate or amodiaquine in uncomplicated malaria." ]	[ "Routine antipyretic therapy in children with infectious diseases has long been the source of controversy. Each year, in addition to antimalarial medication, millions of children with Plasmodium falciparum malaria receive paracetamol to reduce fever. However, the usefulness of this practice has not been proven.\n In a randomised trial in Lambaréné, Gabon, 50 children with P falciparum malaria were treated with intravenous quinine, and received either mechanical antipyresis alone, or in combination with paracetamol. Rectal body temperature and parasitaemia were recorded every 6 h for 4 days. Plasma concentrations and inducible concentrations of tumour necrosis factor (TNF) and interleukin-6 were measured every 24 h. In addition, production of oxygen radicals was measured in both groups.\n The mean fever clearance time was 32 h for children treated with paracetamol and 43 h for those who received mechanical antipyresis alone; however, this 11 h difference was not significant (95% CI -2 to 24 h; p = 0.176). Parasite clearance time was significantly prolonged in patients who received paracetamol with a difference of 16 h (8-24 h; p = 0.004). Plasma concentrations of TNF and interleukin-6 were similar in both groups during the study. However, the induced concentrations of TNF, and the production of oxygen radicals, were significantly lower in children treated with paracetamol than those who received mechanical antipyresis alone.\n These data suggest that paracetamol has no antipyretic benefits over mechanical antipyresis alone in P falciparum malaria. Moreover, paracetamol prolongs parasite clearance time, possibly by decreased production of TNF and oxygen radicals.", "Sulfadoxine/pyrimethamine (SP) is increasingly used against malaria in sub-Saharan Africa because of chloroquine resistance. However, chloroquine may have a beneficial antipyretic effect. We therefore compared the combination of SP plus chloroquine, chloroquine alone, SP alone, and SP plus paracetamol in the treatment of uncomplicated Plasmodium falciparum malaria in 175 Tanzanian children (1-4 years old) in a randomized trial. Outcome variables were axillary temperatures every six hours, daily parasitemias, and serum levels of IgG antibodies to P. falciparum. Lower mean temperatures (6-48 hours) were achieved with SP plus chloroquine or paracetamol than with SP alone (P < 0.001) or chloroquine alone (P < 0.05). All three SP-treated groups showed high and similar parasite reduction (0-48 hours), whereas treatment with chloroquine alone was much less effective. Levels of IgG antibodies to P. falciparum increased significantly (P < 0.001) and similarly in the four treatment groups between days 0, 2, and 3. Thus, the addition of chloroquine or paracetamol to SP improved the clinical outcome, but did not affect the parasitologic response or antibody production.", "Many countries have implemented artemisinin-based combination therapy (ACT) for the first-line treatment of malaria. Although many studies have been performed on efficacy and tolerability of the combination arthemeter-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP), less is known of the effect of these drugs on gametocyte development, which is an important issue in malaria control.\n In this two-arm randomized controlled trial, 146 children were treated with either AL or DP. Both groups received directly observed therapy and were followed for 28 days after treatment. Blood samples were analysed with microscopy and NASBA. In comparison with microscopy NASBA detected much more gametocyte positive individuals. Moreover, NASBA showed a significant difference in gametocyte clearance in favour of AL compared to DP. The decline of parasitaemia was slower and persistence or development of gametocytes was significantly higher and longer at day 3, 7 and 14 in the DP group but after 28 days no difference could be observed between both treatment arms.\n Although practical considerations could favour the use of one drug over another, the effect on gametocytogenesis should also be taken into account and studied further using molecular tools like NASBA. This also applies when a new drug is introduced.\n Current controlled trials ISRCTN36463274.", "A parallel group-randomized comparison of the therapeutic efficacy of chloroquine (CQ), amodiaquine (AM), quinine (QN), sulphadoxine-pyrimethamine (S-P), mefloquine 15 mg kg-1 (M15) and mefloquine 25 mg kg-1 (M25) in acute symptomatic uncomplicated falciparum malaria was carried out in 325 children under the age of five years in Ibadan, southwestern Nigeria, using the 28-day in vivo test. The parasitological cure rate, assessed only up to day 14, was 85% in the CQ group and 100% in the other groups. The mean parasite and fever clearance times were, respectively, 2.64 and 1.20 days in the CQ-sensitive subgroup, 2.32 and 1.13 days in the AM group, 2.27 and 1.17 days in the QN group, 2.23 and 1.76 days in the S-P group, 2.13 and 1.10 days in the M15 group, and 2.07 and 1.09 days in the M25 group. The CQ-treatment failures (seven of 46 patients) were successfully treated with 25 mg kg-1 mefloquine, with parasite and fever clearance times of 1.73 and 1.0 days respectively. The study shows that, in Nigeria, CQ is now less effective than AM, S-P, QN and M in acute falciparum malaria in the group most vulnerable to the infection (the under-five-year-olds).(ABSTRACT TRUNCATED AT 250 WORDS)", "Sixty-three patients with severe falciparum malaria were randomly administered one of the two regimens of a sequential combination of artesunate suppository followed by an oral mefloquine tablet. Thirty-two patients received artesunate suppositories (200 mg/capsule) given rectally at 0, 4, 8, 12, 24, 36, 48, and 60 hr (total = 1,600 mg: Group I). Thirty-one patients received the same artesunate suppositories given rectally at 0, 12, 24, 36, 48, and 60 hr (total = 1,200 mg: Group II). Both regimens were followed by two doses of oral mefloquine, 750 mg given at 72 hr and 500 mg at 84 hr. Patient baseline characteristics were comparable in the two groups. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases to assess efficacy, tolerability, and delayed neuropsychiatric effects. The mean [SD] parasite clearance time was significantly shorter in Group I than Group II (47.3 [12.4] hr versus 55.3 [17.4] hr; P = 0.05) and the rate of parasite reduction was significantly faster in Group I (P = 0.05, by log-rank test). Mean [SD] fever clearance times were similar in the two Groups (71.1 [41.2] hr and 76.9 [47.9] hr, respectively). Twenty-two patients with unrousable coma on admission (median Glasgow Coma Score = 9) regained consciousness after 1-4 days. No deaths occurred. Sixty of sixty-three patients were parasitologically and clinically cured within 3-4 days of treatment. Three patients (5%) with deteriorating conditions required rescue treatment (one patient in Group I was administered intravenous artesunate, and two patients in Group II required two extra doses of suppository). No patients had major adverse drug effects. The cure rates at 28 days of follow-up in Group I were 96% (26 of 27 patients) and 89% (24 of 27 patients) in Group II. Artesunate suppository followed by mefloquine was well tolerated and effective. In severe malaria, the sequential treatment is a suitable alternative treatment to parenteral drugs. Further studies in a larger number of patients under field conditions are required.", "A comparison of different antipyretics in children with malaria showed a small effect of naproxen, but not of metamizol, on the reduction of fever peaks. Antipyretic treatment had no effect on fever clearance and therefore should be used cautiously in the treatment of malaria.", "Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on Plasmodium infections in preschool children.\n A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on Plasmodium infection in children aged 12-59 months. Children were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months.\n 320 Children (out of 1228, 26.1%) complied with all the follow-up assessments. Plasmodium prevalence and mean Plasmodium parasite density was significantly higher in the treatment group (44.9% and 2319 ± SE 511) compared to the placebo group (33.3% and 1471 ± 341) at baseline. The odds of having Plasmodium infection increased over time for children in both the placebo and treatment groups, however this increase was significantly slower for children in the treatment group (P = 0.002). By month 14, mean Plasmodium density had increased by 156% in the placebo group and 98% in the treatment group but the rate of change in Plasmodium density was not significantly different between the groups. The change from baseline in haemoglobin had a steeper increase among children in the treatment group when compared to the placebo group but this was not statistically significant.\n Repeated four-monthly anthelminthic treatments for 14 months resulted in a significantly lower increase in the prevalence of Plasmodium infection in preschool children which coincided with a reduction in both the prevalence and intensity of A. lumbricoides infections.\n Current controlled trials ISRCTN44215995.", "In a randomized prospective trial N-methyl-glucamine antimoniate (Glucantime) and human recombinant interferon-gamma were infiltrated around lesions of cutaneous leishmaniasis caused by Leishmania tropica in Syria. A previous trial had shown that intradermal application of interferon-gamma promoted the healing of similar lesions in the study area. Twenty patients with 38 lesions received 1-3 ml Glucantime and 20 patients with 37 lesions received 25 micrograms of interferon-gamma intradermally once weekly for 5 consecutive weeks. While all lesions treated with Glucantime were free of parasites after the third injection, only 69% of those treated with interferon-gamma were parasitologically cured by week 10. Within 10 weeks, lesions treated with Glucantime healed completely in 29/38, and partially in 9/38, cases, whereas 1/37 and 13/37 lesions treated with interferon-gamma healed completely and partially, respectively. Perilesional application of Glucantime was highly effective and superior to interferon-gamma for treatment of cutaneous leishmaniasis caused by L. tropica.", "The therapeutic efficacy of sulfadoxine-pyrimethamine (SP) alone, SP plus amodiaquine (AQ), and SP plus artesunate (AS) was assessed in a randomized, placebo-controlled, and double-blind trial among 438 children with uncomplicated Plasmodium falciparum malaria in northern Ghana. Clinical and parasitological responses were monitored for 28 days following treatment; 86%, 98% and 97% of SP-, SP + AQ-, and SP + AS-treated patients achieved adequate clinical and parasitological response (ACPR) within 2 weeks, respectively. Parasite clearance was better with SP + AS than with SP or SP + AQ treatment but re-infections were more common. Polymerase chain reaction (PCR)-corrected rates of ACPR at day 28 were 72.2% for SP, 94.1% for SP + AQ (P < 0.0001), and 94.5% for SP + AS (P < 0.0001). Gametocyte prevalence and density 1 week after treatment were highest in children treated with SP, and lowest in patients receiving SP + AS. No severe adverse events attributable to study medication were observed. In northern Ghana, more than one of four children suffered SP treatment failure within 4 weeks. Both SP + AQ and SP + AS are efficacious alternative therapeutic options in this region. Although SP + AS and SP + AQ treatments have virtually identical cure rates, rapid parasite clearance and pronounced gametocidal effects are the advantages of the former, whereas cost and a lower rate of late re-infections are those of the latter." ]	We do not know whether antipyretics alter parasite clearance time. Whether further trials are worthwhile to investigate this or not would require a judgement of whether this was an important question to resolve using interventional trials.
CD000137	[ "1497047", "3630465", "19669019" ]	[ "Maternal hyperoxygenation in the treatment of intrauterine growth retardation.", "[Therapy of suspected intrauterine fetal retardation].", "[Correlation between the inspired fraction of oxygen, maternal partial oxygen pressure, and fetal partial oxygen pressure during cesarean section of normal pregnancies]." ]	[ "In the current study the efficacy of maternal hyperoxygenation on growth-retarded fetuses was evaluated.\n Thirty-six pregnant women with intrauterine growth retardation were studied. The patients were divided in oxygen-treated (n = 17) and untreated (n = 19) groups. Doppler analysis of the fetal circulation was performed on the arrival to the hospital, after 12 hours, and thereafter on alternate days until delivery. Fetal blood was sampled by cordocentesis for immediate blood gas analysis at entrance to the study and the day of delivery.\n Significant improvement in Doppler flow patterns in treated patients were found when compared with untreated women. The Doppler variations were associated with complementary modifications in fetal blood gas. These differences resulted in a significant modification in perinatal mortality with an incidence of 29% and 68% (p less than 0.01) in treated and untreated groups, respectively.\n Our data suggest a benefit of maternal hyperoxygenation in the treatment of fetal growth retardation.", "In a randomized prospective study, performed on 45 pregnancies with clinical and sonographic suspicion for intrauterine fetal growth retardation, examinations were done to evaluate the therapeutic effect of bed rest and of additional daily administered glucose infusions or oral galactose applications respectively on the fetal growth, the hemodynamic, respiratory and endocrine insufficiency of the materno-feto-placental unit as well as selected biochemical parameters of the umbilical blood. There is no positive therapeutic effect, either on the impaired endocrine partial function nor on the reduced respiratory function of the feto-placental unit. It is obvious, that despite the improvement of the nutritional supply of the fetus and the revival of the regular fetal growth, the previous lack of fetal growth can not be altered. This can be demonstrated in all three therapeutic groups due to the fact of a resulting high hypotrophy-rate of the newborns. The results prove that the additional supply of the fetus with glucose or galactose does not remarkably improve the therapeutic effectivity as opposed by strict bed rest alone.", "Despite changes in pulmonary function, maternal oxygenation is maintained during obstetric regional blocks. But in those situations, the administration of supplementary oxygen to parturients is a common practice. Good fetal oxygenation is the main justification; however, this has not been proven. The objective of this randomized, prospective study was to test the hypothesis of whether maternal hyperoxia is correlated with an increase in fetal gasometric parameters in elective cesarean sections.\n Arterial blood gases of 20 parturients undergoing spinal block with different inspired fractions of oxygen were evaluated and correlated with fetal arterial blood gases.\n An increase in maternal inspired fraction of oxygen did not show any correlation with an increase of fetal partial oxygen pressure.\n Induction of maternal hyperoxia by the administration of supplementary oxygen did not increase fetal partial oxygen pressure. Fetal gasometric parameters did not change even when maternal parameters changed, induced by hyperoxia, during cesarean section under spinal block." ]	There is not enough evidence to evaluate the benefits and risks of maternal oxygen therapy for suspected impaired fetal growth. Further trials of maternal hyperoxygenation seem warranted.
CD006032	[ "2036187" ]	[ "The effect of steroid therapy on recovery from tonsillectomy in children." ]	[ "A prospective, randomized, double-blind study to determine the postoperative effects of steroids in tonsillectomy was performed on 25 children from 4 to 12 years of age. A single intravenous dose of dexamethasone or a placebo was administered at onset of surgery. Other preoperative and postoperative medications, including antibiotics, anesthesia, and surgical techniques were standardized as noted in this article. The ability to return to a full or semifull diet occurred on the third and fourth postoperative days, significantly sooner in the steroid-treated patients than in the control patients. By the fifth and sixth days, the control group were eating as well as those children who received steroids. No significant differences were observed in postoperative pain, nausea, emesis, fever, or in the need for postoperative pain medications. This preliminary article concludes that a single preoperative dose of steroid results in an earlier return to a normal (full) diet in children who had undergone tonsillectomy." ]	There is a relatively high rate of spontaneous visual recovery in TON and there is no convincing data that steroids provide any additional visual benefit over observation alone. Recent evidence also suggests a possible detrimental effect of steroids in TON and further studies are urgently needed to clarify this important issue. Each case therefore needs to be assessed on an individual basis and proper informed consent is paramount.
CD002822	[ "10852980", "8130287", "17678655", "15951880", "12971708", "11409225", "15774341", "9052565", "11642642", "11128729" ]	[ "An observer-blinded comparison of supervised and unsupervised aerobic exercise regimens in fibromyalgia.", "Is group physical therapy superior to individualized therapy in ankylosing spondylitis? A randomized controlled trial.", "Circuit class therapy versus individual physiotherapy sessions during inpatient stroke rehabilitation: a controlled trial.", "Comparison of supervised exercise training and home-based exercise training in chronic heart failure.", "The effectiveness of intensive group exercise on patients with ankylosing spondylitis.", "Effects of home versus supervised exercise for patients with intermittent claudication.", "A pilot study of a supervised group exercise programme as a rehabilitation treatment for women with breast cancer receiving adjuvant treatment.", "Value of a supervised exercise program for the therapy of arterial claudication.", "Combined spa-exercise therapy is effective in patients with ankylosing spondylitis: a randomized controlled trial.", "The effectiveness of community-based rehabilitation for stroke patients who remain at home: a pilot randomized trial." ]	[ "To compare a supervised 12-week aerobic exercise class with unsupervised home aerobic exercises in the treatment of patients with fibromyalgia.\n This was a 48-week randomized single (observer) blind study in a teaching hospital rheumatology and physiotherapy department. The subjects were 74 patients who fulfilled the American College of Rheumatology criteria for fibromyalgia. Results and conclusions. A 12-week exercise class programme with home exercises demonstrated no benefit over a single physiotherapy session with home exercises in the treatment of pain in patients with fibromyalgia. Neither group (nor the groups combined) showed an improvement in pain compared with baseline. There was some significant benefit in psychological well-being in the exercise class group and perhaps a slowing of functional deterioration in this group.", "To study the effects of adding supervised group physical therapy to unsupervised individualized therapy in ankylosing spondylitis.\n One hundred forty-four patients were randomized to exercises at home, or the same plus weekly group physical therapy for 9 months. Endpoints were spinal mobility, fitness (maximum work capacity by ergometry), functioning (Sickness Impact Profile, Health Assessment Questionnaire for the Spondylarthropathies, and Functional Index), and patient's global assessment of change on a 10-cm visual analogue scale.\n Thoracolumbar flexion and extension increased by an average of 0.5 cm (9%) after home exercises, and by 0.9 cm (16%) after group therapy. Maximum load in ergometry decreased by 2 W (1%) after home exercises, but increased by 7 W (4%) after group therapy. Global assessment improved by 0.3 (6%) after home exercises, and by 1.7 (34%) after group therapy. These three differences were statistically significant. There were no significant differences in chest expansion, cervical rotation, or the self-assessments of functioning.\n Group physical therapy proved superior to individualized therapy in improving thoracolumbar mobility and fitness, and had an important effect on global health reported by the patients.", "To compare the effectiveness of circuit class therapy and individual physiotherapy (PT) sessions in improving walking ability and functional balance for people recovering from stroke.\n Nonrandomized, single-blind controlled trial.\n Medical rehabilitation ward of a rehabilitation hospital.\n Sixty-eight persons receiving inpatient rehabilitation after a stroke.\n Subjects received group circuit class therapy or individual treatment sessions as the sole method of PT service delivery for the duration of their inpatient stay.\n Five-meter walk test (5MWT), two-minute walk test (2MWT), and the Berg Balance Scale (BBS) measured 4 weeks after admission. Secondary outcome measures included the Iowa Level of Assistance Scale, Motor Assessment Scale upper-limb items, and patient satisfaction. Measures were taken on admission and 4 weeks later.\n Subjects in both groups showed significant improvements between admission and week 4 in all primary outcome measures. There were no significant between group differences in the primary outcome measures at week 4 (5MWT mean difference, .07m/s; 2MWT mean difference, 1.8m; BBS mean difference, 3.9 points). A significantly higher proportion of subjects in the circuit class therapy group were able to walk independently at discharge (P=.01) and were satisfied with the amount of therapy received (P=.007).\n Circuit class therapy appeared as effective as individual PT sessions for this sample of subjects receiving inpatient rehabilitation poststroke. Favorable results for circuit classes in terms of increased walking independence and patient satisfaction suggest this model of service delivery warrants further investigation.", "This study was planned to compare the outcomes between supervised and home-based exercise training in patients with chronic heart failure.\n The study was conducted at the Department of Physical Therapy in Ankara University, Faculty of Medicine, Turkey between 2000 and 2001. Twenty-two patients with stable chronic heart failure were randomly assigned to the supervised exercise training group (n=11) or the home-based exercise training group (n=11). Symptom-limited maximal exercise tests with gas exchange analysis were carried out before randomization. Work load equivalent to 60% of achieved peak heart rate at the tests was determined as exercise training work load for each subject. Both groups participated in a program of 3 exercise training sessions per week for 3 months. The exercise tests were repeated after 3 months.\n After training, peak exercise duration increased significantly in the supervised exercise training group and the home-based exercise training group (p<0.05). There was substantial improvement in peak VO2 with exercise training in the supervised exercise training group (p<0.05) but, peak VO2 did not change significantly in the home-based exercise training group (p>0.05).\n Supervised and home-based exercise training enhanced exercise capacity in patients with chronic heart failure. The training program must be tailored to each patient's specific limitations, individual needs and possibilities. Home-based exercise training may be a training alternative to stable chronic heart failure patients who prefer not to participate in an outpatient supervised training program.", "To compare, in patients with ankylosing spondylitis (AS), the effectiveness on pain, functional and psychological status of an intensive group exercise programme under the supervision of a physiotherapist and a home physiotherapy programme.\n Fifty-one patients with AS were randomly allocated into study and control groups. The study was designed as a prospective, double-blind study.\n Outpatient department, Istanbul Medical Faculty.\n Patients who consulted with complaints of pain, morning stiffness and restricted range of movement with a confirmed diagnosis of ankylosing spondylitis.\n Before exercise, both groups were given an education programme about AS. For group I patients an intensive exercise programme was organized under the supervision of a physiotherapist for six weeks. Group II patients had to practise exercises individually at home.\n Both groups were evaluated and compared for pain, functional and psychological status before treatment, at the end of treatment and three months after treatment using a visual analogue scale (VAS) for pain, Beck Depression Scale and Bath Ankylosing Spondylitis Functional Index (BASFI).\n Six patients withdrew, four from group I. Results from the remaining 45 showed more positive changes in the patients undertaking group exercise at six weeks and three months after treatment. Values showed a statistical significant difference in favour of group I.\n Group exercise in hospital may be more effective than home-based exercises at reducing impairment associated with ankylosing spondylitis.", "This study was performed to test the efficacy of a supervised, hospital-based exercise program compared with a home-based exercise program involving minimal supervision, for both walking ability and quality of life measures in patients with exercise-limiting intermittent leg claudication.\n Twenty-one patients were assigned randomly to 12 weeks of supervised exercise or to a home-based exercise group. After 12 weeks the participants in the supervised group transitioned to a home-based program. Both groups were then reevaluated at the end of 24 weeks. The initial claudication distance (ICD) and absolute claudication distance (ACD) on progressive treadmill exercise was measured at baseline, 12 weeks, and 24 weeks. Additionally, self-reported quality of life status was evaluated using the MOS SF-36 questionnaire.\n Each group improved (P < 0.01) ACD from baseline to 12 weeks, which was sustained at the 24-week follow-up. Both groups experienced similar long-term improvements (P < 0.05) in ACD (521.5 +/- 253.4 meters to 741.9 +/- 365.6 meters for the supervised group, 532.2 +/- 263.5 meters to 715.0 +/- 394.4 meters in the home group, P not significant, between groups). The supervised group experienced a greater improvement (P < 0.01) in the ICD after 12 weeks than the home group but not at 24 weeks. The on-site group also experienced significant improvements in ICD after 24 weeks (P < 0.05). Neither group manifested an improvement in self-reported physical function or mental health as assessed by the MOS SF-36.\n A structured exercise program was more effective in improving the ICD over a 24-week period than a less formal, home-based program. However, if patients are screened properly and receive adequate instruction, a home-based program can be a safe, low-cost alternative providing similar long-term (24 weeks) exercise benefits in ACD.", "This pilot study examined whether exercise as an adjunctive rehabilitation therapy could benefit women who have early stage breast cancer and are currently receiving chemotherapy/radiotherapy. The study was designed as a randomised controlled trial (RCT). Physical functioning, fatigue and Quality of Life (QoL) outcomes were evaluated pre and post a 12-week intervention. The results showed that after 12 weeks the women who participated in the exercise programme (n = 12) displayed significantly higher levels of physical functioning and reported higher QoL scores than the controls (n = 10). Changes in fatigue and satisfaction with life favoured the intervention group but did not reach significance. These results are encouraging and suggest that a structured group exercise programme during adjuvant treatment is a safe, well tolerated and effective way of providing physical and psychological health benefits to women during treatment for early stage breast cancer. Since this was a pilot study the numbers did not allow appropriately powered analyses of some variables of interest and favoured relatively young and socio-economically advantaged women. Future studies need to address these issues and determine if these short-term benefits can be sustained.", "This study was performed to test the effectiveness of a formal supervised exercise program against a home-based exercise program for both walking ability and quality of life endpoints.\n Patients with arterial claudication were randomized to either a 12-week supervised exercise program (SUPEX) with weekly lectures relating to peripheral vascular disease or to a home exercise group (HOMEX) who attended an identical lecture program and received weekly exercise instruction. The study population included 29 men and 26 women, with a mean age of 69.1 +/- 8.1 years. Forty-seven patients completed the 12-week program, 46 were available for testing at completion, and 38 for 6-month testing. Claudication pain time (CPT) and maximum walking time (MWT) on a progressive treadmill exercise test were assessed at baseline, program completion, and 6 months. The Medical Outcomes Study Short Form-36 (SF-36) was administered at these intervals to assess effects on quality of life.\n Each group improved (p < 0.001) in both CPT and MWT at the completion of the 12-week program, which was sustained at the 6-month follow-up. Increase in HOMEX CPT from baseline (3.6 +/- 2.73 minutes) to 6-month follow-up (6.6 +/- 3.17 minutes) was less than for the SUPEX group (3.8 +/- 2.74 to 11.2 +/- 4.02 minutes, respectively); similar results were obtained for MWT. At both completion and 6 months, there was a significant intergroup difference for CPT and MWT (p < 0.004) favoring SUPEX. For both groups, measures of health perception based on the SF-36 demonstrated improvement (p < 0.002) in Physical Function Subscale, Bodily Pain Subscale, and Physical Composite Score. There were no between-group differences on the subsets of the SF-36 at the three assessment intervals.\n Supervised exercise programs provide superior increased walking ability in the noninterventional therapy of arterial claudication, and both supervised and home based exercise therapy result in improved SF-36 functional measures. The lack of intergroup differences in these measures may be a result of the high degree of interaction with healthcare providers in the HOMEX group. Although a supervised program results in optimal walking benefits, a highly structured home-based program provides similar functional improvement and may be a satisfactory alternative for patients with lesser walking requirements.", "To determine the efficacy of combined spa-exercise therapy in addition to standard treatment with drugs and weekly group physical therapy in patients with ankylosing spondylitis (AS).\n A total of 120 Dutch outpatients with AS were randomly allocated into 3 groups of 40 patients each. Group 1 (mean age 48 +/- 10 years; male:female ratio 25:15) was treated in a spa resort in Bad Hofgastein, Austria; group 2 (mean age 49 +/- 9 years; male:female ratio 28:12) in a spa resort in Arcen, The Netherlands. The control group (mean age 48 +/- 10 years; male:female ratio 34:6) stayed at home and continued their usual drug treatment and weekly group physical therapy during the intervention weeks. Standardized spa-exercise therapy of 3 weeks duration consisted of group physical exercises, walking, correction therapy (lying supine on a bed), hydrotherapy, sports, and visits to either the Gasteiner Heilstollen (Austria) or sauna (Netherlands). After spa-exercise therapy all patients followed weekly group physical therapy for another 37 weeks. Primary outcomes were functional ability, patient's global well-being, pain, and duration of morning stiffness, aggregated in a pooled index of change (PIC).\n Analysis of variance showed a statistically significant time-effect (P < 0.001) and time-by-treatment interaction (P = 0.004), indicating that the 3 groups differed over time with respect to the course of the PIC. Four weeks after start of spa-exercise therapy, the mean difference in PIC between group 1 and controls was 0.49 (95% confidence interval [CI] 0.16-0.82, P = 0.004) and between group 2 and controls was 0.46 (95% CI 0.15-0.78, P = 0.005). At 16 weeks, the difference between group 1 and controls was 0.63 (95% CI 0.23-1.02, P = 0.002) and between group 2 and controls was 0.34 (95% CI--0.05-0.73; P = 0.086). At 28 and 40 weeks, more improvement was found for group 1 compared with controls (P = 0.012 and P = 0.062, respectively) but not for group 2 compared with controls.\n In patients with AS, a 3-week course of combined spa-exercise therapy, in addition to drug treatment and weekly group physical therapy alone, provides beneficial effects. These beneficial effects may last for at least 40 weeks.", "To assess the effectiveness of community-based rehabilitation for stroke patients who were not admitted to hospital in South London.\n Randomized controlled trial.\n Patients' homes in South London.\n Stroke patients not admitted to hospital after a stroke.\n Rehabilitation at home by rehabilitation team for up to three months or usual care.\n The primary outcome measure was the Barthel score. Secondary measures included the Motricity Index, Rivermead ADL, Hospital Anxiety and Depression score and Nottingham Health Profile.\n Forty-three patients who remained at home were randomized to rehabilitation team (23) or 'usual' care (20). The mean number of physiotherapy sessions was three (range 1-14) for the rehabilitation team group and two for the usual care group. Patients (with a deficit) in the rehabilitation arm of the trial were more likely to receive occupational, physical and speech therapy than those in the control arm (p = 0.03, 0.01 and 0.008, respectively). For those patients actually receiving therapy, there was no evidence that the amount received differed between the groups. However, the number of patients in each of these comparisons was very small. The outcome for patients in the rehabilitation team arm of the trial was nonsignificantly higher (0.05 < p < 0.2) than for those in the control arm for the areas of Nottingham Health Profile, anxiety, depression, caregiver strain and the proportion of patients living at home. Based on the data observed here, a trial with approximately 150 patients in each arm would be needed to have adequate power to detect a 33% difference between intervention and control groups in these outcomes.\n Community therapy support for patients not admitted to hospital is feasible but to determine whether it is cost- or clinically effective would require trials of adequate size." ]	The results of this review suggest that an individual home-based or supervised exercise program is better than no intervention; that supervised group physiotherapy is better than home exercises; and that combined inpatient spa-exercise therapy followed by group physiotherapy is better than group physiotherapy alone.
CD006719	[ "11516109", "11675332" ]	[ "Evaluating treatment strategies in advanced Waldenström macroglobulinemia: use of quality-adjusted survival analysis.", "Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide-doxorubicin-prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease." ]	[ "A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubicin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemia in first relapse or with primarily resistant disease, was conducted on the behalf of the 'Groupe Coopératif Macroglobulinémie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of overall survival (OS), although a significant benefit in terms of time to disease progression and event-free survival (EFS) was noted. In this rare disorder, where few randomized trials have been conducted, we took advantage of this trial to assess treatment differences while integrating quality of life considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWiST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWiST and summed up giving the so-called Q-TWiST. No difference was found between randomized groups in terms of mean CT. Mean TOX in the two groups were similarly close except when considering alopecia as a relevant toxic event. By contrast, mean TWiST was 5.9 months longer in the FAMP group than in the CAP group (P = 0.006). Unsurprisingly, given the absence of difference in OS but the difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P = 0.047). As a result, benefit of FAMP in terms of average Q-TWiST only relied on the value of the utility coefficient attributed to REL (U(REL)), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely.", "Few reports are available on the treatment of patients with Waldenström macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5). The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P <.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group. There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents." ]	Although alkylating agents have been used for decades they have never actually been tested in a proper randomised trial. This review demonstrated that there is currently no evidence to suggest that alkylating agents are effective in treating Waldenstrom's macroglobulinaemia.
CD000211	[ "7010873", "782141" ]	[ "Lack of effect of theophylline on the outcome of acute cerebral infarction.", "Controlled trial of intravenous aminophylline in acute cerebral infarction." ]	[ "In patients with acute ischemic stroke, dramatic but often transient improvements have been noticed after theophylline injections. Whether better results could be obtained by continuous infusion of the drug was evaluated in a double-blind study. Out of 46 patients with a mean age of 75 years, 22 got theophylline as aminophylline (bolus dose of 230 mg followed by 0.5 mg/kg/h) and 24 placebo during 3 days. The groups were comparable in all aspects at the outset of the trial. Serum theophylline concentrations were kept within the therapeutic range recommended for patients with asthma. No significant difference in outcome was noticed between the groups during the hospital period when repeated neurological assessments by two different scores and mortality were compared.", "In a double-blind trial intravenous aminophylline was compared with placebo in 79 patients with acute cerebral infarction. Immediate improvement in the neurological evaluation score was significantly more frequent in patients receiving aminophylline (38 per cent) than in those on placebo (15 per cent); only patients with mild or moderately severe strokes responded to the injection. After 3 weeks, however, the treated patients did not fare significantly better than the controls in terms of neurological score and residual disability. Survival rate, length of stay in hospital, and social readaptation were similar in the two groups. It is concluded that intravenous aminophylline in patients with ischaemic strokes can bring about an immediate symptomatic relief, but without appreciably influencing the ultimate recovery." ]	There is not enough evidence to assess whether theophylline or its analogues, e.g. aminophylline, are safe and improve outcome in people with acute ischaemic stroke.
CD004839	[ "12064916", "16798652", "16818273", "12670352", "16352812", "16352815" ]	[ "Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial.", "A randomized controlled study evaluating the safety and efficacy of deferiprone treatment in thalassemia major patients from Hong Kong.", "Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload.", "Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients.", "A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia.", "Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis." ]	[ "Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major. To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups. Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.", "A controlled, open-label and randomized study was conducted to evaluate the safety and efficacy of the oral iron chelator deferiprone (L1) in thalassemia major patients from Hong Kong. Forty-nine patients were recruited in total (median age: 20 years; range: 8 to 40 years). The division of the patients was determined based on liver iron content and put into either the poorly-chelated (Group I) or well-chelated (Group II) groups. In Group I, 20 patients received combined therapy of L1 daily plus desferrioxamine (DFO), in a reduced frequency of twice weekly, while the control group consisted of 16 patients who were treated with DFO alone. In Group II, six patients received L1 only, while the control group consisted of seven patients treated with DFO alone. Only patients who participated for longer than 6 months were analyzed for efficacy (n = 44). The median study period was 18 months. Transient and mild gastrointestinal upset (31%), joint pain (15%) and liver enzyme elevation (23%) were the most common side effects noted for L1. No case of neutropenia was observed in this study. Serum ferritin (SF) levels showed significant decline in the poorly-chelated patients using combined therapy (L1 and reduced frequency DFO) as compared to those on DFO alone. However, their pre- and post-study liver iron content was not significantly different. Evaluation of the well-chelated group demonstrated no significant change in SF or liver iron content in both the study and control arms. We conclude that the short-term use of L1, with or without DFO, was safe and efficacious in our Chinese patient cohort. The long-term efficacy of reducing iron overload by treatment regimens including L1 requires further study.", "Iron accumulation is an inevitable consequence of chronic blood transfusions and results in serious complications in the absence of chelation treatment to remove excess iron. Deferoxamine (Desferal, DFO) reduces morbidity and mortality although the administration schedule of slow, parenteral infusions several days each week limits compliance and negatively affects long-term outcome. Deferasirox (Exjade, ICL670) is an oral chelator with high iron-binding potency and selectivity. In a phase II study, the tolerability and efficacy of deferasirox were compared with those of DFO in 71 adults with transfusional hemosiderosis.\n Patients were randomized to receive once-daily deferasirox (10 or 20 mg/kg; n=24 in both groups) or DFO (40 mg/kg, 5 days/week; n=23) for 48 weeks. Results. Both treatments were well tolerated and no patient discontinued deferasirox due to drug-related adverse events. The reported frequency of transient, mild to moderate gastrointestinal disturbances was higher in the deferasirox group than in the DFO group, but these disturbances settled spontaneously without dose interruption in all patients. Decreases in liver iron concentration (LIC) were comparable in the deferasirox 20 mg/kg/day and DFO groups; baseline values of 8.5 and 7.9 mg Fe/g dw fell to 6.6 and 5.9 mg Fe/g dw, respectively, by week 48. Deferasirox showed a plasma elimination half-life of 8-16 hours, supporting its once-daily administration.\n Deferasirox at daily doses of 10 or 20 mg/kg was well tolerated and, at 20 mg/kg, showed similar efficacy to DFO 40 mg/kg in terms of decreases in LIC.", "Desferrioxamine (DFX) alone (40-50 mg/kg/d s.c. over 8-12 h, five times weekly) was compared with combined DFX twice weekly and deferiprone (75 mg/kg/d) over 12 months in previously poorly chelated thalassaemia patients. Serum ferritin fell from 5506 +/- 635 microg/l (mean +/- SEM) to 3998 +/- 604 microg/l (P < 0.001; n = 14) in the DFX group and from 4153 +/- 517 microg/l to 2805 +/- 327 microg/l in the combined group (P < 0.01; n = 11). Deferiprone plus DFX produced a greater mean urine iron excretion (1.01 mg/kg/24 h) than iron intake from blood transfusion in each patient. Main side-effects were skin reactions (DFX alone), nausea and arthralgia (combined therapy). As chelation therapy, the combined protocol was as effective as DFX five times weekly.", "Deferasirox (ICL670) is a once-daily oral iron chelator developed for the treatment of chronic iron overload from blood transfusions. A comparative phase 3 trial was conducted to demonstrate the efficacy of deferasirox in regularly transfused patients with beta-thalassemia aged 2 years or older. Patients were randomized and received treatment with deferasirox (n = 296) or deferoxamine (n = 290), with dosing of each according to baseline liver iron concentration (LIC). The primary endpoint was maintenance or reduction of LIC; secondary endpoints included safety and tolerability, change in serum ferritin level, and net body iron balance. In both arms, patients with LIC values of 7 mg Fe/g dry weight (dw) or higher had significant and similar dose-dependent reductions in LIC and serum ferritin, and effects on net body iron balance. However, the primary endpoint was not met in the overall population, possibly due to the fact that proportionally lower doses of deferasirox relative to deferoxamine were administered to patients with LIC values less than 7 mg Fe/g dw. The most common adverse events included rash, gastrointestinal disturbances, and mild nonprogressive increases in serum creatinine. No agranulocytosis, arthropathy, or growth failure was associated with deferasirox administration. Deferasirox is a promising once-daily oral therapy for the treatment of transfusional iron overload.", "Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2()) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% +/- 5.3% and 93% +/- 9.7% (P = .81), respectively. The improvement in myocardial T2() was significantly greater for deferiprone than deferoxamine (27% vs 13%; P = .023). Left ventricular ejection fraction increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P = .003). The changes in liver iron level (-0.93 mg/g dry weight vs -1.54 mg/g dry weight; P = .40) and serum ferritin level (-181 microg/L vs -466 microg/L; P = .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferiprone-treated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major." ]	We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.
CD005989	[ "8673548", "10534147", "1351600", "12665160", "9570235", "8297057", "15750359", "10391656", "17015192", "9447569", "1536784", "16619567", "17609679", "1443954", "15015612", "18721085", "16696907", "10751856", "18005909", "9288368" ]	[ "Pilot randomized controlled trial of Chinese herbal treatment for HIV-associated symptoms.", "Randomized, placebo-controlled trial of Chinese herb therapy for HIV-1-infected individuals.", "Efficacy of traditional Chinese herbal therapy in adult atopic dermatitis.", "Evaluation of the efficacy of a combined formulation (Grippostad-C) in the therapy of symptoms of common cold: a randomized, double-blind, multicenter trial.", "Preliminary report of a randomized, double-blind placebo-controlled trial of a Chinese herbal medicine preparation CH-100 in the treatment of chronic hepatitis C.", "The efficacy of psychological, educational, and behavioral treatment. Confirmation from meta-analysis.", "A pilot, randomized, double-blinded, placebo-controlled trial of individualized homeopathy for symptoms of estrogen withdrawal in breast-cancer survivors.", "Impact of study quality on outcome in placebo-controlled trials of homeopathy.", "Evaluation of specific and non-specific effects in homeopathy: feasibility study for a randomised trial.", "Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type.", "A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema.", "Quality of life is improved in breast cancer patients by Standardised Mistletoe Extract PS76A2 during chemotherapy and follow-up: a randomised, placebo-controlled, double-blind, multicentre clinical trial.", "Issues that may determine the outcome of antipsychotic trials: industry sponsorship and extrapyramidal side effect.", "Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness?", "Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial.", "The beneficial effects of the herbal medicine Free and Easy Wanderer Plus (FEWP) and fluoxetine on post-stroke depression.", "Improving the quality of randomized controlled trials in Chinese herbal medicine, part IV: applying a revised CONSORT checklist to measure reporting quality.", "Effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia.", "Efficacy of a pelargonium sidoides preparation in patients with the common cold: a randomized, double blind, placebo-controlled clinical trial.", "Analgesic effect of a herbal medicine for treatment of primary dysmenorrhea--a double-blind study." ]	[ "We wished to determine the short-term safety and efficacy of a Chinese medicinal herb preparation in treating symptoms of human immunodeficiency virus (HIV) infection in a 12-week randomized, double-blind, placebo-controlled clinical trial in a University-affiliated acquired immunodeficiency syndrome (AIDS) clinic at a public general hospital. Thirty adults with symptomatic HIV infection, no previous AIDS-defining diagnosis, and CD4+ counts of 0.200-0.499 x 10(9)/L (200-499/mm3) received 28 tablets each day of either a standardized oral preparation of 31 Chinese herbs or a cellulose placebo. Primary outcome measures were changes in life satisfaction, perceived health, and number and severity of symptoms. Other outcomes included adherence, and changes in weight, CD4+ count, depression, anxiety, physical and social function, and mental health. Two placebo- and no herb-treated subjects had mild adverse events (AE). Subjects on both arms reported taking 94% of prescribed tablets. No differences between treatment groups reached the p < 0.05 level. Life satisfaction improved in herb-treated [+0.86, 95% confidence interval (CI): +0.29, +1.43] but not in placebo-treated subjects (+0.20, 95% CI -0.35, + 0.75). Number of symptoms was reduced in subjects receiving herbs (-2.2, 95% CI -4.1, -0.3) but not in those receiving placebo (-0.3, 95% CI -3.2, +2.7). There were trends toward greater improvements among herb-treated subjects on all symptom subscales except dermatologic. Believing that one was receiving herbs was strongly associated with reporting that the treatment had helped (p < 0.005), but not with changes in life satisfaction or symptoms. There were improvements in life satisfaction and symptoms among subjects receiving the herbal therapy. Whether Chinese herbs are effective in the management of symptomatic HIV infection can be adequately addressed only by larger trials of longer duration.", "Alternative medicine or complementary remedies that have not been scientifically tested are nonetheless widely used to treat chronic illnesses, particularly if curative options are limited.\n To assess the effectiveness of Chinese medicinal herbs in reducing symptoms and improving the quality of life of HIV-infected persons.\n Prospective, placebo-controlled double-blind study.\n University-based HIV outpatient clinic.\n 68 HIV-infected adults with CD4 cell counts <0.5 x 10(9)/L.\n Participants were randomized to receive four daily doses of seven pills containing a standardized preparation of 35 Chinese herbs or placebo for 6 months.\n Symptoms, HIV disease progression, HIV-1 RNA plasma viral loads, CD4 and CD8 cell counts, and scores on standard questionnaires for quality of life, depression, anxiety, and coping.\n Intervention and placebo groups were equivalent at baseline regarding, respectively, previous antiretroviral therapy (74% versus 79%), median CD4 cell counts (0.20 x 10(9)/L versus 0.25 x 10(9)/L), and median HIV-1 plasma viral loads (35,612 copies/ml versus 52,027 copies/ml). At enrollment, none of the study subjects was seriously ill or depressed, and average coping and quality of life scores were in the normal range. In all, 53 (78%) participants completed the study. Patients taking Chinese herbs reported significantly more gastrointestinal disturbances (79% versus 38%; p = .003) than those receiving placebo. No therapy-related toxicities were observed. At completion of the study, no significant differences between the intervention and placebo groups were found regarding plasma viral loads, CD4 cell counts, symptoms, and psychometric parameters. HIV-1 RNA level was unchanged at study end. Among participants who were not on concomitant antiretroviral therapy, median CD4 cell counts declined by 0.05 x 10(9)/L in both the intervention and placebo groups.\n This standardized formulation of Chinese herbs for HIV-infected individuals did not improve quality of life, clinical manifestations, plasma virus loads, or CD4 cell counts. The data suggest that this formulation of Chinese herbs is not effective when administered in a Western medicine setting.", "There has been considerable interest in traditional Chinese herbal therapy (TCHT) as a new treatment for atopic dermatitis. To establish the efficacy and safety of this treatment, a daily decoction of a formula containing ten herbs that has been found to be beneficial in open studies was tested in a double-blind placebo-controlled study. 40 adult patients with longstanding, refractory, widespread, atopic dermatitis were randomised into two groups to receive 2 months' treatment of either the active formulation of herbs (TCHT) or placebo herbs, followed by a crossover to the other treatment after a 4-week washout period. The main outcome measures were extent and severity of erythema and surface damage as judged by standardised body scores. The patients' own assessments of the overall response to treatment were also sought. The geometric mean score for erythema at the end of active treatment was 12.6 (95% confidence interval [CI] 5.9 to 22.0) and at the end of the placebo phase was 113 (65 to 180). The geometric mean score for surface damage was 11.3 (5.8 to 21.8) and 111.0 (68 to 182), respectively. The 95% CI for the mean geometric ratio for the two values with active treatment was 0.04 to 0.22 for erythema (p less than 0.0005) and 0.04 to 0.27 for surface damage (p less than 0.0005). Of the 31 patients who completed the study and expressed a preference, 20 preferred that phase of the trial in which they received TCHT whereas 4 patients preferred placebo (p less than 0.02). There was a subjective improvement in itching (p less than 0.001) and sleep (p less than 0.078) during the TCHT treatment phase. No side-effects were reported by the patients although many commented on the unpalatability of the decoction. TCHT seems to benefit patients with atopic dermatitis. Palatability of the treatment needs to be improved and its safety assured.", "The aim of the present trial was to evaluate the efficacy of a combined product in the treatment of common cold and to examine the contribution of the separate components. In the published literature there is conflicting data on the efficacy of agents used in the treatment of common cold, especially when given in drug combinations.\n A prospective, randomized, double-blind, multicenter, 4-arm, controlled trial was carried out in 1,167 patients with common cold treated with one of the following medications: Grippostad-C, a combination of acetaminophen, caffeine, chlorpheniramine and ascorbic acid (verum), ascorbic acid (control), chlorpheniramine and ascorbic acid (reference 1), as well as acetaminophen, caffeine, and ascorbic acid (reference 2). A score of common cold symptoms (headache, throat pain, extremities and joint pain, cough, blocked nose, and disturbances of sleep quality) was the primary outcome. The test drug was first compared with the control using a hierarchic test strategy, then with reference 1, followed by reference 2 with the aim of proving superiority.\n A clinically relevant and statistically significant difference was demonstrated at each level of the hierarchy. Grippostad-C was significantly superior to all other treatment groups, the combination of acetaminophen, caffeine, and ascorbic acid was significantly superior to the control, and the combination of chlorpheniramine and ascorbic acid was not statistically different from the control.\n The efficacy of Grippostad-C for the treatment of common cold was proven. The findings demonstrate that the combination is superior to each of its separate components and each of the components has its own distinctive contribution to the efficacy of the combination product.", "The treatment of chronic hepatitis C is relatively unsatisfactory and many patients have turned to unproven alternative medicines to modify the course of their illness. We report a study of a Chinese herbal medicine preparation CH-100 in the management of chronic hepatitis C. Patients with documented chronic hepatitis C were randomly allocated to receive active herbal or placebo tablets (five tablets thrice daily). Patients were followed monthly and evaluated by a Western and a traditional Chinese medical practitioner. Therapy was monitored by measurement of liver function tests, creatinine and full blood count on a monthly basis. Twenty patients in each group were well matched for age, sex, duration of illness, previous interferon therapy and alcohol intake. Active Chinese herbal medication was associated with a significant reduction in alanine aminotransferase (ALT) levels over the 6 month study period (P < 0.03). No patient cleared the virus but four normalized their ALT on treatment. Appropriately prescribed Chinese herbal medicine may have a role in the management of chronic hepatitis C and further controlled studies are indicated.", "Conventional reviews of research on the efficacy of psychological, educational, and behavioral treatments often find considerable variation in outcome among studies and, as a consequence, fail to reach firm conclusions about the overall effectiveness of the interventions in question. In contrast meta-analytic reviews show a strong, dramatic pattern of positive overall effects that cannot readily be explained as artifacts of meta-analytic technique or generalized placebo effects. Moreover, the effects are not so small that they can be dismissed as lacking practical or clinical significance. Although meta-analysis has limitations, there are good reasons to believe that its results are more credible than those of conventional reviews and to conclude that well-developed psychological, educational, and behavioral treatment is generally efficacious.", "To pilot an investigation of individualized homeopathy for symptoms of estrogen withdrawal in breast cancer survivors.\n Randomized, double-blinded, placebo-controlled trial.\n Outpatient department of a National Health Service (NHS) homeopathic hospital.\n Fifty-seven (57) women met inclusion criteria and 53 were randomized to the study.\n After 2 weeks of baseline assessment, all participants received a consultation plus either oral homeopathic medicine or placebo, assessed every 4 weeks for 16 weeks.\n The primary outcome measures were the activity score and profile score of the Measure Yourself Medical Outcome Profile (MYMOP).\n Eighty-five percent (85%) (45/53) of women completed the study. There was no evidence of a difference seen between groups for either activity (adjusted difference =-0.4, 95% confidence interval CI -1.0 to 0.2, p = 0.17) or profile scores (adjusted difference = -0.4, 95% CI -0.9 to 0.1, p = 0.13) using this trial design, although post hoc power calculations suggests that 65-175 would be needed per group to detect differences of this magnitude with sufficient precision. Clinically relevant improvements in symptoms and mood disturbance were seen for both groups over the study period.\n Improvements were seen for symptom scores over the study period. However, presuming these improvements were caused by the individualized homeopathic approach, the study failed to show clearly that the specific effect of the remedy added further to the nonspecific effects of the consultation. Future trial design must ensure adequate power to account for the nonspecific impact of such complex individualized interventions while pragmatic designs may more readily answer questions of clinical and cost effectiveness.", "We investigated the influence of indicators of methodological quality on study outcome in a set of 89 placebo-controlled clinical trials of homoeopathy in three different ways: (1) The results of studies meeting single criteria (explicit statement of random allocation, allocation concealment, double-blinding, completeness of follow-up) of methodological quality were compared with those of studies not meeting the criteria in univariate and multivariate analyses; (2) The results of studies scoring above and below predefined scores in two quality assessment scales were compared; (3) Primary studies were consecutively entered into a cumulative meta-analysis according to the summary scores derived from the quality assessment scales. All analyses were performed using meta-regression methods. Studies that were explicitly randomized and were double-blind as well as studies scoring above the cut-points yielded significantly less positive results than studies not meeting the criteria. In the cumulative meta-analyses, there was a trend for increasing effect sizes when more studies with lower-quality scores were added. However, there was no linear relationship between quality scores and study outcome. We conclude that in the study set investigated, there was clear evidence that studies with better methodological quality tended to yield less positive results. Because summarizing disparate study features into a single score is problematic, meta-regression methods simultaneously investigating the influence of single study features seem the best method for investigating the impact of study quality on outcome.", "To determine the feasibility, in terms of acceptability to patients, physicians and other staff; data return and statistical power of a study to elucidate the relative contributions of specific and non-specific effects in homeopathic treatment of dermatitis.\n Randomised, controlled 4-arm trial, 2 arms double-blind.\n Outpatient clinic, Royal London Homoeopathic Hospital.\n Seventy-five adult patients with dermatitis.\n Patients were randomly allocated to: 'fast track' open verum homeopathy, 'fast track' double-blind verum homeopathy, 'fast track' double-blind placebo homeopathy or waiting list control.\n One hundred millimeter visual analogue scale of overall symptom severity; 10 point digital scores of sleep, itching, skin condition; weekly 5-point Likert scale of topical steroid use; Dermatology Life Quality Index at entry and completion.\n Recruitment was below target, but the study was acceptable to staff and feasible. Blinded patients were more likely to withdraw (P=0.021, chi2 test). After correction for baseline differences and multiple comparisons, no outcome measure showed statistically significant between group differences. Blindness appeared to have a negative effect, but this was confounded by differential withdrawal.\n A definitive trial of this design is unlikely to discriminate the relative contributions of the non-specific and specific effects to the outcome of homeopathic treatment of dermatitis, because of patient preference issues.", "Among the psychiatric illnesses associated with old age primary degenerative dementia of the Alzheimer type (DAT) has gained increasing importance in recent years. Even though a curative treatment of the disease is currently impossible, various drugs can be used to slow down its progression. In the present study the influence of oral treatment with 240 mg/day of Ginkgo bilabo special extract EGb 761 (Tebonin forte, manufactured by Dr Willmar Schwabe, Karlsruhe) on the clinical course of DAT was investigated in a double-blind, randomized, placebo-controlled parallel-group design in 20 outpatients. The duration of treatment was 3 months. The primary outcome variable was the sum score in the SKT-test for the determination of attention and memory. Other psychometric tests (trailmaking test, ADAS, CGI) and electrophysiological investigations (EEG topography) were evaluated descriptively. Although the active-treatment group, with a mean sum score of 19.67 points in the, S.K.T., had a poorer baseline level than the placebo group (18.11 points), it experienced an improvement to 16.78 points under treatment with EGb 761 whereas the placebo group deteriorated to 18.89 points. The differences between the baseline and final values formed the basis for a statistical group comparison, which gave a result favourable to EGb 761, at a significance level of p < .013. In addition to this psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological (Clinical Global Impression) and dynamic functional (EEG findings) levels, which can be interpreted as evidence of effectiveness of Ginkgo biloba special extract EGb 761 in mild to moderate dementia and of local effects in the central nervous system. Inter-group differences in the ADAS cognitive and non-cognitive subscales did not reach statistical significance, probably because of the small sample size.", "Severe and widespread atopic eczema often fails to respond adequately to currently available therapies. Following the observation of substantial benefit in patients receiving oral treatment with daily decoctions of traditional Chinese medicinal plants, we undertook a placebo-controlled double-blind trial of a specific prescription formulated for widespread non-exudative atopic eczema. Forty-seven children were given active treatment and placebo in random order, each for 8 weeks, with an intervening 4-week wash-out period. Thirty-seven children tolerated the treatment and completed the study. Response to active treatment was superior to response to placebo, and was clinically valuable. There was no evidence of haematological, renal or hepatic toxicity. These findings anticipate a wider therapeutic potential for traditional Chinese medicinal plants in this disease, and other skin diseases.", "The objective of this randomised, multicentre, double-blind clinical trial was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to mistletoe lectins, on quality of life (QoL) in breast cancer patients. A total of 352 patients were randomly allocated to 2 groups receiving PS76A2 (15 ng mistletoe lectin/0.5 ml) or matching placebo twice weekly for 4 to 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy followed by 2 months follow-up. The primary efficacy end-point was the change from baseline of 3 FACT-G subscales (physical, emotional and functional well-being) during the fourth CMF cycle. Secondary measures included GLQ-8 (8 linear analogue self-assessment scales), Spitzer's uniscale and haematological variables. The main variables of safety analysis were adverse events, including injection site reactions and clinical laboratory tests. The results showed that physical, emotional and functional well-being improved upon PS76A2, but deteriorated following placebo. The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G, which was analysed as O'Brien's rank sum of its 3 subscales: The total score increased by 4.40 +/- 11.28, indicating a higher QoL after PS76A2, but decreased by 5.11 +/- 11.77 with placebo (p<0.0001). The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 (sum of item nos. 1, 5, 6, 7, 8) and GLQ-3 (sum of item nos. 2, 3, 4). GLQ-5 characterises typical aspects of QoL, while GLQ-3 consists of 3 side-effects of CMF (feeling sick, numbness or pins and needles, loss of hair). GLQ-5 decreased by 42.9 +/- 125.0 upon PS76A2, indicating an improvement in QoL, but increased by 60.3 +/- 94.0 upon placebo (p<0.0001). GLQ-3 deteriorated in both groups (PS76A2: 13.9 +/- 52.4; placebo: 34.5 +/- 57.0), but the differences in favour of PS76A2 were, nevertheless, statistically significant (p=0.0007). The total score GLQ-8 improved by 28.9 +/- 154.6 after PS76A2 and deteriorated by 94.8 +/- 141.1 after placebo (p<0.0001). Spitzer's uniscale improved by 12.2 +/- 30.7 upon PS76A2 and deteriorated by 10.8 +/- 26.1 with placebo (p<0.0001). After follow-up without chemotherapy, a significant treatment difference in favour of PS76A2 was determined by means of FACT-G, GLQ-8 and Spitzer's uniscale. PS76A2 was well tolerated in this trial, with the exception of slight local reactions in 17.6% of the PS76A2 group. In conclusion, PS76A2 (15 ng mistletoe lectin/0.5 ml twice weekly) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up.", "This study presents a meta-analysis of the influence of several potentially biasing factors (eg industry support, extrapyramidal side effects) on efficacy of studies comparing second-generation antipsychotic (SGA) with first-generation antipsychotic (FGA) medications. We used the dataset from our previously published meta-analysis of 124 randomized controlled trials (RCTs) comparing SGAs with FGAs, to evaluate whether certain possible biases could influence the actual outcome on the total score of the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), and Clinical Global Impressions (CGI) scores. Industry sponsorship was determined by contact with authors or publication statement. We calculated whether (1) industry sponsorship, (2) study quality, (3) extrapyramidal symptoms (EPS) properties, or (4) prophylactic antiparkinsonian medications influenced SGA vs FGA efficacy for each drug and averaged overall by two Hedges and Olkin-based meta-analyses. The analysis found that none of the factors was significantly associated with a particular outcome. While industry-sponsored articles may conclude their medication to be more favorable than that of a competitor in an RCT, we found that the observed efficacy was not influenced by sponsorship. Many attribute the finding that SGAs appears to be more efficacious than FGAs to be a result of EPS-decreasing efficacy (or its measurement). We were unable to confirm that the drug's EPS properties or antiparkinsonian management altered actual efficacy.", "To compare clinicians' ratings of therapeutic effectiveness when different trial end points were presented as percent reductions in relative compared with absolute risk and as numbers of patients treated to avoid one adverse outcome.\n Survey, with random allocation of two questionnaires.\n Toronto teaching hospitals.\n Convenience sample of 100 faculty and housestaff in internal medicine and family medicine.\n One questionnaire presented results for three end points of the Helsinki Heart Study as separate drug trials using only absolute differences in events; the other showed the same end points as relative differences. Both questionnaires included a fourth \"trial,\" showing person-years of treatment needed to prevent one myocardial infarction.\n The \"trials\" were each rated on an 11-point scale, from treatment \"harmful\" to \"very effective.\"\n Respondents' ratings of effectiveness varied with the end point. Controlling for end point, ratings of effectiveness by the 50 participants receiving absolute event data were lower than those by 50 participants responding to relative risk reductions (P < 0.001); however, no end-point difference was more than 0.6 scale points. For a \"trial\" reporting that 77 persons were treated for 5 years to prevent one myocardial infarction, mean ratings were 2.3 or 1.8 scale points lower, respectively (both P < 0.001), than when the same data were shown as relative or absolute risk reductions.\n Clinicians' views of drug therapies are affected by the common use of relative risk reductions in both trial reports and advertisements, by end-point emphasis, and, above all, by underuse of summary measures that relate treatment burden to therapeutic yields in a clinically relevant manner.", "Standardized aqueous mistletoe extracts have been applied to cancer patients for several decades as complementary medicine. A multicentric, randomized, open, prospective clinical trial was conducted in three oncological centers in the People's Republic of China in Bejing, Shenyang and Tianjin. Following the guidelines of \"Good Clinical Practice\" (GCP) this study was performed to get information on efficacy safety and side-effects of the standardized mistletoe extract (sME). Two hundred and thirty-three patients with breast (n=68), ovarian (n=71) and non-small cell lung cancer (NSCLC; n=94) were enrolled into this study. Two hundred and twenty-four patients fulfilled the requirements for final analysis (n=115 treated with sME HELIXOR A; n=109 comprising the control group being treated with the approved immunomodulating phytopharmacon Lentinan). All patients were provided with standard tumor-destructive treatment schedules and complementarily treated with sME or Lentinan during chemotherapy according to treatment protocol. Biometrically, the patients of the control and sME treatment group were comparable regarding distribution, clinical classification (WHO) and treatment protocols. Analysis was performed according to the \"Intention to treat principle\". Quality of life (QoL) was significantly (p<0.05) improved for patients who were complementarily treated with sME, as determined by the questionnaires FLIC (Functional Living Index-Cancer), TCM (Traditional Chinese Medicine Index) and the KPI (Karnofsky Performance Index) in comparison to the control group. Additionally, the occurrence of adverse events (AEs) was less frequent in the sME than in the control group (total number of AEs 52 versus 90 and number of serious AEs 5 versus 10 in study and control group, most of them due to chemotherapy). Only one serious AE was allocated to complementary treatment in each group (1 angioedema in sME group). All other side-effects of the sME (7 harmless local inflammatory reactions at subcutaneous injection site, 4 cases with fever) were self-limiting and did not demand therapeutic intervention. This study showed that complementary treatment with sME can beneficially reduce the side-effects of chemotherapy in cancer patients and thus improve quality of life.", "Depression occurs frequently in post-stroke patients and appears to be associated with impairment of their rehabilitation and functional recovery. In this study, we evaluated the efficacy and tolerability of the herbal drug, Free and Easy Wanderer Plus (FEWP), in patients affected by post-stroke depression (PSD).\n One hundred fifty (150) moderately to severely depressed patients as determined by a score >20 on the Hamilton Depression Scale (HDS) after a single ischemic or hemorrhagic stroke were randomly divided into the FEWP group (n = 60), the fluoxetine group (n = 60), and the placebo group (n = 30). The FEWP, fluoxetine, and placebo were administered to the patients over a period of 8 weeks. Depression was evaluated by HDS and the Barthel Index (BI) before, during, and after the treatment.\n Significantly higher clinical response rates were observed in both the FEWP and fluoxetine groups compared to the placebo group (60% and 65.5% versus 21.4%, chi(2) = 15.9, p < 0.01) and there was no difference in the response rates between the FEWP group and the fluoxetine group at the end of this study (60% versus 65.5%, chi(2) = 0.38, p > 0.05). Compared to fluoxetine, FEWP produced significantly greater improvement in depression at week 2 (15% versus 3.3%, chi(2) = 4.9, p < 0.05). Furthermore, FEWP produced significantly greater improvement in the activities of daily living (ADL) than fluoxetine at the end of this trial (BI: 43.8 +/- 5.6 versus 40.7 +/- 3.7, p < 0.01).\n FEWP showed good efficacy, safety, and tolerability in PSD patients. We conclude that FEWP is well tolerated and may be a useful therapeutic option in patients with PSD.", "To discuss the quality of reporting in randomized controlled trials (RCTs) of Chinese herbal medicine (CHM), and to provide suggestions for improving the reporting of future clinical studies in this therapeutic area.\n A search of the Cochrane Library was conducted to identify RCTs of CHM. A revised CONSORT checklist designed for CHM clinical studies was implemented. The revised CONSORT checklist contained 63 items, including the following new items added specifically for CHM: (1) \"syndrome of disease\" based on Chinese medicine theories; (2) rationale of CHM formula; (3) formula composition; (4) preparation form of CHM; (5) quality control of CHM.\n The overall reporting quality of the RCTs as assessed with the revised CONSORT checklist varied between 19% and 44%, with a median score of 32% (standard deviation 8%).\n The overall quality of reporting of RCTs of CHM evaluated with a revised CONSORT checklist was poor, reflecting the need for improvements in reporting future clinical trials in this area.\n To improve the quality of reporting of RCTs of CHM, we recommend adopting a revised CONSORT checklist that includes items specific to CHM. We also recommend that editors of CHM journals require authors to use a structured approach to presenting their trials as a condition of publication.", "We tested the effects of a saw palmetto herbal blend in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled trial.\n We randomized 44 men 45 to 80 years old with symptomatic BPH into a trial of a saw palmetto herbal blend versus placebo. End points included routine clinical measures (symptom score, uroflowmetry and post-void residual urine volume), blood chemistry studies (prostate specific antigen, sex hormones and multiphasic analysis), prostate volumetrics by magnetic resonance imaging, and prostate biopsy for zonal tissue morphometry and semiquantitative histology studies.\n Saw palmetto herbal blend and placebo groups had improved clinical parameters with a slight advantage in the saw palmetto group (not statistically significant). Neither prostate specific antigen nor prostate volume changed from baseline. Prostate epithelial contraction was noted, especially in the transition zone, where percent epithelium decreased from 17.8% at baseline to 10.7% after 6 months of saw palmetto herbal blend (p <0.01). Histological studies showed that the percent of atrophic glands increased from 25. 2% to 40.9% after treatment with saw palmetto herbal blend (p <0.01). The mechanism of action appeared to be nonhormonal but it was not identified by tissue studies of apoptosis, cellular proliferation, angiogenesis, growth factors or androgen receptor expression. We noted no adverse effects of saw palmetto herbal blend. When the study was no longer blinded, 41 men elected to continue therapy in an open label extension.\n Saw palmetto herbal blend appears to be a safe, highly desirable option for men with moderately symptomatic BPH. The secondary outcome measures of clinical effect in our study were only slightly better for saw palmetto herbal blend than placebo (not statistically significant). However, saw palmetto herbal blend therapy was associated with epithelial contraction, especially in the transition zone (p <0.01), indicating a possible mechanism of action underlying the clinical significance detected in other studies.", "The common cold is a viral infection with symptoms such as sneezing, sore throat, and running nose. It is one of the most prevalent illnesses in the world, and although commonly caused by rhinoviruses, antibiotics are often prescribed unnecessarily. Therefore, it is of utmost importance to evaluate alternative treatments such as herbal medications, whose efficacy and safety is proven by pharmacological and clinical studies.\n The aim of the present study was to evaluate the efficacy of a liquid herbal drug preparation from the roots of Pelargonium sidoides compared with placebo in adult patients with the common cold.\n The study was designed as a multicenter, prospective, randomized, double blind, parallel group, placebo-controlled phase III clinical trial with an adaptive group-sequential design.\n The study took place in eight outpatient departments affiliated with hospitals.\n One hundred three male and female adult patients with at least two major and one minor or with one major and three minor cold symptoms (maximum symptom score of 40 points), present for 24 to 48 hours, and who gave provision of informed consent were randomized to receive either 30 drops (1.5 mL) of the liquid herbal drug preparation EPs or placebo three times a day.\n Patients received randomized treatment for a maximum period of 10 days.\n The primary outcome criterion was the sum of symptom intensity differences (SSID) of the cold intensity score (CIS) from day one to day five. The CIS consists of the following 10 cold symptoms: nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headache, muscle aches, and fever.\n From baseline to day five, the mean SSID improved by 14.6 +/- 5.3 points in the EPs group compared with 7.6 +/- 7.5 points in the placebo group. This difference was statistically significant (P < .0001). The mean CIS decreased by 10.4 +/- 3.0 points and 5.6 +/- 4.3 points in EPs and placebo-treated patients, respectively. After 10 days, 78.8% versus 31.4% in the EPs versus placebo group were clinically cured (CIS equals zero points or complete resolution of all but a maximum of one cold symptom; P < .0001). The mean duration of inability to work was significantly lower in the EPs treatment group (6.9 +/- 1.8 days) than in the placebo group (8.2 +/- 2.1 days; P = .0003). Treatment outcome (rates of complete recovery or major improvement from disease [integrative medicine outcomes scale]) was assessed better in the EPs treatment group than in the placebo group by both the investigator and the patient on day five (P < .0001). Adverse events occurred in three of 103 patients (2.9%), with two of 52 (3.8%) and one of 51 (2.0%) patients in the EPs and placebo group, respectively. All adverse events were assessed as nonserious. At the end of treatment, all patients (100%) in the active treatment group judged the subjective tolerability of EPs as good or very good.\n EPs represents an effective treatment of the common cold. It significantly reduces the severity of symptoms and shortens the duration of the common cold compared with placebo. The herbal drug is well tolerated.", "We evaluated the analgesic effect of Toki-shakuyaku-san (TSS) in women who had a combination of \"deficiency,\" of \"Yin,\" \"cold,\" and \"stagnated blood\" syndromes, and were suffering from dysmenorrhea. A diagnostic scoring system was used for determination of these conditions. We treated patients with either TSS or placebo during 2 menstrual cycles with a double-blind technique, and we followed them for 2 additional cycles. A significant alleviation of dysmenorrhea was observed in patients treated with TSS as compared to those treated with placebo. Our results suggest that TSS is effective for treatment of dysmenorrhea in patients with the above-mentioned conditions." ]	The evidence base for the effects of herbal treatments is hampered by the variety of treatments assessed, poor reporting quality of the studies and lack of available data. The data that are available from the studies provide only a small insight into the long-term efficacy and harm profiles of these treatments. The absence of common endpoint measurements limits the validity of our findings further. Positive findings in this review warrant additional well-designed trials in this area.
CD000112	[ "8329110", "7520770", "10649166", "1735830", "11134430", "9323798", "2738720", "7670096", "1386063", "1614462", "7869205", "9651406", "8079448" ]	[ "Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: results of a controlled trial.", "A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia.", "A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group.", "Randomized trial of granulocyte transfusions versus intravenous immune globulin therapy for neonatal neutropenia and sepsis.", "A randomized, double-masked, placebo-controlled trial of recombinant granulocyte colony-stimulating factor administration to preterm infants with the clinical diagnosis of early-onset sepsis.", "The effect of recombinant human erythropoietin on circulating hematopoietic progenitor cells in anemic premature infants.", "A randomized, double-blind, placebo-controlled investigation of the safety of intravenous immune globulin administration to preterm neonates.", "Results of a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in very low birthweight neonates: significant induction of circulatory neutrophils, monocytes, platelets, and bone marrow neutrophils.", "An efficacy trial of a mammalian cell-derived recombinant DNA hepatitis B vaccine in infants born to mothers positive for HBsAg, in Shanghai, China.", "Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates. The Multicenter Group for the Study of Immune Globulin in Neonates.", "Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo-controlled trial.", "A randomized, placebo-controlled trial of granulocyte colony-stimulating factor administration to newborn infants with neutropenia and clinical signs of early-onset sepsis.", "No beneficial effect of low-dose fetal intravenous gammaglobulin administration in combination with intravascular transfusions in severe Rh D haemolytic disease." ]	[ "It remains unclear whether maternal immunization with paternal lymphocytes prior to conception improves the reproductive outcome in women with recurrent abortion in whom all secondary causes have been excluded.\n A double-blind placebo controlled trial was instituted in women with unexplained recurrent spontaneous abortion, comparing immunization with 400 million paternal to 400 million maternal (autologous) lymphocytes. The groups were compared in a paired sequential trials chart, by logistic regression, and, in addition, a meta-analysis of this and other published trials was carried out.\n The live birth rate among pregnancies in paired couples with paternal lymphocyte immunization was 68% compared to 47% in the women who received their own cells. The results bordered on, but did not achieve, statistical significance. The women in each group were thoroughly investigated to exclude known causes of recurrent pregnancy loss and appeared to have been well matched in all variables. Women with lymphocytotoxic antibodies against paternal lymphocytes were excluded. Unlike our previous study there was not association between the time to conception and the chance of a successful outcome. Indeed, the time to conception was relatively short, 12 wk in all groups. The meta-analysis supported an overall modest favorable experience with paternal cells.\n The study is consistent with a general trend favoring paternal over maternal lymphocyte immunization but reinforces the need for larger multicenter controlled trials as well as more detailed biological study in humans to understand the nature of the maternal-fetal interface and its breakdown.", "Host defenses in the human neonate are limited by immaturity in phagocytic immunity. Such limitations seem to predispose infected newborns to neutropenia from an exhaustion of the neutrophil reserve. Among the critical defects thus far identified in neonatal phagocytic immunity is a specific reduction in the capacity of mononuclear cells to express granulocyte colony-stimulating factor (G-CSF) after stimulation. However, the safety, pharmacokinetics, and biological efficacy of administration of recombinant human (rh)G-CSF to infected human newborns to compensate for this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of age) with presumed bacterial sepsis within the first 3 days of life were randomized to receive either placebo or varying doses of rhG-CSF (1.0, 5.0 or 10.0 micrograms/kg every 24 hours [36 patients] or 5.0 or 10.0 micrograms/kg every 12 hours [6 patients]) on days 1, 2, and 3. Complete blood counts with differential and platelet counts were obtained at hours 0, 2, 6, 24, 48, 72, and 96. Circulating G-CSF concentrations were determined at hours 0, 2, 6, 12, 14, 16, 18, 24, and 36. Tibial bone marrow aspirates were obtained after 72 hours for quantification of the bone marrow neutrophil storage pool (NSP), neutrophil proliferative pool, granulocyte progenitors, and pluripotent progenitors. Functional activation of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or placebo administration. Intravenous rhG-CSF was not associated with any recognized acute toxicity. RhG-CSF induced a significant increase in the blood neutrophil concentration 24 hours after the 5 and 10 micrograms/kg doses every 12 and 24 hours and it was sustained as long as 96 hours. A dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil C3bi expression was significantly increased at 24 hours after 10 micrograms/kg every 24-hour dose of rhG-CSF. The half-life of rhG-CSF was 4.4 +/- 0.4 hours. The rhG-CSF was well tolerated at all gestational ages treated. The rhG-CSF induced a significant increase in the peripheral blood and bone marrow absolute neutrophil concentration and in C3bi expression. Future clinical trials aimed at improving the outcome of overwhelming bacterial sepsis and neutropenia in newborn infants might include the use of rhG-CSF.", "Treatment with heparin and low-dose aspirin improves fetal survival among women with antiphospholipid syndrome. Despite treatment, however, these pregnancies are frequently complicated by preeclampsia, fetal growth restriction, and placental insufficiency, often with the result of preterm birth. Small case series suggest that intravenous immune globulin may reduce the rates of these obstetric complications, but the efficacy of this treatment remains unproven. This pilot study was undertaken to determine the feasibility of a multicenter trial of intravenous immune globulin and to assess the impact on obstetric and neonatal outcomes among women with antiphospholipid syndrome of the addition of intravenous immune globulin to a heparin and low-dose aspirin regimen.\n This multicenter, randomized, double-blind pilot study compared treatment with heparin and low-dose aspirin plus intravenous immune globulin with heparin and low-dose aspirin plus placebo in a group of women who met strict criteria for antiphospholipid syndrome. All patients had lupus anticoagulant, medium to high levels of immunoglobulin G anticardiolipin antibodies, or both. Patients with a single live intrauterine fetus at </=12 weeks' gestation were randomly assigned to receive either intravenous immune globulin (1 g/kg body weight) or an identical-appearing placebo for 2 consecutive days each month until 36 weeks' gestation in addition to a heparin and low-dose aspirin regimen. Maternal characteristics, obstetric complications, and neonatal outcomes were compared with the Student t test and the Fisher exact test as appropriate.\n Sixteen women were enrolled during a 2-year period; 7 received intravenous immune globulin and 9 were given placebo. The groups were similar with respect to age, gravidity, number of previous pregnancy losses, and gestational age at the initiation of treatment. Obstetric outcomes were excellent in both groups, with all women being delivered of live-born infants after 32 weeks' gestation. The rates of antepartum complications such as preeclampsia, fetal growth restriction, and placental insufficiency (as manifested by fetal growth restriction or fetal distress) were similar between the 2 groups. Gestational age at delivery (intravenous immune globulin group, 34.6 +/- 1.1 weeks; placebo group, 36.7 +/- 2.1 weeks) and birth weights (intravenous immune globulin group, 2249.7 +/- 186.1 g; placebo group; 2604.4 +/- 868.9 g) were similar between the 2 groups. There were fewer cases of fetal growth restriction (intravenous immune globulin group, 0%; placebo group, 33%) and neonatal intensive care unit admission (intravenous immune globulin group, 20%; placebo group, 44%) among the infants in the intravenous immune globulin group than those in the placebo group, but these differences were not significant.\n A multicenter treatment trial of intravenous immune globulin is feasible. In this pilot study intravenous immune globulin did not improve obstetric or neonatal outcomes beyond those achieved with a heparin and low-dose aspirin regimen. Although not statistically significant, the findings of fewer cases of fetal growth restriction and neonatal intensive care unit admissions among the intravenous immune globulin-treated pregnancies may warrant expansion of the study.", "We prospectively studied newborn infants with sepsis and neutropenia who were randomly selected to receive standard supportive care and either adjuvant granulocyte transfusions or intravenous immune globulin (IVIG) infusions; 21 infants received granulocyte transfusions and 14 received IVIG infusions. Half of the patients were premature (gestational age less than or equal to 32 weeks); the average postnatal age was 5 days (range 3 to 8 days). All infants had neutropenia by the criteria of Manroe et al., and the mean average bone marrow neutrophil storage pool ranged between 35% and 37%. There were no significant differences with respect to serum IgG, IgA, IgM, and total hemolytic complement values between treatment groups or between survivors and nonsurvivors. Clinical severity as defined by hypoxia, acidosis, and hypotension was similar between treatment groups. Group B streptococcus was the most common organism identified and accounted for almost 33% of all bacterial isolates. There was a significantly different survival rate in the group receiving polymorphonuclear leukocyte transfusions (100%, 21/21) compared with the group receiving IVIG infusions (64%, 9/14; p = less than 0.03). There were no significant complications in either treatment group with respect to fluid overload, secondary infection, blood group sensitization, pulmonary complications, or graft-versus-host disease. This pilot study suggests a possible benefit of granulocyte transfusions compared with 'IVIG therapy in the adjuvant treatment of neonatal neutropenia and overwhelming bacterial sepsis.", "We performed a randomized, double-masked, parallel-groups, placebo-controlled trial of recombinant granulocyte colony-stimulating factor (rG-CSF) administration to 44 preterm neonates who had blood cultures obtained and antibiotics begun because of the clinical diagnosis of early-onset sepsis. Two primary outcome variables were tested 1) mortality and 2) development of nosocomial infections over the 2-week period after dosing.\n The treatment group (n = 22) received 10 microgram/kg/day of intravenous rG-CSF once daily for 3 days and the placebo group (n = 22) received the same volume of a visually indistinguishable vehicle. Mortality and culture-proven nosocomial infections were recorded. Immediately before the first, second, and third doses, and again 10 days after the first dose, serum concentrations were determined for tumor necrosis factor-alpha, interleukin 6, granulocyte-macrophage colony stimulating factor, and G-CSF, and blood leukocyte counts, absolute neutrophil counts, immature/total neutrophil ratios, platelet counts, and hemoglobin concentrations were measured.\n The treatment and placebo groups were of similar gestational age (29 +/- 3 vs 31 +/- 3 weeks) and birth weight (1376 +/- 491 vs 1404 +/- 508 g), and had similar Apgar scores and 24-hour Score for Neonatal Acute Physiology scores. The mortality rate was not different between treatment and placebo groups. However, the occurrence of a subsequent nosocomial infection was lower in the rG-CSF recipients (relative risk:.19; 95% confidence interval:.05-.78). rG-CSF treatment did not alter the serum concentrations of the cytokines measured (except for G-CSF). Serum G-CSF levels and blood neutrophil counts were higher in the treatment than in the placebo group 24 hours and 48 hours after dosing.\n Administration of 3 daily doses of rG-CSF (10 microgram/kg/day) to premature neonates with the clinical diagnosis of early-onset sepsis did not improve mortality but was associated with acquiring fewer nosocomial infections over the subsequent 2 weeks.", "In vitro and animal studies suggest that high concentrations of recombinant human erythropoietin (rHuEPO) might divert multipotent progenitors into erythroid maturation at the expense of granulocyte production. We determined whether changes of number and lineage commitment of peripheral blood progenitor cells occur in premature infants during therapy with rHuEPO. Thirty preterm infants were randomly assigned either to receive 300 IU of eopoetin alpha s.c. per kilogram body weight three times a week for four weeks or to a control group. At study entry and after two weeks of treatment the numbers of circulating BFU-E, granulocyte-macrophage colony-forming units (CFU-GM) and granulocyte-erythrocyte-macrophage-megakaryocyte CFU (CFU-GEMM) were analyzed by semisolid culture technique, CD34+ cells and early myeloid CD34+CD45RA- progenitors by flow cytometry. As compared with the control group, rHuEPO treatment did not exert any significant modulatory effect on numbers of CFU-GM, nor was there a significant change in numbers of BFU-E, CFU-GEMM, total-CFU, percentage of CD34+ or CD34+CD45RA- cells. Mean neutrophil count was not significantly reduced at any period during the study. Compared with the control group, the infants receiving rHuEPO had higher hematocrit values (p = 0.003) and absolute reticulocyte counts (p < 0.001). The median cumulative volume of blood transfused per kilogram per day was 0.86 ml (first quartile 0.5 ml; third quartile 1.1 ml) in the control group and 0 ml (first quartile 0 ml; third quartile 0.47 ml) in the rHuEPO group (p = 0.038). We conclude using a relatively high dose of rHuEPO in premature infants, no significant in vivo effect on circulating peripheral blood progenitor or neutrophil count could be detected.", "Intravenous immune globulin (750 mg/kg), or an equivalent volume of a placebo, was administered during the first week of life, in a randomized trial, to 20 preterm neonates weighing 710 to 1800 g. A variety of laboratory and clinical values were measured serially and analyzed for possible untoward effects. Serum IgG levels were also determined serially. No differences in heart rate, respiratory rate, urine output, blood glucose, serum osmolality, BUN, SGPT, pH, blood gasses, serum electrolytes, total or direct bilirubin, blood leukocyte concentration, absolute neutrophil count, or blood platelet concentration were observed between the intravenous immune globulin (IVIG) and placebo recipients before or following IVIG administration. The red blood cell concentration of IVIG recipients diminished transiently and only slightly (P less than .05). Serum IgG levels increased from 503 +/- 162 mg/dL (X +/- SD) to 1492 +/- 201 mg/dL 15 minutes after the IVIG administration (P less than .001). After 8 days, serum IgG levels were still elevated, at 675 +/- 297 mg/dL. All patients randomized to receive the placebo experienced a diminution in serum IgG over this 8-day period (P less than .01). All 20 patients survived and none in either group had a documented nosocomial infection. This study suggests that IVIG can safely be administered to preterm neonates, resulting in serum IgG levels comparable to those of term infants.", "Neonates, especially those of very low birthweight (VLBW), have an increased risk of nosocomial infections secondary to deficiencies in development. We previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) production and mRNA expression from stimulated neonatal mononuclear cells are significantly less than that from adult cells. Recombinant murine GM-CSF administration to neonatal rats has resulted in neutrophilia, increased neutrophil production, and increased survival of pups during experimental Staphylococcus aureus sepsis. In the present study, we sought to determine the safety and biologic response of recombinant human (rhu) GM-CSF in VLBW neonates. Twenty VLBW neonates (500 to 1,500 g), aged < 72 hours, were randomized to receive either placebo (n = 5) or rhuGM-CSF at 5.0 micrograms/kg once per day (n = 5), 5.0 micrograms/kg twice per day (n = 5), or 10 micrograms/kg once per day (n = 5) given via 2-hour intravenous infusion for 7 days. Complete blood counts, differential, and platelet counts were obtained, and tibial bone marrow aspirate was performed on day 8. Neutrophil C3bi receptor expression was measured at 0 and 24 hours. GM-CSF levels were measured by a sandwich enzyme-linked immunosorbent assay at 2, 4, 6, 12, and 24 hours after the first dose of rhuGM-CSF. At all doses, rhuGM-CSF was well tolerated, and there was no evidence of grade III or IV toxicity. Within 48 hours of administration, there was a significant increase in the circulating absolute neutrophil count (ANC) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day, which continued for at least 24 hours after discontinuation of rhuGM-CSF. When the ANC was normalized for each patient's first ANC, there was a significant increase in the ANC on days 6 and 7 at each dose level. By day 7, all tested doses of rhuGM-CSF resulted in an increase in the absolute monocyte count (AMC) compared with placebo-treated neonates. In those receiving rhuGM-CSF 5.0 micrograms/kg twice per day, there was additionally a significant increase in the day 7 and 8 platelet count. Tibial bone marrow aspirates demonstrated a significant increase in the bone marrow neutrophil storage pool (BM NSP) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day. Neutrophil C3bi receptor expression was significantly increased 24 hours after the first dose of rhuGM-CSF at 5.0 micrograms/kg once per day. The elimination half-life (T1/2) of rhuGM-CSF was 1.4 +/- 0.8 to 3.9 +/- 2.8 hours.(ABSTRACT TRUNCATED AT 400 WORDS)", "We conducted a randomized, double-blind clinical trial of an experimental mammalian cell-derived DNA hepatitis B vaccine (Betagen, Connaught Laboratories Ltd, Toronto, Canada) to determine its efficacy in infants born to mothers who were carriers of hepatitis B surface antigen (HBsAg). Four groups of 55 infants received injections as follows: (1) a licensed plasma-derived vaccine (Lanzhou, Lanzhou Institute for Biological Products, Lanzhou, People's Republic of China), 20 micrograms; (2) Betagen, 20 micrograms; (3) Betagen, 20 micrograms+hepatitis B immune globulin (HBIG); and (4) Betagen, 10 micrograms+HBIG. Vaccine injections were given at birth and at 1 and 6 months and HBIG was given at birth. The vaccines were compared to a historical placebo control group. The efficacy of Betagen alone was 82.6% compared to 51.0% for the Lanzhou. Efficacy of Betagen increased with the concomitant use of HBIG. No infants who were HBsAg negative at birth and/or were born to hepatitis B e antigen (HBeAg) negative mothers became carriers. The rate of HBsAg in infants receiving Betagen alone, and born to mothers who were HBeAg positive, decreased from 60% at birth to 20% by the ninth month, compared to 62.5% and 50% (respectively) for Lanzhou. The percentage of infants with protective levels of antiHBs was significantly higher for Betagen alone than for Lanzhou, but the geometric mean titre of antiHBs for responders was not significantly different. We have shown that Betagen alone is highly efficacious in preventing the development of hepatitis B in infants born to mothers who are carriers of HBsAg and is also highly effective in reducing the carriage of HBsAg in infants who are HBsAg positive at birth and/or born to HBeAg positive mothers.", "Nosocomial infection is a major risk for premature infants with very low birth weights. One reason for their susceptibility to infection may be antibody deficiency, since there is little transfer of maternal IgG to the fetus before 32 weeks' gestation.\n We conducted a multicenter, double-blind study of neonates weighing 500 to 1750 g at birth. A total of 588 neonates were randomly assigned, with stratification for birth weight, to receive periodic intravenous infusions of either immune globulin (500 mg per kilogram of body weight per day) or a placebo. Mortality, morbidity, and nosocomial infection during the next 56 days were assessed.\n The infusions were well tolerated; mild, reversible adverse reactions occurred in five infants in each group. There was a significant reduction in the risk of a first nosocomial infection in the recipients of immune globulin as compared with the placebo recipients (relative risk, 0.7; 95 percent confidence interval, 0.5 to 0.9). About 85 percent of the nosocomial infections were bacterial; the majority of these were caused by coagulase-negative staphylococci or Staphylococcus aureus. The neonates who received immune globulin had fewer mean days of hospitalization than the controls (62 vs. 68, P = 0.15); among the infants with infections, the difference in the mean length of the hospital stay was even greater (80 days vs. 101 days, P = 0.02).\n For premature infants weighing between 500 and 1750 g at birth, treatment with intravenous infusions of immune globulin is safe and reduces the risk of nosocomial infection.", "We hypothesized that using a higher dose of erythropoietin (Epo) and starting treatment on the first day of life would reduce the transfusion requirements of ventilator-dependent and non-ventilator-dependent very low birth weight (VLBW) infants. Moreover, we hypothesized that this treatment would be cost-effective.\n We randomly assigned 20 ill newborn VLBW infants to receive either Epo (200 units/kg per day) or placebo during their first 2 weeks of life. The caregivers were unaware of the treatment assignments, and erythrocyte transfusions were administered according to hematocrit and signs of anemia.\n On day 1, reticulocyte counts and hematocrits were similar in the two groups. During the subsequent 2 weeks, reticulocyte counts of the placebo recipients fell significantly below those of the Epo recipients, but hematocrits in the two groups did not differ. More transfusions were received by the placebo recipients (mean = 1.4 per patient) than by the Epo recipients (mean = 0.2 per patient; p < 0.01). No adverse effects of Epo were noted, and the costs in the placebo group exceeded those in the Epo group.\n We conclude that administration of Epo to VLBW infants during the first 2 weeks of life results in fewer transfusions and is cost-effective.", "To determine whether recombinant human granulocyte colony-stimulating factor (G-CSF) administration: 1) accelerates production of neutrophils; 2) increases bone marrow stored and precursor neutrophils; and 3) is safe in newborn infants with neutropenia and clinical signs of early-onset sepsis.\n We randomized 20 infants with neutropenia and clinical signs of early-onset sepsis in the first 3 days of life to receive G-CSF (10 microg/kg/d) or placebo for 3 days. Entry criteria included neutropenia as defined by Manroe criteria, an elevated immature to total neutrophil ratio [(I/T) >/=0.25], and a requirement for ventilatory support. Cultures were obtained and antibiotics initiated on all study infants. Circulating absolute neutrophil count (ANC), I/T ratio, bone marrow neutrophil storage pool (NSP) and neutrophil proliferative pool (NPP), and plasma G-CSF concentrations were evaluated. Also, severity of illness as determined using the Score for Neonatal Acute Physiology (SNAP), morbidity, and mortality were recorded.\n Circulating ANC increased in both G-CSF and placebo recipients by day 1. Also, the I/T neutrophil ratio decreased in both G-CSF and placebo recipients. There were no significant differences in the ANC or I/T ratio between the two groups during the study period. Similarly, bone marrow NSP and NPP did not differ between G-CSF and placebo recipients at study entry or day 2. No differences were observed in the secondary outcome measures including severity of illness, morbidity, and mortality.\n Administration of recombinant G-CSF to infants with neutropenia and clinical signs of early-onset sepsis did not increase circulating ANC, or bone marrow NSP and NPP compared with placebo. No differences were observed between G-CSF and placebo recipients in severity of illness, morbidity, or mortality. No adverse effects of G-CSF administrations were noted.", "Recent observations have shown that treatment with high-dose intravenous gammaglobulin (IVIgG) given to the mother may improve fetal outcome in cases of severe Rh D alloimmunization. Unfortunately, the costs of this new method of treatment are too high for routine use. Therefore, we decided to apply this treatment to the fetus and to investigate whether the effect of IVIgG might be attributable to blockade of the fetal mononuclear phagocyte system. We have performed a randomized study in which 20 fetuses with severe Rh D-haemolytic disease (HDN) were treated with intrauterine intravascular red cell transfusions (IUT). In 10 of these 20 cases transfusions were followed by administration to the fetus of low-dose IVIgG (85.7 +/- 11.6 mg/kg by ultrasound-estimated fetal weight because of fetal vascular volume considerations). We compared the number of IUTs, postnatal exchange transfusions, haematocrit (Ht) and haemoglobulin (Hb) values before and after transfusion (s) needed by the newborns of the two groups. No significant differences in the transfusion requirements of the fetuses and in the clinical outcome could be demonstrated. However, the 95% confidence interval for the difference in the improvement of cord blood Ht was too wide for any conclusions. The 95% confidence interval for the difference in the improvement of Hb levels suggests that any clinically relevant advantage of IVIgG on Hb is unlikely." ]	Paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin provide no significant beneficial effect over placebo in improving the live birth rate.
CD008628	[ "12377902", "8245085", "19169102" ]	[ "Operative compared with nonoperative treatment of displaced intra-articular calcaneal fractures: a prospective, randomized, controlled multicenter trial.", "Intra-articular fractures of the calcaneum treated operatively or conservatively. A prospective study.", "Elastic stable intramedullary nailing versus nonoperative treatment of displaced midshaft clavicular fractures-a randomized, controlled, clinical trial." ]	[ "Open reduction and internal fixation is the treatment of choice for displaced intra-articular calcaneal fractures at many orthopaedic trauma centers. The purpose of this study was to determine whether open reduction and internal fixation of displaced intra-articular calcaneal fractures results in better general and disease-specific health outcomes at two years after the injury compared with those after nonoperative management.\n Patients at four trauma centers were randomized to operative or nonoperative care. A standard protocol, involving a lateral approach and rigid internal fixation, was used for operative care. Nonoperative treatment involved no attempt at closed reduction, and the patients were treated only with ice, elevation, and rest. All fractures were classified, and the quality of the reduction was measured. Validated outcome measures included the Short Form-36 (SF-36, a general health survey) and a visual analog scale (a disease-specific scale).\n Between April 1991 and December 1997, 512 patients with a calcaneal fracture were treated. Of those patients, 424 with 471 displaced intra-articular calcaneal fractures were enrolled in the study. Three hundred and nine patients (73%) were followed and assessed for a minimum of two years and a maximum of eight years of follow-up. The outcomes after nonoperative treatment were not found to be different from those after operative treatment; the score on the SF-36 was 64.7 and 68.7, respectively (p = 0.13), and the score on the visual analog scale was 64.3 and 68.6, respectively (p = 0.12). However, the patients who were not receiving Workers' Compensation and were managed operatively had significantly higher satisfaction scores (p = 0.001). Women who were managed operatively scored significantly higher on the SF-36 than did women who were managed nonoperatively (p = 0.015). Patients who were not receiving Workers' Compensation and were younger (less than twenty-nine years old), had a moderately lower Böhler angle (0 degrees to 14 degrees ), a comminuted fracture, a light workload, or an anatomic reduction or a step-off of < or =2 mm after surgical reduction (p = 0.04) scored significantly higher on the scoring scales after surgery compared with those who were treated nonoperatively.\n Without stratification of the groups, the functional results after nonoperative care of displaced intra-articular calcaneal fractures were equivalent to those after operative care. However, after unmasking the data by removal of the patients who were receiving Workers' Compensation, the outcomes were significantly better in some groups of surgically treated patients.", "We report a prospective trial of 66 patients with intraarticular fractures of the calcaneum. All fractures were assessed by CT. Patients with displaced fractures were randomised to receive either conservative (n = 31) or operative treatment (n = 25). Undisplaced fractures (n = 10) were treated conservatively. Operation involved open reduction of the posterior subtalar joint, and fixation with Kirschner wires. All 66 patients were reviewed at a minimum of one year (mean 23 months). After conservative treatment the undisplaced fractures had slightly better results than the displaced fractures. There was no significant difference in outcome between the operatively and the conservatively treated displaced fractures. We have also documented prospectively the natural history of the injury, which is of use in assessing prognosis for both clinical and medicolegal purposes.", "To compare elastic stable intramedullary nailing (ESIN) with nonoperative treatment of fully displaced midshaft clavicular fractures in adults.\n The study was a randomized, controlled, clinical trial.\n Level 1 trauma center.\n Sixty patients between 18 and 65 years of age participated and completed the study. They were randomized to either operative or nonoperative treatment with a 2-year follow-up.\n Thirty patients were treated with a simple shoulder sling and 30 patients with ESIN within 3 days after trauma.\n Complications after operative and nonoperative treatments, Disabilities of the Arm, Shoulder and Hand (DASH) score and Constant Shoulder Score for outcome measurement, and clavicular shortening.\n Fracture union was achieved in all patients in the operative group, whereas nonunion was observed in 3 of 30 patients of the nonoperative group. Two symptomatic malunions required corrective osteotomy in the nonoperative group. Medial nail protrusion occurred in 7 cases in the operative group. Implant failure with revision surgery was necessary in 2 patients after an additional adequate trauma. DASH scores were lower in the operative group throughout the first 6 months and 2 years after trauma, with a significant difference during the first 18 weeks. Constant scores were significantly higher after 6 months and 2 years after intramedullary stabilization. Patients in the operative group showed a significant improvement of posttraumatic clavicular shortening; they were also more satisfied with cosmetic appearance and overall outcome.\n ESIN of displaced midshaft clavicular fractures resulted in a lower rate of nonunion and delayed union, a faster return to daily activities, and a better functional outcome. Clavicular shortening was significantly lower, and overall satisfaction was higher in the operative group." ]	The bulk of the evidence in this review derives from one large multi-centre but inadequately reported trial conducted over 15 years ago. This found no significant differences between surgical or conservative treatment in functional ability and health related quality of life at three years after displaced intra-articular calcaneal fracture. Though it reported a greater risk of major complications after surgery, subtalar arthrodeses for the development of subtalar arthritis was significantly greater after conservative treatment. Overall, there is insufficient high quality evidence relating to current practice to establish whether surgical or conservative treatment is better for adults with displaced intra-articular calcaneal fracture. Evidence from adequately powered randomised, multi-centre controlled trials, assessing patient-centred and clinically relevant outcomes is required. However, it would be prudent to reassess this need after an update of the review that incorporates new evidence from a currently ongoing multi-centre trial.
CD001118	[ "2071729", "10048112", "1776536", "10890303", "11302275", "20060229", "8442622", "17365759", "18188753", "12603234", "2030194", "16873594", "7608359", "15991780", "19357315", "15264976", "11761737", "15586837", "6666695", "6437257", "15165654", "2926945", "11800220", "7740017", "3369327", "8543703", "1873454", "16838818", "3592033", "1999752", "17372796", "19524389", "8907100", "11906689", "11900495", "9690101", "11509461", "3070047", "19023834", "16116148", "11072391", "19087949", "9396102", "7327784", "16377603", "15893085", "15013579", "17173716", "2636539", "17995993", "17523995", "18236303", "10181019", "8433182", "16788278", "19959695", "3336245", "12573179", "7971879", "15530588", "17074945", "15805374", "16499517", "9808825" ]	[ "Self-help quit smoking interventions: effects of self-help materials, social support instructions, and telephone counseling.", "Targeting smokers with low readiness to change with tailored and nontailored self-help materials.", "A comparison of self-help approaches to smoking cessation.", "Evaluating two self-help interventions for smokeless tobacco cessation.", "Effectiveness of personalized written feedback through a mail intervention for smoking cessation: a randomized-controlled trial in Spanish smokers.", "A pilot study of mailed nicotine lozenges with assisted self-help for the treatment of smokeless tobacco users.", "Nurse-assisted counseling for smokers in primary care.", "Self-help cessation programs for smokeless tobacco users: long-term follow-up of a randomized trial.", "Evaluating the effectiveness of a single telephone contact as an adjunct to a self-help intervention for smoking cessation in a randomized controlled trial.", "A controlled trial of an expert system and self-help manual intervention based on the stages of change versus standard self-help materials in smoking cessation.", "Evaluation of intrinsic and extrinsic motivation interventions with a self-help smoking cessation program.", "Integrated tobacco cessation counseling in a diabetes self-management training program: a randomized trial of diabetes and reduction of tobacco.", "Nicotine gum and self-help behavioral treatment for smoking relapse prevention: results from a trial using population-based recruitment.", "A randomised controlled trial to evaluate the efficacy of a nurse-provided intervention for hospitalised smokers.", "Feasibility of a telephone-based intervention for support persons to help smokers quit: a pilot study.", "A randomized trial comparing the effects of self-help materials and proactive telephone counseling on teen smoking cessation.", "Evaluation of the amount of therapist contact in a smoking cessation program.", "Results of a randomized controlled trial of intervention to implement smoking guidelines in Veterans Affairs medical centers: increased use of medications without cessation benefit.", "An investigation of a minimal contact brand fading program for smoking treatment.", "Self-help smoking cessation and maintenance programs: a comparative study with 12-month follow-up by the American Lung Association.", "Training support persons to help smokers quit: a pilot study.", "A randomized trial to increase smoking intervention by physicians. Doctors Helping Smokers, Round I.", "Effectiveness of telephone contact as an adjunct to a self-help program for smoking cessation: a randomized controlled trial in Spanish smokers.", "Evaluation of a Dutch community-based smoking cessation intervention.", "Behavioral self-help materials as an adjunct to nicotine gum.", "A randomized trial of self-help materials, personalized feedback, and telephone counseling with nonvolunteer smokers.", "A randomized trial of smoking cessation interventions in general practice in Italy.", "The costs and effectiveness of different benefit designs for treating tobacco dependence: results from a randomized trial.", "Evaluation of a minimal-contact smoking cessation intervention in an outpatient setting.", "Can residents be trained to counsel patients about quitting smoking? Results from a randomized trial.", "Randomized controlled trial of a computer-based, tailored intervention to increase smoking cessation counseling by primary care physicians.", "Impact of a brief motivational smoking cessation intervention the Get PHIT randomized controlled trial.", "Telephone counseling for smoking cessation: effects of single-session and multiple-session interventions.", "Pilot evaluation of a population-based health intervention for reducing use of smokeless tobacco.", "Efficacy of resident training in smoking cessation: a randomized, controlled trial of a program based on application of behavioral theory and practice with standardized patients.", "Long-term effectiveness of two Dutch work site smoking cessation programs.", "Effectiveness of a cognitive behaviour therapy self-help programme for smokers in London, UK.", "The effectiveness of a worksite self-help smoking cessation program: a randomized trial.", "A randomized controlled trial of Telephone Counseling with smokeless tobacco users: the ChewFree Minnesota study.", "Peer-delivered smoking counseling for childhood cancer survivors increases rate of cessation: the partnership for health study.", "Using tailored interventions to enhance smoking cessation among African-Americans at a community health center.", "A digital smoking cessation program delivered through internet and cell phone without nicotine replacement (happy ending): randomized controlled trial.", "Self-help interventions for older smokers.", "Utility of behavioral self-help manuals in a minimal-contact smoking cessation program.", "A randomized controlled trial of multiple tailored messages for smoking cessation among callers to the cancer information service.", "Brief motivational intervention for adolescent smokers in medical settings.", "Effectiveness of smoking cessation self-help materials in a lung cancer screening population.", "Efficacy of an emergency department-based motivational teenage smoking intervention.", "A worksite smoking cessation intervention involving the media and incentives.", "Proactive interventions for smoking cessation in general medical practice: a quasi-randomized controlled trial to examine the efficacy of computer-tailored letters and physician-delivered brief advice.", "Effectiveness of individually tailored smoking cessation advice letters as an adjunct to telephone counselling and generic self-help materials: randomized controlled trial.", "ChewFree.com: evaluation of a Web-based cessation program for smokeless tobacco users.", "Long-term effectiveness of computer-generated tailored feedback in smoking cessation.", "Promoting smoking cessation at the workplace. Results of a randomized controlled intervention study.", "Effectiveness of a low-intensity intra-worksite intervention on smoking cessation in Japanese employees: a three-year intervention trial.", "Effectiveness of a nurse-managed, lay-led tobacco cessation intervention among ohio appalachian women.", "Effectiveness of smoking cessation interventions integrated into primary care practice.", "Computer and manual self-help behavioral strategies for smoking reduction: initial feasibility and one-year follow-up.", "A 2-year self-help smoking cessation manual intervention among middle-aged Finnish men: an application of the transtheoretical model.", "Smoking reduction intervention in a large population-based study. The Inter99 study.", "A randomized controlled trial of a smoking cessation intervention among people with a psychotic disorder.", "Teen reach: outcomes from a randomized, controlled trial of a tobacco reduction program for teens seen in primary medical care.", "Helping smokers to decide on the use of efficacious smoking cessation methods: a randomized controlled trial of a decision aid.", "A self-help intervention for African American smokers: tailoring cancer information service counseling for a special population." ]	[ "Smokers requesting self-help materials for smoking cessation (N = 2,021) were randomized to receive (a) an experimental self-quitting guide emphasizing nicotine fading and other nonaversive behavioral strategies, (b) the same self-quitting guide with a support guide for the quitter's family and friends, (c) self-quitting and support guides along with four brief counselor calls, or (d) a control guide providing motivational and quit tips and referral to locally available guides and programs. Subjects were predominantly moderate to heavy smokers with a history of multiple previous quit attempts and treatments. Control subjects achieved quit rates similar to those of smokers using the experimental quitting guide, with fewer behavioral prequitting strategies and more outside treatments. Social support guides had no effect on perceived support for quitting or on 8- and 16-month quit rates. Telephone counseling increased adherence to the quitting protocol and quit rates.", "Few smoking cessation self-help materials are available for smokers who are not planning to quit. However, computer-tailored interventions can be designed specifically for these smokers.\n In a large randomized field trial (N = 843), two different tailored smoking cessation self-help interventions (multiple tailoring and single tailoring) and one standardized smoking cessation self-help guide were compared with a no-information control group and with each other. The contents of the tailored interventions were adapted to individuals' self-reported stage of change, outcome expectations, self-efficacy levels, and smoking behavior.\n The primary outcome measure was forward stage transition. The standardized self-help guide had no effect. Among smokers who were not planning to quit within the next 5 years the multiple-tailored intervention was more effective than the single-tailored intervention. This pattern was supported by the cognitive changes caused by the interventions. Among smokers who were planning to quit within the next 5 years but not within the next 6 months, none of the self-help materials had any effect.\n The present results show that the self-help material currently available in the Netherlands, the standardized self-help guide, was not effective among smokers with low readiness to change. However, computer-generated tailored interventions seem a promising means of communicating information on smoking and smoking cessation to these smokers.", "The current study evaluated the effectiveness of widely used self-help materials for quitting smoking. Five hundred and seventy smokers volunteered during a baseline survey to participate in the evaluation. After random assignment, 200 were mailed National Cancer Institute (NCI) \"Quit for Good\" materials, 200 the Minnesota \"Quit and Win\" program, and the remaining 170 were assigned to a nonintervention control condition. Results at 7-month follow-up failed to indicate treatment effects either for abstinence or for reported quit attempts. A number of smokers quit prior to the mailing of self-help materials, suggesting that a telephone prompt in itself may have been an important stimulus to cessation. Overall abstinence at follow-up was 10%. Contrary to expectation, successful participants were less likely to use a number of specific preparation strategies for quitting. The results are instructive in providing a large-scale assessment of self-help materials in a population of smokers that was not specifically seeking treatment.", "The need for effective, low-cost self-help treatment methods for smokeless tobacco (ST) addiction becomes more evident as rates of product use and associated morbidities increase. This study evaluated two self-help methods for ST cessation. One hundred ninety-eight ST users were randomized into two conditions: half received the LifeSign, a credit card-sized computer designed for gradual ST cessation, and half received the Enough Snuff self-help manual and a video. Subjects in both conditions received telephone support for their quit effort. The study was conducted entirely through phone and mail, allowing delivery of the intervention to both rural and urban users. Self-reported rates of sustained abstinence (no tobacco use at two months and six months) were 24.5% for the manual/video condition, and 18.4%, for the LifeSign condition.", "This study evaluated the effects of written feedback adapted to a self-help mail intervention. The efficacy of the standard mail intervention treatment was 37% at the end of treatment, 22% at the 3-month follow-up, 19% at the 6-month follow-up, and 13% at the 12-month follow-up. In contrast, the standard mail program combined with personalized written feedback resulted in an efficacy of 51% at the end of treatment, 37% at the 3-month follow-up, 32% at the 6-month follow-up, and 27% at the 12-month follow-up. Both groups were significantly different from the control group at the end of treatment (0%), at the 3-month follow-up (1%), and at the 6-month follow-up (1%). There was a significant reduction in the number of cigarettes smoked daily among continuing smokers under both experimental conditions. The authors conclude that written feedback substantially increases abstinence rates when it is applied following similar guidelines to those used in clinical settings.", "Smokeless tobacco (ST) is associated with adverse health consequences yet treatment resources for ST are not widely available. Cost-effective behavioral interventions incorporating self-help materials and counseling calls have been demonstrated to reduce ST use rates and can be easily disseminated, but the feasibility and effectiveness of incorporating pharmacotherapy into this approach have not been evaluated. We conducted a clinical pilot study randomizing 60 patients to 12 weeks of the 4-mg nicotine lozenge or placebo delivered through the mail. All subjects received an assisted self-help intervention (ASH) with telephone support. At the end of the medication phase, lozenges were being used by 63% of subjects in the 4-mg nicotine lozenge group and 43% in placebo. The nicotine lozenge decreased composite withdrawal symptoms and adverse events were minimal. No significant differences were observed in abstinence rates between the two groups at 3 or 6 months. We conclude that the mailing of nicotine lozenges to ST users is a feasible and safe strategy the efficacy of which needs to be evaluated.\n Copyright (c) 2009 Elsevier Ltd. All rights reserved.", "Physician-delivered advice to stop smoking is effective, but time demands often reduce the number of smokers who receive assistance. We evaluated three nurse-assisted interventions designed to minimize physician burden and increase counseling in primary care settings.\n Randomized controlled trial with a 12-month follow-up.\n Internal medicine and family practice offices in a health maintenance organization.\n Smokers (n = 3161) who were patients of participating physicians or other medical care providers (n = 60).\n Medical care providers delivered a 30-second stop-smoking prompt to 2707 smokers and referred them to an on-site nurse smoking counselor. The nurse randomly provided a two-page pamphlet (advice control) or one of three nurse-assisted interventions: 1) self-quit training; 2) referral to a group cessation program; or 3) a combination of self-quit training and referral. Each nurse-delivered intervention included a 10-minute video, written materials, and a follow-up phone call.\n Physicians delivered brief advice to 86% of identified smokers during the 1-year program. The proportion of participants reporting abstinence after both 3 and 12 months of follow-up nearly doubled (P = 0.01) for the nurse-assisted self-quit (7.1%), group-referral (7.6%), and combination (6.9%) interventions, compared to brief physician advice alone (3.9%) (P < 0.05). Saliva cotinine tests confirmed these effects (P < 0.004), although quit rates were lower (3.4%, 4.7%, 4.3%, and 2.3%, respectively) because roughly one half of quitters chose not to provide a saliva sample and were counted as smokers.\n Involving nurses in counseling smokers reduces physician burden, makes counseling more likely, and significantly increases cessation rates compared with brief physician advice alone.", "This paper presents long-term outcomes of the largest clinical trial of smokeless tobacco (SLT) cessation reported to date. SLT users in five northwestern states were recruited to call a toll-free number, and 1,069 users were randomized to one of two self-help conditions: either a manual-only condition or an assisted self-help condition, which included the manual, a targeted video, and two support phone calls. Significant between-group differences were not found for either the 12- or 18-month point-prevalence measure of abstinence from either SLT only or all tobacco products using outcomes based on either the responder or intention-to-treat outcomes. However, using a repeated point-prevalence measure across all three assessment points, we found that significantly more assisted self-help participants reported abstinence, compared with manual-only participants. Compared with manual-only participants, those in the assisted self-help condition were significantly more likely to use recommended cessation techniques. Results demonstrate that low-cost, minimal interventions delivered by mail and phone can help a sizable proportion of individuals quit using SLT.", "This study evaluated the effects of including a single brief prequit telephone counseling session in a self-help program for smoking cessation conducted through the mail, by comparison with the effects of the self-help program alone. Volunteer participants from northwestern Spain (N = 228) were randomly assigned to one of two groups: (a) the self-help-only group (n = 110, mean age = 37.4 years, pretreatment cigarette consumption = 26.5 cigarettes/day) or (b) the telephone-support group (n = 118, mean age = 36.8 years, pretreatment cigarette consumption = 27.7 cigarettes/day). Using a conservative data analysis method (missing data considered as treatment failures), we found that the point-prevalence abstinence rate was significantly higher in the telephone-support group than in the self-help-only group at the end of treatment (44.9% vs. 21.8%) and at the 3-month follow-up (39.0% vs. 26.4%). Likewise, sustained abstinence was significantly higher in the telephone-support group at the 3-month follow-up (33.9% vs. 13.6%), the 6-month follow-up (25.4% vs. 12.7%), and the 12-month follow-up (21.2% vs. 9.1%). The results of this randomized controlled trial indicate that both treatments are an effective aid for smoking cessation, and that a single brief telephone call before the quit date is a low-cost and effective procedure for improving abstinence rates in a mailed self-help program.", "To examine the population impact and effectiveness of the Pro-Change smoking cessation course based on the Transtheoretical Model (TTM) compared to standard self-help smoking cessation literature.\n Randomized controlled trial.\n Sixty-five West Midlands general practices.\n Randomly sampled patients recorded as smokers by their general practitioners received an invitation letter and 2471 current smokers agreed.\n Responders were randomized to one of four interventions. The control group received standard self-help literature. In the Manual intervention group, participants received the Pro-Change system, a self-help workbook and three questionnaires at 3-monthly intervals, which generated individually tailored feedback. In the Phone intervention group, participants received the Manual intervention plus three telephone calls. In the Nurse intervention group, participants received the Manual intervention plus three visits to the practice nurse.\n Biochemically confirmed point prevalence of being quit and 6-month sustained abstinence, 12 months after study commencement.\n A total of 9.1% of registered current smokers participated, of whom 83.0% were not ready to quit. Less than half of participants returned questionnaires to generate second and third individualized feedback. Telephone calls reached 75% of those scheduled, but few participants visited the nurse. There were small differences between the three Pro-Change arms. The odds ratio (95% confidence intervals) for all Pro-Change arms combined versus the control arm were 1.50 (0.85-2.67) and 1.53 (0.76-3.10), for point prevalence and 6-month abstinence, respectively. This constitutes 2.1% of the TTM group versus 1.4% of the control group achieving confirmed 6-month sustained abstinence.\n There was no statistically significant benefit of the intervention apparent in this trial and the high relapse of quitters means that any population impact is small.", "Personalized feedback and a financial incentive, developed from an intrinsic/extrinsic motivation framework, were evaluated as adjuncts to self-help materials for smoking cessation. Ss (N = 1,217) were randomized to 4 treatment groups and were followed up at 3 and 12 months. Consistent with hypotheses derived from the motivation framework, the financial incentive increased the use of self-help materials, did not increase cessation rates among program users, and was associated with higher relapse rates among those who did manage to quit. The personalized feedback increased both smoking cessation and use of the materials 3 months after distribution of the materials. Continuous abstinence (abstinence at 3 and 12 months) in the group that received the personalized feedback alone was twice the rate of the other groups.", "The purpose of this study was to evaluate the impact of a tobacco cessation intervention using motivational interviewing on smoking cessation rates during diabetes self-management training (DSMT).\n A randomized controlled trial was conducted with subjects recruited from an ongoing type 2 diabetes adult education program at a large diabetes center. A total of 114 subjects were randomized to intervention (n = 57; face-to-face motivational interviewing plus telephone counseling and offering of medication) or standard care (n = 57). Outcome measures included tobacco cessation rates, mean number of cigarettes smoked, A1C, weight, blood pressure, and lipids.\n Intensive intervention using motivational interviewing integrated into a standard DSMT program resulted in a trend toward greater abstinence at 3 months of follow-up in those receiving the intervention. However, this same trend was not observed at 6 months. The addition of this structured smoking cessation intervention did not negatively affect either diabetes education or other measures of diabetes management, including A1C values.\n Structured tobacco cessation efforts can be readily integrated into established diabetes education programs without a negative impact on diabetes care or delivery of diabetes education. However, an intervention of moderate intensity for smoking cessation was no more effective than usual care in assisting patients with tobacco cessation after 6-month follow-up. Whether a more intensive intervention, targeting patients expressing a readiness to discontinue tobacco use, and/or a longer duration or a more cumulative effect of treatment will be more effective must be evaluated.", "Smokers aged 18 to 65 years (N = 1,044) who were able to quit for 24 hr were randomized using a 2 x 2 factorial design to compare nicotine gum to no gum use and self-help materials to no use of materials. All participants were offered a $100 incentive to quit and stay quit for 6 months. Six-month abstinence was 27% in the gum groups, compared with 19% in the no-gum group (p = .002). Compared with the no-gum group, relapse occurred at a significantly lower rate in the gum group for the entire 12 months of follow-up (odds of relapse in the gum group was 0.72, 95% confidence interval, 0.62 to 0.83). There was no significant main effect for the self-help materials, no interaction between gum and materials, and no evidence that the effectiveness of gum differed between the sexes or between heavy and light smokers. Nicotine gum is an effective adjunct to minimal-contact smoking cessation materials plus monetary incentive in a population-based sample of smokers.", "Does the provision of a nurse-based intervention lead to smoking cessation in hospital patients?\n At tertiary teaching hospital in Newcastle, Australia, 4,779 eligible (aged 18-80, admitted for at least 24 hours, and able to provide informed consent) and consenting (73.4%) in-patients were recruited into a larger cross-sectional survey. 1,422 (29.7%) smokers (in the last 12 months) were randomly assigned to control (n = 711) or intervention group (n = 711). The brief nurse-delivered intervention incorporated: tailored information, assessment of withdrawal, offer of nicotine replacement therapy, booklets, and a discharge letter. Self-reported cessation at 12 months was validated with CO and salivary cotinine.\n There were no significant differences between groups in self-reported abstinence at three or 12 months post intervention, based on an intention to treat analysis. At three months, self-reported abstinence was 27.3% (I) and 27.5% (C); at 12 months was 18.5% (I) and 20.6% (C). There were no differences in validation of self-report between intervention and control groups at 12 months.\n This brief nurse-provided in-patient intervention did not significantly increase the smoking cessation rates compared with the control group at either three or 12-month follow-up.\n A systematic total quality improvement model of accountable outcome-focused treatment, incorporating assertive physician-led pharmacotherapy, routine assessment and recording of nicotine dependence (ICD 10 coding), in- and outpatient services and engagement from multidisciplinary teams of health professionals may be required to improve treatment modalities for this chronic addictive disorder.", "Nonsmokers have a potentially supportive role in tobacco cessation efforts. The present study examined the feasibility, acceptability, and potential efficacy of a telephone-based intervention for nonsmoking support persons.\n A total of 59 support persons (mean age = 36 years, 92% female, 95% White) were randomly assigned to a control condition (N = 30; written materials only) or to a social cognitive theory-based intervention (N = 29; written materials and 5 weekly, 20- to 30-min telephone counseling sessions). Both support persons and smokers completed assessments separately by mail at baseline and at weeks 6 (end of treatment) and 26.\n Two thirds of the smokers reported low-moderate levels of motivation to quit at baseline as assessed by the contemplation ladder. Study retention rates were excellent, with 95% of both support persons and smokers completing the week 26 assessment. Moreover, 86% of support persons in the intervention group completed all five telephone sessions. Treatment acceptability was high for both support persons and smokers. Compared with the control condition, the intervention was associated with a significant increase in support person self-efficacy to help their smoker (p = .034) and outcome expectancies (p = .025) from baseline to week 6. However, the intervention was not associated with higher smoking abstinence rates or quit attempts.\n The program was successful in reaching smokers with lower levels of readiness to quit. The intervention was feasible and acceptable to both support persons and smokers. Although support persons and smokers can be engaged in this type of outreach program, refinements in the intervention approach are needed to improve the smoking outcomes.", "We conducted a 2-arm randomized trial to test the efficacy of self-help materials with or without proactive telephone counseling to increase cessation among teen smokers. Teen smokers (N = 402) recruited from 11 shopping malls and 1 amusement park in the southeastern United States were randomized to 1 of 2 groups: written self-help material plus video; or written self-help material, video, and telephone counseling. Cessation rates based on 7-day point-prevalent abstinence for the self-help and counseling arms were 11% and 16%, respectively (p = .25), at 4 months postbaseline and 19% and 21%, respectively (p = .80), at 8 months postbaseline. Sustained abstinence, reflecting 7-day abstinence at both time points, in the self-help and counseling arms was 7% and 9% (p = .59). Results suggest that minimal self-help cessation approaches that target youth have comparable success to that shown among adult smokers. However, refinements in telephone-counseling approaches may be needed to achieve the success observed in adult populations.\n Copyright 2004 American Psychological Association", "This research tested a multicomponent self-help manual that contained nicotine fading and some behavioral techniques. It also evaluated the incremental effects of using higher amounts of therapist contact on quitting rates. 114 smokers were randomly assigned to one of four treatment groups: (1) A 10-session multicomponent program (n = 25); (2) a 5-session multicomponent program (n = 31); (3) a 5-session multicomponent plus a self-help manual program (n = 25); and (4) a self-help-manual-only program (n = 33). A control group (n = 48) did not receive any treatment. The distinctive characteristic of the treatments was the different amount of therapist contact. Common components of the programs were a refundable deposit, self-monitoring, information on smoking, stimulus control, CO feedback, nicotine fading, and strategies to avoid withdrawal symptoms. End-of-treatment quit rates ranged from 36% (self-help manual) to 68% (10-session multicomponent program). At 12-month follow-up there were significant differences between groups, and the most effective group was the 5-session plus manual group, with an abstinence rate of 48%.", "The AHRQ Clinical Practice Guideline for Treating Tobacco Use and Dependence recommends screening and treatment of all tobacco users. Effective methods to implement recommendations are needed because simple guideline dissemination does not necessarily result in changes in practice.\n The Guideline Implementation for Tobacco (GIFT) study tested an organizational intervention to improve Guideline implementation.\n GIFT randomized 20 Veterans Affairs medical centers to intervention or control conditions. We trained prime movers at each site to improve identification of smoking status, promote primary care interventions and increase availability of smoking cessation medications. Sites and patients were evaluated before and after intervention.\n GIFT included 20 Veterans Affairs medical centers and 5678 subjects.\n Data regarding smoking status, delivery of treatment, medication use, and smoking cessation were collected from participant surveys, medical record review, survey of site leaders, and Pharmacy Benefits Management.\n The intervention did not increase participant report of being asked about smoking status or receipt of counseling. It did increase the rate of identification of smoking status in the medical record (P = 0.0001) but did not increase the rate of counseling to stop smoking. Site level data showed no increase in the number of patients receiving smoking cessation medications or dollars spent on medications. Individual smoker data showed a significant increase in the use of medications for smoking cessation in intervention sites (odds ratio = 6.89, P < 0.0001); however, only a small minority of smokers received medication even after the intervention. There was no difference in smoking cessation rates between participants at the intervention and treatment sites.\n We conclude that improvements in smoking cessation rates are likely to require more intensive intervention in this population.", "Self-help methods are preferred by smokers over clinic-based treatments providing more traditional services. Unfortunately, these more popular methods have not been extremely successful in getting smokers to quit. The poor success rates may be partially related to the lack of structure inherent in these treatment approaches. The present study examined a self-help program delivered to smokers via a written manual and limited duration phone calls--the latter to add structure to the treatment procedures. The results, a 23% abstinent rate, indicate that this approach has some promise for treating chronic smokers.", "One thousand two hundred thirty seven smokers responding to lung association announcements in five geographic areas were randomly assigned to one of four groups and mailed American Lung Association materials: 1) leaflets (L); 2) leaflets plus maintenance manual (L + M); 3) cessation manual (C); and 4) cessation and maintenance manuals (C + M). Five telephone interviews over one year achieved a 95 per cent follow-up completion rate. Nonrespondents as well as exclusive cigar and pipe users were classified as smokers. Twenty per cent quit initially, with 5 per cent continually abstinent in (C + M) at 12 months vs 2 per cent in (L) (p less than .05). Nonsmoking prevalence rates (no tobacco smoking in the past month), on the other hand, gradually increased after six months; at 12 months those with the maintenance component, (L + M) and (C + M), had higher rates (18 per cent) than (L) (12 per cent) or (C) (15 per cent). Leaflets and manual alone were least cost effective. Rising nonsmoking prevalence rates observed in all groups suggest that successful attempts to quit increased over time and that a contributing factor might have been the follow-up method. Although achieving lower quit rates than methods requiring attendance at a course, the self-help intervention has the advantages of greater availability, flexibility, and in some instances lower cost.", "Evaluate the feasibility, acceptability, and potential efficacy of a skills-training intervention for adults interested in helping someone to stop smoking (i.e., support persons).\n Sixty adult support persons (77% female) were directly recruited from the community and randomly assigned to this intervention (manual plus five weekly group-based sessions) or a control condition (one-page leaflet). All intervention and outcome assessments occurred through the support persons. Assessments occurred at weeks 0 (baseline), 6 (end of treatment), 12, and 24. The study was conducted from 1998 to 2001; data collection occurred from 1999 to 2000. Outcomes were ratings of treatment acceptability, recruitment and retention rates, supportive behaviors provided to the smoker, and smoking behavior change in the smoker as reported by the support person.\n Support persons were recruited in a timely manner and study retention rates were high. Support persons in skills training showed significant increases in their supportive behavior scores compared with control subjects at weeks 6 and 12. Although not statistically significant, the skills-training intervention was associated with more quit attempts, greater improvement in stage of change, and higher 7-day point prevalence abstinence rates in the smokers than the control condition.\n A skills training intervention for support persons is feasible and acceptable. Further studies are needed to test the efficacy of this approach for smoking cessation.", "Sixty-six physicians were randomized to three groups to conduct a 1-month campaign to help their patients stop smoking. The workshop group received free patient education materials and a 6-hour training workshop. The materials group received free patient education materials, and the no-assistance group received nothing. A telephone interview was completed with 89% of the 6767 eligible adult patients seen during the month of the campaign. The brief training program and patient education materials marginally increased the smoking intervention activities of volunteer physicians in private practice. Both workshop and materials physicians asked 54% of their smoking patients to stop; no-assistance physicians asked 40%. One year later, 36% of patients who had not even been asked by their doctors if they smoked reported that they had tried to stop smoking. If the physician had asked the patient if he or she smoked, the probability of a quit attempt was 47%. Patients who had been asked if they smoked were more likely to claim to have stopped (13%) than patients who had not been asked (9%). However, the proportion of patients claiming continued abstinence (range, 12% to 14%) was not related to the group of the physician.", "This study evaluated the effect of telephone counseling as an adjunct to a self-help program for smoking cessation conducted through the mail. We obtained demographic and consumption information on those smokers who requested participation in the study. These participants (N = 200) were randomized into two study groups: (1) the standard self-help group (n = 100) (median age: 35.1 years; pretreatment consumption of 28.0 cigarettes/day); (2) the self-help group receiving additional multiple-contact telephone counseling (n = 100) (median age: 36.7 years; pretreatment consumption of 27.3 cigarettes/day). At the 12-month follow-up, the carbon monoxide in expired air was used to distinguish nonsmokers from smokers. Significant differences were found in the rates of continuous abstinence in both groups for each period evaluated. In the standard self-help group, the continuous abstinence rate at the 3-month follow-up was 21%, 18% at the 6-month follow-up, and 14% at the 12-month follow-up. The telephone counseling group yielded a 48% continuous abstinence rate at the 3-month follow-up, 40% at the 6-month follow-up, and 27% at the 12-month follow-up. The results of this randomized controlled trial show that telephone counseling was an effective aid for the smoking cessation program.", "Until 1990, smoking cessation interventions in the Netherlands were limited. The utility and effectiveness of community-based smoking cessation programs have not been examined.\n In a treatment city (Den Bosch) a multicomponent community-based smoking cessation intervention was implemented in which local mass media and general practitioners draw smokers' attention to a local quit line. Telephone counselors advised applicants on their choice between self-help and group treatment and optional telephone counseling. Another Dutch city (Apeldoorn) served as a control. Population samples of smokers (n = 547 and n = 546) were interviewed three times at approximately 7-month intervals. Self-help manual requesters (n = 84) and group participants (n = 83) were interviewed before and 6 months after treatment.\n Treatment modalities were successful; 13% of self-help manual requesters and 22% of group participants were abstinent after 6 months. On a population level the intervention resulted in significantly higher recall of self-help manual and group program in the treatment city. A modest intervention effect on prevalence of abstinence was found at the community level.\n Treatment modalities were effective within their participants, but the intervention effectiveness on a community level was limited. No significant difference was found between quit rates after 14 months (7% in treatment city and 9% in control city). Several system failures could be identified. However, probably the intervention effect was seriously confounded by two national governmental publicity campaigns introducing and reinforcing a mandatory smoking ban and a series of national campaigns initiated by the united Dutch tobacco producers opposing the ban.", "The present study assessed the incremental effectiveness of behavioral self-help materials specifically written to accompany nicotine gum. Subjects (187 women and 117 men) were randomly assigned either behavioral self-help booklets or a factual information pamphlet. All subjects received prescriptions for Nicorette from study physicians. Contrary to prediction, subjects provided self-help booklets fared no better than did subjects provided comparison pamphlets. Overall abstinence levels were encouraging, however. Nicotine gum users were far more likely than nonusers to maintain abstinence through 6-month follow-up. Perhaps self-help materials could be improved by condensing and simplifying content and by adopting a more attractive multicolored pictorial format.", "The incremental effects of (a) a self-help booklet alone, (b) self-help booklet with computer-generated personalized feedback, and (c) self-help booklet, personalized feedback, and outreach telephone counseling were evaluated in a population-based, nonvolunteer sample of smokers. Smokers (N = 1,137) were identified through a telephone survey of a random sample of 5,903 enrollees in a health maintenance organization and randomized to a no-treatment control group or 1 of the 3 intervention conditions. Smoking status was ascertained 3, 12, and 21 months postrandomization. Cotinine validation of self-reported cessation was obtained at the 12-month follow-up. Overall, the telephone counseling significantly increased smoking cessation at the 3-month follow-up, but not at 12 or 21 months. Among smokers who were precontemplative at baseline, telephone counseling significantly increased prevalent abstinence at 3 and 12 months and continuous abstinence at 21 months (defined as self-reported abstinence at 3, 12, and 21 months).", "The purpose of this study was to examine the effectiveness of different practice-based approaches to assist patients of primary care physicians to quit smoking and sustain cessation. Forty-four nonsmoking general practitioners volunteered for the study. After a period of training, they randomized 923 smoking clients, unselected for motivation toward quitting, to four different intervention groups: (i) minimal intervention, consisting of one single counselling session and a brief handout on quitting techniques; (ii) repeated counselling including reinforcing sessions at Months 1, 3, 6, and 9; (iii) repeated counselling and use of nicotine gum; and (iv) repeated counselling and spirometry. Biochemically validated smoking status was assessed at six and 12 months after recruitment. The proportion of verified quitters at 12 months was 4.8 percent among subjects randomized to the minimal intervention group, compared to 5.5 percent, 7.5 percent, and 6.5 percent among those randomized to the three repeated-counselling groups. In no treatment group was the outcome significantly different from that for one-time counselling at the (P less than 0.05) level. Lack of power, contamination, and low attendance at reinforcing sessions should be taken into account in interpreting the results.", "This research estimated the costs and effectiveness of three different benefit designs for treating tobacco dependence: drugs only (nicotine replacement therapy patch, nasal spray, inhaler, and Zyban); drugs and counseling (drugs and proactive telephone counseling); and drugs if counseling (drugs conditional on enrollment in counseling). A sample of 393 adult smokers enrolled in a California preferred provider organization was randomly assigned to one of three study groups. After eight months, there were no significant increases in quit attempts or quit rates in the groups with covered drugs and counseling compared to the group with drug coverage only. Therefore, costs rose with no increase in quit rates when proactive telephone counseling was added to coverage of pharmacotherapy, regardless of benefit design.", "We examined the ability of a provider-initiated, minimal-contact intervention to modify the smoking behavior of ambulatory clinic patients. Smokers at two outpatient sites were assigned to one of three groups: provider intervention only (PI); provider intervention plus self-help manual (PI/M); and usual care (control) group (C). The physician message emphasized the patient's personal susceptibility, the physician's concern, and the patient's ability to quit (self-efficacy). The nurse consultation concentrated on benefits and barriers associated with stopping, and on strategies for cessation. Telephone interviews were conducted with the 250 participants within a few days of their clinic visit and again at one and six months. Both PI and PI/M proved to be superior to usual care in motivating attempts to quit at both one-month and six-month follow-ups, and logistic regression analyses indicated that participants receiving the self-help manual in addition to the health provider message were between two and three times more likely to quit smoking during the study period than were participants in either of the other study groups.", "To evaluate the effectiveness of two teaching interventions to increase residents' performance of smoking cessation counseling.\n Randomized controlled factorial trial.\n Eleven residency programs, in internal medicine (six), family medicine (three), and pediatrics (two). Programs were located in three university medical centers and four university-affiliated community hospitals.\n 261 residents who saw ambulatory care patients at least one half-day per week, and 937 returning patients aged 17 to 75 years who reported having smoked five or more cigarettes in the preceding seven days. Of the 937, 843 were eligible for follow-up, and 659 (78%) were interviewed by phone at six months.\n Two interventions (tutorial and prompt) and four groups. The tutorial was a two-hour educational program in minimal-contact smoking cessation counseling for residents. The prompt was a chart-based reminder to assist physician counseling. One group of residents received the tutorial; one, the prompt; and one, both. A fourth group received no intervention.\n Six months after the intervention, physician self-reports showed that residents in the tutorial + prompt and tutorial-only groups had used more counseling techniques (1.5-1.9) than had prompt-only or control residents (0.9). Residents in all three intervention groups advised more patients to quit smoking (76-79%) than did control group residents (69%). The tutorial had more effect on counseling practices than did the prompt. Physician confidence, perceived preparedness, and perceived success followed similar patterns. Exit interviews with 937 patients corroborated physician self-reports of counseling practices. Six months later, self-reported and biochemically verified patient quitting rates for residents in the three intervention groups (self-reported: 5.3-8.2%; biochemically verified: 3.4-5.7%) were higher than those for residents in the control group (self-reported: 5.2%; biochemically verified: 1.7%), though the differences were not statistically significant.\n A simple and feasible educational intervention can increase residents' smoking cessation counseling.", "The primary care visit represents an important venue for intervening with a large population of smokers. However, physician adherence to the Smoking Cessation Clinical Guideline (5As) remains low. We evaluated the effectiveness of a computer-tailored intervention designed to increase smoking cessation counseling by primary care physicians.\n Physicians and their patients were randomized to either intervention or control conditions. In addition to brief smoking cessation training, intervention physicians and patients received a one-page report that characterized the patients' smoking habit and history and offered tailored recommendations. Physician performance of the 5As was assessed via patient exit interviews. Quit rates and smoking behaviors were assessed 6 months postintervention via patient phone interviews. Intervention effects were tested in a sample of 70 physicians and 518 of their patients. Results were analyzed via generalized and mixed linear modeling controlling for clustering.\n Intervention physicians exceeded controls on \"Assess\" (OR 5.06; 95% CI 3.22, 7.95), \"Advise\" (OR 2.79; 95% CI 1.70, 4.59), \"Assist-set goals\" (OR 4.31; 95% CI 2.59, 7.16), \"Assist-provide written materials\" (OR 5.14; 95% CI 2.60, 10.14), \"Assist-provide referral\" (OR 6.48; 95% CI 3.11, 13.49), \"Assist-discuss medication\" (OR 4.72;95% CI 2.90, 7.68), and \"Arrange\" (OR 8.14; 95% CI 3.98, 16.68), all p values being < 0.0001. Intervention patients were 1.77 (CI 0.94, 3.34,p = 0.078) times more likely than controls to be abstinent (12 versus 8%), a difference that approached, but did not reach statistical significance, and surpassed controls on number of days quit (18.4 versus 12.2, p < .05) but not on number of quit attempts.\n The use of a brief computer-tailored report improved physicians' implementation of the 5As and had a modest effect on patients' smoking behaviors 6 months postintervention.", "Few studies have rigorously evaluated whether providing biologically based health-risk feedback is more effective than standard interventions in increasing smokers' motivation to quit and their long-term abstinence.\n An RCT was conducted from 2005 to 2008. Data were analyzed in 2008.\n Smokers (N=536) were recruited from the community, regardless of their interest in quitting smoking.\n Smokers either received brief ( approximately 20 minutes), personally tailored counseling sessions based on their lung functioning, carbon monoxide (CO) exposure, and smoking-related health conditions, or they received generic smoking-risk information and personalized counseling about their diet, BMI, and physical activity. All were advised to quit smoking and were offered access to a free phone-counseling program.\n Treatment utilization and abstinence at 6 and 12 months post-intervention.\n Participants who received the experimental treatment demonstrated no greater motivation to quit, use of treatment services, or abstinence compared to controls at either follow-up assessment. In fact, controls reported greater motivation to quit at 12 months (M 3.42 vs 3.20, p=0.03), greater use of pharmacotherapy at 6 months (37.8% vs 28.0%, p=0.02), and greater 30-day point prevalent abstinence at 6 months, after controlling for relevant covariates (10.8% vs 6.4%, adjusted p=0.04).\n The present study found no support for adding a personalized health-risk assessment emphasizing lung health and CO exposure to generic cessation advice and counseling for community-based smokers not otherwise seeking treatment.\n NCT00169260.", "Smokers (N = 3,030) were randomized to receive 1 of 3 interventions: (a) a self-help quit kit, (b) a quit kit plus 1 telephone counseling session, or (c) a quit kit plus up to 6 telephone counseling sessions, scheduled according to relapse probability. Both counseling groups achieved significantly higher abstinence rates than the self-help group. The rates for having quit for at least 12 months by intention to treat were 5.4% for self-help, 7.5% for single counseling, and 9.9% for multiple counseling. The 12-month continuous abstinence rates for those who made a quit attempt were 14.7% for self-help, 19.8% for single counseling, and 26.7% for multiple counseling. A dose-response relation was observed, as multiple sessions produced significantly higher abstinence rates than a single session. The first week after quitting seems to be the critical period for intervention.", "Smokeless tobacco (ST) use has been associated with numerous negative health consequences, yet the prevalence of ST has increased dramatically since the 1970s. Young males in the military are at an elevated risk for ST use relative to the general population. Sixty active-duty male participants were identified as ST users during their annual preventive health screening and randomly assigned to minimal-contact intervention or usual care. Intervention participants were proactively contacted by phone and recruited, using a motivational interviewing style, for a cessation program consisting of a treatment manual, video, and two supportive phone calls from a cessation counselor. Sixty-five per cent (20/31) agreed to participate in the minimal-contact intervention. Three- and 6-month follow-up contacts found that the cessation rates reported by intervention participants were double those reported by participants receiving usual care (41% vs. 17% at 3 months, 37% vs. 19% at 6 months). These pilot study data suggest that proactive recruitment using a motivational interviewing approach to offer a treatment provides a good opportunity to reduce the use of ST in military settings.", "New educational programs must be developed to improve physicians' skills and effectiveness in counseling patients about smoking cessation.\n To assess the efficacy of an educational program based on behavioral theory, active learning methods, and practice with standardized patients in helping patients abstain from smoking and changing physicians' counseling practices.\n Cluster randomized, controlled trial.\n Two general internal medicine clinics in Switzerland.\n 35 residents and 251 consecutive smoking patients.\n A training program administered over two half-days, during which physicians learned to provide counseling that matched smokers' motivation to quit and practiced these skills with standardized patients acting as smokers at different stages of change. The control intervention was a didactic session on management of dyslipidemia.\n Self-reported abstinence from smoking at 1 year of follow-up, which was validated by exhaled carbon monoxide testing at one clinic; score of overall quality of counseling based on use of 14 counseling strategies; patient willingness to quit; and daily cigarette consumption.\n At 1 year of follow-up, abstinence from smoking was significantly higher in the intervention group than in the control group (13% vs. 5%; P = 0.005); this corresponded to a cluster-adjusted odds ratio of 2.8 (95% CI, 1.4 to 5.5). Residents who received the study training provided better counseling than did those who received the control training (mean score, 4.0 vs. 2.7; P = 0.002). Smokers' willingness to quit was also higher in the intervention group (94% vs. 80%; P = 0.007). A nonsignificant trend toward lower daily cigarette consumption in the intervention group was observed.\n A training program in smoking cessation administered to physicians that was based on behavioral theory and practice with standardized patients significantly increased the quality of physicians' counseling, smokers' motivation to quit, and rates of abstinence from smoking at 1 year.", "This article reports on one of the few experimental studies in Europe to examine work site smoking cessation. The study examined whether a comprehensive intervention (self-help manuals, group courses, a mass media campaign, smoking policies, and a second-year program) is more effective than a minimal intervention (self-help manuals only). Eight work sites participated in the study. The effect of treatment on smoking cessation depended on nicotine dependency levels: Heavy smokers had more success with the comprehensive smoking cessation intervention than with the minimal intervention (with respect to both 14-month quit rate and 6-month prolonged abstinence). For heavy smokers, exposure to mass media exhibitions or to group courses had a beneficial effect on prolonged abstinence. Comprehensive programs may be most appropriate in Dutch work sites with large proportions of heavily addicted smokers.", "One of the key goals of health promotion strategies in the UK and other developed countries is to reduce the prevalence of cigarette consumption. While overall smoking rates in the UK have fallen over the last few decades, they have barely fallen for the least advantaged adults (Department of Health, 1998a). There is a need for interventions that are suitable for lower socio-economic status (SES) smokers that have undergone rigorous evaluation. This study describes a randomized controlled trial of cognitive behaviour therapy (CBT) with smokers from a deprived area of London. At 6 months follow-up, 21 (17.2%) of 122 participants receiving therapy were abstinent and 14 (11.5%) had reduced cigarette consumption by at least 25% of pre-treatment level. Six (5.6%) of 107 participants in the control group were abstinent and none had reduced consumption. These results suggest that this self-help CBT intervention has the potential to reduce the prevalence of smoking among lower SES smokers.", "A 2 x 2 randomized, factorial pretest/posttest group design was used to evaluate the effectiveness of self-help smoking cessation methods at the worksite. The study investigated the effect of a multicomponent health education and skill intervention versus the effect of a monetary incentive to the employee for quitting. All employees received, in addition, a standardized self-help smoking cessation manual and maintenance manual. Following agreement to participate and a baseline smoking history, all participants were followed for 6 weeks, 6 months, and 12 months. Saliva was obtained for thiocyanate (SCN) analysis of smoking status. Of the estimated 2000 smokers at the site, 387 smokers were recruited. Employees were randomly assigned to one of four groups. Results of this random trial indicate that those employees receiving a multicomponent program were most successful in quitting and remaining abstinent. The monetary incentive appears to have no effect on quit rate.", "Although a considerable body of evidence supports telephone quit lines for smoking cessation, much less is known about the effectiveness of proactive Telephone Counseling with smokeless tobacco (ST) users. We conducted a randomized controlled trial comparing Telephone Counseling with the distribution of a self-help manual for ST cessation. We recruited 406 adult ST users throughout the state of Minnesota and randomized them to receive either: (a) a self-help manual (Manual only) or (b) a self-help manual plus proactive telephone-based cessation counseling (Telephone Counseling). The telephone-based treatment included up to four calls in support of quitting, and personalized various cognitive and behavioral strategies that are generally considered effective in tobacco cessation (such as setting a quit date, examining patterns of use, developing stress reduction skills, avoiding known triggers to use). Participants were surveyed by phone at 3 and 6 months to assess both point prevalence and continued abstinence. Prolonged abstinence from all tobacco was 6.8% and 30.9% (p < .001) at 3 months and 9.8% and 30.9% (p < .001) at 6 months in Manual only and Telephone Counseling, respectively. We found older age, lower dependency, and increased readiness predicted quitting success. Proactive telephone-based counseling is an effective strategy for improving cessation rates among ST users. Future research should determine the components contributing to the intervention success.", "Cancer survivors smoke at rates that are only slightly lower than the general population. This article reports on the final outcomes of Partnership for Health, a smoking cessation intervention for smokers in the Childhood Cancer Survivors Study (CCSS).\n This study is a randomized control trial with follow-up at 8 and 12 months that involved smokers (n = 796) enrolled onto the CCSS cohort. Participants were randomly assigned to either a self-help or a peer-counseling program that included up to six telephone calls from a trained childhood cancer survivor, tailored and targeted materials, and free nicotine replacement therapy. The intervention was delivered by telephone and postal service mail.\n The quit rate was significantly higher in the counseling group compared with the self-help group at both the 8-month (16.8% v 8.5%; P < .01) and 12-month follow-ups (15% v 9%; P < or = .01). Controlling for baseline self-efficacy and readiness to change, the intervention group was twice as likely to quit smoking, compared with the self-help group. Smoking cessation rate increased with an increase in the number of counseling calls. The cost of delivering the intervention was approximately 300 dollars per participant. The incremental cost-effectiveness of the intervention compared with controls was 5,371 dollars per additional quit.\n Interventions to prevent future illnesses are of critical importance to childhood cancer survivors. The Partnership for Health intervention resulted in a doubling of smoking cessation quit rates. Because of the seriousness of smoking among childhood cancer survivors, this intervention model may be appropriate as a multicomponent treatment program for survivors who smoke.", "This prospective randomized study examined the impact of three tailored intervention approaches to increase quitting rates among African-American smokers who were clients of a community health center that serves primarily low-income and indigent persons. Smokers were randomized to one of three groups: (1) health care provider prompting intervention alone, (2) health care provider prompting intervention with tailored print communications, and (3) health care provider prompting intervention with tailored print communications and tailored telephone counseling. Among the 160 smokers who completed the study, 35 (21.8%) had quit smoking at follow-up. Smokers who received the provider prompting intervention with tailored print materials were more likely to report having quit than smokers who received the provider intervention alone (32.7% vs. 13.2%, p < 0.05). Smokers who received all three intervention components were not more likely to report having quit at follow-up than those who only received the provider intervention (19.2% vs. 13.2%). Smokers who at baseline were less educated, smoked less than half a pack of cigarettes per day, had a stronger desire to quit, felt more efficacious, and had thought about quitting were more likely to report having quit at follow-up. These results provide support for continued refinement of tailored communications to aid smoking cessation among African-American smokers.", "Happy Ending (HE) is an intense 1-year smoking cessation program delivered via the Internet and cell phone. HE consists of more than 400 contacts by email, Web pages, interactive voice response, and short message service technology. HE includes a craving helpline and a relapse prevention system, providing just-in-time therapy. All the components of the program are fully automated.\n The objectives were to describe the rationale for the design of HE, to assess the 12-month efficacy of HE in a sample of smokers willing to attempt to quit without the use of nicotine replacement therapy, and to explore the potential effect of HE on coping planning and self-efficacy (prior to quitting) and whether coping planning and self-efficacy mediate treatment effect.\n A two-arm randomized controlled trial was used. Subjects were recruited via Internet advertisements and randomly assigned to condition. Inclusion criteria were willingness to quit on a prescribed day without using nicotine replacement and being aged 18 years or older. The intervention group received HE, and the control group received a 44-page self-help booklet. Abstinence was defined as \"not even a puff of smoke, for the last seven days\" and was assessed by means of Internet surveys or telephone interviews 1, 3, 6, and 12 months postcessation. The main outcome was repeated point abstinence (ie, abstinence at all four time points). Coping planning and self-efficacy were measured at baseline and at the end of the preparation phase (ie, after 2 weeks of treatment, but prior to cessation day).\n A total of 290 participants received either the HE intervention (n=144) or the control booklet (n=146). Using intent-to-treat analysis, participants in the intervention group reported clinically and statistically significantly higher repeated point abstinence rates than control participants (20% versus 7%, odds ratio [OR] = 3.43, 95% CI = 1.60-7.34, P = .002). Although no differences were observed at baseline, by the end of the preparation phase, significantly higher levels of coping planning (t(261) = 3.07, P = .002) and precessation self-efficacy (t(261) = 2.63, P = .01) were observed in the intervention group compared with the control group. However, neither coping planning nor self-efficacy mediated long-term treatment effect. For point abstinence 1 month after quitting, however, coping planning and self-efficacy showed a partial mediation of the treatment effect.\n This 12-month trial documents a long-term treatment effect of a fully automated smoking cessation intervention without the use of nicotine replacement therapy. The study adds to the promise of using digital media in supporting behavior change.", "To evaluate the relative effectiveness of two self-help smoking interventions as adjuncts to a self-help manual and telephone support service (hotline) for older smokers.\n Subjects were stratified on baseline variables and randomised to one of two treatment conditions in a methods development study.\n 177 community-dwelling smokers aged 60 years and older.\n All subjects received a self-help manual and access to a smokers' telephone hotline. Subjects also received either mailings (Letters condition) or counselling telephone calls (Proactive condition) at four and eight weeks after enrollment.\n Use of the hotline and prevalence of abstinence lasting at least 48 hours (verified by a \"significant other\") were assessed at three and six months for the full sample. Seven-day abstinence was calculated for comparison with previous research. A subsample of 91 subjects was followed up at 12 months.\n Overall abstinence rates for the two conditions were in the range of typical self-help interventions. Men were more likely to be abstinent than women at follow up at three and six months. A significant gender x treatment interaction was found, with abstinence rates higher for men in the Letters condition, and women in the Proactive condition. Hotline use was high, with nearly half of subjects calling by 12 months.\n Both interventions appear promising for older smokers, but may be differentially effective for men and women. Older smokers will use a hotline; whether Letters and Proactive interventions can improve on manual and hotline effectiveness rates alone is being tested in a subsequent controlled trial.", "The effectiveness of two commercially available smoking cessation manuals was evaluated under minimal therapist contact conditions. Forty cigarette smokers who volunteered to participate in a self-help quit smoking program were randomly assigned to one of three conditions: 18 to Pomerleau and Pomerleau's 1977 manual, 13 to Danaher and Lichtenstein's 1978 manual, and nine to a waiting-list control. Six-month follow-ups indicate that the former manual offers a useful treatment approach, while no firm conclusions can be made regarding the latter manual. Utility of self-help manuals in multilevel treatment programs is discussed.", "Self-help materials computer-tailored to the specific needs of smokers have shown promise as a high-reach, low-cost intervention for smoking cessation. Adding tailored cessation materials to telephone-based cessation counseling may be a way of generating greater efficacy in promoting and maintaining cessation. The objective of this study is to assess the efficacy of adding different types of behavioral smoking cessation materials to brief telephone-based cessation counseling.A total of 1,978 smokers calling the National Cancer Institute's (NCI's) Cancer Information Service (CIS) for help in quitting smoking initially received brief cognitive-behavioral cessation counseling from a CIS information specialist. Following a baseline interview administered by the information specialist, subjects were randomly assigned to one of four conditions, each delivered by U.S. mail: a single, untailored smoking cessation guide (SU); a single, tailored smoking cessation guide (ST); a series of four (multiple) printed materials tailored only to baseline data (MT); and a series of four (multiple) printed materials tailored to baseline as well as retailored using 5-month interim progress data (MRT). The primary outcome measure was 7-day point prevalence abstinence rates assessed using a computer-assisted telephone interview (CATI) at 12-month follow-up.At 12-month follow-up, using intent-to-treat, imputed, and per-protocol analyses, no differences were found among the four experimental conditions (linear trend), or when the ST, MT, and MRT groups were compared with the control (SU) group. Participants in the two multiple message group conditions combined (MT + MRT), however, had significantly higher abstinence rates than participants in the two single message group conditions combined (SU + ST). Moreover, among subjects who reported quitting at the 5-month follow-up, participants receiving the MRT materials reported higher abstinence rates at 12 months than the other three groups combined (SU + ST + MT). The results of this study support the effectiveness, over and above a single telecounseling interaction, of multiple tailored print material contacts on cessation. These effects, however may be due to tailoring, or the longitudinal nature of the two multiple tailored conditions, or both. The strongest evidence for tailoring occurred in the MRT condition for relapse prevention, suggesting that print materials tailored to interim progress may be especially effective in this context. The qualities of specific psychosocial and communication elements in tailored materials should receive attention in future research.", "This study evaluated the efficacy of using a brief motivational intervention to reduce smoking among adolescent patients treated in a hospital outpatient clinic or Emergency Department. Patients aged 14-19 years (N=85) were randomly assigned to receive either one session of motivational interviewing (MI) or standardized brief advice (BA) to quit smoking. The assessment and intervention were conducted in the medical setting proximal to the patient's medical treatment. Patients were proactively screened and recruited, and were not seeking treatment for smoking. Follow-up assessments were conducted at 1, 3, and 6 months post-intervention. Self-report data indicated that 7-day abstinence rates at 6-month follow-up were significantly higher in the MI group than in the BA group, but this difference was not confirmed biochemically. Self-reported smoking rate (average cigarettes per day) was significantly lower at 1, 3, and 6 months follow-up than it was at baseline. Cotinine levels indicated reduced smoking for both groups at 6 months, but not at 1 month. At 3-month follow-up, only those in MI showed cotinine levels that were significantly reduced compared to baseline. Findings offer some support for MI for smoking reduction among non-treatment-seeking adolescents, but overall changes in smoking were small.", "Randomized controlled trials of smoking interventions have not been well-documented for lung cancer screening populations. In this study, we randomly assigned 171 current smokers who were undergoing low-dose fast spiral chest CT (SCTS) for lung cancer screening to receive either standard written self-help materials or a written list of Internet resources for smoking cessation. At the 1-year follow-up, more of the subjects receiving Internet-based resources reported making a stop attempt (68% versus 48%, P=0.011). However, there were no statistically significant differences in 7-day point prevalence quit rates (5% versus 10%) or advancement in motivational readiness to stop smoking (27% versus 30%), respectively, between the groups. Clearly, more investigation is warranted into how to tailor smoking interventions for cancer screening participants.", "Motivational interviewing techniques have been minimally researched as a function of a teenage smoking intervention. The present study examined the efficacy of a theory-based motivational tobacco intervention (MTI).\n A randomized two-group design was used to compare 6-month post-baseline quit and reduction rates among teenagers who received the MTI with those who received brief advice or care as usual. Participants were smokers aged 14 to 19 years (N = 75) who presented for treatment in a university-affiliated hospital emergency department (ED). Motivational interviewing techniques were used by trained providers to facilitate individual change; stage-based take-home materials also were provided.\n Similar to past clinic-based studies of motivational interviewing with teenage smokers, our study found negative results in terms of intervention efficacy for cessation. Six-month follow-up cessation rates were nonsignificant--two teenagers quit smoking. Among teenagers who were available at follow-up, a medium effect size (Cohen's h = .38) was found for reduction and a large effect size (Cohen's h = .69) was found for percentage reduction, although these results also were not statistically significant.\n Although the major findings of this study were not significant, the reductions in tobacco use suggest that motivational interviewing may be a clinically relevant counseling model for use in teenage smoking interventions. However, many questions remain, and the current literature lacks studies on trials with significant outcomes using motivational interviewing in smoking cessation. Additionally, more research is needed to examine the suitability of the ED for MTI-type interventions.", "This study evaluated an attempt at 38 workplaces to help employees stop or reduce their levels of smoking. In past research, worksite support groups, in combination with a media smoking cessation program and self-help manuals, were found to be effective in helping employees quit smoking. Unfortunately, recidivism was found at the follow-up evaluations. The present study replicated the results of the previous worksite smoking cessation program with support groups, a television intervention, and self-help manuals. At this postpoint, 42% of employees provided groups plus incentives were abstinent compared to only 15% who were only provided self-help materials. An important difference in this study was that there were also monthly follow-up support groups and incentives. Work settings can be a source of stress and conflict, which can precipitate relapse. At a 12-month follow-up, 26% of those participants who were provided support and incentives were abstinent compared to 16% who were only provided the self-help materials.", "To test the efficacy of (i) computer-generated tailored letters and (ii) practitioner-delivered brief advice for smoking cessation against an assessment-only condition; and to compare both interventions directly.\n Quasi-randomized controlled trial.\n A total of 34 randomly selected general practices from a German region (participation rate 87%).\n A total of 1499 consecutive patients aged 18-70 years with daily cigarette smoking (participation rate 80%).\n The tailored letters intervention group received up to three individualized personal letters. Brief advice was delivered during routine consultation by the practitioner after an onsite training session. Both interventions were based on the Transtheoretical Model of behaviour change.\n Self-reported point prevalence and prolonged abstinence at 6-, 12-, 18- and 24-month follow-ups.\n Among participants completing the last follow-up, 6-month prolonged abstinence was 18.3% in the tailored letters intervention group, 14.8% in the brief advice intervention group and 10.5% in the assessment-only control group. Assuming those lost to follow-up to be smokers, the rates were 10.2%, 9.7% and 6.7%, respectively. Analyses including all follow-ups confirmed statistically significant effects of both interventions compared to assessment only. Using complete case analysis, the tailored letters intervention was significantly more effective than brief advice for 24-hour [odds ratio (OR) = 1.4; P = 0.047] but not for 7-day point prevalence abstinence (OR = 1.4; P = 0.068) for prolonged abstinence, or for alternative assumptions about participants lost to follow-up.\n The study demonstrated long-term efficacy of low-cost interventions for smoking cessation in general practice. The interventions are suitable to reach entire populations of general practices and smoking patients. Computer-generated letters are a promising option to overcome barriers to provide smoking cessation counselling routinely.", "To evaluate the effectiveness of individually tailored smoking cessation advice letters as an adjunct to telephone counselling and generic self-help materials.\n Randomized controlled trial.\n The UK Quitline.\n A total of 1508 current smokers and recent ex-smokers.\n The control group received usual care (telephone counselling and an information pack sent through the post). The intervention group received in addition a computer-generated individually tailored advice letter.\n All outcomes were assessed at 6-month follow-up. The primary outcome measure was self-reported prolonged abstinence for at least 3 months. Secondary outcomes were self-reported prolonged abstinence for at least 1 month and 7-day and 24-hour point-prevalence abstinence.\n For the sample as a whole, quit rates did not differ significantly between the two conditions. However, among the majority (n = 1164) who were smokers at baseline, quit rates were consistently higher in the intervention group: prolonged abstinence for 3 months, 12.2% versus 9.0% [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 0.96-2.04, P = 0.080); prolonged abstinence for 1 month, 16.4% versus 11.3% (OR = 1.53, 95% CI = 1.09-2.15, P = 0.013); 7-day point-prevalence abstinence, 18.9% versus 12.7% (OR = 1.59, 95% CI = 1.15-2.19, P = 0.004); 24-hour point-prevalence abstinence, 20.9% versus 15.4% (OR = 1.45, 95% CI = 1.07-1.96, P = 0.015).\n The results for the smokers are encouraging in showing a small but useful effect of the tailored letter on quit rate. Versions of the tailoring program could be used on the web and in general practices, pharmacies and primary care trusts.", "The sizeable percentage of adults who use smokeless tobacco (ST) represents an important public health target since the majority of ST users have a strong desire to quit, but many lack resources. We tested the impact of an interactive, tailored Web-based intervention (Enhanced Condition) versus a more linear, text-based website (Basic Condition) in a randomized trial with 2523 adult ST users. As is common in Internet-based research, there was considerable attrition: follow-up rates at 3 months, 6 months, and for both 3 and 6 months were 48%, 45% and 34%, respectively. Results using repeated point prevalence of all tobacco use at 3 and 6 months showed that participants in the Enhanced Condition quit at significantly higher rates than those in the Basic Condition. Using a Complete Case analysis, abstinence was 40.6% in the Enhanced Condition vs. 21.2% in the Basic Condition (p< .001). Using intent-to-treat analysis, quit rates were 12.6% vs. 7.9%, respectively (p< .001). Similar results were obtained for only ST use. Unobtrusive measures of program exposure indicated that program use was significantly related to outcome as well as to attrition. We conclude that a tailored, interactive Web-assisted cessation program can be an efficacious method for assisting adult ST users to quit.", "Although tailored interventions consisting of only a few pages of information lead to more quitting than no intervention in the short term, the long-term efficacy of a single tailored intervention still has to be proven. In the present study smokers were reactively recruited and randomly allocated to one of four intervention conditions: (1) outcome information, (2) self-efficacy enhancing information, (3) both sorts of information or (4) no information. Smokers in the three experimental groups received computer-generated tailored feedback containing the condition-specific information, by mail. The results from the 14 months follow-up can be summarized as follows. Compared to the no information condition, all three experimental conditions led to significantly more smokers who had engaged in 24-h quit attempts. However, no experimental condition led to more 7-day quitting than the no information condition. With regard to continuous abstinence, the experimental condition offering a combination of outcome information and self-efficacy enhancing information had a significant effect, compared to the no information condition. It is concluded that a minimal six-page tailored intervention can be beneficial in supporting smokers to quit smoking, even after 14 months.", "This paper presents results from a preliminary short-term work-site intervention study aimed at smoking cessation. The 3-month intervention included consultation for employers on the adoption of a nonsmoking policy, training for nonsmokers to provide assistance to smokers attempting to quit, and cessation classes for smokers. Eight work sites from Bloomington, Minnesota were recruited to the study and randomly assigned to an intervention or comparison condition after a baseline survey of all employees. To assess the effect of the intervention, smokers were surveyed 1 and 6 months after the intervention was completed. At the 1-month follow-up, the overall quit rate in the intervention group was 12% compared to 5% in the control group (P < .05). At the 6-month follow-up, 12% of smokers in the intervention group reported quitting, compared to 9% in the control group (P < .05). Co-worker support for quitting was higher in the intervention group compared to the comparison group. Cessation was highest overall among smokers whose co-workers frequently asked them not to smoke and among those who worked with a high proportion of nonsmokers. These results indicate that a short-term, multifaceted smoking cessation program implemented in work sites can affect smoking cessation rates as well as the work-site norms about smoking.", "To test the effectiveness of a low-intensity intervention program for smoking cessation targeting the worksite environment in employees who had a low readiness to quit, we conducted an intervention trial at six intervention and six control worksites in Japan. A total of 2,307 smokers at baseline who remained at their worksite throughout the three-year study period were analyzed (1,017 in intervention and 1,290 in control groups). The multi-component program at the worksites consisted of (1) presenting information on the harms of tobacco smoking and the benefits of cessation by posters, websites, and newsletters; (2) smoking cessation campaigns for smokers; (3) advice on designation of smoking areas; and (4) periodic site-visits of the designated smoking areas by an expert researcher. At baseline, the intervention and control groups each had high prevalence of immotive or precontemplation, that reflected low readiness to quit (71.5% and 73.2%, respectively). The smoking cessation rate, as not having smoked for the preceding six months or longer, assessed at 36 months after the baseline survey by a self-administered questionnaire was significantly higher in the intervention group than the control group (12.1%, vs. 9.4%, p=0.021). The intervention program still had a significant effect on the smoking cessation rate after multiple logistic regression analysis adjusted for sex, age, type of occupation, age of starting smoking, quit attempts in the past, number of cigarettes per day, and readiness to quit (odds ratio: 1.38, 95% confidence interval: 1.05-1.81, p=0.02). The cost per additional quitter due to the intervention was calculated to be Yen 70,080. These findings indicate that this program is effective and can be implemented in similar workplaces where the prevalence of smoking is high and smokers' readiness to cease smoking is low.", "The purpose of this study was to evaluate a nurse-managed, lay-led tobacco cessation intervention delivered to adult women in Ohio Appalachia.\n A randomized controlled experimental design included intervention participants (n = 147) enrolled in a nurse-managed, lay-led protocol that incorporated nicotine replacement and behavioral counseling. Control participants (n = 155) received a personalized letter from their clinic physician, who advised them to quit smoking and requested they schedule a clinic appointment to discuss cessation.\n Self-reported and cotinine-validated quit rates were significantly higher among intervention group participants compared with control group participants at 3-and 6-month follow-up (P < 0.02). At 12 months, self-reported abstinence was 19.1% (intervention group) and 9.0% (control group), with cotinine-validated rates of 12.2% and 7.1%, respectively (P = 0.13). Prolonged abstinence rates were significantly different between groups at 3, 6, and 12 months (P < 0.02). Logistic regression analyses indicated adjusted odds of cotinine-validated quitting was associated with cigarette consumption per day (odds ratio, 0.94; 95% confidence interval, 0.89-0.99) and Center for Epidemiologic Studies Depression Scale score > or = 16 (odds ratio, 0.39; 95% confidence interval, 0.17-0.90).\n A lay-led approach that is managed by a nurse may serve as an effective cessation strategy among this high-risk population. Additional efforts are needed to sustain long-term abstinence, even after intensive intervention.", "Using a complete factorial design, we tested three interventions for smoking cessation in routine primary care practice. The interventions tested were 1) physician counseling, 2) mailed letters and educational materials designed by the National Cancer Institute (NCI), and 3) referral to smoking cessation classes. Thirty-seven family practice physicians at three of Group Health's outpatient facilities participated. Patient participation rates were 95%, and follow-up was complete for 92% of those participating. None of the interventions had any effect on point prevalence of quitting as determined 8-9 months later by self-report. However, the combination of physician counseling and NCI materials doubled the odds of occurrence of significant antismoking behavior (quit, quit and relapse, or cut down) during the ensuing 8-9 months in those individuals receiving that combination. Referral to smoking cessation classes was strikingly ineffective in this setting. Of 369 individuals designated by study design for referral, only 14% even investigated the classes. This compares with a 10% self-referral rate for those persons not designated for referral by our study design. Our results and other recent work suggest that more intensive interventions on multiple occasions based on relapse prevention strategies hold promise for future success in smoking cessation efforts in primary care.", "This study sought to test the feasibility of two self-help behavioral interventions to reduce and maintain a 50% reduction in smoking among those unable or unwilling to quit, and to evaluate the impact of smoking reduction on subsequent quit attempts. Ninety-three smokers who desired to reduce rather than quit smoking were entered in the study and randomly assigned to either computerized scheduled gradual reduction (CSGR) or to a manual-based selective elimination reduction (SER). Both groups produced significant reductions in smoking (approximately 10 cigarettes per day, during the 7-week treatment phase), which were maintained over one year. The CSGR group reported greater mean percent reductions in smoking from pre- to post-treatment (37% for CSGR, 20% for SER) and a greater percentage of subjects meeting the 50% reduction goal (30% for CSGR, 16% for SER) compared with the SER group. The groups were comparable, however, on all other outcome measures at post-treatment and at 6- and 12-month follow-up. Although subjects with a current desire for smoking cessation were excluded from this study, one-third of the subjects reported a 24-hour quit attempt in the year following study initiation, and 8.6% of the subjects met 7-day point-prevalence criteria for abstinence (CO validated) at the 12-month follow-up. The results of this study lend support to the feasibility of self-help behavioral interventions to produce sustained reductions in smoking rates without apparent negative impact on subsequent quit attempts.", "A 2-year self-help manual smoking cessation intervention was conducted among a panel of middle-aged Finnish men (n = 265) who were recruited proactively in a longitudinal cardiovascular risk factor surveillance study.\n Intervention utilized the stages of change concept of the transtheoretical model. The stages were assessed in the treatment condition at baseline of the cessation study and after that by mail every sixth month. Assessments were followed by an immediate mailing of a stage-based self-help manual matching the stage of change at that time. A usual care group was assessed annually but received no treatment.\n A significant time x intervention effect (P < 0.05) and time x baseline stage effect (P < 0.001) on quit rates were observed in the panel data over the 2-year period. An analysis of changes in the stages of change also revealed an accelerated cessation process in the treatment condition.\n We conclude that mailed stage-matched self-help smoking cessation manuals were able to accelerate the smoking cessation process but manuals alone may not constitute a sufficient long-term intervention. The effects of differential exposure to intervention, subject characteristics, measurement reactivity, and secular trends are discussed as potential confounds.", "Smoking reduction has been introduced as an alternative to smokers unable or unwilling to quit but has never been implemented in a population-based intervention.\n Two thousand four hundred eight daily smokers in all motivational stages were included in a randomised population-based intervention study, in Copenhagen, Denmark. Smokers, unwilling or unable to quit, were encouraged to reduce their tobacco consumption. Furthermore, smokers in the high-intensity intervention were offered participation in smoking reduction groups.\n Twenty-three percent of those who attended both baseline and 1 year visit reported reduction by at least 5 g and 8% reported a halving or more. Halving of tobacco consumption was achieved significantly more often than in the background population, OR = 2.6 (1.6-4.4), even when assuming that non-participants had not reduced, OR = 1.7 (1.0-2.8). Reduction of at least 5 g doubled the probability of increased motivation to quit and a halving increased it more than four times. The reductions were not validated. Less than 2% attended the smoking reduction groups.\n The smoking reduction intervention was significant in self-reported reduction of tobacco consumption and subsequently increased motivation to quit. This may open new perspectives, with reduction as a first step towards cessation, a possible supplement to smoking cessation strategies.", "Despite extremely high rates of smoking among individuals with psychotic disorders and the associated financial and health costs, few studies have investigated the efficacy of smoking cessation interventions among this group. The purpose of this study was to compare an integrated psychological and nicotine replacement therapy intervention for people with a psychotic disorder with routine care alone.\n The authors recruited 298 regular smokers with a psychotic disorder residing in the community and randomly assigned them to a routine care comparison condition (N=151) or an eight-session, individually administered smoking cessation intervention (N=147), which consisted of nicotine replacement therapy, motivational interviewing, and cognitive behavior therapy. Outcome variables included continuous and point-prevalence abstinence rates, smoking reduction status, and changes in symptoms and functioning.\n While there were no overall differences between the treatment group and comparison group in abstinence rates, a significantly higher proportion of smokers who completed all treatment sessions stopped smoking at each of the follow-up occasions (point-prevalence rates: 3 months, 30.0% versus 6.0%; 6 months, 18.6% versus 4.0%; and 12 months, 18.6% versus 6.6%). Smokers who completed all treatment sessions were also more likely to have achieved continuous abstinence at 3 months (21.4% versus 4.0%). There was a strong dose-response relationship between treatment session attendance and smoking reduction status, with one-half of those who completed the intervention program achieving a 50% or greater reduction in daily cigarette consumption across the follow-ups, relative to less than one-fifth of the comparison subjects. There was no evidence of any associated deterioration in symptoms or functioning.\n These findings demonstrate the utility of a nicotine replacement therapy plus motivational interviewing/cognitive behavior therapy smoking cessation intervention among individuals with a psychotic disorder. Further development of more efficacious interventions is required for those who do not respond to existing interventions.", "To test the long-term efficacy of brief counseling plus a computer-based tobacco intervention for teens being seen for routine medical care.\n Both smoking and nonsmoking teens, 14 to 17 years of age, who were being seen for routine visits were eligible for this 2-arm controlled trial. Staff members approached teens in waiting rooms of 7 large pediatric and family practice departments within a group-practice health maintenance organization. Of 3747 teens invited at > or =1 visits, 2526 (67%) consented and were randomized to tobacco intervention or brief dietary advice. The tobacco intervention was individually tailored on the basis of smoking status and stage of change. It included a 30-second clinician advice message, a 10-minute interactive computer program, a 5-minute motivational interview, and up to two 10-minute telephone or in-person booster sessions. The control intervention was a 5-minute motivational intervention to promote increased consumption of fruits and vegetables. Follow-up smoking status was assessed after 1 and 2 years.\n Abstinence rates after 2 years were significantly higher for the tobacco intervention arm, relative to the control group, in the combined sample of baseline smokers and nonsmokers (odds ratio [OR]: 1.23; 95% confidence interval [CI]: 1.03-1.47). Treatment effects were particularly strong among baseline self-described smokers (OR: 2.42; 95% CI: 1.40-4.16) but were not significant for baseline nonsmokers (OR: 1.25; 95% CI: 0.97-1.61) or for those who had \"experimented\" in the past month at baseline (OR: 0.95; 95% CI: 0.45-1.98).\n Brief, computer-assisted, tobacco intervention during routine medical care increased the smoking cessation rate among self-described smokers but was less effective in preventing smoking onset.", "Most smokers attempt to stop smoking without using help. We evaluated the efficacy of a decision aid to motivate quitters to use efficacious treatment. SETTING AND PARTICIPANTS, A total of 1,014 were recruited from a convenience sample of 3,391 smokers who intended to quit smoking within 6 months. DESIGN AND Smokers were assigned randomly to either receive the decision aid or no intervention. The decision aid was expected to motivate quitters to use efficacious cessation methods and contained neutral information on treatment methods, distinguishing between efficacious and non-efficacious treatments. MEASUREMENTS Baseline questionnaire and follow-ups were used 2 weeks and 6 months after the start of the intervention.\n The decision aid increased knowledge of cessation methods and induced a more positive attitude towards these methods. Furthermore, 45% reported increased confidence about being able to quit and 43% said it helped them to choose between treatments. However, no clear effect on usage of treatment aids was found, but the intervention group had more quit attempts (OR=1.52, 95% CI 1.14-2.02) and higher point prevalence abstinence at 6-month follow-up (20.2% versus 13.6%; OR=1.51, 95% CI=1.07-2.11). CONCLUSIONS An aid to help smokers decide to use efficacious treatment when attempting to quit smoking had a positive effect on smoking cessation, while failing to increase the usage of efficacious treatment. This finding lends support to the notion that the mere promotion of efficacious treatments for tobacco addiction might increase the number of quit attempts, irrespective of the actual usage of treatment.", "African Americans remain a critically underserved group for smoking cessation interventions. This study tested the effectiveness of a tailored, culturally sensitive intervention for African American smokers who called the NCI Cancer Information Service (CIS) for help to quit smoking.\n This paper presents results of a 2-year study of tailored counseling strategies among African American smokers (n = 1,422) who called four regional CIS offices in response to a radio-based media campaign in 14 communities. Callers were randomly assigned to receive either the standard CIS quit smoking counseling and guide (Clearing the Air) or counseling and a guide (Pathways to Freedom) tailored to the quitting needs and barriers of African American smokers. Callers were predominantly female (63.6%). ages 20-49 (88%), with a high school education or more (84%). Median smoking history was 17 years; median smoking rate was 20 cigarettes/day. Standard (n = 689) and Tailored (n = 733) group subjects did not differ on most baseline measures.\n On most measures, Standard and Tailored counseling/guides received similar ratings, but the Tailored guide was rated as having more appealing photos (P = 0.001) and as being more appropriate for family members (P = 0.003). Six-month follow-up with 893 subjects (response rates were 63% Standard, 62% Tailored, ns) showed significantly more quit attempts (P = 0.002) and greater use of prequitting strategies (P < 0.05) among Tailored than among Standard subjects, but no differences in self-reported 1-week abstinence (14.4% Standard, 16.2% Tailored) (ns). An opportunistic 12-month follow-up of subjects recruited in the last year of the study (n = 445) (response rates were 57% Standard, 60% Tailored, ns) showed a significantly higher quit rate (15.4% Standard, 25.0% Tailored) for Tailored subjects (P = 0.034).\n Results show promise for tailored approaches to boost quit attempts and success rates among African American smokers.\n Copyright 1998 American Health Foundation and Academic Press." ]	Standard self-help materials may increase quit rates compared to no intervention, but the effect is likely to be small. We failed to find evidence that they have an additional benefit when used alongside other interventions such as advice from a healthcare professional, or nicotine replacement therapy. There is evidence that materials that are tailored for individual smokers are more effective than untailored materials, although the absolute size of effect is still small.
CD008062	[ "18794427" ]	[ "Significant reduction in incidence of wound contamination by skin flora through use of microbial sealant." ]	[ "Application of skin sealant prior to incision reduces microbial contamination of the wound.\n Prospective, randomized, multicenter clinical trial.\n Six teaching hospitals.\n A total of 177 adult patients undergoing elective open inguinal hernia repair were randomized to either standard skin preparation with 10% povidone-iodine or skin preparation followed by cyanoacrylate-based liquid microbial sealant.\n Wound contamination was assessed during surgery by microbial sampling inside the wound at initiation of skin incision and prior to skin closure.\n The primary outcome measures were the safety and effectiveness of cyanoacrylate-based microbial sealant to reduce bacterial contamination during surgery. The secondary outcome measure was reduction of postoperative surgical site infections using microbial sealant.\n Demographics were similar. Patients treated with sealant were more likely to have no bacterial cells found in the wound than control participants (47% vs 31%; P = .04). Three patients developed surgical site infections; all were in the control group (P = .25). Independent factors that reduced wound contamination were use of microbial sealant (odds ratio, 0.45; confidence interval, 0.23-0.88; P = .02) and perioperative antibiotics (odds ratio, 0.24; confidence interval, 0.10-0.58; P = .001).\n Cyanoacrylate-based microbial sealant may be an important tool to reduce wound contamination and potentially prevent surgical site infections." ]	There is currently insufficient evidence as to whether the use of microbial sealants reduces the risk of surgical site infection in people undergoing clean surgery and further rigorous RCTs are required.
CD005540	[ "21335510", "12610188", "3881176", "14745745", "15986401", "15226321", "12350480", "15046691", "950706" ]	[ "Lifestyle intervention in men with advanced prostate cancer receiving androgen suppression therapy: a feasibility study.", "Randomized, multicenter, phase II trial of two multicomponent regimens in androgen-independent prostate cancer.", "Randomized trial of combination chemotherapy in hormone-resistant metastatic prostate carcinoma.", "The effect of dyadic intervention on self-efficacy, social support, and depression for men with prostate cancer.", "Improving the quality of life of patients with prostate carcinoma: a randomized trial testing the efficacy of a nurse-driven intervention.", "Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer.", "Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia.", "Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a prospective randomized multicenter trial.", "The continued evaluation of the effects of chemotherapy in patients with advanced carcinoma of the prostate." ]	[ "Healthy lifestyle behaviors could have a role in ameliorating some of the adverse effects of androgen suppression therapy (AST) in men with prostate cancer. The primary aim of this study was to assess the feasibility of a tapered supervised exercise program in combination with dietary advice in men with advanced prostate cancer receiving AST.\n Advanced prostate cancer patients receiving AST for a minimum of 6 months were randomized to a 12-week lifestyle program comprising aerobic and resistance exercise, plus dietary advice (n = 25), or standard care (n = 25). Exercise behavior, dietary macronutrient intake, quality of life, fatigue, functional fitness, and biomarkers associated with disease progression were assessed at baseline, after the intervention, and at 6 months.\n The lifestyle group showed improvements in exercise behavior (P < 0.001), dietary fat intake (P = 0.001), total energy intake (P = 0.005), fatigue (P = 0.002), aerobic exercise tolerance (P < 0.001), and muscle strength (P = 0.033) compared with standard care controls. Although a high rate of attrition (44%) was observed at 6 months, the improvements in key health outcomes were sustained. No effects on clinical prostate cancer disease markers were observed.\n This preliminary evidence suggests that pragmatic lifestyle interventions have potential to evoke improvements in exercise and dietary behavior, in addition to other important health outcomes in men with advanced prostate cancer receiving AST.\n This study shows for the first time that pragmatic lifestyle interventions are feasible and could have a positive impact on health behaviors and other key outcomes in men with advanced prostate cancer receiving AST.", "Several multicomponent regimens have been reported to be useful in advanced androgen-independent prostate cancer. We used a randomized phase II design to evaluate and compare two such regimens. Patients were accrued primarily in the community setting.\n Patients with progressive, androgen-independent prostate cancer were randomly assigned to one of two treatments: either ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide (TEE). Patients were prospectively stratified on the basis of disease volume. The primary end points were response and overall survival time.\n A total of 75 patients were registered; 71 are included in the analysis. By the criterion of an 80% prostate-specific antigen reduction maintained for at least 8 weeks, 11 (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI], 10.5 to 21.2 months) in the TEE arm and 23.4 months (95% CI, 12.9 to 30.6 months) for patients treated with KA/VE. Many patients (24%) failed to complete at least 6 weeks of therapy, including five (8%) treatment-related early deaths.\n Each of these regimens produced clinically significant responses, and the observed median survival (18.9 months for all 71 patients) compares favorably with previously published results, especially in the community setting. Nonetheless, it is apparent that these first-generation regimens must be applied judiciously, and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting.", "A prospective randomized study was conducted in 51 patients with stage D hormone-resistant prostatic carcinoma, comparing a combination of doxorubicin and lomustine (DC) with cyclophosphamide and 5-FU (CF). Patients were assessed objectively (employing National Prostate Cancer Project criteria) and subjectively (using a numerical scoring scheme). Each regimen was well tolerated with acceptable levels of myelosuppression. The objective partial response rate was 57% for DC and 8% for CF. Objective stabilization occurred, respectively, in 14% and 44% of the patients. Similarly, DC demonstrated a significantly superior subjective response rate (partial plus complete) of 82%, compared to 48% for CF. Patients with poor initial performance status or liver involvement had significantly lower response rates and reduced survival. Overall, there was no significant difference in survival between the two arms, reflecting the similarity between DC and CF in total objective response rate (partial response plus stable disease). DC provided superior palliation and was well tolerated by an essentially geriatric population.", "Urinary and sexual dysfunctions are side effects of radical prostatectomy (RP) for prostate cancer (PC) that contribute to depression. Despite the effectiveness of support groups at reducing depression in cancer patients, men typically do not participate in them. The purpose of this pilot study was to test the effects of a dyadic intervention (one-to-one support) on social support (Modified Inventory of Socially Supportive Behaviors), self-efficacy (Stanford Inventory of Cancer Patient Adjustment), and depression (Geriatric Depression Scale). Subjects were randomized to group. Controls (N=15; Mage=59.7) received usual care. Experimentals were paired with long-term survivors (LTS) who had RP and who had treatment side effects in common. Experimentals (N=15; Mage=57.5) met with a LTS 8 times in 8 weeks to discuss concerns associated with survivorship. No significant differences were detected on social support, but after 4 weeks, significant differences were present on depression between controls and experimentals, however these differences were not seen at 8 weeks. After 8 weeks, there were also significant differences on self-efficacy between controls and experimentals. Weekly anecdotal data supported the feasibility and acceptance of the intervention that was a low cost strategy effective at reducing depression and increasing self-efficacy in men treated by RP. Future research directions and clinical application is presented.\n Copyright 2003 John Wiley & Sons, Ltd.", "Treatments for clinically localized prostate carcinoma are accompanied by sexual, urinary, and bowel dysfunction and other sequelae that can result in significant distress and reduced well being. Methods capable of improving quality of life are needed that can be integrated into clinical practice. To address this need, a nurse-driven, cancer care intervention was developed and tested.\n Within 6 weeks after completing treatment, 99 patients, along with their partners, were enrolled into a prospective, controlled trial and were randomized to receive the cancer care intervention or to receive standard care. Participants in the intervention arm met once each month for 6 months with an oncology nurse intervenor, who helped patients identify their quality-of-life needs using an interactive computer program. The intervener then provided education and support tailored to participants' needs. Primary outcome variables included 1) disease-specific quality of life, including sexual, urinary, and bowel outcomes and cancer worry; 2) depression; 3) dyadic adjustment; and 4) general quality of life. Outcomes data were collected prior to randomization and again at 4 months, 7 months, and 12 months posttreatment.\n Patients in the intervention arm experienced long-term improvements in quality-of-life outcomes related to sexual functioning and cancer worry compared with patients who received standard care. Baseline depression moderated the impact of the intervention on several other quality-of-life outcomes.\n The findings of the current study indicated that a computer-assisted, nurse-driven intervention was capable of providing durable improvements in the quality of life of men who underwent treatment for clinically localized prostate carcinoma.", "Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC.\n Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m(2) intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression.\n After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P =.32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group.\n In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.", "To study the efficacy and safety of dutasteride, a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II.\n A total of 4325 men (2951 completed) with clinical benign prostatic hyperplasia, moderate to severe symptoms (American Urological Association-Symptom Index score of 12 points or greater), a peak flow rate of 15 mL/s or less, a prostate volume of 30 cm3 or greater (as measured by transrectal ultrasonography), and a serum prostate-specific antigen level of 1.5 to 10.0 ng/mL (inclusive) were enrolled into three identical clinical trials and randomized to 0.5 mg dutasteride daily or placebo. After a 1-month, single-blind, placebo lead-in, patients were followed up for 24 months in a double-blind trial with multiple interval assessments.\n At 24 months, serum dihydrotestosterone was reduced from baseline by a mean of 90.2% (median -93.7%; P <0.001), and the total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (P <0.001). The symptom score was improved by as early as 3 months, with pooled significance from 6 months onward (P <0.001) and a reduction of 4.5 points (21.4%) at 24 months (P <0.001). The maximal flow rate improved significantly from 1 month (P <0.01), with an increase of 2.2 mL/s reported at 24 months (P <0.001). Hence, the risk reduction of acute urinary retention was 57% and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48% compared with placebo. The drug was well tolerated.\n Dutasteride is a potent inhibitor of dihydrotestosterone production that is safe and effective in terms of the reduction of prostate volume and symptoms, flow rate improvement, and the reduction of the risk of acute urinary retention and surgery during a 24-month study period.", "The aim of this study was to compare the efficacy of total intermittent androgen deprivation (IAD) versus total continuous androgen deprivation (CAD) for treating patients with advanced prostate cancer in a phase III randomized trial. A total of 68 evaluable patients with hormone-naive advanced or relapsing prostate cancer were randomized to receive combined androgen blockade according to a continuous (n = 33) or intermittent (n = 35) regimen. Therapeutic monitoring was assessed by use of serum prostate-specific antigen (PSA) measurements. Patients in the CAD and IAD groups were equally stratified for age, biopsy Gleason score, and baseline serum PSA levels. The outcome variable was time to androgen-independence of the tumor, which was defined as increasing serum PSA levels despite androgen blockade. Mean follow-up was 30.8 months. The 35 IAD-treated patients completed 91 cycles, and 19 of them (54.3%) completed > or = 3 cycles. Median cycle length and percentage of time off therapy were 9.0 months and 59.5, respectively. The estimated 3-year progression rate was significantly lower in the IAD group (7.0% +/- 4.8%) than in the CAD group (38.9% +/- 11.2%, P = 0.0052). Our data suggest that IAD treatment may maintain the androgen-dependent state of advanced human prostate cancer, as assessed by PSA measurements, at least as long as CAD treatment. Further studies with longer follow-up times and larger patient cohorts are needed to determine the comparative impacts of CAD and IAD on survival.", "The response and duration of survival were evaluated for patients with stage D relapsing prostatic cancer who were randomized to cyclophosphamide (cytoxan), 5-fluorouracil (5-FU) or standard therapy, or to subsequent chemotherapies. The chemotherapies on initial randomization were superior to the standard therapy in the number of responders and duration of response. Survival was longer for responders (stable or partial regression) on chemotherapy by comparison to responders (stable only) on standard therapy. The survival for patients receiving initial and crossover chemotherapy was significantly improved for patients who responded to therapy. Chemotherapy of advanced relapsing stage D prostatic cancer is more beneficially treated by specific chemotherapy as shown in this randomized study." ]	PDE5 inhibitors are an effective treatment for SD secondary to treatments for prostate cancer. Other interventions identified need to be tested in further RCTs. The SD interventions in this review are not representative of the range available for men and women. Further evaluations are needed for these interventions for SD following cancer treatments.
CD001390	[ "3545418", "16227328", "9382120", "11642629", "16297507" ]	[ "Efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease.", "Clinical efficacy of anti-pneumococcal vaccination in patients with COPD.", "Clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial.", "Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees.", "Response to pneumococcal vaccine in chronic obstructive lung disease--the effect of ongoing, systemic steroid treatment." ]	[ "Although pneumococcal vaccine has been recommended for patients with chronic obstructive pulmonary disease (COPD), its efficacy in this population has not been shown. A double-blind randomized controlled trial of 14-valent pneumococcal vaccine was carried out in 189 men and women aged 40 to 89 years with a clinical diagnosis of COPD and a forced expiratory volume in 1 second of less than 1.5 L. Of the 189, 92 received the vaccine and 97 received saline placebo. In a randomly chosen subsample of those who received the vaccine the mean titres of specific IgG antibody to selected pneumococcal polysaccharide serotypes increased two- to threefold by 4 weeks after vaccination. Over a 2-year period the rates of death, hospital admissions and emergency visits and the mean length of hospital stay were not significantly different in the two groups. Although a protective effect of 14-valent pneumococcal vaccine could not be shown, the small size of the sample and the relatively low follow-up rates preclude firm conclusions about efficacy from these data alone. The elevated antibody levels before vaccination in some of the patients, suggesting prior infection with Diplococcus pneumoniae, may partly explain the findings.", "A study was undertaken to evaluate the clinical efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPV) in immunocompetent patients with chronic obstructive pulmonary disease (COPD).\n A randomised controlled trial was carried out in 596 patients with COPD of mean (SD) age 65.8 (9.7) years, 298 of whom received PPV. The main outcome was radiographically proven community acquired pneumonia (CAP) of pneumococcal or unknown aetiology after a mean period of 979 days (range 20-1454).\n There were 58 first episodes of CAP caused by pneumococcus or of unknown aetiology, 25 in the intervention group and 33 in the non-intervention group. Kaplan-Meier survival curves for CAP did not show significant differences between the intervention and non-intervention arms (log rank test = 1.15, p = 0.28) in the whole group of patients. The efficacy of PPV in all patients was 24% (95% CI -24 to 54; p = 0.333). In the subgroup aged <65 years the efficacy of PPV was 76% (95% CI 20 to 93; p = 0.013), while in those with severe functional obstruction (forced expiratory volume in 1 second <40%) it was 48% (95% CI -7 to 80; p = 0.076). In younger patients with severe airflow obstruction the efficacy was 91% (95% CI 35 to 99; p = 0.002). There were only five cases of non-bacteraemic pneumococcal CAP, all in the non-intervention group (log rank test = 5.03; p = 0.025). Multivariate analysis gave a hazard ratio for unknown and pneumococcal CAP in the vaccinated group, adjusted for age, of 0.20 (95% CI 0.06 to 0.68; p = 0.01).\n PPV is effective in preventing CAP in patients with COPD aged less than 65 years and in those with severe airflow obstruction. No differences were found among the other groups of patients with COPD.", "To study the efficacy of pneumococcal capsular polysaccharide vaccine among the elderly by use of a population-based intervention in one township, Varkaus, Eastern Finland.\n A randomized, controlled trial in which elderly inhabitants (aged 60 years or older) of the catchment area were randomized to receive either pneumococcal and influenza vaccines (PI group = vaccinated) or influenza vaccine alone (I group = controls) and offered participation. The response rate was 67.4%. The PI group consisted of 1,364 persons and the I group of 1,473 persons. The vaccinations were performed in the municipal health center in the fall of 1982, and all elderly inhabitants were followed for 3 years for the development of radiologically confirmed pneumonia. Pneumococcal etiology was identified by serological methods.\n The incidence of pneumonia was 18.8 per 1,000 person-years in the PI group (73 pneumonia episodes) and 16.6 per 1,000 person-years in the I group (69 episodes). Pneumococcal etiology was found in 27 episodes in the PI group (incidence 7.0 per 1,000 person-years) and in 36 episodes in the I group (incidence 8.6 per 1,000 person-years). In controls (I group) the incidence of pneumococcal pneumonia was significantly higher among persons with increased risk for contracting pneumonia (19 per 1,000 person-years) than among controls with low risk status (4 per 1,000 person-years). No significant protection from pneumococcal pneumonia was found in the study group as a whole (vaccine efficacy 15%, 95% CI -43% to 50%). However, in persons with medical risk factors for contracting pneumonia, there was a statistically significant protective efficacy of 59% (95% CI, 6% to 82%).\n Pneumococcal vaccination significantly reduced the incidence of pneumococcal pneumonia in elderly persons at increased risk for contracting pneumonia. This increased/high-risk category comprised 34% of the population aged 60 years or older. Because targeted vaccination of this large group may be difficult to organize in an efficient manner, vaccinating all elderly persons may be the best strategy to prevent this rather common and often fatal disease.", "Incidence and severity of respiratory infections are increased in day-care center attendees. Streptococcus pneumoniae is an important contributor to these infections.\n To examine whether the use of a pneumococcal conjugate vaccine could reduce the occurrence of respiratory infections and the ensuing antibiotic drug use in the day care.\n In this double blind, randomized, controlled study performed in 8 day-care centers located in Beer-Sheva, Israel, 264 toddlers ages 12 to 35 months at enrollment were randomized to receive either a 9-valent conjugate pneumococcal vaccine (conjugated to CRM197) or a control vaccine [conjugate meningococcus C vaccine (conjugated to CRM197)] and were followed for an average of 22 months. The main outcome measures were respiratory morbidity and antibiotic use.\n An overall reduction of 7% in child months with > or = 1 reported illness episodes was observed among vaccinees (P = 0.008), and 85% of all episodes were related to the respiratory tract. Reductions of 15, 16 and 17% were observed in upper respiratory infections, lower respiratory problems and otitis media, respectively. An overall reduction of 17% in antibiotic days was observed [10% for upper respiratory infections, 20% for otitis and 47% for lower respiratory problems (P < or = 0.005 for each entity)]. The reduction in episodes and antibiotic use was greater for those <36 months of age than for the older children.\n The reduction of respiratory problems, including those not traditionally considered of pneumococcal origin and the ensuing lowered antibiotic use in day-care center attendees by pneumococcal conjugate vaccination suggest a broader benefit from the vaccine than preventing invasive disease only.", "Forty-nine patients with chronic obstructive lung disease (COPD) were block-randomized in four groups to investigate, if different degrees of steroid-load influenced the effect of pneumococcal-vaccination on antibody level and clinical variables during 6 months of follow-up. The groups included 13 patients without systemic steroids for the previous 3 months, all vaccinated at entrance in the study and treated with steroids for 4 weeks. Nine patients had chronic steroid treatment both before and during the investigation; they were vaccinated at the entrance in the study. Fifteen patients without systemic steroids for the previous 3 months were vaccinated after the end of a 4-week steroid treatment. Twelve patients served as controls, and were not vaccinated. Totally, 60%-78% of vaccinated patients in the three groups had a rise in antibody level, and a later decrease compared to two of the 12 control patients (p<0.01). This difference was also significant (p<0.05) for the patients vaccinated at entrance in the hospital. No differences were observed among the clinical variables: pneumonia, exacerbations, admittance to hospital, increase in the use of steroids or beta-agonists, and the use of antibiotics. We conclude that a rise in antibody level after pneumococcal vaccination can be expected in patients with COPD despite of the use of systemic steroids. The clinical effect of vaccination is debatable." ]	The limited evidence from randomised controlled trials (RCTs) included in this review suggests that, while it is possible that injectable polyvalent pneumococcal vaccines may provide some protection against morbidity in persons with COPD, no significant effect on any of the outcomes was shown. Further large RCTs in this population would be needed to confirm effectiveness of the vaccine suggested by results from longitudinal studies.
CD002854	[ "2643513", "320856" ]	[ "A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children.", "Quantitative evaluation of vitamin E in the treatment of angina pectoris." ]	[ "In 24 epileptic children refractory to antiepileptic drugs (AEDs) with generalized tonic-clonic and other types of seizures, addition of D-alpha-tocopheryl acetate (Vitamin E 400 IU/day) to existing AEDs was accompanied by a significant reduction of seizures in 10 of 12 cases. This was significantly different from controls given placebo (0 of 12, p less than 0.05). This result did not appear to be due to the effects of changes in the plasma levels of the comedication. There were no adverse side effects. The Vitamin E levels steadily increased in the responders in the trial phase but this did not occur in two clinically noncompliant subjects or in 12 patients receiving placebo. No other clinically significant alterations in hematologic or biochemical test results were observed. No treatment-related changes in plasma concentration of concomitant AEDs were noted. These findings justify further clinical controlled trials of Vitamin E as adjunctive therapy for childhood epilepsy intractable to the usual antiepileptic therapy.", "Because of previous reports of the beneficial effect of vitamin E in angina pectoris patients, 48 patients, with both stable angina and positive (chest pain plus ishemic ST depression) maximal exercise treadmill tests, participated in a double-blind cross-over study of 6 months of vitamin E and 6 months of placebo therapy, separated by a 2 month no treatment period. All 48 patients had positive selective coronary arteriograms (75 per cent obstruction of at least a major coronary artery) and/or Q wave ECG evidence of previous myocardial infarction (Minnesota criteria). Evaluation of drug effectiveness was based on performance of serial maximal exercise treadmill tests, serial systolic time interval measurements, and daily angina diaries. No statistically significant differences between the two treatment studied. It is concluded that a large dose of vitamin E (1,600 I.U. of d-alpha-tocopherol succinate daily) for 6 months in patients with stable angina pectoris fails to increase the exercise capacity, improve left ventricular function, or reduce the frequency of chest pain." ]	No convincing evidence that vitamin E is of benefit in the treatment of AD or MCI. Future trials assessing vitamin E treatment in AD should not be restricted to alpha-tocopherol.
CD002947	[ "9476272", "9433873", "22427772", "11037895", "15517622" ]	[ "Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial.", "Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect.", "Mixture of Arnebia euchroma and Matricaria chamomilla (Marhame-Mafasel) for pain relief of osteoarthritis of the knee - a two-treatment, two-period crossover trial.", "Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group.", "Efficacy and safety of willow bark extract in the treatment of osteoarthritis and rheumatoid arthritis: results of 2 randomized double-blind controlled trials." ]	[ "One of the objectives of symptomatic slow-acting drugs for osteoarthritis is to reduce the need for drugs with a less favorable safety profile, mainly analgesics and nonsteroidal antiinflammatory drugs (NSAIDs). We conducted a three-month, prospective, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of avocado/soybean unsaponifiables in terms of NSAID use reduction. Patients with primary femorotibial or hip osteoarthritis (OA) (ACR criteria and Kellgren-Lawrence radiological stage IB, II, or III) of at least six months' duration with regular pain for more than three months requiring therapy with NSAID (visual analog scale score > or = 25 mm and Lequesne's index on therapy > or = 4) were given one capsule per day of avocado/soybean unsaponifiables or a placebo for three months. During the first 45 days, patients in both groups were also given one of seven predefined NSAIDs. The primary efficacy criteria was the rate of patients taking back a NSAID and the delay before re-intake. Secondary efficacy criteria were the total dose of NSAID, overall ratings by the patient and by the physician, the visual analog scale pain score and the functional index. Of the 164 included patients, 163 were evaluable, 80 in the active drug group and 83 in the placebo group. Mean age was 62.9 +/- 8.8 years. The diagnosis was femorotibial OA in 101 patients and hip OA in 62. Data were collected on day 45 in 153 patients (77 on the active drug and 76 on the placebo). The number of patients who took back NSAID therapy was significantly smaller in the group treated by avocado/soybean unsaponifiables (33; 43.4%) than in the placebo group (53; 69.7%) (P < 0.001). Also, beyond day 54, the time spent off NSAID therapy was shorter in the placebo group. The functional index showed a significantly greater improvement in the active drug group (-2.3 +/- 2.6) than in the placebo group (-1.0 +/- 2.6) (P < 0.01). Pain scores over time were similar in the two groups. Overall patient ratings were significantly better in the active drug group (P < 0.01). Safety was oggd in both groups. After six weeks, avocado/soybean unsaponifiables reduced the need for NSAID in patients with lower limb OA.", "To assess the efficacy and safety of avocado/soybean unsaponifiables (ASU) in the treatment of patients with symptomatic osteoarthritis (OA) of the knee or hip, as well as the potential residual effects of ASU after stopping treatment, to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA.\n One hundred sixty-four patients with regular, painful, primary OA of the knee (n = 114) or hip (n = 50) entered a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial with a 6-month treatment period and a 2-month posttreatment followup. A 15-day washout period for nonsteroidal antiinflammatory drugs (NSAIDs) preceded the study. Efficacy was judged according to 1) Lequesne's functional index (LFI) and 2) pain on Huskisson's visual analog scale (VAS; 100-mm scale), intake of NSAIDs/analgesics, and overall disability score (by 100-mm VAS).\n Eighty-five patients received ASU; 79 received placebo. One hundred forty-four patients were evaluable at month 6 (75 taking ASU; 69 taking placebo). The mean +/- SEM LFI score decreased from 9.7 +/- 0.3 to 6.8 +/- 0.4 in the ASU group and from 9.4 +/- 0.3 to 8.9 +/- 0.4 in the placebo group (P < 0.001 for intergroup difference at month 6). Pain decreased from 56.1 +/- 1.6 mm to 35.3 +/- 2.3 in the ASU group and from 56.1 +/- 1.8 mm to 45.7 +/- 2.6 in the placebo group (P = 0.003 at month 6). NSAID consumption was slightly lower in the ASU group. Fewer patients in the ASU group required NSAIDs (48%, versus 63% in the placebo group; P = 0.054). The success rate was 39% in the ASU group and 18% in the placebo group. Overall functional disability was significantly reduced in the ASU group. Improvement appeared more marked in patients with hip OA. A residual effect was observed at month 8. Tolerance was good to excellent for most patients.\n ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA, acting from month 2 and showing a persistent effect after the end of treatment.", "Osteoarthritis is the most prevalent chronic non-infective joint arthritis. Because of its chronic disease nature, local drugs are preferred due to lower complications. In the present study, the new herbal pomade Marhame-Mafasel for knee osteoarthritis was used in a double-blind crossover trial. The aim of the study was to assess the efficacy and safety of Marhame-Mafasel pomade, which consists of several medical herbs including Arnebia euchroma and Matricaria chamomilla, in osteoarthritis of the knee.\n This study was a placebo-controlled double-blind crossover trial. Forty-two patients with pain associated with osteoarthritis of the knee (diagnosed by criteria of the European League against Rheumatism and physical examination) were drawn from patients attending the Clinic of Mostafa-Khomeini Hospital. In this study we assessed efficacy (analgesic effect and improved function) of herbal pomade Marhame-Mafasel, which was used locally in patients with primary osteoarthritis of the knee over three weeks. The instrument of the study was the Western Ontario and McMaster Universities (WOMAC) LK3.1 standard questionnaires.\n The participants in each group were 21 patients; 30 (71.4%) were women and 12 (28.6%) of them were men. The participants were between 40 and 76 years old. Six patients had mild arthritis, 15 had moderate arthritis and 21 had severe arthritis. The positive analgesic effect of the herbal pomade Marhame-Mafasel in primary knee osteoarthritis was proven. The herbal joint pomade Marhame-Mafasel had a significantly greater mean change in score compared to the placebo group for osteoarthritis severity (p < 0.05).\n Herbal pomade Marhame-Mafasel in comparison to placebo has more effect on reduction of pain of primary knee osteoarthritis.", "To evaluate the efficacy and safety of diacerein, a drug with interleukin-1beta--inhibitory activity in vitro, in patients with knee osteoarthritis (OA).\n A total of 484 patients fulfilling the American College of Rheumatology criteria for knee OA were enrolled in this 16-week, randomized, double-blind, placebo-controlled, parallel study group with 3 diacerein dosages of 50 mg/day, 100 mg/day, and 150 mg/day (administered twice daily).\n In the intent-to-treat population, 100 mg/day diacerein (50 mg twice daily) was significantly superior (P < 0.05) to placebo using the primary criterion (visual analog scale [VAS] assessment of pain on movement). Significant improvement (P < 0.05) was also observed for the secondary criteria, which included the Western Ontario and McMaster Universities OA Index (WOMAC), the WOMAC subscores, and the VAS assessment of handicap. In patients treated with diacerein dosages of 50 mg/day and 150 mg/day, favorable but not significant results were observed for the primary criterion. The best daily dosage of diacerein, calculated from the effect on the VAS assessment of pain on movement, was 90.1 mg. In the per-protocol population, the analysis of the primary criterion showed significant dose-dependent differences (P < 0.05) between each of the 3 diacerein dosages and the placebo. No differences were observed among the 3 diacerein groups. A significantly higher incidence (P < 0.05) of adverse events (AEs), as well as a higher rate of dropoout due to AEs, was observed in patients treated with 150 mg/day diacerein versus those treated with placebo, 50 mg/day diacerein, or 100 mg/day diacerein. Mild-to-moderate transient changes in bowel habits were the most frequent AEs, increasing with the dosage.\n Diacerein, a drug for the treatment of OA, was shown to be an effective treatment for symptoms in patients with knee OA. Taking into account both efficacy and safety, the optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).", "To investigate the efficacy and safety of a standardized willow bark extract in patients with osteoarthritis (OA) and rheumatoid arthritis (RA).\n We studied 127 outpatients with hip or knee OA and a WOMAC pain score of at least 30 mm and 26 outpatients with active RA in 2 randomized, controlled, double-blind trials with followup for 6 weeks. OA trial: Patients were randomized to receive willow bark extract, corresponding to 240 mg of salicin/day, diclofenac 100 mg/day, or placebo (n = 43, 43, and 41, respectively). Main outcome measure was the pain subscore of the WOMAC OA Index. RA trial: Patients were randomized to receive willow bark extract, corresponding to 240 mg salicin/day (n = 13) or placebo (n = 13). Main outcome measure was the patient's assessment of pain rated on a 100 mm visual analog scale (VAS).\n OA trial: WOMAC pain scores decreased by 8 mm (17%) in the willow bark group and by 23 mm (47%) in the diclofenac group, compared with 5 mm (10%) in the placebo group. The difference between willow bark extract and placebo was not statistically significant (-2.8 mm; 95% CI -12.1 to 6.4 mm; p = 0.55, ANCOVA), but the difference between diclofenac and placebo was highly significant (-18.0 mm; 95% CI -27.2 to -8.8 mm; p = 0.0002, ANCOVA). RA trial: The mean reduction of pain on the VAS was -8 mm (15%) in the willow bark group compared with -2 mm (4%) in the placebo group. The difference was not statistically significant (estimated difference -0.8 mm; 95% CI -20.9 to 19.3 mm; p = 0.93, ANCOVA).\n The OA study suggested that the willow bark extract showed no relevant efficacy in patients with OA. Similarly, the RA trial did not indicate efficacy of this extract in patients with RA." ]	The evidence for avocado-soybean unsaponifiables in the treatment of osteoarthritis is convincing but evidence for the other herbal interventions is insufficient to either recommend or discourage their use.
CD004853	[ "8063980", "18615497", "11680552", "11941174", "17007812", "8894955", "14997954", "10474848" ]	[ "Comparative effects of cognitive-behavioral and brief psychodynamic psychotherapies for depressed family caregivers.", "A pilot randomised controlled trial of a brief cognitive behavioural group intervention to reduce recurrence rates in late life depression.", "A randomized trial of the effectiveness of cognitive-behavioral therapy and supportive counseling for anxiety symptoms in older adults.", "Weekly ECT in Geriatric Depression.", "Randomized trial of a brief depression prevention program: an elusive search for a psychosocial placebo control condition.", "Controlled trial of a brief cognitive-behavioural intervention in adolescent patients with depressive disorders.", "Cognitive therapy for depression: a comparison of individual psychotherapy and bibliotherapy for depressed older adults.", "A group cognitive behaviour therapy programme with metastatic breast cancer patients." ]	[ "Clinically depressed family caregivers (N = 66) of frail, elderly relatives were randomly assigned to 20 sessions of either cognitive-behavioral (CB) or brief psychodynamic (PD) individual psychotherapy. At posttreatment, 71% of the caregivers were no longer clinically depressed according to research diagnostic criteria (RDC), with no differences found between the 2 outpatient treatments. The results suggested therapy specificity; there was an interaction between treatment modality and length of caregiving on symptom-oriented measures. Clients who had been caregivers for a shorter period showed improvement in the PD condition, whereas those who had been caregivers for at least 44 months improved with CB therapy. These findings suggest that patient-specific variables should be considered when choosing treatment for clinically depressed family caregivers.", "To standardise the delivery of a brief group cognitive behaviour therapy intervention (CBT-G). To apply the intervention in a research setting and to estimate its effect on recurrence rates in recently depressed older adults, in preparation for a definitive study.\n A CBT-G therapy manual was produced and the Cognitive Therapy Rating Scale (CTS-R) modified to assess therapy delivery. Forty-five adults aged 60 and over who had met ICD-10 criteria for major depression in the previous year and were still taking antidepressant medication were randomly allocated to CBT-G/antidepressant combination or antidepressant alone. Depression severity was measured at baseline, randomisation and 6 and 12 months after start of CBT-G using the Montgomery Asberg Rating Scale for Depression (MADRS).\n One-year recurrence rates on the MADRS were encouragingly lower in participants receiving CBT-G [5/18 (27.8%)] compared with controls [8/18 (44.4%)] although this did not achieve statistical significance (adjusted RR 0.70 [95% CI 0.26-1.94]). In contrast, overall scores on the secondary outcome measure, the Beck Depression Inventory, increased in participants receiving CBT-G. The CBT-G manual was successfully implemented and therapy delivery achieved an overall satisfactory level of competence. We believe that evaluation of this promising intervention in a full-scale trial is warranted.\n (c) 2008 John Wiley & Sons, Ltd.", "The authors used a randomized trial to compare cognitive-behavioral therapy (CBT) and supportive counseling (SC) in the treatment of anxiety symptoms in older adults who met Diagnostic and Statistical Manual of Mental Disorders (4th ed.: American Psychiatric Association, 1994) criteria for anxiety disorders. Both conditions had a 6-week baseline no-treatment phase. Treatment was delivered primarily in patients' own homes and in an individual format. Outcomes were assessed at posttreatment and at 3-, 6-, and 12-month follow-ups. There was no spontaneous improvement during the baseline phase. Both groups showed improvement on anxiety measures following treatment, with a better outcome for the CBT group on self-rating of anxiety and depression. Over the follow-up period, the CBT group maintained improvement and had significantly greater improvement than the SC group on anxiety and 1 depression measure. Treatment response for anxiety was also superior for the CBT group, although there was no difference between groups in endstate functioning.", "Fifteen elderly depressed psychiatric inpatients were randomly assigned to receive either standard three-times-weekly electroconvulsive therapy (ECT) or once-weekly ECT. Outcome measures included cognitive assessment and antidepressant response. Although both groups improved with treatment, the three-times-weekly group improved substantially more quickly. There was no difference in cognitive effect between the two groups. We conclude that the traditional three-times-weekly schedule of ECT may optimally balance speed of antidepressant response and cognitive impairment.", "This trial compared a brief group cognitive-behavioral (CBT) depression prevention program to a waitlist control condition and four placebo or alternative interventions. High-risk adolescents with elevated depressive symptoms (N=225, M age=18, 70% female) were randomized to CBT, supportive-expressive group intervention, bibliotherapy, expressive writing, journaling, or waitlist conditions and completed assessments at baseline, termination, and 1- and 6-month follow-up. All five active interventions showed significantly greater reductions in depressive symptoms at termination than waitlist controls; effects for CBT and bibliotherapy persisted into follow-up. CBT, supportive-expressive, and bibliotherapy participants also showed significantly greater decreases in depressive symptoms than expressive writing and journaling participants at certain follow-up points. Findings suggest there may be multiple ways to reduce depressive symptoms in high-risk adolescents, although expectancies, demand characteristics, and attention may have contributed to the observed effects.", "Fifty-three child and adolescent psychiatric patients with depressive disorders were randomly allocated to brief cognitive-behaviour therapy (CBT) or to a control treatment, relaxation training. Forty-eight patients completed the treatment phase of the trial, which comprised 5-8 treatment sessions. Post-treatment assessments showed a clear advantage of CBT over relaxation on measures of both depression and overall outcome. However, there were no significant differences between the treatments on comorbid anxiety and conduct symptoms. At follow-up, the differences between the groups were reduced, partly because of a high relapse rate in the DTP group and partly because subjects in the relaxation group continued to recover.", "Thirty-one community-residing older adults age 60 or over either received 16 sessions of individual cognitive psychotherapy (Beck, Rush, Shaw, & Emery, 1979) or read Feeling Good (Bums, 1980) for bibliotherapy. Posttreatment comparisons with the delayed-treatment control indicated that both treatments were superior to a delayed-treatment control. Individual psychotherapy was superior to bibliotherapy at posttreatment on self-reported depression, but there were no differences on clinician-rated depression. Further, bibliotherapy participants continued to improve after posttreatment. and there were no differences between treatments at 3-month follow-up. Results suggest that bibliotherapy and that individual psychotherapy are both viable treatment options for depression in older adults.", "One-hundred and twenty-four patients with metastatic breast cancer were randomised to either a group Cognitive Behaviour Therapy (CBT) intervention, or to a no-therapy control group condition. Both groups received standard oncological care; however, therapy recipients also attended eight weekly sessions of group CBT, followed by a family night, and three further monthly sessions. Patients completed the 'Profile of Mood States' (POMS) and the Coopersmith Self-esteem Inventory (CSI) before and after therapy, and at 3 and 6 month follow-up periods. Outcome data in the period following therapy showed reduced depression and total mood disturbance, as well as improved self-esteem amongst therapy participants, relative to a no-therapy control group. These improvements were no longer evident at the 3 or 6 month follow-up assessments. We also report on the difficulties associated with conducting a group intervention with this patient cohort." ]	Only a small number of studies and patients were included in the meta-analysis. If taken on their own merit, the findings do not provide strong support for psychotherapeutic treatments in the management of depression in older people. However, the findings do reflect those of a larger meta-analysis that included patients with broader age ranges, suggesting that CBT may be of potential benefit.
CD003193	[ "18977983", "12696778", "9638316", "12905110", "20943711", "7905226", "17010005", "20212061", "10569604", "7049301", "15276691", "2666205", "11435842", "17113893", "12201616", "7997065" ]	[ "Combination therapy with desmopressin and an anticholinergic medication for nonresponders to desmopressin for monosymptomatic nocturnal enuresis: a randomized, double-blind, placebo-controlled trial.", "Neuromodulative treatment of overactive bladder--noninvasive tibial nerve stimulation.", "[Intravesical instillation of trospium chloride, oxybutynin and verapamil for relaxation of the bladder detrusor muscle. A placebo controlled, randomized clinical test].", "[Postoperative routine use of physostigmine on vigilance, cardiovascular parameters and need of analgesics].", "Comparison of different treatment protocols in the treatment of idiopathic detrusor overactivity: a randomized controlled trial.", "Efficacy of maintenance use of anticholinergic agents.", "Naftopidil monotherapy vs naftopidil and an anticholinergic agent combined therapy for storage symptoms associated with benign prostatic hyperplasia: A prospective randomized controlled study.", "Comparison of intravaginal electrical stimulation and trospium hydrochloride in women with overactive bladder syndrome: a randomized controlled study.", "Desmopressin resistant enuresis: pathogenetic and therapeutic considerations.", "Urinary incontinence in old age. A controlled clinical trial of emepronium bromide.", "Effect of switching to atypical antipsychotics on memory in patients with chronic schizophrenia.", "Efficacy of benztropine therapy for drooling.", "A short-term, multicenter, randomized double-blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence.", "Comparison of electric stimulation and oxybutynin chloride in management of overactive bladder with special reference to urinary urgency: a randomized placebo-controlled trial.", "Treatment of overactive bladder with once-daily extended-release tolterodine or oxybutynin: the antimuscarinic clinical effectiveness trial (ACET).", "Interaction between psychological and pharmacological treatment in cognitive impairment." ]	[ "Desmopressin is an approved medical therapy for the treatment of monosymptomatic primary nocturnal enuresis. In cases of limited response to desmopressin, we have added anticholinergic therapy to desmopressin (combination therapy). To evaluate this treatment strategy, we examined the efficacy of combination therapy for primary nocturnal enuresis in desmopressin-nonresponders.\n Only patients with primary nocturnal enuresis refractory to the maximal dosage of desmopressin were enrolled. Children with lower urinary tract symptoms or bowel dysfunction were excluded, on the basis of a 3-day, 24-hour, frequency-volume chart and elimination record. Children continued to take desmopressin and were assigned randomly, in a double-blind manner, to receive either extended-release anticholinergic medication or placebo. Patients were reassessed after 1 month of therapy, with a 1-week nocturnal record.\n Forty-one desmopressin-nonresponders were enrolled, and 7 patients were excluded because of noncompliance. The treatment groups were equally matched with respect to age, gender, functional bladder capacity, and number of wet nights per week. After 1 month of treatment, there was a significant reduction in the mean number of wet nights in the combination therapy group, compared with the placebo group. With a generalized estimating equation approach, there was a significant 66% decrease in the risk of a wet episode, compared with the placebo group.\n This study represents the first prospective, placebo-controlled trial examining the effect of desmopressin in combination with long-acting, anticholinergic, bladder-relaxing therapy for monosymptomatic primary nocturnal enuresis.", "Conservative treatment of overactive bladder employes behavioral or invasive neuromodulatory inhibition of miction reflex and administration of anticholinergic drugs.\n The aim of this study was to use non-invasive stimulation of the tibial nerve with the intention to achieve desired therapeutic effects without iatrogenic nerve damage using a superficial electrostimulation.\n All patients suffered from overactive bladder (OAB) without bladder outlet obstruction. OAB was examined by the Behavioral urge score BUS (0.0--the best and 1.0--the worst score), the International prostate symptom score IPSS (0--the best and 35--the worst score) and the Incontinence quality of life questionnaire IQOL (0.0--the worst and 1.0--the best index). The patients were divided into 3 groups: Group I--patients with electrode attached behind the medial ankle of the left lower extremity. The intensity of stimulation corresponded to 70% of the maximum amplitude of response from musculus abductor hallucis. Frequency of stimulation was 1 Hz and duration of the square impulse was 0.1 ms. Surface stimulation lasted 30 minutes and was repeated once a week. Group II--patients were treated by oral oxybutynin 5 mg t.i.d. Group III--patients without treatment. The BUS, IPSS, and IQOL were repeated after the treatment.\n The study included 28 females of average age 54 year (range 45 to 63). Mean IPSS was 17 (range 12 to 21), mean index of quality of life IQOL was 30 (range 12 to 78) and mean BUS score was 0.68 (range 0.50 to 0.86). Group I with stimulation did achieve statistically significant changes following the treatment: decrease of mean IPSS from 17 +/- 3 points to 6 +/- 4 points after the treatment, increase in mean IQOL from 36 +/- 10 to 68 +/- 20 and decrease of mean BUS from 0.65 +/- 0.12 to 0.43 +/- 0.16. Group II had similar statistically significant differences after the treatment of OAB. Group III noted no changes in the complaints.\n Noninvasive stimulation had improved subjective symptom related to overactive bladder, had no adverse events and was well tolerated. (Fig. 1, Tab. 1, Ref. 18.).", "Therapy of detrusor hyperactivity with anticholinergic agents often is followed by adverse drug reactions. Intravesical application may be an interesting alternative. A randomised, single-blind, placebo-controlled, mono-centre clinical trial was carried out in 84 patients with urgency or urge incontinence. Due to intravesical administration of oxybutynin (CAS 5633-20-5) (n = 21) and trospium chloride (CAS 10405-02-4) (n = 21), respectively, a significant increase in maximum bladder capacity and decrease of detrusor pressure accompanied by an increase of residual urine were found in comparison to placebo in urodynamical investigations. Improvement of uninhibited bladder contractions occurred leading to higher filling volume. Under verapamil (CAS 152-11-4) (n = 21) no marked changes in the efficacy variables were found compared with placebo. All patients completed the study and were assessed with regard to efficacy and safety. No adverse events or marked changes in the vital signs were reported. The immediate onset of effect and the lack of adverse drug reactions suggest that treatment with topical oxybutynin or trospium chloride is an effective alternative in patients with intolerable side effects when orally treated. In addition, intravesical administration may be indicated in patients with bladder spasms due to indwelling catheter or in order to increase bladder capacity before percutaneous cystostomy.", "A central anticholinergic syndrome (CAS) can be related to the majority of anesthetic agents, but is often not recognized as such. Thus, most anesthesiologists seem to miss the occurrence of an anticholinergic syndrome especially when agitation and/or restlessness are the major symptoms. Therefore, the following study was undertaken to test the hypothesis that routine administration of the anticholinergic agent physostigmin is of benefit for patients in regard to vigilance, the cardiovascular system and the need of analgesics easing the time in the post anesthesia care unit (PACU).\n After approval by the local ethics committee and written informed consent, 100 patients undergoing a cholecystectomy or a struma resection, were given either physostigmin (n = 51) or saline 0.9 % (n = 49) in a randomized fashion. The study was conceived to block a possible isoflurane-N2O/O2 (opioid-based plus relaxant) induced central anticholinergic syndrome and to evaluate the effects on the cardiovascular system on vigilance and on postoperative analgesic demand. Following parameters were measured: systolic and diastolic blood pressure, heart rate, respiratory rate, and arterial blood gases. In addition, vigilance was determined and typical anticholinergic symptoms (disorientation, slurred speech, agitation, nausea, emesis, cardiac arrhythmia and muscle shivering) were determined 10, 20, 40 and 60 minutes following the intravenous injection of physostigmin. Also, the need for the postoperative analgesic pethidine was evaluated among the two groups.\n Except for a significant reduction in the need of analgesics, a reduced diastolic pressure and heart rate and a lower incidence of muscle shivering there was no difference among the two groups. One major side effect following the use of physostigmin was the higher incidence of nausea in the im mediate minutes following injection. This effect may be due to the rapid injection of the anticholinergic compound. Otherwise there were no detrimental effects of physostigmin in patients.\n From the results it can be concluded that routine administration of an anticholinergic agent results in a short term beneficial effect in regard to vigilance, a lesser incidence of muscle shivering and a lesser demand for analgesics. However, because of the low incidence of a classical central anticholinergic syndrome, routine physostigmine is only indicated when agitation is diagnosed.", "To investigate and compare the effectiveness of various treatment protocols for the treatment of women with idiopathic detrusor overactivity.\n Prospective, randomized controlled trial.\n Departments of Physiotherapy and Rehabilitation and Obstetrics and Gynaecology, Hacettepe University.\n Forty-six subjects were randomized to three groups.\n The first group received only pharmacotherapy, the second group received only physiotherapy and in the third group pharmacotherapy was combined with physiotherapy (combined therapy group).\n All patients were evaluated at the beginning and at the end of treatment. Assessment parameters were maximum cystometric capacity, electromyographic activity of pelvic floor muscles, voiding diary parameters, the amount of urine leakage and the quality of life score.\n The maximum cystometric capacity and the electromyographic activity of pelvic floor muscles increased significantly and the number of voids/day and incontinence episodes/day, and the amount of urine leakage reduced significantly (P < 0.05) in both physiotherapy and combined therapy groups while there was no significant difference in the pharmacotherapy group. After treatment, the number of voids/day increased by 0.3 ± 3.4 in the pharmacotherapy group (P > 0.05) and decreased by 5.1 ± 5.5 and 4.7 ± 5.6 in the physiotherapy and combined therapy groups, respectively (P < 0.05). Statistically significant improvements were observed in all groups according to the number of voids/night and the quality of life scores at the end of the treatment.\n The physiotherapy protocol we introduced in the present study with or without anticholinergic therapy has a substantial positive impact on the treatment of female patients with idiopathic detrusor overactivity.", "Twenty-seven long-term psychiatric inpatients maintained on neuroleptics with concomitant antiparkinsonian medication were entered into a study in which anticholinergic medication was gradually withdrawn in a randomized double-blind within-subjects design. The extrapyramidal symptoms of each patient were compared when taking their usual anticholinergic medication, when taking placebo and when taking no antiparkinsonian drug. The relapse rate on no medication was 14%, and if patients relapsed on no medication they also relapsed on placebo. The relapse rate was not significantly different on active medication. Nor were there significant differences in ratings of parkinsonism or dyskinesia. The lack of difference between double-blind and overt withdrawal does not mean that studies that find a much higher relapse rate are necessarily unaffected by nonspecific factors, as significant unblinding may occur in clinical trials.", "The aim of this study was to compare the efficacy and safety of alpha1-adrenoceptor (alpha1-AR) antagonist monotherapy with combination therapy using alpha1-AR antagonist and anticholinergic agent for benign prostatic hyperplasia (BPH) with storage symptoms as the chief complaint.\n In this prospective comparative study, either 25-75 mg/day of naftopidil monotherapy (monotherapy group) or combination therapy using 25-75 mg/day of naftopidil and an anticholinergic agent (10-20 mg/day of propiverine hydrochloride or 2-6 mg/day of oxybutynin hydrochloride; cotherapy group) were administered for 12 weeks to 101 BPH patients with storage symptoms.\n International prostate symptom score (IPSS) and quality of life (QOL) index improved significantly in both groups, with no marked differences between groups. Maximum flow rate (Qmax) and residual urine volume (RUV) tended to improve in both groups, again with no marked differences between groups. However, median post-therapeutic RUV was significantly worse for the cotherapy group (45.0 mL) than for the monotherapy group (13.5 mL; P = 0.0210). Ratio of patients with increased RUV was also significantly worse for cotherapy (22.9%) than for monotherapy (5.0%; P = 0.038).\n Although the anticholinergic dosage was low, the present results suggest that naftopidil monotherapy was as useful as combination therapy of naftopidil and an anticholinergic agent. Therefore, naftopidil is a useful agent as the first choice in BPH patients with storage symptoms.", "To compare the effects of trospium hydrochloride and electrical stimulation on urodynamic parameters, bladder diary, quality of life and psychological symptoms in female patients with overactive bladder syndrome.\n Prospective, randomized controlled trial.\n Department of Physical Medicine and Rehabilitation, University Hospital.\n Thirty-five patients were divided into either trospium chloride (Group 1) or intravaginal electrical stimulation therapy (Group 2).\n All patients were assessed at the beginning of the treatment, at weeks 6 (end of treatment), 10 and 18 according to urodynamic parameters, voiding diary parameters, severity of urgency (visual analogue scale, VAS), the Incontinence Impact Questionnaire Short Form (IIQ-7), and the Beck Depression Inventory.\n Statistically significant improvements were observed in both groups according to some urodynamic parameters, voiding diary parameters, VAS urgency severity, Incontinence Impact Questionnaire Short Form and Beck Depression Inventory scores at the end of the treatment (P<0.05). During the 18-week follow-up period, deteriorations were observed in many parameters in both groups although improvements in the frequency of urgency, the frequency of incontinence episodes, VAS urgency severity, and Beck Depression Inventory score in Group 2 persisted (P<0.05). Significant differences were not detected between groups at the end of the treatment or during the posttreatment follow-up controls (P>0.05).\n No difference was detected between trospium hydrochloride and intravaginal electrical stimulation in the treatment of female overactive bladder syndrome. Discontinuation of both treatments caused deterioration in most of the objective and subjective symptoms of overactive bladder syndrome.", "We tested the role of the bladder in the pathogenesis of desmopressin resistant enuresis by evaluating the influence of urine production on the timing of the enuretic event and the response to anticholinergic medication.\n We gave 33 children with monosymptomatic nocturnal enuresis resistant to the standard 0.4 mg. oral dose of desmopressin 0.4 and 0.8 mg. desmopressin and placebo tablets for 5 nights each in a double-blind crossover fashion. The time of enuresis or nocturia was documented. All 9 children who had at least 1 dry treatment period during the randomized portion of the study then received open label treatment with 0.8 mg. desmopressin. Nonresponders to this regimen and the remainder of the children were offered anticholinergic treatment.\n Average time between bedtime and voiding was 5.0, 5.6 and 5.0 hours during the nights with placebo, and 0.4 and 0.8 mg. desmopressin, respectively (p = 0.12). Of the 9 children subsequently treated with 0.8 mg. desmopressin 5 became completely dry. Of the remaining 28 children given anticholinergic treatment 20 responded.\n Antidiuresis does not delay the enuretic event in children with desmopressin resistant enuresis. This finding and the favorable response to anticholinergic medication favor the hypothesis that these children have nocturnal bladder instability. A subgroup of enuretic children responds to high but not normal doses of desmopressin.", "The effect of the anticholinergic agent, emepronium bromide (Cetiprin), was studied in a double blind crossover study of a group of elderly patients with urinary incontinence and uninhibited bladder contractions during cystometry. There was no statistically significant difference between the subjective effect of emepronium bromide and that of placebo, and no change in the cystometric parameters. The overall subjective cure or improvement rate was 79%. The effect of anticholinergic drugs in the treatment of urinary incontinence in elderly patients with uninhibited bladder contractions might to some extent be due to an improvement in the patients' understanding and acceptance of the bladder disorders.", "While the usefulness of atypical antipsychotics for improving cognitive function has been proven, the specific effects of these drugs are still unknown. The objective of this study was to investigate changes of the immediate memory and verbal working memory in patients with chronic schizophrenia after switching to one of four atypical antipsychotic agents and cessation of anticholinergic therapy. The subjects included 77 schizophrenic patients who were treated primarily with typical antipsychotics. Treatment was randomly switched to one of four atypical antipsychotics (olanzapine, perospirone, quetiapine, or risperidone) over a 4-week period, and then the drug was continued for another 4 weeks while the patient was taken off anticholinergics. The immediate memory, verbal working memory, and symptoms were evaluated. Significant improvement of immediate memory was only seen with olanzapine and risperidone. Improvement was also seen after switching to perospirone, but immediate memory worsened after treatment with this anticholinergic drug was discontinued. Deterioration was seen after switching to quetiapine, but immediate memory improved and reached the previous level after treatment with anticholinergic drugs was discontinued. Significant improvement of the verbal working memory was only seen during risperidone administration. The findings suggested that switching chronic schizophrenic patients to atypical antipsychotics can improve both the immediate memory and the verbal working memory when risperidone is used, while improvement of immediate memory can be expected with olanzapine. From the viewpoint of improving the memory, quetiapine should not be administered concomitantly with anticholinergic drugs, and caution should be exercised when discontinuing anticholinergic drugs during treatment with perospirone.", "This study assessed the efficacy of synthetic anticholinergic benztropine and incidence of side-effects in 20 developmentally-disabled patients with severe drooling. The double-blind, placebo-controlled, crossover protocol included one-week baseline, two-week placebo and two-week benztropine conditions (mean dose 3.8 mg). A significant decrease in drooling during the benztropine condition relative to placebo was demonstrated and conservative response rates (calculated by deleting placebo responders), ranged up to 65 to 70 per cent. For patients completing the protocol the incidence of side-effects did not differ across conditions and minor problems such as a dry mouth were eliminated by small dose adjustments. More serious cholinergic side-effects, which resolved within 24 to 48 hours, necessitated discontinuation of the drug in three patients. This study demonstrates that synthetic anticholinergics can provide an important therapeutic alternative to surgical and behavioral therapies for drooling.", "We compared the short-term efficacy, safety and tolerability of transdermal versus oral oxybutynin in adults with urge urinary incontinence.\n Volunteers with detrusor instability currently responding to oral immediate release oxybutynin were enrolled in our study. Those patients presenting with recurrence of incontinent symptoms after a 2-week washout underwent confirmatory cystometrogram with subsequent randomization to transdermal or oral treatment. Matching active and placebo medications included matrix patches applied twice weekly and capsules taken 2 or 3 times daily. Dose titration was based on anticholinergic symptoms. Outcome measures included comparison of baseline to 6 week changes in incontinence episodes on a 3 day urinary diary, a visual analog scale for efficacy and anticholinergic symptoms reported on a questionnaire. Safety monitoring included adverse events and skin tolerability of the transdermal system.\n A total of 76 patients were enrolled and 74 completed at least 4 weeks of treatment. Mean age in the transdermal and oral groups was 64 and 63 years, and 87% and 97% were female, respectively. Daily incontinent episodes decreased in the transdermal and oral groups (7.3 to 2.4 [66%] and 7.4 to 2.6 [72%], respectively, p = 0.39). The visual analog scale reduction in urinary leakage improved from washout in both groups (p <0.0001) with no difference between them (p = 0.9). Dry mouth occurred in significantly fewer patients in the transdermal (38%) compared with those in the oral group (94%, p <0.001). Of the patients in the transdermal group 67% noticed a reduction in dry mouth severity compared with previous oral treatment, and 90% had none or mild skin erythema.\n Transdermal delivery of oxybutynin resulted in comparable efficacy and a significantly improved anticholinergic side effect profile compared with oral administration in adults with urge urinary incontinence.", "To compare the efficacy of electric stimulation (ES), oxybutynin, and placebo in managing the symptom complex of overactive bladder (OAB), particularly urgency.\n A randomized placebo-controlled trial was conducted for 68 patients with OAB, placing emphasis on urinary urgency. The interventions for the 12-week treatment period, conducted by the physiotherapist, who was unaware of the progress and outcome, included a vaginal ES program using biphasic symmetric, pulsed current with a 10-Hz frequency, 400-micros pulse width, 10/5 duty cycle, and varying intensity; and oxybutynin (2.5 mg) or placebo three times per day. Identical preintervention and postintervention assessments included the measurement of warning time, urodynamics, voiding diaries, and King's Health Questionnaire.\n Of the 68 women who completed this study, 24 were in the ES, 23 in the oxybutynin, and 21 in the placebo group. The between-group comparison showed that significant improvements in daily voided volume, pad count, number of urgency and nocturia episodes, and the domain 2 score and total score of the King's Health Questionnaire existed between the ES and the other groups (all P < or = 0.050). The changes in warning time, maximal voided volume, number of urgency episodes, and frequency were significantly improved between oxybutynin and placebo (all P < 0.013). Additionally, a comparison of the voided volume in uroflowmetry between the ES and placebo groups revealed a greater difference after treatment (P = 0.013). The reduction rate of OAB was 58.4% for the ES, 39.1% for the oxybutynin, and 9.5% for the placebo group (P = 0.036).\n ES had the greatest subjective outcome for OAB and was the most effective of the three treatments. Oxybutynin was more effective than placebo.", "Treatment with the antimuscarinic agents tolterodine and oxybutynin is the mainstay of therapy for overactive bladder, a chronic and debilitating condition characterized by urinary urgency with or without urge incontinence, usually in combination with urinary frequency and nocturia. This study consisted of two trials; in one, patients with overactive bladder were randomized to 8 weeks of open-label treatment with either 2 mg or 4 mg of once-daily extended-release tolterodine (TER), and in the other to 5 mg or 10 mg of extended-release oxybutynin (OER). The study protocol and design were identical for the two trials and site selection ensured that there was no bias in either trial for the tendency of investigators to prescribe one drug rather than the other, or for geographical location. A total of 1289 patients were enrolled, 669 in the tolterodine trial (TER 2 mg, n = 333; TER 4 mg, n = 336) and 620 in the oxybutynin trial (OER 5 mg, n = 313; OER 10 mg, n = 307). Fewer patients prematurely withdrew from the trial in the TER 4 mg group (12%) than either the OER 5 mg (19%; p = 0.01) or OER 10 mg groups (21%; p = 0.002). More patients in the OER 10 mg group than the TER 4 mg group withdrew because of poor tolerability (13% vs 6%; p = 0.001). After 8 weeks, 70% of patients in the TER 4 mg group perceived an improved bladder condition, compared with 60% in the TER 2 mg group, 59% in the OER 5 mg group and 60% in the OER 10 mg group (all p < 0.01 vs TER 4 mg). Response to therapy was greater in a subgroup of patients whose perception of bladder condition was moderate to severe at baseline (TER 4 mg 77% vs OER 10 mg 65%; p < 0.01). Dry mouth was dose-dependent with both agents, although differences between doses only reached statistical significance in the oxybutynin trial (OER 5 mg vs OER 10 mg; p = 0.05). Patients treated with TER 4 mg reported a significantly lower severity of dry mouth compared with OER 10 mg. In conclusion, the greater efficacy and tolerability of tolterodine ER 4 mg suggests improved clinical effectiveness compared with oxybutynin ER 10 mg.", "In contrast to other kinds of psychotropic drugs, nootropics or cognition enhancing drugs may be indicated, not for the direct treatment of the pathology itself, but for improving or restoring the remaining brain functions. Brain functions are normally trained during various kinds of non-medical therapy, such as physiotherapy, speech therapy, occupational therapy, memory training etc... In research little attention has been paid to the combination of both kinds of therapeutic approaches, probably because of the important methodological difficulties. This combination however, offers various interesting perspectives: L. ISRAEL examined in two placebo-controlled studies the effects of either 160 mg/d of ginkgo biloba extractum (GBE) or piracetam 2.4 or 4.8 g/d, combined with a memory training program, in nondemented patients complaining of memory problems. The results of both studies suggest that nootropic drug treatment and memory training have each an effect on different cognitive functions and, hence, are complementary. Some functions, like attention/perception in the GBE study and learning in the piracetam study, seem to benefit from both treatments, suggesting a mutually potentiating effect of drug treatment and training. This potentiation is very clear in the treatment of dyslexic children: in a placebo-controlled study piracetam 3.3 g/d, in combination with normal school teaching and more specific logopedic therapy, allowed a normal progression during the full school year in reading accuracy and reading comprehension, while the placebo treated children getting a similar training progressed only with 50%. Recently promising results were obtained in the treatment of dysphasic patients with a combination of speech therapy and piracetam 4.8 g/d, especially when given during the first months after the stroke, or otherwise in combination with an intensive speech training. In both double-blind studies the piracetam treated group improved about 60% more than the group who only got speech therapy and placebo. All these data may be explained by the restorative or enhancing influence of nootropic drugs on neurotransmitter systems closely related to learning and memory functions. E.g. piracetam restores the availability and function of muscarinic and NMDA receptors in aging animals, most probably through a modulation of the psychico-chemical properties of the neuronal membrane such as the membrane fluidity." ]	The use of anticholinergic drugs in the management of overactive bladder syndrome is well established when compared to placebo treatment. During initial treatment of overactive bladder syndrome there was more symptomatic improvement when (a) anticholinergics were compared with bladder training alone, and (b) anticholinergics combined with bladder training were compared with bladder training alone. Limited evidence from small trials might suggest electrical stimulation is a better option in patients who are refractory to anticholinergic therapy, but more evidence comparing individual types of electrostimulation to the most effective types of anticholinergics is required to establish this. These results should be viewed with caution in view of the different classes and varying doses of individual anticholinergics used in this review. Anticholinergics had well recognised side effects, such as dry mouth.
CD009805	[ "20103449", "15105064", "6804162" ]	[ "Intrauterine contraception for adolescents aged 14-18 years: a multicenter randomized pilot study of levonorgestrel-releasing intrauterine system compared to the Copper T 380A.", "Clinical performance of a levonorgestrel-releasing intrauterine system and oral contraceptives in young nulliparous women: a comparative study.", "A randomized, double-blind study of two combined and two progestogen-only oral contraceptives." ]	[ "Intrauterine contraception can provide adolescents with effective, long-term contraception as well as with other health benefits. In adult populations, intrauterine contraception rates highly in patient satisfaction and safety. It is rarely prescribed to adolescents because of limited data.\n Multicenter, randomized, controlled, participant-blinded pilot study of 14-18-year-old females assigned to the Copper T 380A intrauterine device or the Levonorgestrel Intrauterine System. Participants were followed up for 6 months following insertion.\n We enrolled 23 participants; 12 received the Levonorgestrel Intrauterine System, and 11 received the Copper T 380A. At 6 months, the continuation rates were 75% for the Levonorgestrel Intrauterine System users and 45% for the Copper T 380A users (p=.15). Two Copper T 380A users experienced partial expulsion. Heavy bleeding and pelvic pain were the most commonly reported side effects. Participants rated both methods favorably.\n This study shows that at 6 months, though not statistically significant, adolescent continuation rates trended towards being greater with the Levonorgestrel Intrauterine System compared to the Copper T 380A. These pilot data will be helpful in the design of a larger trial of intrauterine contraception use among adolescents.", "This 1-year randomized study was carried out at family-planning clinics of two university hospitals to compare the safety and acceptability of a levonorgestrel-releasing intrauterine system (LNG IUS) and oral contraceptives (OCs) in young nulliparous women. The study population consisted of 200 women aged 18-25 years seeking contraception. Ninety-four women entered the LNG IUS group and 99 entered the OC group. Continuation rates, reasons leading to discontinuation, adverse events, menstrual questionnaires, subjective well-being and sexual behavior were evaluated. Nineteen women (20%) in the LNG IUS group discontinued the study during the 1-year observation period, and 27 discontinued (27%) in the OC group. The most common reason (31%) for discontinuation in the IUS group was pain. In the OC group, hormonal side effects were the predominant medical reason for study termination. The safety and acceptability of the LNG IUS for contraception was observed to be as good as with OCs, with a high continuation rate.", "A randomized double-blind study of two combined oral contraceptives and two progestogen-only oral contraceptives was conducted using the same protocol at WHO Collaborating Centres for Clinical Research in Human Reproduction in Bombay and Ljubljana of the 518 women admitted to the trial, 123 received mestranol 50 micrograms + norethisterone 1mg (MES 50 + NET 1); 137 received ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (EE 30 + LNG 150); 130 received norethisterone 350 micrograms/NET 350); and 128 received levonorgestrel 30 micrograms (LNG 30). At one year, between 52.6 and 61.0 percent of those recruited had discontinued oral contraceptive use for all reasons, and by two years, between 70.5 and 76.5 percent had discontinued the treatment. These rates did not differ between the four treatment groups. However, discontinuation rates for all medical reasons at one and two years, and at two years pregnancy rates and discontinuation rates for bleeding disturbances, were significantly lower in the EE/LNG preparation. The groups receiving the MES/NET, LNG and NET had similar pregnancy rates, discontinuation rates for all medical reasons and all bleeding disturbances. There were two ectopic pregnancies among the 22 pregnancies in the progestogen-only groups. Discontinuation because of headache, dizziness and other central nervous system symptoms were significantly more common in those receiving MES/NET compared to EE/LNG. In contrast, discontinuation for gastro-intestinal disturbances were significantly higher in the EE/LNG combined preparation. Bleeding disturbances in the first few cycles tended to be higher in NET than in the LNG group. The data suggest that greater consideration be given to the benefits and risks of including progestogen-only oral contraceptives in the family planning programmes of some countries." ]	Current evidence is insufficient to compare contraceptive efficacy and continuation rates for hormonal and intrauterine methods in women aged 25 years and younger. Limited data suggests that the levonorgestrel intrauterine system may be an acceptable alternative to the combined oral contraceptive in this population.
CD007396	[ "15502060", "11864673", "2924990", "7566849", "11641687", "10549964", "19468617", "20394251", "9855591", "9316951", "9856707", "10529851", "11424777", "3524668", "8238138", "9429041", "12411035", "6696222", "15851889", "11380379", "10403865", "11873026", "3380504", "10925565", "1378707", "9893537", "10730733", "12832372", "6387560", "17176461", "990784", "9423752", "1443741", "9113175", "8773867", "12193488", "10895743", "12366485", "11213000", "3901375", "11926643", "378732", "3278653", "6393827" ]	[ "A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor.", "A randomized trial of intrapartum analgesia in women with severe preeclampsia.", "Epidural block or parenteral pethidine as analgesic in labour; a randomized study concerning progress in labour and instrumental deliveries.", "Randomized trial of epidural versus intravenous analgesia during labor.", "A randomized trial of labor analgesia in women with pregnancy-induced hypertension.", "Intramuscular opioids for maternal pain relief in labour: a randomised controlled trial comparing pethidine with diamorphine.", "Labor analgesia: a comparative study between combined spinal-epidural anesthesia versus continuous epidural anesthesia.", "Labor analgesia in preeclampsia: remifentanil patient controlled intravenous analgesia versus epidural analgesia.", "The influence of epidural analgesia on cesarean delivery rates: a randomized, prospective clinical trial.", "Cesarean delivery: a randomized trial of epidural versus patient-controlled meperidine analgesia during labor.", "A randomized study of combined spinal-epidural analgesia versus intravenous meperidine during labor: impact on cesarean delivery rate.", "Prospective, randomized comparison of epidural and combined spinal epidural analgesia during labor.", "[Evaluation of the peripartum effects of 2 analgesics: meperidine and tramadol, used in labor].", "Pain relief in labour using transcutaneous electrical nerve stimulation (TENS). A TENS/TENS placebo controlled study in two parity groups.", "The effect of intrapartum epidural analgesia on nulliparous labor: a randomized, controlled, prospective trial.", "Intravenous fentanyl PCA during labour.", "Clinical study on labor pain relief using the combined spinal-epidural analgesia and inhaling nitrous oxide.", "Postoperative analgesia for Caesarean section using epidural methadone.", "Intravenous butorphanol, meperidine, and their combination relieve pain and distress in women in labor.", "Immersion in water in the first stage of labor: a randomized controlled trial.", "Effect of maternal ambulation on labour with low-dose combined spinal-epidural analgesia.", "Cesarean delivery: a randomized trial of epidural analgesia versus intravenous meperidine analgesia during labor in nulliparous women.", "Patient-controlled analgesia for post-cesarean section pain.", "Effects of epidural fentanyl on labor pain during the early period of the first stage of induced labor in nulliparous women.", "Epidural patient-controlled analgesia: an alternative to intravenous patient-controlled analgesia for pain relief after cesarean delivery.", "Regional analgesia in early active labour: combined spinal epidural vs. epidural.", "Comparison of combined spinal-epidural and low dose epidural for labour analgesia.", "Electro-acupuncture as a peroperative analgesic method and its effects on implantation rate and neuropeptide Y concentrations in follicular fluid.", "Submucous paracervical blockade compared with intramuscular meperidine as analgesia during labor: a double-blind study.", "Effects of epidural lidocaine analgesia on labor and delivery: a randomized, prospective, controlled trial.", "Reversal of narcotic depression in the neonate by nalozone.", "Nulliparous active labor, epidural analgesia, and cesarean delivery for dystocia.", "A comparison of intrathecal, epidural, and intravenous sufentanil for labor analgesia.", "Anesthetic quality during cesarean section following subarachnoid or epidural administration of bupivacaine with or without fentanyl.", "Epidural morphine vs hydromorphone in post-caesarean section patients.", "Iliohypogastric-ilioinguinal peripheral nerve block for post-Cesarean delivery analgesia decreases morphine use but not opioid-related side effects.", "Randomized controlled comparison of epidural bupivacaine versus pethidine for analgesia in labour.", "Acupuncture in the management of pain in labor.", "A randomised controlled trial of epidural compared with non-epidural analgesia in labour.", "Continuous epidural infusion for analgesia after major abdominal operations: a randomized, prospective, double-blind study.", "The impact of intrapartum analgesia on labour and delivery outcomes in nulliparous women.", "Double-blind comparison of maternal analgesia and neonatal neurobehaviour following intravenous butorphanol and meperidine.", "Epidural narcotic and patient-controlled analgesia for post-cesarean section pain relief.", "[Transcutaneous cerebral electric stimulation by Limoge current during labor]." ]	[ "In this multicenter, randomized, controlled trial, we sought to determine whether patient-controlled epidural analgesia (PCEA) for labor affected the incidence of cesarean delivery when compared with patient-controlled IV opioid analgesia (PCIA). Healthy, term nulliparous patients in 4 Canadian institutions were randomly assigned to receive PCIA with fentanyl (n = 118) or PCEA with 0.08% bupivacaine and fentanyl 1.6 microg/mL (n = 124). There was no difference in the incidence of cesarean delivery-10.2% (12 of 118) versus 9.7% (12 of 124)-or instrumental vaginal delivery-21.2% (25 of 118) versus 29% (36 of 124)-between groups. The duration of the second stage of labor was increased in the PCEA group by a median of 23 min (P = 0.02). Fifty-one patients (43%) in the PCIA group received epidural analgesia: 39 (33%) because of inadequate pain relief and 12 (10%) to facilitate operative delivery. Patients in the PCIA group required more antiemetic therapy (17% versus 6.4%; P = 0.01) and had more sedation (39% versus 5%; P < 0.001). Maternal mean pain and satisfaction with analgesia scores were better in the PCEA group (P < 0.001 and P = 0.02, respectively). More neonates in the PCIA group required active resuscitation (52% versus 31%; P = 0.001) and naloxone (17% versus 3%; P < 0.001). These observations support the hypothesis that PCEA does not result in an increased incidence of obstetrical intervention compared with PCIA. PCEA provides superior analgesia and less maternal and neonatal sedation compared with PCIA.", "To estimate whether the cesarean delivery rate differs between women with severe preeclampsia who receive intrapartum epidural analgesia versus patient-controlled intravenous opioid analgesia.\n Women with severe preeclampsia at at least 24 weeks' gestation were randomly assigned to receive either intrapartum epidural (n = 56) versus patient-controlled intravenous opioid analgesia (n = 60), and each was administered by a standardized protocol. The sample size was selected to have 80% power to detect at least a 50% difference in the predicted intergroup cesarean delivery rates. Data were analyzed by intent to treat.\n Selected maternal characteristics and neonatal outcomes were similar in the two groups. The cesarean delivery rates in the epidural group (18%) and the patient-controlled analgesia group (12%) were similar (P =.35). Women who received epidural analgesia were more likely to require ephedrine for the treatment of hypotension (9% versus 0%, P =.02), but their infants were less likely to require naloxone at delivery (9% versus 54%, P <.001). Epidural analgesia provided significantly better pain relief as determined by a visual analogue intrapartum pain score (P <.001) and a postpartum pain management survey (P =.002).\n Compared with patient-controlled intravenous opioid analgesia, intrapartum epidural analgesia did not significantly increase the cesarean delivery rate in women with severe preeclampsia at our level III center, and it provided superior pain relief.", "A prospective randomized study was performed to evaluate the influence of epidural analgesia compared to parenteral pethidine in parturients with pain in the first stage of labour on the progress of labour and the frequency of instrumental deliveries. There was no significant difference in the two groups in the duration of either the first or second stage of labour. The overall instrumental delivery rate was 25%, with no difference between the groups. The analgesic efficacy of the epidural blockade was significantly better than that of parenteral pethidine. We conclude that epidural bupivacaine with our technique and obstetric practice did neither prolong labour nor increase the frequency of instrumental delivery.", "To compare the effects of epidural analgesia with intravenous (IV) analgesia on the outcome of labor.\n Thirteen hundred thirty women with uncomplicated term pregnancies and in spontaneous labor were randomized to be offered epidural bupivacaine-fentanyl or IV meperidine analgesia during labor.\n Comparison of the allocation groups by intent to treat revealed a significant association between epidural allocation and operative delivery for dystocia. However, only 65% of each randomization group accepted the allocated treatment. Four hundred thirty-seven women accepted and received meperidine as allocated, and they were compared with 432 women accepting epidural allocation. Significant associations resulted between epidural administration and prolongation of labor, increased rate of oxytocin administration, chorioamnionitis, low forceps, and cesarean delivery. Because of the high rate of noncompliance with treatment allocation, a multifactorial regression analysis was performed on the entire cohort, and a twofold relative risk of cesarean delivery persisted in association with epidural treatment. The impact of epidural treatment on cesarean delivery was significant for both nulliparous and parous women (risk ratios 2.55 and 3.81, respectively). Epidural analgesia provided significantly better pain relief in labor than did parenteral meperidine.\n Although labor epidural analgesia is superior to meperidine for pain relief, labor is prolonged, uterine infection is increased, and the number of operative deliveries are increased. A two- to fourfold increased risk of cesarean delivery is associated with epidural treatment in both nulliparous and parous women.", "The purpose of this study was to compare the peripartum and perinatal effects of epidural with intravenous labor analgesia in women with pregnancy-induced hypertension.\n Women with pregnancy-induced hypertension who had consented to participate were randomized to receive either epidural or intravenous analgesia for labor pain. Both methods were given according to standardized protocols. All women received magnesium sulfate seizure prophylaxis. Obstetric and neonatal outcomes were compared according to intent-to-treat allocation.\n Seven hundred thirty-eight women were randomized: 372 women were given epidural analgesia, and 366 women were given intravenous analgesia. Maternal characteristics were similar, including the severity of hypertension. Epidural analgesia was associated with a significantly prolonged second-stage labor, an increase in forceps deliveries, and an increase in chorioamnionitis. Cesarean delivery rates and neonatal outcomes were similar. Pain relief was superior with the epidural method. Hypotension required treatment in 11% of women in the epidural group.\n Epidural labor analgesia provides superior pain relief but no additional therapeutic benefit to women with pregnancy-induced hypertension.", "To compare the pain relief and side effects of intramuscular pethidine with intramuscular diamorphine in labour.\n Double-blind randomised controlled trial.\n The labour ward in a UK teaching hospital.\n Sixty-nine nulliparous women and 64 multiparous women in labour who requested narcotic analgesia and remained undelivered one hour after trial entry.\n Nulliparous women were randomised to receive either 150 mg intramuscular pethidine or 7.5 mg intramuscular diamorphine. Multiparous women were randomised to receive either 100 mg intramuscular pethidine or 5 mg intramuscular diamorphine. All participants received the anti-emetic prochloroperazine at the same time as the trial drugs.\n Maternal analgesia assessed by a visual analogue score and verbal scales of pain intensity and pain relief, maternal sedation and vomiting, neonatal outcome assessed by Apgar scores and the need for resuscitation.\n More women allocated to receiving pethidine than to diamorphine reported slight or no pain relief at 60 minutes after administration of these drugs (P = 0.03). This trend was repeated in most of the other measures for maternal analgesia. There was no difference in maternal sedation, but the incidence of vomiting within 60 minutes was lower for women who received diamorphine (P = 0.02). Pethidine was associated with lower Apgar scores at 1 minute (P < 0.05).\n Intramuscular diamorphine in labour appears to have some benefits, compared with intramuscular pethidine, but the trial was small and further research, particularly into alternative opioids and long term effects on the infants is still needed.", "Pain relief during labor is a permanent concern, aiming at the maternal well being, decreasing the stress secondary to pain, and reducing its consequences on the fetus. Several analgesia techniques can be used during labor. The aim of this study was to compare continuous and combined epidural analgesia, both of them using 0.25% bupivacaine with 50% enantiomeric excess and fentanyl.\n Forty pregnant women, in labor, with cervical dilation between 4 and 5 cm, were randomly divided in two groups. Group I received continuous epidural anesthesia. Group II received combined anesthesia. The following parameters were evaluated: anthropometric measurements, gestational age, cervical dilation, length of time between the blockade and absence of pain according to the visual analogic scale, ability to walk, length of time between analgesia and complete cervical dilation, duration of the expulsive phase, maternal hemodynamic parameters, and vitality of the newborn. Possible complications, such as respiratory depression, maternal hypotension, pruritus, nausea, and vomiting were also evaluated. The Student t test was used to compare the means and the Chi-square test was used to compare the number of pregnancies and type of labor.\n There were no statistically significant differences between both groups regarding the length of time between the beginning of analgesia and complete cervical dilation, as well as regarding the duration of the expulsive phase, incidence of cesarean section related to the analgesia, maternal hemodynamic parameters, and vitality of the newborn.\n Both techniques are effective and safe for labor analgesia, although the combined technique provided fast and immediate pain relief. Clinical studies with a larger number of patients are necessary to evaluate the differences in the incidence of cesarean sections.", "Epidural analgesia is considered to be the preferred method of labor analgesia in preeclamptic patients. Systemic opioids are another good effective, easy to administer alternative but may cause maternal and fetal respiratory depression. Remifentanil's rapid onset and offset of effects, should make it an ideal drug for the intermittent painful contraction during labor. Method. 30 preeclamptic patients were randomly assigned to one of two equal groups; Epidural Group: received epidural analgesia according to a standardized protocol using bupivacaine plus fentanyl. REMIFENTANIL GROUP: PCA was set up to deliver remlfentanil 0.5 microg/kg as a loading bolus infused over 20 seconds, lockout time of 5 minutes, PCA bolus of 0.25 microg/kg, continuous background infusion of 0.05 microg/kg/min, and maximum dose is 3 mg in 4 hours. Women were advised to start the PCA bolus when they feel the signs of a coming uterine contraction.\n All women demonstrated a significant decrease in VAS score in the first hour after administration of analgesia (P < 0.05). Analgesic quality as regard Visual Analog Pain Scores, sedation score, and post-delivery patient satisfaction in both groups, are comparable (P > 0.05). PCA remifentanil infusion until time of delivery produce no observable maternal, fetal or neonatal side effects (P < 0.05).\n PCA intravenous remifentanil is an effective option for pain relief with minimal maternal and neonatal side effects in labor for preeclamptic patients with contraindications to epidural analgesia or requesting opioid analgesia.", "The effects of epidural analgesia on the progress of labor are controversial. The objective of this study was to determine the effect of epidural analgesia on cesarean delivery rates in a population of patients randomly assigned to receive either epidural analgesia or intravenous opioids for intrapartum pain relief.\n From January 1995 to May 1996, 318 spontaneously laboring, term, nulliparous patients were randomly assigned to receive either intravenous opioids or epidural analgesia for pain relief. Labor was managed according to the principles of active management of labor. Cesarean delivery was performed for obstetric indications. Data analysis was conducted on an intent-to-treat basis. A subanalysis was subsequently performed on patients who were compliant with the allocated form of treatment.\n One hundred sixty-two patients were randomly assigned to receive intravenous meperidine and 156 were randomly assigned to receive epidural analgesia. Maternal age, gravidity, race, gestational age, and cervical dilatation at admission and at first analgesic dose did not differ between the groups. Intent-to-treat data analysis revealed no significant difference in the cesarean delivery rate between the 2 groups, being 13.6% in the opioid group and 9.6% in the epidural group (relative risk 0.70, 95% confidence interval 0.38-1.31, P >.05). Cesarean delivery rates for the indication of dystocia also did not differ, being 10.5% in the opioid group and 5.8% in the epidural group (relative risk 0.56, 95% confidence interval 0.26-1.21, P >.05). Subanalysis of the data from patients who were compliant with the allocated form of treatment revealed that patients in the epidural group (n = 147) were 3 times more likely to have an active phase duration >/=8 hours and were 10 times more likely to require >/=2 hours in the second stage of labor than were those in the opioid group (n = 78). There were no significant differences in cesarean delivery rates in this subanalysis, being 7.7% in the opioid group and 8.8% in the epidural group (relative risk 1.15, 95% confidence interval 0.45-2.91, P >. 05). The cesarean delivery rates for dystocia were also similar in the subanalysis, being 3.8% in the opioid group and 5.5% in the epidural group (relative risk 1.42, 95% confidence interval 0.39-5. 22, P >.05).\n Epidural analgesia provides safe and effective intrapartum pain control and may be administered without undesirable effects on labor outcome.", "Reports indicate that the administration of epidural analgesia for pain relief during labor interferes with labor and increases cesarean deliveries. However, only a few controlled trials have assessed the effect of epidural analgesia on the incidence of cesarean delivery. The authors' primary purpose in this randomized study was to evaluate the effects of epidural analgesia on the rate of cesarean deliveries by providing a suitable alternative: patient-controlled intravenous analgesia.\n Seven hundred fifteen women of mixed parity in spontaneous labor at full term were randomly assigned to receive either epidural analgesia or patient-controlled intravenous meperidine analgesia. Epidural analgesia was maintained with a continuous epidural infusion of 0.125% bupivacaine with 2 microg/ml fentanyl. Patient-controlled analgesia was maintained with 10-15 mg meperidine given every 10 min as needed using a patient-controlled pump. Procedures recorded in a manual that prescribed the intrapartum management were followed for each woman randomized in the study.\n A total of 358 women were randomized to receive epidural analgesia, and 243 (68%) of these women complied with the epidural analgesia protocol. Similarly, 357 women were randomized to receive patient-controlled intravenous meperidine analgesia, and 259 (73%) of these women complied with the patient-controlled intravenous analgesia protocol. Only five women who were randomized and received patient-controlled intravenous meperidine analgesia according to the protocol crossed over to epidural analgesia due to inadequate pain relief. There was no difference in the rate of cesarean deliveries between the two analgesia groups using intention-to-treat analysis based on the original randomization (epidural analgesia, 4% [95% CI: 1.9-6.2%] compared with patient-controlled intravenous analgesia, 5% [95% CI: 2.6-7.2%]). Similar results were observed for the analysis of the protocol-compliant groups (epidural analgesia, 5% [95% CI: 2.6-8.5%] compared with patient-controlled intravenous analgesia, 6% [95% CI: 3-8.9%]). Women who received epidural analgesia reported lower pain scores during labor and delivery compared with women who received patient-controlled intravenous analgesia.\n Epidural analgesia was not associated with increased numbers of cesarean delivery when compared with a suitable alternative method of analgesia.", "Combined spinal-epidural (CSE) analgesia produces rapid-onset pain relief and allows ambulation in early labor. Epidural local anesthetics may contribute to an increase in operative deliveries by decreasing perineal sensation and causing motor weakness. Operative delivery rates might be reduced with CSE, by avoiding or delaying administration of local anesthetics. This study compares the operative delivery rates associated with a CSE technique and those associated with intravenous meperidine for labor analgesia.\n Healthy parturients at full term were assigned randomly to receive CSE or intravenous meperidine analgesia. The CSE group received 10 microg intrathecal sufentanil, followed by epidural bupivacaine and fentanyl at their next request for analgesia. Parturients receiving intravenous meperidine had 50 mg on demand (maximum, 200 mg in 4 h). Labor and delivery outcomes in both groups were recorded and compared.\n An intent-to-treat analysis of 1,223 women indicated that CSE does not increase the rate of cesarean delivery for dystocia in nulliparous and parous women (CSE, 3.5% vs. intravenous meperidine, 4; P=not significant) or in nulliparous women alone (CSE, 7% vs. intravenous meperidine, 8%; P=not significant). Profound fetal bradycardia that necessitated emergency cesarean delivery within 1 h of the time the mother received sufentanil occurred in 8 of 400 parturients (compared with 0 of 352 who received meperidine; P < 0.01). However, the method of fetal monitoring differed between the two groups. Despite this, neonatal outcomes were similar overall.\n Combined spinal-epidural analgesia during labor does not increase the cesarean delivery rate for dystocia in healthy parturient patients at full term, regardless of parity. However, an unexpected increase in the number of cesarean deliveries for profound fetal bradycardia after intrathecal sufentanil was observed. Further investigation is warranted.", "The analgesic efficacy and incidence of maternal, fetal and neonatal side-effects of combined spinal epidural (CSE) and epidural (EPI) analgesia, using a mixture of bupivacaine 0.125%, epinephrine (1.25 micrograms.ml-1) and sufentanil (0.75 microgram.ml-1) for the relief of labor pain, were randomly and prospectively compared in 110 parturients. A 29 gauge Whitacre tip spinal needle was used to perforate the dura in CSE patients. Compared to EPI, CSE resulted in rapid (326 +/- 22 vs 766 +/- 79 sec, p < 0.05), excellent analgesia, using less bupivacaine (23.5 +/- 2.3 vs 33.9 +/- 2.9 mg, p < 0.05) and sufentanil (12.5 +/- 1.0 vs 16.5 +/- .7 micrograms, p < 0.05). A tendency to improved patient satisfaction in the CSE group was observed. The incidence of maternal or neonatal side effects was similar in both groups. No PDPH was observed. We conclude that CSE analgesia results in excellent pain relief during labor with immediate gratification as compared to epidural analgesia.", "The need for analgesia to overcome pain in labour is highly requested by women today. Various ways either non pharmachologic e.g. Emotional sustain, psycho-prophylactic preparation, yoga and hypnosis or pharmachologic such as epidural blockade or parenteral are used. Therefore in our study we evaluated the efficacy and tolerability of the two opioids usually used today in parenteral analgesia to reduce pain during labour: Tramadol and Meperidine. We studied two groups of patients each made up of 20 women in labour, all at term and with a physiologic course of pregnancy. 75 mg i.m. of Meperidine chloryhydrate were somministered in the first group while in the second group 100 mg i.m. of tramadol chloryhydrate were somministered. Various maternal, fetal and neonatal parameters were then monitored demonstrating--A moderate maternal analgesic effect in both drugs (evaluated through the analogic grading of pain). In the group to whom Meperidine was given, sedative effects on the mother were observed associated with respiratory depression in the newborn (the latter evaluated through the Apgar index at 1st and 5th minute of life and pH of the blood obtained at the umbilical cord. The data obtained permitted us to conclude that Tramadol in accordance to the obtained in literature gives an analogous analgesic effect, with better tolerability for the absence of collateral effects on the mother, fetus and newborn.", "The analgesic effects of transcutaneous electrical nerve stimulation (TENS) in labour and effects on outcome were investigated in a double-blind TENS/TENS placebo controlled trial in 100 primigravidae and 50 women in their third labour. There were no differences between the TENS and the TENS placebo users in terms of pain concept or relief, and only 12 and 13% of primigravidae and 48 and 39% of the para 2 women completed labour without requiring other analgesia in their respective groups. The primigravidae who used either TENS or TENS placebo alone had shorter labours than those who required further analgesia. Although the outcome of labour for mother and infant were similar in the two groups, there was a higher operative delivery rate in women who also had epidural analgesia. There were highly significant differences between the TENS and the TENS placebo users in terms of favourable and unfavourable comments by the mothers and the midwives at 1 and 24 h after delivery. The evident consumer satisfaction for TENS suggests TENS has a part to play in analgesia in labour but the equivocal findings in terms of factors associated with pain relief points to the need for apparatus more specifically designed to cope with the special characteristics of the pain of labour.", "Our purpose was to determine the effect of epidural analgesia on nulliparous labor and delivery.\n Normal term nulliparous women in early spontaneous labor were randomized to receive either narcotic or epidural analgesia.\n When compared with the group receiving narcotic analgesia (n = 45), the group receiving epidural analgesia (n = 48) had a significant prolongation in the first and second stages of labor, an increased requirement for oxytocin augmentation, and a significant slowing in the rate of cervical dilatation. Epidural analgesia was associated with a significant increase in malposition (4.4% vs 18.8%, p < 0.05). Cesarean delivery occurred more frequently in the epidural group (2.2% vs 25%, p < 0.05), primarily related to an increase in cesarean section for dystocia (2.2% vs 16.7%, p < 0.05).\n In a randomized, controlled, prospective trial epidural analgesia resulted in a significant prolongation in the first and second stages of labor and a significant increase in the frequency of cesarean delivery, primarily related to dystocia.", "To evaluate the usefulness of intravenous patient-controlled analgesia (PCA) fentanyl for labour analgesia, its effectiveness for maternal pain and safety for the fetus and newborn.\n Twenty primigravidas were randomised to receive intravenous PCA fentanyl or epidural analgesia for labour pain. Maternal pain, heart rate and arterial oxyhaemoglobin saturation (SpO2) were monitored. Fetal and neonatal monitoring included cardiotocogram (CTG), APGAR, neurological scoring and static-charge-sensitive bed (SCSB) recording for 12 hr postnatally with ECG and SpO2. Fentanyl concentrations and pH of umbilical artery and vein were analysed.\n Initially, epidural analgesia was more effective (P = 0.01), and three patients in the fentanyl group were given epidural due to unsatisfactory pain relief. Overall satisfaction for analgesia did not differ between the groups. Maternal side-effects were more frequent in the fentanyl group (dizziness and tiredness most often, P = 0.0001). Severe side-effects were not reported. In CTG there were no differences between groups. All the newborns were healthy, APGAR and pH were normal. Naloxone was not used. Neurological scoring was similar in both groups. In 12 hr monitoring heart rate, breathing frequency and movement time were similar in both groups, but SpO2 was lower in the fentanyl group (P < 0.001). Umbilical cord fentanyl concentrations were low or beyond the detection limit.\n Intravenous fentanyl can be used for labour analgesia with the doses reported here as an alternative to epidural analgesia. However, the fetus and neonate must be appropriately monitored. Naloxone and oxygen should be available if neonatal distress occurs.", "To study the pain relief effectiveness of the combined spinal-epidural analgesia (CSEA) and the inhalation of nitrous oxide, and the influences on the mothers and infants.\n The 300 cases of pregnant women were randomly divided into 3 groups: CSEA group, nitrous oxide group and control group. The nitrous oxide group was that pregnant women inhaled nitrous oxide premixed with oxygen (50%:50%), the pregnant women of the CSEA group were injected fentanyl and bupivacaine in the subarachnoid and epidural space, analgesic was not used in the control group. The degree of labor pain, duration of the labor, way of delivery, bleeding volume, rate of anoxia of newborn, blood gas analysis to maternal radius artery and fetal umbilical blood among 3 groups were observed.\n The effect for analgesia labor of the CSEA group was much better than that of the nitrous oxide group (P < 0.01). In the first stage of labor and total stage of labor, the CSEA group was shorter than the others (P < 0.05), but there was no difference between the nitrous oxide group and the control group (P > 0.05). In the second stage of labor, the 3 groups were alike to each other. The bleeding volume of caesarean section (373 +/- 77) ml in the nitrous oxide group was much more than the other 2 groups, there was no difference between the CSEA group (259 +/- 78) ml and the control group (239 +/- 89) ml. The rate of obstetric forceps of CSEA group was higher than the control group (P < 0.01), and the rate of caesarean section of the nitrous oxide group was much higher than the CSEA group. The blood gas analysis to maternal radius artery and fetal umbilical blood and the rate of anoxia of newborn of 3 groups revealed no significant difference.\n The effectiveness of the combined spinal-epidural analgesia CSEA for analgesia labor is confirmed and has rarely side-effect, and it can be the first choice, and the inhalation of nitrous oxide can safely provide effective labor analgesia, too.", "A prospective randomised double blind study was carried out to compare the use of epidural methadone, morphine and bupivacaine for pain relief after Caesarean section. The results indicate that methadone is the most effective agent with few side effects. Subsequently this method was used routinely for postoperative analgesia in all patients undergoing Caesarean section. A retrospective study of 178 patients having this method of analgesia was carried out and indicated that epidural methadone is an effective and safe method of postoperative pain relief.", "Systemic opioids are commonly administered during labor, but their efficacy has been recently questioned. In addition, laboratory and clinical studies provide a strong rationale for combining mu- and kappa-opioid receptor agonists for analgesia. The authors therefore studied, using validated intensity and affective scales and definitions of effective pain relief, the efficacy of intravenous meperidine, butorphanol, and their combination for labor analgesia.\n Healthy women with singleton term pregnancy requesting analgesia during active labor were studied. Women were randomly assigned to receive 50 mg meperidine, 1 mg butorphanol, or 25 mg meperidine plus 0.5 mg butorphanol (n = 15/group). Pain intensity was assessed using a 0-10 numerical rating scale, and affective magnitude was assessed using a ratiometric descriptive scale before drug administration and between the sixth and seventh uterine contractions after drug administration.\n All three treatments reduced pain intensity equally. Butorphanol alone did not reduce pain affective magnitude, whereas the other treatments did. There was a significant correlation between reduction in pain intensity and affective magnitude in all groups, with greater reductions in affective magnitude than intensity. Overall, 29% of women exhibited clinically meaningful pain relief, with no difference among groups. Groups did not differ in incidence of opioid-induced adverse effects.\n These doses of meperidine and butorphanol do reduce pain intensity and affective magnitude, although a minority of patients achieve meaningful pain relief as defined in multiple patient populations, including laboring women. Combination of these drugs did not improve their therapeutic benefit.", "Current forms of analgesia often have significant side effects for women in labor. Bathing in warm water during labor has been reported to increase a woman's comfort level and cause a reduction in painful contractions. The objective of this trial was to compare immersion in warm water during labor with traditional pain management for a range of clinical and psychological outcomes.\n A prospective randomized controlled trial of 274 pregnant women, who were free from medical and obstetric complications and expecting a singleton pregnancy at term, was conducted at the Women's and Children's Hospital, a maternity tertiary referral center in Adelaide, South Australia. Women in labor were randomized to an experimental group who received immersion in a bath or to a nonbath group who received routine care. Pharmacological pain relief was the primary outcome that was measured, and secondary outcomes included maternal and neonatal clinical outcomes, factors relating to maternal and neonatal infectious morbidity, psychological outcomes, and satisfaction with care.\n The use of pharmacological analgesia was similar for both the experimental and control groups; 85 and 77 percent, respectively, used major analgesia. No statistical differences were observed in the proportion of women requiring induction and augmentation of labor or in rates of perineal trauma, length of labor, mode of delivery, or frequency of cardiotocographic trace abnormalities. Neonatal outcomes (birthweight, Apgar score, nursery care, meconium-stained liquor, cord pH estimations) revealed no statistically significant differences. Infants of bath group women required significantly more resuscitation than routine group women. Routine group women rated their overall experience of childbirth more positively than bath group women. Psychological outcomes, such as satisfaction with care or postnatal distress, were the same for both groups.\n Bathing in labor confers no clear benefits for the laboring woman but may contribute to adverse effects in the neonate.", "Two hundred and twenty-nine nulliparous women who requested regional analgesia during labour were given a combined spinal-epidural block. They were randomly allocated to stay in bed or spend at least 20 min of every hour out of bed. There was no significant difference in duration of labour, analgesia requirements, mode of delivery or condition of the baby between the groups. Ambulation appeared to be safe for the mother and baby. Maternal satisfaction with the low-dose combined spinal-epidural was high in both groups.", "Controversy concerning increased cesarean births as a result of epidural analgesia for relief of labor pain has been attributed, in large part, to difficulties interpreting published studies because of design flaws. In this study, the authors compared epidural analgesia to intravenous meperidine analgesia using patient-controlled devices during labor to evaluate the effects of labor epidural analgesia, primarily on the rate of cesarean deliveries while minimizing limitations attributable to study design.\n Four hundred fifty-nine nulliparous women in spontaneous labor at term were randomly assigned to receive either epidural analgesia or intravenous meperidine analgesia. Epidural analgesia was initiated with 0.25% bupivacaine and was maintained with 0.0625% bupivacaine and fentanyl 2 microg/ml at 6 ml/h with 5-ml bolus doses every 15 min as needed using a patient-controlled pump. Women in the intravenous analgesia group received 50 mg meperidine with 25 mg promethazine hydrochloride as an initial bolus, followed by 15 mg meperidine every 10 min as needed, using a patient-controlled pump. A written procedural manual that prescribed the intrapartum obstetric management was followed for each woman randomized in the study.\n A total of 226 women were randomized to receive epidural analgesia, and 233 women were randomized to receive intravenous meperidine analgesia. Protocol violations occurred in 8% (38 of 459) of women. There was no difference in the rate of cesarean deliveries between the two analgesia groups (epidural analgesia, 7% [16 of 226; 95% confidence interval, 4-11%] vs. intravenous meperidine analgesia, 9% [20 of 233; 95% confidence interval, 5-13%]; P = 0.61). Significantly more women randomized to epidural analgesia had forceps deliveries compared with those randomized to meperidine analgesia (12% [26 of 226] vs. 3% [7 of 233]; P < 0.001). Women who received epidural analgesia reported lower pain scores during labor and delivery compared with women who received intravenous meperidine analgesia.\n Epidural analgesia compared with intravenous meperidine analgesia during labor does not increase cesarean deliveries in nulliparous women.", "Recent reports have suggested that patient-controlled analgesia is an effective means of narcotic administration in postoperative patients. This prospective investigation was undertaken to determine the efficacy and safety of patient-controlled anesthesia infusion after cesarean section. During a recent ten-month period, 130 patients were assigned randomly to receive meperidine by pump or intramuscular injection. Meperidine consumption using the device varied widely to meet individual needs. Overdosage and drug dependence were not encountered with the prescribed drug concentrations. The patient-controlled analgesia method provided less sedation and more immediate pain relief without the need for painful injections. The additional cost of renting the infuser device was offset by combined patient and nursing satisfaction. We conclude that patient-controlled infusion of meperidine is safe and effective in satisfying individual patient needs after cesarean section.", "It is generally accepted that epidural injection with local anesthetics and narcotics administered when the cervix has dilated to a diameter exceeding 4 cm can adequately control labor pain. However, many nulliparous women still suffer from labor pain for a few hours prior to the administration of epidural analgesia. This study examined the effectiveness of relief of labor pain obtained by injection of narcotics epidurally once the labor pain begins and the subject requests analgesia.\n Subjects scheduled for induced labour were divided into three groups: Group A (n = 60) received 5 x 10(-4)% fentanyl (10-20 mL) administered epidurally to relieve early first-stage labor pain. Group B (n = 60) received no analgesic in the early first stage of labor. For groups A and B, when cervical dilatation exceeded 4 cm, 10 to 15 mL of 5 x 10(-2)% bupivacaine and 2 x 10(-4)% fentanyl were injected epidurally and a continuous low dosage was maintained until full dilatation of the cervix resulted. Group C (n = 198) received no analgesic during the entire labor course.\n There were no significant differences in the duration of the early period of the first stage of labor, the duration of the late period of the first stage, the duration of the second stage, the Apgar score, or the arterial blood gas of neonates among the three groups. However, group C had a significantly higher cesarean section rate (28.8%) than group A (16.7%) or group B (15%). Pain scores assessed with the Visual Analog Scale (VAS) throughout the entire labor course, were lower in group A than in group B; particularly during the early period of the first stage. The VAS scores in both groups A and B were significantly lower than those in group C during the late period of the first stage of labor.\n The results indicate that once labor pain begins and the subject requests analgesia, epidural injection with fentanyl alone can relieve labor pain during the early period of the first stage. The analgesia does not cause adverse effects to the mothers or neonates. In addition, the labor course and the method of delivery are not affected.", "Epidural administration of an opioid analgesic by means of a patient-controlled analgesia (PCA) system was compared with conventional intravenous PCA for pain relief after cesarean delivery. One hundred seventeen healthy women were randomly assigned to receive hydromorphone either intravenously (IV-PCA) or epidurally (EPI-PCA) after cesarean delivery with epidural bupivacaine for operative anesthesia. The hydromorphone requirements were 3.4 and 4.2 times more in the IV-PCA group on the first (P less than 0.01) and second (P less than 0.01) postoperative days, respectively. The mean number (+/- SD) of PCA demands during the first 24 h after the operation was 105 (+/- 88) for the IV-PCA group and 33 (+/- 48) for the EPI-PCA group (P less than 0.01). This difference was also significant 24-48 h after surgery. Although the EPI-PCA group utilized significantly less opioid medication, pain and sedation scores were similar in the two treatment groups; however, a significantly larger percentage of patients in the IV-PCA group (46% vs 22%) stated that they felt drowsy during the first postoperative day. Pruritus was reported more frequently in the EPI-PCA (67%) than in the IV-PCA (33%) group. Nausea was experienced by only 10% of patients in the IV-PCA and 6% in the EPI-PCA group. There was no evidence of postoperative respiratory depression, with minimal oxygen saturation values of 93% (+/- 3%) and 94% (+/- 1%) in the IV-PCA and EPI-PCA groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)", "We randomly allocated 93 women in early active labour and requesting epidural analgesia to receive either epidural (n = 48) or combined spinal-epidural analgesia (n = 45). For epidural analgesia 15 ml of bupivacaine 0.1% with 75 micrograms of fentanyl were injected into the epidural space. For combined spinal-epidural analgesia 1 ml of bupivacaine 0.25% with 25 micrograms of fentanyl were injected into the subarachnoid space. For both groups subsequent top-ups of 10 ml of bupivacaine 0.1% with fentanyl 20 micrograms were given using a lightweight patient-controlled epidural analgesia (PCEA) pump with a lockout time of 30 min. We assessed analgesia and the degree of motor blockade and found no significant differences in pain or maternal satisfaction scores between the two groups. The time to first top-up was significantly longer in the epidural group than in the CSE group (p = 0.01). The combined spinal-epidural group had significantly greater motor blockade at 30 min than the epidural group (p = 0.01), but there was no difference after this. The PCEA machine failed completely twice and temporarily many times. We conclude that the combined spinal-epidural technique confers no advantages in early active labour. Also, a lightweight PCEA pump needs to be more reliable before we can recommend its use.", "To compare the combined spinal-epidural (CSE) technique with the epidural technique with regard to time to initiate and manage, motor block, onset of analgesia and satisfaction during labour.\n Upon requesting analgesia, 50 healthy term parturients were randomized in a prospective, double-blind fashion to receive either CSE analgesia or lumbar epidural analgesia in the labour floor of a university hospital at an academic medical centre. The epidural group (n = 24) received bupivacaine 0.0625%-fentanyl 0.0002% with 0.05 ml in 10 ml local anesthetic sodium bicarbonate 8.4% and epinephrine 1:200,000. The CSE group (n = 26) received intrathecal 25 microg fentanyl and 2.5 mg bupivacaine. Additional analgesia was provided upon maternal request.\n There were no differences (P>0.05) in time to perform either technique, motor blockade, or parturient satisfaction or in the number of times that the anesthesiologist was called to perform any intervention. Although the first sign of analgesia was not different between the two groups, the onset of complete analgesia was more rapid with the CSE technique (Visual Analogue Pain Score (VAPS) at five minutes < three: 26/26 vs. 17/24, P+/-0.001).\n Although epidural analgesia with a low concentration of local anesthetic and opioid mixture takes longer to produce complete analgesia, it is a satisfactory alternative to CSE.", "In a previous study on the effect of electro-acupuncture (EA) in combination with a paracervical block (PCB) as an analgesic method during oocyte aspiration in IVF treatment, EA appeared to increase the pregnancy rate. This study was designed to test the hypothesis that EA as an analgesic during oocyte aspiration would result in: (i) a better IVF pregnancy rate than with alfentanil; (ii) peroperative analgesia that was as good as that produced by alfentanil; (iii) less postoperative abdominal pain, nausea and stress; and (iv) a reduction in the use of additional analgesics. Neuropeptide Y (NPY) concentrations in follicular fluid (FF) were analysed when possible.\n In this prospective, randomized, multicentre clinical trial, 286 women undergoing oocyte aspiration were randomly allocated to the EA group (EA plus a PCB) or to the alfentanil group (alfentanil plus a PCB). No significant differences were found between the EA and alfentanil groups in any of the IVF variables. NPY concentrations in FF were significantly higher in the EA group compared with the alfentanil group. No correlation between pregnancy rate and NPY concentrations was found in either analgesic group. Both EA plus a PCB and alfentanil plus a PCB induced adequate peroperative analgesia during oocyte aspiration evaluated using the visual analogue scale. After 2 h, the EA group reported significantly less abdominal pain, other pain, nausea and stress than the alfentanil group. In addition, the EA group received significantly lower amounts of additional alfentanil than the alfentanil group.\n EA does not improve pregnancy rate in the present clinical situation. The observation that NPY concentrations in FF were higher in the EA group may be important for human ovarian steroidogenesis. The analgesic effects produced by EA are as good as those produced by conventional analgesics, and the use of opiate analgesics with EA is lower than when conventional analgesics alone are used.", "A double-blind study was carried out to compare the effect of submucous paracervical blockade using 12 mL 0.25% bupivacaine (55 women) to the effect of intramuscular injection of 75 mg meperidine (62 women) during the first stage of labor. All 117 were normal primiparous pregnancies. Seventy-eight percent of the women in the paracervical blockade group achieved full or acceptable pain relief against 31% in the meperidine group (P less than .01). Transient fetal bradycardia occurred in two cases in the paracervical blockade group and one in the meperidine group; all infants were born in good condition. Fetal distress, defined as an umbilical artery pH of 7.15 or less and/or a one-minute Apgar score of 7 or less was more frequent in the meperidine group (16 infants) than in the paracervical blockade group (six infants) (P less than .05). Submucous paracervical blockade is superior to intramuscular meperidine as pain relief during labor. Furthermore, meperidine results in more infants with asphyxia as compared with paracervical blockade.", "Whether epidural analgesia for labor prolongs the active-first and second labor stages and increases the risk of vacuum-assisted delivery is a controversial topic. Our study was conducted to answer the question: does lumbar epidural analgesia with lidocaine affect the progress of labor in our obstetric population?\n 395 healthy, nulliparous women, at term, presented in spontaneous labor with a singleton vertex presentation. These patients were randomized to receive analgesia either, epidural with bolus doses of 1% lidocaine or intravenous, with meperidine 25 to 50 mg when their cervix was dilated to 4 centimeters. The duration of the active-first and second stages of labor and the neonatal apgar scores were recorded, in each patient. The total number of vacuum-assisted and cesarean deliveries were also measured.\n 197 women were randomized to the epidural group. 198 women were randomized to the single-dose intravenous meperidine group. There was no statistical difference in rates of vacuum-assisted delivery rate. Cesarean deliveries, as a consequence of fetal bradycardia or dystocia, did not differ significantly between the groups. Differences in the duration of the active-first and the second stages of labor were not statistically significant. The number of newborns with 1-min and 5-min Apgar scores less than 7, did not differ significantly between both analgesia groups.\n Epidural analgesia with 1% lidocaine does not prolong the active-first and second stages of labor and does not increase vacuum-assisted or cesarean delivery rate.", "Naloxone 40 mug was administered intravenously one minute after birth to 20 out of 44 neonates whose mother had been given pethidine in labour. These neonates were compared with 20 others whose mothers had had only lumbar epidural block. Alveolar PCO2, alveolar ventilation, and ventilatory rate were measured 10 and 30 minutes after birth. The untreated neonates of mothers who had had pethidine showed significant ventilatory depression compared with infants in the epidural and naloxone-treated groups. The naloxone-treated neonates were comparable with the epidural group, although the effects of naloxone were diminishing at 30 minutes. Naloxone is an effective narcotic antagonist which should be considered to be the drug of choice for treating narcotic depression in the neonate.", "Our purpose was to examine the effect of epidural analgesia on dystocia-related cesarean delivery in actively laboring nulliparous women.\n Active labor was confirmed in nulliparous women by uterine contractions, cervical dilatation of 4 cm, effacement of 80%, and fetopelvic engagement. Patients were randomized to one of two groups: epidural analgesia or narcotics. A strict protocol for labor management was in place. Patients recorded the level of pain at randomization and at hourly intervals on a visual analog scale. Elective outlet operative vaginal delivery was permitted.\n One hundred women were randomized. No difference in the rate of cesarean delivery for dystocia was noted between the groups (epidural 8%, narcotic 6%; p = 0.71). No significant differences were noted in the lengths of the first (p = 0.54) or second (p = 0.55) stages of labor or in any other time variable. Women with epidural analgesia underwent operative vaginal delivery more frequently (p = 0.004). Pain scores were equivalent at randomization, but large differences existed at each hour thereafter. The number of patients randomized did not achieve prestudy estimates. A planned interim analysis of the results demonstrated that we were unlikely to find a statistically significant difference in cesarean delivery rates in a trial of reasonable duration.\n With strict criteria for the diagnosis of labor and with use of a rigid protocol for labor management, there was no increase in dystocia-related cesarean delivery with epidural analgesia.", "A number of recent studies have suggested that the analgesic effects of highly lipid-soluble opioids are similar when these agents are administered either epidurally or intravenously. We sought to test whether the lipid-soluble opioid sufentanil was more effective when administered intrathecally than when administered epidurally or intravenously. Twenty-four women during active labor received sufentanil 10 micrograms either intrathecally (n = 9), epidurally (n = 8), or intravenously (n = 7), using a combined spinal-epidural technique. The sufentanil was administered alone, without concomitant local anesthetics. Analgesia was assessed using the visual analogue score as well as the time elapsed from the administration of study drug to the patient's request for additional analgesia via the epidural catheter (bupivacaine 0.25%). The median duration of analgesia (median, interquartile range) was 84 (70-92) min in the intrathecal group, 30 (23-32) min in the epidural group, and 34 (17-30) min in the intravenous group (P < 0.001). The intrathecal group showed rapid and significant decrease in visual analogue scale scores, whereas visual analogue scale scores in the other two groups did not decrease and remained significantly elevated compared to those of the intrathecal group at all observation points. Side effects were limited to pruritus in 3 patients (2 moderate and 1 severe) in the intrathecal group. No patient developed post-dural puncture headache. We conclude that sufentanil 10 micrograms intrathecally provides rapid and effective analgesia of 1-2-h duration during labor. Epidural and intravenous use of this dose of sufentanil did not provide evidence of satisfactory analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)", "It is often assumed that subarachnoid administration of local anesthetics produces a more profound blockade than epidural anesthesia. Furthermore, the addition of fentanyl has been reported to increase preferentially intraoperative analgesia. In the present study we set out to study these two issues in a randomized and controlled study with respect to perceived pain and discomfort during surgery and postoperative pain.\n In the present study, 100 parturients subjected to elective cesarean section, 34 nullipara and 66 multipara, received one out of four combinations of the local anesthetic bupivacaine and the opioid fentanyl; group A--bupivacaine 12.5 mg + 10 micrograms fentanyl subarachnoidally, group B--bupivacaine 12.5 mg + saline subarachnoidally, group C--bupivacaine 100 mg + 100 micrograms fentanyl epidurally, group D--bupivacaine 100 mg + saline epidurally; N = 25 in each group. Pain intensity and discomfort during surgery was assessed with a visual analogue scale (VAS). Postoperative pain intensity and need for analgesics postoperatively, ketobemidone, was registered for 24 h following surgery.\n Intraoperative pain intensity and discomfort did not differ significantly between parturients in any of the four groups Postoperative pain was significantly more intense in parturients receiving local anesthetics subarachnoidally as compared to the epidural groups during the first 6-h period. This difference was also reflected in a significantly increased consumption of analgesics during this period. No significant differences between the groups were observed with regard to hemodynamics (blood pressure), respiration (oxygen saturation) or other effects such as nausea or itching. All neonates had normal Apgar and neonatal adaptive capacity scores (NACS).\n We conclude that subarachnoidal (12.5 mg) and epidural (100 mg) injections with bupivacaine both produced adequate anesthetic quality in women undergoing elective cesarean section. The addition of fentanyl (10 micrograms subarachnoidally or 100 micrograms epidurally) did not significantly improve the quality of these already profound blockades.", "The purpose of this randomized controlled double blind study was to compare the efficacy of pain relief and the side effects of epidural hydromorphone and morphine in post-Caesarean patients.\n In all patients, epidural anaesthesia was induced using carbonated lidocaine 2% with 1:200,000 epinephrine and 50 micrograms fentanyl, given in incremental doses. Patients in Group 1 (n = 24) received 0.6 mg hydromorphone and patients in Group 2 (n = 22) received 3 mg morphine after delivery of the infant. Pain, pruritus and nausea were measured using a visual analog scale (at times: baseline, on admission to the recovery room, 3, 6, 12, 18 and 24 hr postoperatively), by the number of requests for additional medications and by an overall satisfaction score.\n There was no difference between the groups in pain relief of in the incidence and severity of side effects. Pruritus was more pronounced within the first six hours in Group 1 and at 18 hr in Group 2.\n Hydromorphone provides no clinical benefit over epidural morphine for post operative analgesia following Caesarean section.", "To examine if ilioinguinal-iliohypogastric nerve block could reduce the need for post-Cesarean delivery morphine analgesia and thus reduce the incidence of opioid related adverse-effects.\n A multi-level technique for performing the nerve block with bupivacaine was developed and then utilized in this two-part study. Part one was a retrospective assessment of Cesarean delivery patients with and without ilioinguinal-iliohypogastric blocks to determine if the technique reduced patient controlled analgesia morphine use and thus would warrant further study. The second phase was a randomized double-blind placebo-controlled trial to compare post-Cesarean morphine use and the appearance of opioid-related side effects between the anesthetic and placebo-injected groups.\n Both phases demonstrated that our method of ilioinguinal-iliohypogastric nerve block significantly reduced the amount of iv morphine used by patients during the 24 hr following Cesarean delivery. In the retrospective assessment, morphine use was 49 +/- 30 mg in the block group vs 79 +/- 25 mg in the no block group (P = 0.0063). For the prospective trial, patients who received nerve blocks with bupivacaine had a similar result, self-administering 48 +/- 27 mg of morphine over 24 hr compared to 67 +/- 28 mg administered by patients who received infiltrations of saline. However, despite the significant decrease in morphine use, there was no reduction in opioid-related adverse effects: the incidences of nausea were 41% and 46% (P = 0.70) and for itching were 79% and 63% (P = 0.25) in the placebo and nerve block groups, respectively.\n A multi-level ilioinguinal-iliohypogastric nerve block technique can reduce the amount of systemic morphine required to control post-Cesarean delivery pain but this reduction was not associated with a reduction of opioid related adverse effects in our study group.", "We compared the incidence of Caesarean delivery in nulliparous women randomized to receive epidural analgesia with those randomized to intramuscular (i.m.) pethidine. On admission to the delivery suite in established labour, 802 nulliparae had already agreed to be randomized with respect to their first analgesia. One hundred and eighty-eight women required either no analgesia or 50% nitrous oxide in oxygen (Entonox) only. Of the remaining 614 women, 310 were randomly allocated to receive i.m. pethidine up to 300 mg and 304 to receive epidural bupivacaine. Labour management was standardized according to the criteria for active management of labour. The intention-to-treat analysis showed similar Caesarean section rates in those randomized to epidural (12%) or pethidine analgesia (13%). The difference in Caesarean rate was -1.1% with 95% confidence intervals from -6.3% to +4.1%. The normal vaginal delivery rates were similar (epidural, 59%; pethidine, 61%).", "To assess if acupuncture could be a reasonable option for pain relief in labor and to look at possible effects of acupuncture on the progress of labor.\n In a controlled, single blind study, 210 healthy parturients in spontaneous, active labor at term were randomly assigned to receive either real acupuncture or false acupuncture. Visual analog scale assessments were used to evaluate subjective effect on pain. The objective parameter of outcome was the need for analgesic medication in each group.\n There were significantly lower mean pain scores and significantly less need for pharmacological analgesia in the study group compared with the control group. The women given real acupuncture spent less time in active labor and needed less augmentation than the control group.\n The results indicate that acupuncture reduces the experience of pain in labor. A secondary outcome of acupuncture was a shorter delivery time, which mainly, if not exclusively, can be explained by the reduced need for epidural analgesia. Acupuncture may be useful for parturients who wish a nonpharmacological analgesia without side-effects. For others it could be the analgesic method of choice, with pharmacological analgesics as supplements.", "To investigate possible short and long term side effects of epidural analgesia, compared with non-epidural analgesia for pain relief in labour.\n Randomised controlled study, with long term follow up by questionnaire. Analysis by intention-to-treat.\n Busy maternity unit within a district general hospital in England.\n Three hundred and sixty nine primigravid women in labour were included (randomised allocation: epidural n = 184, non-epidural n = 185).\n Backache at three and twelve months after delivery, instrumental delivery rates and maternal opinion of pain relief in labour.\n No significant differences were found in the reported incidence of backache between the groups at three months: middle backache [22% vs 20%, chi2 = 0.057, P = 0.81; odds ratio (95% CI) 1.4(0.9-2.3)]; low backache [35% vs 34%, chi2 = 0.009, P = 0.92; odds ratio (95% CI) 1.0(0.6-1.6)]. Nor were there significant differences at 12 months: [middle backache 16% vs 16%, chi2 = 0.013, P = 0.91; odds ratio (95% CI) 1.0(0.5-1.8)]; or low backache [35% vs 27%, chi2 = 1.91, P = 0.17; odds ratio (95% CI) 1.4(0.9-2.3)]. The incidence of instrumental delivery was somewhat higher in the epidural group [30% vs 19%, odds ratio (95% CI) 1.77(1.09-2.86)]. Maternal satisfaction was not significantly different between the groups.\n This study provided no evidence to support the suggestion of a direct association between the use of epidural anaesthesia in labour and the incidence of long term backache. Despite a significant proportion of women in each group not receiving their allocated analgesia, a significant difference in terms of instrumental delivery rates remained. Satisfaction in both groups of women was high.", "We performed a prospective, randomized, double-blind study of continuous epidural analgesia for 72 hours after major abdominal procedures. Patients were randomly assigned to one of five treatment groups: epidural morphine, epidural bupivacaine, a combination of morphine and bupivacaine, epidural saline solution, and no epidural catheter. All patients received supplemental morphine sulfate or meperidine hydrochloride, intramuscularly or intravenously, as needed. Epidural infusion was begun at 2 to 4 ml/hr, depending on age and height, with two increments of 1 ml/hr allowed if pain relief was insufficient. All pain management decisions were made by nurses, who also monitored epidural function. Performance was measured four ways: pain as measured at regular intervals in the 72-hour period with a visual analog, pain as measured after 72 hours with the McGill Pain Questionnaire, amount of supplemental narcotics needed, and recovery of respiratory function and ambulation as percent of preoperative levels. The group that received the combination of morphine and bupivacaine did best on all measures; in most instances the difference between the results seen with the combination regimen and those seen with saline solution or no catheter were significant at the 0.05 level. With the exception of pruritus, complications were evenly distributed among all treatment groups, including noncatheterized controls. We conclude that epidural analgesia with the combination of morphine and bupivacaine is safe, is easily managed, and gives pain relief superior to that provided by traditional, systemic administration of narcotics.", "To determine if nulliparous women intending to have epidural analgesia have a similar labour profile and delivery outcome to women who intend to have their labour managed using alternative forms of pain relief.\n A prospective randomised controlled clinical trial conducted at a tertiary obstetric institution. Nulliparous women intending to deliver vaginally with a term singleton fetus were eligible for recruitment.\n 1159 women were recruited, of whom 992 were subsequently randomised to receive continuous midwifery support (CMS) or epidural analgesia (EPI) on presentation for delivery. The duration of labour was shorter in the CMS group compared with EPI (10.7 hours (inter quartile (IQ) 7.0,15.2) versus 11.4 hours (IQ 8.2,15.2), p = 0.039). The median duration of the first stage was 8.9 hours (IQ 6,12.5) versus 9.5 hours (IQ 7,12.7) (p = 0.069), and the median duration of the second stage was 1.33 hours (IQ 0.6,2.5) versus 1.48 hours (IQ 0.77,2.6) (p = 0.034). The requirement for oxytocin augmentation in spontaneous labour was 39.8% CMS versus 46.2% EPI (p = 0.129). There was no significant difference in the caesarean section rates. The need for any operative delivery was significantly lower in CMS (43.9% CMS versus 51.5% EPI, p = 0.019).\n Nulliparous women have a high usage of epidural analgesia, regardless of their prelabour intentions. In women who do not intend to use epidural analgesia, the temporal delay in insertion compared with those who use epidural analgesia as their primary analgesic modality is associated with a small but statistically significant reduction in overall labour duration and operative delivery rates.", "Butorphanol (1 mg and 2 mg) and meperidine (40 mg and 80 mg), given intravenously, were evaluated for analgesic efficacy and safety in a double-blind randomized study employing 200 consenting pre-partum patients in moderate to severe pain during the late first stage of labour. Both drugs provided adequate relief of pain to the mothers. There was no significant difference in the rate of cervical dilation, the foetal heart rate, the Apgar score, pain relief or neonatal neurobehavioural scores betweeen those receiving butorphanol and those receiving meperidine. Twenty-two mothers who received butorphanol and eleven who received meperidine nursed their infants with no adverse effects observed. Side-effects were generally infrequent in this study; however, more side-effects were reported by the patients and observed by the investigator in the meperidine-treated cases (13%) than in the cases treated with butorphanol (2%).", "nan", "In order to test the analgesic efficacy of Anesthelec (transcutaneous cranial electrical stimulation with Limoge currents) during labour and delivery, a double blind study was performed in 20 cases for whom analgesia was necessary. In 10 cases Anesthelec was used with the Limoge currents on and in 10 cases as a sham. Labour and delivery were carried out by a medical team different from that which set up the Anesthelec. The results showed that this method, with or without nitrous oxide inhalation, decreased by 80% the number of epidural and general anaesthesias that would otherwise have been unavoidable. To define the effects of this new method, maternal and foetal parameters of 50 deliveries carried out under Anesthelec were compared with 50 deliveries carried out under epidural analgesia. Anesthelec was used only if analgesia was required. This study was a retrospective comparison between two similar non paired series. Despite the fact that analgesia obtained with Anesthelec was less powerful than with epidural analgesia, this method showed many advantages: total safety for the child and the mother, easy utilization, shorter labour time, decreased number of instrumental extractions and potentially reduced costs. Good acceptance and satisfaction for the mother should allow a rapid evolution of this new method." ]	Parenteral opioids provide some relief from pain in labour but are associated with adverse effects. Maternal satisfaction with opioid analgesia was largely unreported but appeared moderate at best. This review needs to be examined alongside related Cochrane reviews examining pain management in labour. More research is needed to determine which analgesic intervention is most effective, and provides greatest satisfaction to women with acceptable adverse effects for mothers and their newborn.
CD006902	[ "7787918", "15840076", "11604980", "21278165", "16983853", "17322014" ]	[ "Psychophysiologic responses of mechanically ventilated patients to music: a pilot study.", "Music and its effect on the physiological responses and anxiety levels of patients receiving mechanical ventilation: a pilot study.", "Effects of music therapy on anxiety in ventilator-dependent patients.", "Evidence that music listening reduces preoperative patients' anxiety.", "The effect of music listening on older adults undergoing cardiovascular surgery.", "Influence of music on the stress response in patients receiving mechanical ventilatory support: a pilot study." ]	[ "Although mechanically ventilated patients experience numerous stressors, they have not been included in music therapy stress reduction and relaxation studies.\n To examine selected psychophysiologic responses of mechanically ventilated patients to music.\n A two-group experimental design with pretest, posttest, and repeated measures was used. Twenty mechanically ventilated patients were randomized to a music-listening group or a nonmusic (headphones only) group. Physiologic dependent measures--heart rate and rhythm, respiratory rate, systolic and diastolic blood pressure, oxygen saturation, and airway pressure--were collected at timed intervals. Psychologic data were collected before and after intervention using the Profile of Mood States.\n Using repeated measures analysis of variance, results for heart rate and respiratory rate over time and over time between groups were significant. Between-group differences were significant for respiratory rate. Significant differences were found via t test for the music group's Profile of Mood States scores. No adverse cardiovascular responses were noted for either group.\n Data indicated that music listening decreased heart rate, respiratory rate, and Profile of Mood States scores, indicating relaxation and mood improvement.", "The aim of this study was to investigate the effects of music on the anxiety of patients on mechanical ventilation, as assessed by objective parameters and a subjective validated anxiety scale.\n Mechanical ventilation, although sometimes lifesaving, is often associated with levels of anxiety requiring sedatives, which has inevitable implications on costs and complications.\n A randomized controlled trial design.\n A total of 64 subjects was randomly assigned to undergo either 30 minutes of music intervention or a rest period. The subjects were asked to answer the Chinese State Trait Anxiety Inventory scale before and after the study period and physiological indices and resting behaviours were recorded before and after the study period in both groups. The subjects' satisfaction with music was also obtained after music intervention.\n The findings indicate that patients on mechanical ventilation that listened to a single 30-minute session of music appeared to show greater relaxation as manifested by a decrease in physiological indices and an increase in comfortable resting behaviours.\n Music can provide an effective method of reducing potentially harmful physiological responses arising from anxiety in mechanically ventilated patients.\n As indicated by the results of this study, music therapy can act as a simple and safe nursing intervention to allay anxiety and promote patient comfort. Interest and comments on music therapy provided as a relaxation technique should be elicited from both nurses and patients.", "The purpose of this study was to assess the effectiveness of music therapy in decreasing anxiety in ventilator-dependent patients.\n A crossover repeated measures design with random assignment was used.\n The intensive care unit of a university hospital in Hong Kong was used as the setting for this study.\n Twenty patients who were ventilator-dependent were recruited for the study. They were all Chinese with a mean age of 58.25 years (range, 19-84 y). Most (75%) were men. Outcome Measures: Physiologic measures of anxiety assessed in this study were mean blood pressure and respiratory rate. An additional measure was the Chinese version of the Spielberger State-Trait Anxiety Inventory.\n Patients were randomized to receive either 30 minutes of uninterrupted rest and then 30 minutes of music therapy or the music therapy first and then the uninterrupted rest period. Patients listened to relaxing music by using audiocassette players and headphones. Subjects selected the music of their choice from a selection including both Chinese and Western music. Subjects had physiologic measures taken immediately before the intervention (or rest period) and at 5-minute intervals throughout the intervention. The Chinese version of Spielberger's State-Trait Anxiety Inventory was completed before the intervention and immediately after the intervention.\n Findings indicated that music therapy was more effective in decreasing state anxiety than was an uninterrupted rest period (P <.01). As measured by analysis of variance with repeated measures, blood pressure and respiratory rate showed no significant differences in the 2 conditions over time. However, significant differences were observed at the end of the intervention (after 30 minutes) between the 2 conditions, with music therapy being superior to the rest period.\n Music therapy is an effective nursing intervention in decreasing anxiety in ventilator-dependent patients and its use should be incorporated into the care of mechanically ventilated patients. For the Chinese patients, culture and language were the predominant factors in their choice of music.", "Patients often exhibit preoperative fear and anxiety that may influence the process of induction and recovery from anesthesia. Music is thought to be an alternative to medication for relief of fear and anxiety.\n The purpose of the present study was to explore the feasibility of using heart rate (HR) variability (HRV) for evaluating the efficacy of music listening to relieve the patients' anxiety during their stay in the operation room waiting area and to compare the HRV measures with subjective Visual Analogue Scale (VAS) scores. Methods: In total, 140 patients were randomly assigned to the experimental (n = 64) or control group (n = 76). The intervention consisted of a 10-min period of exposure to relaxing music delivered through headphones. Anxiety levels were measured by VAS (a 10-point scale) and 5 min of HRV monitoring before and after the music intervention.\n The music group demonstrated significant reductions in VAS scores, mean HR, low-frequency HRV, and low- to high-frequency ratio and an increase in high-frequency HRV, while patients in the control group showed no changes. The subjective results of patients' VAS anxiety scores were consistent with the objective results of HRV parameters.\n Listening to music can significantly lower the anxiety levels of patients before surgery. The frequency-domain parameters of HRV can be indicators for monitoring the change in anxiety level of preoperative patients.", "The purpose of this study was to determine the effect of music listening on postoperative anxiety and intubation time in patients undergoing cardiovascular surgery. Coronary artery disease and valvular heart disease affect approximately 15 million Americans and 5 million persons in the U.K. annually, with the majority of these patients being older adults. The anxiety experienced before, during and after surgery increases cardiovascular workload, thereby prolonging recovery time. Music listening as a nursing intervention has shown an ability to reduce anxiety. The study used a randomized control trial design. Sixty adults older than 65 years were randomly assigned to the control and the experimental groups. The experimental group listened to music during and after surgery, while the control group received standard postoperative care. The Spielberger State Trait Anxiety Inventory was administered to both groups before surgery and 3 days postoperatively. The mean of the differences between scores was compared using analysis of variance. Differences in mean intubation time were measured in both groups. Older adults who listened to music had lower scores on the state anxiety test (F = 5.57, p = .022) and had significantly fewer minutes of postoperative intubation (F = 5.45, p = .031) after cardiovascular surgery. Older adults undergoing cardiovascular surgery who listen to music had less anxiety and reduced intubation time than those who did not.", "Music is considered an ideal therapy for reducing stress in patients receiving mechanical ventilation. Previous studies of the effect of music on stress in such patients have focused solely on indirect markers of the stress response rather than on serum biomarkers.\n To explore the influence of music on serum biomarkers of the stress response in patients receiving ventilatory support.\n A convenience sample of 10 patients receiving mechanical ventilation was recruited from an 11-bed medical intensive care unit. Patients were randomly assigned to listen to music or to rest quietly for 60 minutes. Levels of corticotropin, cortisol, epinephrine, and norepinephrine were measured 4 times during the 60 minutes.\n The levels of the 4 biomarkers of the stress response did not differ significantly between patients who listened to music and patients who rested quietly, though the levels of corticotropin and cortisol showed interesting trends.\n Additional research is needed with a larger sample size to evaluate further the influence of music on biochemical markers of the stress response in patients receiving mechanical ventilatory support. In future studies, confounding factors such as endotracheal suctioning and administration of medications that influence the stress response should be controlled for." ]	Music listening may have a beneficial effect on heart rate, respiratory rate, and anxiety in mechanically ventilated patients. However, the quality of the evidence is not strong. Most studies examined the effects of listening to pre-recorded music. More research is needed on the effects of music offered by a trained music therapist.
CD002805	[ "7707405", "1651304", "7452872", "9857997", "6307516" ]	[ "Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.", "Prophylactic cranial irradiation for lung cancer patients at high risk for development of cerebral metastasis: results of a prospective randomized trial conducted by the Radiation Therapy Oncology Group.", "Cranial irradiation in cancer of the lung of all cell types.", "Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission.", "Value of prophylactic cranial irradiation given at complete remission in small cell lung carcinoma." ]	[ "Prophylactic cranial irradiation in patients with small-cell lung cancer decreases the overall rate of brain metastases without an effect on overall survival. It has been suggested that this treatment may increase neuropsychological syndromes and brain abnormalities indicated by computed tomography scans. However, other retrospective data suggested a beneficial effect on overall survival for patients in complete remission.\n Our purpose was to evaluate the effects of prophylactic cranial irradiation on brain metastasis, overall survival, and late-occurring toxic effects in patients with small-cell lung cancer in complete remission.\n We conducted a prospective study of 300 patients who had small-cell lung cancer that was in complete remission. The patients were randomly assigned to receive either prophylactic cranial irradiation delivering 24 Gy in eight fractions during 12 days (treatment group) or no prophylactic cranial irradiation (control group). A neuropsychological examination and a computed tomography scan of the brain were performed at the time of random assignment and repeatedly assessed at 6, 18, 30, and 48 months. Patterns of failure were analyzed according to total event rates and also according to an isolated first site of relapse, using a competing-risk approach.\n Two hundred ninety-four patients who did not have brain metastases at the time of random assignment were analyzed. The 2-year cumulative rate of brain metastasis as an isolated first site of relapse was 45% in the control group and 19% in the treatment group (P < 10(-6)). The total 2-year rate of brain metastasis was 67% and 40%, respectively (relative risk = 0.35; P < 10(-13)). The 2-year overall survival rate was 21.5% in the control group and 29% in the treatment group (relative risk = 0.83; P = .14). There were no significant differences between the two groups in terms of neuropsychological function or abnormalities indicated by computed tomography brain scans.\n Prophylactic cranial irradiation given to patients with small-cell lung cancer in complete remission decreases the risk of brain metastasis threefold without a significant increase in complications. A possible beneficial effect on overall survival should be tested with a higher statistical power.\n The results of the trial favor, at present, the indication of prophylactic cranial irradiation for patients who are in complete remission. A longer follow-up and confirmatory trials are needed to fully assess late-occurring toxic effects. The possible effect on overall survival needs to be evaluated with a larger number of patients in complete remission, and a meta-analysis of similar trials is recommended.", "Beginning in February 1984, 187 evaluable patients with adenocarcinoma or large cell carcinoma of the lung clinically confined to the chest were randomized to receive either conventionally fractionated thoracic irradiation alone or thoracic irradiation with concurrent, prophylactic cranial irradiation. The study population included 161 patients treated for medically or surgically inoperable primary cancers, and 26 patients undergoing adjuvant postoperative mediastinal irradiation following attempted curative resection of primary cancers found to have metastasized to hilar or mediastinal lymph nodes. Elective brain irradiation was not effective in preventing the clinical appearance of brain metastases, although the time to develop brain metastases appears to have been delayed. Eighteen of 94 patients (19%) randomized to chest irradiation alone have developed brain metastases as opposed to 8/93 patients (9%) randomized to receive prophylactic cranial irradiation (p = .10). No survival difference was observed between the treatment arms. Among the 26 patients undergoing prior resection of all gross intrathoracic disease, brain metastases were observed in 3/12 patients (25%) receiving adjuvant chest irradiation alone, compared to none of 14 receiving prophylactic cranial irradiation (p = .06). In the absence of fully reliable therapy for the primary disease, and without effective systemic therapy preventing dissemination to other, extrathoracic sites, prophylactic cranial irradiation for inoperable non-small cell lung cancer cannot be justified in routine clinical practice. Further investigation in the adjuvant, postoperative setting may be warranted.", "The Veterans Administration Lung Group conducted a prospective study of irradiation for subclinical brain metastases in patients with inoperable carcinoma of the lung between 1975 and 1978. Patients were randomized to receive whole-brain irradiation (2,000 rads in two weeks) or no brain treatment, and to receive one of two regimens of thoracic irradiation. Three hundred twenty-three patients with normal radionuclide brain scans were able to be evaluated. The rate of clinical brain metastasis was 26% for patients with small cell carcinoma vs 10% for the \"non-small-cell\" group. A statistically insignificant decrease in the rate of brain metastasis was found among irradiated patients with small cell carcinoma. The frequency of brain metastasis in the non-small-cell patients was reduced from 13% to 6% by irradiation. Prophylactic cranial irradiation can decrease morbidity from non-small-cell carcinoma of the lung.", "We conducted a randomised clinical trial on 211 patients with small-cell lung cancer in complete remission (CR). The aim of this trial was to evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival. Eligible patients were randomly assigned to receive either PCI (100 patients) or no PCI (111 patients). Each centre was allowed to use its own PCI protocol as long as the total dose was within the range of 24-30 Gy and delivered in less than 3 weeks with fractions of 3 Gy or less. The mean follow-up is 5 years. The survival curves do not differ significantly (P = 0.25) between the two groups. The 4-year overall survival rate (95% confidence interval) is 22% [15-32%] in the PCI group versus 16% [10-25%] in the control group. The relative risk of death in the PCI group compared to the control group is 0.84 (95% CI = [0.62-1.13]). The incidence of brain metastasis is lower in the PCI group, but the difference is not statistically significant (P = 0.14). The 4-year cumulative rate of brain metastasis is 44% [32-57%] in the PCI group compared to 51% [38-63%] in the control group. In conclusion, in this study, which had to be closed prematurely, no significant difference was found in terms of the incidence of brain metastases nor in survival.", "The optimal use of \"prophylactic\" cranial irradiation (PCI) in patients with small cell lung cancer remains undetermined. This study reviews the impact of PCI, given at complete remission (CR), on neurologic relapse in 172 consecutive patients with small cell lung cancer treated in three sequential chemotherapy protocols at the University of Maryland Cancer Center. In the first study of 38 patients, none received PCI. In the second study of 109 patients, the first 28 achieving CR were randomized to 3000 rad of PCI in ten fractions (PCI+) or to observation (PCI-). Thereafter, based on interim analysis, all patients achieving CR received PCI. In the third study, to date, 25 patients achieving CR have received PCI. Overall, 169 patients were evaluable for neurologic relapse, and 30 of 90 patients achieving CR received PCI. Among all patients with CR, with adjustment for disease extent, there was a significant delay to any neurologic relapse (P = 0.01) and cerebral metastases (P = 0.02) for PCI+ compared to PCI- patients. Among PCI- patients with CR, cerebral metastases alone occurred in 28% as the sole site and in 33% as the initial site, whereas cerebral relapse occurred prior to systemic relapse in only one PCI+ patient with CR. Patient survival however, was not significantly altered by PCI. PCI at CR confers effective and worthwhile local control in the CNS, especially during periods of systemic response, and a small percentage of patients may benefit. Systemic drug resistance still determines overall survival." ]	Prophylactic cranial irradiation significantly improves survival and disease-free survival for patients with small cell lung cancer in complete remission. Further clinical trials are needed to confirm the potential greater benefit on brain metastasis rate suggested when cranial irradiation is given earlier or at higher doses.
CD007622	[ "15064028", "8595286" ]	[ "Clinical, psychosocial, and economic effects of antenatal day care for three medical complications of pregnancy: a randomised controlled trial of 395 women.", "A randomised controlled trial comparing two schedules of antenatal visits: the antenatal care project." ]	[ "Day care is increasingly being used for complications of pregnancy, but there is little published evidence on its efficacy. We assessed the clinical, psychosocial, and economic effects of day care for three pregnancy complications in a randomised trial of day care versus standard care on an antenatal ward.\n 395 women were randomly assigned day (263) or ward (132) care in a ratio of two to one, stratified for major diagnostic categories (non-proteinuric hypertension, proteinuric hypertension, and preterm premature rupture of membranes). The research hypothesis was that for these disorders, as an alternative to admission, antenatal day care will reduce specified interventions and investigations, result in no differences in clinical outcome, lead to greater satisfaction and psychological wellbeing, and be more cost-effective. Data were collected through case-note review, self-report questionnaires (response rates 81.0% or higher) and via the hospital's financial system. Analysis was by intention to treat.\n All participants were included in the analyses. There were no differences between the groups in antenatal tests or investigations or intrapartum interventions. The total duration of antenatal care episodes was shorter in the day-care group than in the ward group (median 17 [IQR 5-9] vs 57 [35-123] h; p=0.001). Overall stay was also significantly shorter in the day-care group (mean 7.22 [SE 0.31] vs 8.53 [0.44]; p=0.014). The median number of care episodes was three (range one to 14) in the day-care group and two (one to nine) in the ward group (p=0.01). There were no statistically or clinically significant differences in maternal or perinatal outcomes. The day-care group reported greater satisfaction, with no evidence of unintended psychosocial sequelae. There was no significant difference in either average cost per patient or average cost per day of care.\n Since clinical outcomes and costs are similar, adoption by maternity services of a policy providing specified women with the choice between admission and day-unit care seems appropriate.", "To compare the clinical and psychological effectiveness of the traditional British antenatal visit schedule (traditional care) with a reduced schedule of visits (new style care) for low risk women, together with maternal and professional satisfaction with care.\n Randomised controlled trial.\n Places in south east London providing antenatal care for women receiving shared care and planning to deliver in one of three hospitals or at home.\n 2794 women at low risk fulfilling the trial's inclusion criteria between June 1993 and July 1994.\n Measures of fetal and maternal morbidity, health service use, psychosocial outcomes, and maternal and professional satisfaction.\n Pregnant women allocated to new style care had fewer day admissions (0.8 v 1.0; P=0.002) and ultrasound scans (1.6 v 1.7; P=0.003) and were less often suspected of carrying fetuses that were small for gestational age (odds ratio 0.73; 95% confidence interval 0.54 to 0.99). They also had some poorer psychosocial outcomes; for example, they were more worried about fetal wellbeing antenatally and coping with the baby postnatally, and they had more negative attitudes to their babies, both in pregnancy and postnatally. These women were also more dissatisfied with the number of visits they received (odds ratio 2.50; 2.00 to 3.11).\n Patterns of antenatal care involving fewer routine visits for women at low risk may lead to reduced psychosocial effectiveness and dissatisfaction with frequency of visits. The number of antenatal day admissions and ultrasound scans performed may also be reduced. For the variables reported, the visit schedules studied are similar in their clinical effectiveness. Uncertainty remains as to the clinical effectiveness of reduced visit schedules for rare pregnancy problems." ]	The available evidence suggests that group antenatal care is positively viewed by women with no adverse outcomes for themselves or their babies. This review is limited owing to the small number of studies/women and the majority of the analyses are based on a single study. More research is required to determine if group antenatal care is associated with significant benefits.
CD001224	[ "19623481", "17991688", "10963246", "20390477", "20163346", "17301567", "11399987", "12704016", "20081382", "16919803", "15166533", "16451341", "9505096", "15764856", "8018438", "15838199" ]	[ "Patterns of self-reported behaviour change associated with receiving voluntary counselling and testing in a longitudinal study from Manicaland, Zimbabwe.", "Behaviour change in clients of health centre-based voluntary HIV counselling and testing services in Kenya.", "Efficacy of voluntary HIV-1 counselling and testing in individuals and couples in Kenya, Tanzania, and Trinidad: a randomised trial. The Voluntary HIV-1 Counseling and Testing Efficacy Study Group.", "A randomized controlled trial to evaluate the relative efficacy of adding voluntary counseling and testing (VCT) to information dissemination in reducing HIV-related risk behaviors among Hong Kong male cross-border truck drivers.", "Does HIV VCT reduce risk behaviors? An observational study in Guatemala City.", "HIV incidence during a cluster-randomized trial of two strategies providing voluntary counselling and testing at the workplace, Zimbabwe.", "Positive and negative life events after counselling and testing: the Voluntary HIV-1 Counselling and Testing Efficacy Study.", "Reducing the sexual risk behaviors of HIV+ individuals: outcome of a randomized controlled trial.", "Providing family planning in Ethiopian voluntary HIV counseling and testing facilities: client, counselor and facility-level considerations.", "A brief individualized computer-delivered sexual risk reduction intervention increases HIV/AIDS preventive behavior.", "Effect of brief safer-sex counseling by medical providers to HIV-1 seropositive patients: a multi-clinic assessment.", "Condom use after voluntary counselling and testing in central Mozambique.", "Effectiveness of an HIV risk reduction counseling intervention for out-of-treatment drug users.", "Voluntary HIV counseling and testing acceptance, sexual risk behavior and HIV incidence in Rakai, Uganda.", "Outcome of psychoeducation for HIV risk reduction.", "Effects of a peer-led behavioral intervention to reduce HIV transmission and promote serostatus disclosure among HIV-seropositive gay and bisexual men." ]	[ "Voluntary counselling and testing (VCT) is promoted as a potential HIV prevention measure. We describe trends in uptake of VCT for HIV, and patterns of subsequent behaviour change associated with receiving VCT in a population-based open cohort in Manicaland, Zimbabwe. The relationship between receipt of VCT and subsequent reported behaviour was analysed using generalized linear models with random effects. At the third survey, 8.6% of participants (1,079/12,533), had previously received VCT. Women who received VCT, both those positive and negative, reduced their reported number of new partners. Among those testing positive, this risk reduction was enhanced with time since testing. Among men, no behavioural risk reduction associated with VCT was observed. Significant increases in consistent condom use, with regular or non-regular partners, following VCT, were not observed. This study suggests that, among women, particularly those who are infected, behavioural risk reduction does occur following VCT.", "To explore behaviour change, baseline risk behaviour, perception of risk, HIV disclosure and life events in health centre-based voluntary counselling and testing (VCT) clients.\n Single-arm prospective cohort with before-after design at three (one urban and two rural) government health centres in Kenya; study duration 2 years, 1999-2001.\n Consecutive eligible adult clients.\n Numbers of sexual partners, partner type, condom use, reported symptoms of sexually transmitted infection, HIV disclosure and life events.\n High rates of enrollment and follow-up provided a demographically representative sample of 401 clients with mean time to follow-up of 7.5 months. Baseline indicators showed that clients were at higher risk than the general population, but reported a poor perception of risk. Clients with multiple partners showed a significant reduction of sexual partners at follow-up (16% to 6%; p<0.001), and numbers reporting symptoms of sexually transmitted infection decreased significantly also (from 40% to 15%; p<0.001). Condom use improved from a low baseline. Low rates of disclosure (55%) were reported by HIV-positive clients. Overall, no changes in rates of life events were seen.\n This study suggests that significant prevention gains can be recorded in clients receiving health centre-based VCT services in Africa. Prevention issues should be considered when refining counselling and testing policies for expanding treatment programmes.", "Our aim was to determine the efficacy of HIV-1 voluntary counselling and testing (VCT) in reducing unprotected intercourse among individuals and sex-partner couples in Nairobi (Kenya), Dar es Salaam (Tanzania), and Port of Spain (Trinidad).\n Individual or couple participants were randomly assigned HIV-1 VCT or basic health information. At first follow-up (mean 7.3 months after baseline) health-information participants were offered VCT and all VCT participants were offered retesting. Sexually transmitted infections were diagnosed and treated at first follow-up. The second follow-up (mean 13.9 months after baseline) involved only behavioural assessment, and all participants were again offered VCT.\n 3120 individuals and 586 couples were enrolled. The proportion of individuals reporting unprotected intercourse with non-primary partners declined significantly more for those receiving VCT than those receiving health information (men, 35% reduction with VCT vs 13% reduction with health information; women, 39% reduction with VCT vs 17% reduction with health information), and these results were maintained at the second follow-up. Individual HIV-1-infected men were more likely than uninfected men to reduce unprotected intercourse with primary and non-primary partners, whereas HIV-1-infected women were more likely than uninfected women to reduce unprotected intercourse with primary partners. Couples assigned VCT reduced unprotected intercourse with their enrolment partners significantly more than couples assigned health information, but no differences were found in unprotected intercourse with non-enrolment partners. Couples in which one or both members were diagnosed with HIV-1 were more likely to reduce unprotected intercourse with each other than couples in which both members were uninfected. These changes were replicated by those in the health-information group diagnosed with HIV-1 at first follow-up.\n These data support the efficacy of HIV-1 VCT in promoting behaviour change.", "Mobile populations are vulnerable to contracting HIV. The present study aims to evaluate the relative efficacy of the voluntary counseling and testing plus information dissemination (VCT-ID) approach versus the information dissemination (ID) approach for promoting HIV preventive behaviors in a mobile population, cross-border truck drivers. A total of 301 adult male cross-border truck drivers who self-reported having had sex with female sex workers (FSW) or non-regular sex partners (NRPs) in mainland China in the last 12 months were recruited and randomized into the VCT-ID intervention group (Group I) or ID control group (Group C). Anonymous structured questionnaires, administered through a computer-assisted method, were used to collect data. At the follow-up survey (about 8-9 weeks since the baseline survey), Group I participants, as compared to Group C participants, were more likely to be consistent condom users when having sex with FSW (85.5% versus 68.5%, p<0.05) and with NRP (54.8% versus 36.4%, p<0.1), more knowledgeable about HIV, and were less likely to have contracted sexually transmitted diseases (STD) in the last two months. The VCT-ID approach is shown to be more efficacious than the ID approach in promoting safer sex and HIV-related knowledge among local cross-border truck drivers. Feasibility of providing voluntary counseling and testing (VCT) services at locations which are convenient to the target population is demonstrated. It also shows that VCT services can be used as a means of HIV prevention. The findings of this study resulted in up-scaled VCT services for the local target population.", "We examined the impact of HIV voluntary counseling and testing on self-reported behavioral risks three months after HIV testing.\n Cohort study comparing self-reported risk behaviors prior to and three months after HIV testing. Setting: Clinica Familiar Luis Angel Garcia, an HIV specialty clinic located in a Guatemalan National Hospital.\n 144 people undergoing HIV testing were enrolled. 44 were HIV positive. 41 HIV positive and 49 HIV negative subjects returned for follow-up interviews. Intervention: All subjects were tested and received voluntary counseling regarding HIV infection, transmission, prevention, and interpretation of HIV test results.\n The primary study outcome measure was change in self-reported risk behaviors three months after voluntary counseling and testing.\n Men were more likely than women to report a history of sexually transmitted diseases, more than 2 sexual partners, using alcohol with sex, and receiving money for sex; they were less likely to have a regular partner. 26% of men reported non-heterosexual orientation; no woman did. Alcohol was the primary drug of abuse in both men and women. At three month follow-up HIV positive subjects showed decreases in the average number of sexual partners, use of alcohol with sex, and episodes of unprotected sex.\n Voluntary counseling and testing resulted in changes in some self-reported risk behaviors, but only among HIV positive subjects. On nearly all measures men report riskier behavior than women. Alcohol is the most commonly used drug in this population and is often used with sex.", "To investigate HIV incidence during a trial of two voluntary counselling and testing (VCT) strategies. Counselling may promote beneficial behavioural change, although knowledge of negative status does not appear to contribute further benefit.\n The parent cluster-randomized trial demonstrated much greater uptake of VCT when counselling and rapid testing were available on-site (intensive VCT) than through pre-paid vouchers to an external provider (standard VCT). Anonymous HIV tests had been requested from all employees at enrolment and after 2 years intervention.\n The study setting was 22 businesses in Harare, Zimbabwe. Participants were 3146 HIV-negative individuals remaining in employment at the end of intervention, of whom 2966 (94.3%) consented to repeat testing. VCT linked to basic HIV care was provided and the main outcome measures were HIV incidence under each study arm, as a retrospective secondary analysis.\n Mean VCT uptake in this cohort was 70.7 and 5.2%, respectively, in the intensive and standard arms. Crude HIV incidence was 1.21 per 100 person-years, with non-significantly higher rates in the intensive VCT arm [mean site incidence 1.37 and 0.95 per 100 person-years, respectively; adjusted rate ratio 1.49 (95% confidence interval 0.79-2.80).\n Highly acceptable VCT did not reduce HIV incidence in this predominantly male cohort. HIV incidence was highest in the high uptake VCT arm, lending support to a US trial in which rapid testing appeared to have adverse behavioural consequences in some HIV-negative clients. Careful comparison of outcomes under different counselling and testing strategies is needed to maximize HIV prevention from global scale-up of VCT.", "The results of the Voluntary HIV-1 Counselling and Testing Efficacy Study support the efficacy and cost-effectiveness of HIV voluntary counselling and testing (VCT) for reducing risk behaviors in three developing countries.\n This report explores the social consequences of HIV VCT by examining the incidence of positive and negative life events at the first follow-up (an average of 7.3 months after recruitment). The incidence of positive and negative life events was compared between: (i) those who were randomly assigned to HIV VCT versus health information (HI); (ii) those who tested seronegative and those who tested seropositive; and (iii) those who disclosed their serostatus and those who did not.\n The occurrence of most negative life events was rare (0--4%); positive life events were more common (17--39%). With few exceptions, those assigned to HIV VCT were no more likely to experience negative life events than those who were assigned to HI. For individuals, positive serostatus was associated with increased support from health professionals, the break-up of a marriage and being neglected or disowned by their family. Serodiscordant couples with an HIV-positive woman were most likely to report the break-up of a marriage (20 versus 0--7% for other groups) and the break-up of a sexual relationship (45 versus 22--38% for other groups). Disclosure was associated with strengthening of a sexual relationship except for HIV-seropositive women.\n These findings, in combination with findings supporting the efficacy and cost-effectiveness of HIV VCT, support the dissemination of HIV VCT with appropriate support services in developing countries.", "Testing behavioral interventions to increase safer sex practices of HIV+ individuals has the potential to significantly reduce the number of new infections. This study evaluated a behavioral intervention designed to reduce the sexual risk behaviors of HIV+individuals. HIV+individuals (N = 387) who reported engaging in unprotected sex with HIV- or partners of unknown serostatus were randomly assigned to (a) a single counseling session targeting problem areas identified by the participant in 3 possible intervention domains (i.e., condom use, negotiation, disclosure); (b) a single-session comprehensive intervention that covered all 3 intervention domains; (c) the same comprehensive intervention, plus 2 monthly booster sessions; or (d) a 3-session diet and exercise attention-control condition. The median number of unprotected sex acts decreased from 14 at baseline to 6, 6, and 4 at 4-, 8-, and 12-month follow-ups, respectively. A repeated measures analysis of variance revealed a significant decrease in unprotected sex acts across all groups across time. A significant Group x Time interaction revealed that the comprehensive-with-boosters group had the most unprotected sex at 8-month follow-up as compared to the other 3 groups. These findings suggest that a brief intervention can result in large reductions in HIV transmission risks among HIV+individuals, but the relative benefit of one intervention approach over another remains unclear.", "Governments and donors encourage the integration of family planning into voluntary HIV counseling and testing (VCT) services. We aimed to determine whether VCT counselors could feasibly offer family planning and whether clients would accept such services.\n We employed a quasi-experimental, pre and postintervention survey design, interviewing 4019 VCT clients attending eight Ethiopian public sector facilities and 4027 additional clients 18 months after introducing family planning services in the same facilities. We constructed sex-stratified multilevel models assessing three outcomes: whether clients received contraceptive counseling, whether clients obtained contraceptive methods during VCT and whether clients intended to use condoms consistently after VCT.\n Clients demonstrated lower than expected immediate need for contraception. After intervention, only 29% of women had sex in the past 30 days, and 74% of these women were already using contraceptives. Despite the relatively low risk this population had for unwanted pregnancy, family planning counseling in VCT increased from 2 to 41% for women and from 3 to 29% for men (P < 0.01). Approximately, 6% of clients received contraceptive methods. However, sexually active men and women and those with more perceived HIV risk were more likely to obtain contraceptives and intend to use condoms consistently. Men attending facilities with higher client loads were 88% less likely to receive family planning information and 93% less likely to receive contraceptives than those attending facilities with lower client loads. Male and female clients whose counselors perceived contraceptive availability to be adequate were four and two times more likely, respectively, to receive contraceptive methods than those counseled by providers who felt supplies were inadequate (P < 0.01).\n Integrating VCT and family planning services is likely to be an effective programmatic option, but populations at risk for HIV or unintended pregnancy should be targeted.", "One objective of translational science is to identify elements of human immunodeficiency virus (HIV) risk-reduction interventions that have been shown to be effective and find new ways of delivering these interventions to the community to ensure that they reach the widest possible audience of at-risk individuals. The current study reports the development and evaluation of a computer-delivered, theory-based, individually tailored HIV risk-reduction intervention.\n This study evaluated the effectiveness of a custom computerized HIV/AIDS risk reduction intervention at increasing HIV/AIDS preventive behaviors in a randomized trial with 157 college students. The intervention content and delivery were based on the Information-Motivation-Behavioral Skills Model of Health Behavior Change and used Motivational Interviewing techniques. Participants completed a baseline assessment of HIV prevention information, motivation, behavioral skills and behavior, attended two brief computer-delivered intervention sessions, and completed a follow-up assessment.\n As compared to the control group (a nutrition education tutorial), participants who interacted with the computer-delivered HIV/AIDS risk reduction intervention exhibited a significant increase in risk reduction behavior. Specifically, participants reported a greater frequency of keeping condoms available and displayed greater condom-related knowledge at a four-week follow-up session; among sexually active participants, there was a significant increase in self-reported condom use.\n Delivery of brief individually tailored HIV/AIDS risk reduction interventions via computer may be an effective HIV/AIDS prevention approach for adolescents. More research is needed to further support the effectiveness of this type of intervention and determine the generalizability of these findings to economically and educationally disadvantaged adolescents.", "To test the efficacy of brief, safer-sex counseling by medical providers of HIV-positive patients during medical visits.\n Six HIV clinics in California.\n Clinics were randomized to intervention arms evaluated with cohorts of randomly selected patients measured before and after the intervention.\n Five-hundred and eighty-five HIV-positive persons, sexually active prior to enrollment.\n Prevention counseling from medical providers supplemented with written information. Two clinics used a gain-framed approach (positive consequences of safer-sex), two used a loss-frame approach (negative consequences of unsafe sex), and two were attention-control clinics (medication adherence). Interventions were given to all patients who attended the clinics.\n Self-reported unprotected anal or vaginal intercourse (UAV).\n Among participants who had two or more sex partners at baseline, UAV was reduced 38% (P < 0.001) among those who received the loss-frame intervention. UAV at follow-up was significantly lower in the loss-frame arm [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.19-0.91; P = 0.03] compared with the control arm. Using generalized estimating equations (GEE) to adjust for clustering did not change the conclusions (OR, 0.34; 95% CI, 0.24-0.49; P = 0.0001). Similar results were obtained in participants with casual partners at baseline. No effects were seen in participants with only one partner or only a main partner at baseline. No significant changes were seen in the gain-frame arm.\n Brief provider counseling emphasizing the negative consequences of unsafe sex can reduce HIV transmission behaviors in HIV-positive patients presenting with risky behavioral profiles.", "To evaluate the efficacy of voluntary counselling and testing (VCT) for HIV/AIDS in changing risky sexual behaviour in central Mozambique.\n Longitudinal cohort study of men and women aged at least 18 years from October 2002 to June 2003. We interviewed 622 participants in VCT groups and 598 in non-VCT groups. The interviews occurred before counselling and 4 and 6 months afterwards.\n Reported use of condoms while having sex with a friends/prostitute increased over each time period in the VCT group and between baseline and first visit in the non-VCT group. Both men and women in the VCT group increased their condom use over time, but the women in the non-VCT group did not. Reported always/sometimes use of condoms for both literate and illiterate subjects was higher and rose over time in the VCT group.\n People who undergo voluntary counselling and testing fro HIV/AIDS change their behaviour, presumably as a result of their counselling.", "This study examined and compared the effectiveness of two counseling interventions designed to reduce the HIV drug and sexual risk behaviors of 684 out-of-treatment drug users recruited from South Philadelphia, PA. All study participants received a standard intervention and one half were randomly assigned to also receive the enhanced intervention. The standard intervention provided HIV risk reduction education, HIV testing with pretest and posttest counseling, and training in condom use and needle cleaning. The enhanced intervention provided additional information on STD risk reduction. Both interventions were effective in influencing behavior change between baseline and 6-month follow-up. A higher proportion of persons reduced their drug risk behaviors compared to their sexual risk behaviors. As sexual risk behaviors are more resistant to change, there is a need for tailored interventions that target out-of-treatment drug users.", "To assess the acceptance of voluntary HIV counseling and testing (VCT) and the effects of VCT on sexual risk behavior and HIV acquisition in Rakai, Uganda.\n In a rural cohort, 10 694 consenting adults were interviewed, provided blood for HIV testing and were offered free VCT by community resident counselors. The proportions receiving VCT and the adjusted risk ratio (adj. RR) of VCT acceptance were estimated by log binomial regression. Risk behaviors and HIV incidence per 100 person-years (PY) in HIV-negative acceptors and non-acceptors of VCT were assessed prospectively.\n Although 93% initially requested HIV results, 62.2% subsequently accepted VCT. VCT acceptance was lower among persons with no prior VCT [Adj. RR = 0.88; 95% confidence interval (CI), 0.85-0.90], individuals with primary education (adj. RR = 0.94; 95% CI, 0.90-0.99) or higher (adj. RR = 0.91; 95% CI, 0.87-0.97), individuals who were HIV-positive (adj. RR = 0.72; 95% CI, 0.68-0.76), and persons reporting condom use in the past 6 months (inconsistent users, adj. RR = 0.95; 95% CI, 0.90-0.99; consistent users, adj. RR = 0.88; 95% CI, 0.82-0.95). VCT acceptance was higher among the currently married (adj. RR = 1.14; 95% CI, 1.08-1.20) and previously married (adj. RR = 1.11; 95% CI, 1.04-1.18). Receipt of results was not significantly associated with age, gender, and self-perception of HIV risk. There were no significant differences in sexual risk behaviors, or in HIV incidence between acceptors (1.6/100 PY) and non-acceptors (1.4/100 PY) of VCT.\n In this rural cohort where VCT services are free and accessible, there is self-selection of individuals accepting VCT, and no impact of VCT on subsequent risk behaviors or HIV incidence.", "Our objectives were to assess the effects of a psychoeducational (PE) program designed to reduce HIV risk behaviors in recovering drug abusers and to evaluate mediating variables associated with risk reduction as described by the AIDS Risk Reduction Model (ARRM). Consecutive admissions to a Department of Veterans Affairs drug dependence inpatient treatment program (n = 152) were randomly assigned to PE or a standard information (INFO) condition. PE involved a 6-hour small group intervention designed to enhance knowledge and attitudes regarding HIV prevention, improve skills in condom use and needle sterilization, and modify high-risk sex- and drug-related behaviors. The INFO condition involved presentation of audiovisual and printed HIV prevention material with similar content. Following intervention, PE subjects showed significantly enhanced self-efficacy, condom use skills, and sexual communication skills relative to the INFO group. At 3-month follow-up, the PE group showed significantly greater reductions on some measures of sexual HIV risk behaviors relative to the INFO group. Hypotheses derived from the ARRM regarding presumed relationships between positive changes in mediating variables (e.g., self-efficacy and sexual communication) and ultimate outcome variables (e.g., condom use) were supported.", "To evaluate the effects of an enhanced peer-led intervention on transmission risk behavior and serostatus disclosure of HIV-seropositive gay and bisexual men.\n A randomized intervention trial.\n HIV-seropositive gay and bisexual men were recruited from New York City and San Francisco and were randomly assigned to either a standard or an enhanced intervention. The standard intervention consisted of one session that provided safer sex information. The enhanced intervention consisted of six sessions and included safer sex information, interactive learning activities, and discussion groups that were facilitated by HIV-seropositive peers. Participants completed audio computer-assisted self interview (A-CASI) assessments at baseline and 3 and 6-month follow-ups. Optional testing for sexually transmitted infections was offered at baseline and the 6-month follow-up.\n A total of 811 participants met the inclusion criteria for outcome analyses. Of these, 85 and 90% were retained for the 3 and 6-month follow-ups, respectively. Compared with the standard intervention, fewer men assigned to the enhanced intervention reported unprotected receptive anal intercourse with a negative or unknown-serostatus partner at 3 months (21 versus 26%, P < 0.05). However, there were no other significant differences in transmission risk or serostatus disclosure at 3 or 6 months.\n The enhanced intervention was associated with only a limited reduction in transmission risk at 3 months relative to the standard intervention. The characteristics of the intervention that may have reduced its efficacy are identified and directions for future research are suggested." ]	These findings add to growing evidence that VCT can change HIV-related sexual risk behaviors thereby reducing HIV-related risk, and confirming its importance as an HIV prevention strategy. To maximize the effectiveness of VCT, more studies should be conducted to understand which modalities and counseling strategies produce significant reductions in risky behaviors and lead to the greatest uptake of VCT.
CD001130	[ "8053353", "2686575", "2655719", "1103574", "8559866", "10698807", "3881418", "538213", "9246253", "9054788", "22058460", "10315165", "7811160", "11026946", "8328559", "2405806", "11000645", "9495601", "10473477", "14632962" ]	[ "[Comparison of the effect of amisulpride and viloxazine in the treatment of dysthymia].", "Relevance of DMS-III depressive subtype and chronicity of antidepressant efficacy in atypical depression. Differential response to phenelzine, imipramine, and placebo.", "Reduced REM latency predicts response to tricyclic medication in depressed outpatients.", "A double-blind trial of maprotiline (Ludiomil) and amitriptyline in depressed outpatients.", "Cognitive behavior therapy, relaxation training, and tricyclic antidepressant medication in the treatment of depression.", "Compliance with antidepressant medication in the treatment of major depressive disorder in primary care: a randomized comparison of fluoxetine and a tricyclic antidepressant.", "Trimipramine in physical illness with depression.", "Changes in weight during treatment for depression.", "Controlled efficacy study of fluoxetine in dysthymia.", "Double-blind comparison of sertraline, imipramine, and placebo in the treatment of dysthymia: psychosocial outcomes.", "d-AMPHETAMINE AS A PREDICTOR FOR RESPONSE TO IMIPRAMINE AND AMITRIPTYLINE.", "Tricyclic antidepressant education program and its evaluation.", "Pharmacotherapy of impaired affect in recovering schizophrenic patients.", "The London Depression Intervention Trial. Randomised controlled trial of antidepressants v. couple therapy in the treatment and maintenance of people with depression living with a partner: clinical outcome and costs.", "A randomized double-blind study of fluoxetine versus placebo in the treatment of dysthymia.", "A comparison study of antidepressants and structured intensive group psychotherapy in the treatment of bulimia nervosa.", "Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults.", "Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study.", "Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial.", "Double-blind comparison of fluoxetine and nortriptyline in the treatment of moderate to severe major depression." ]	[ "An evaluation of the therapeutic efficacy of Amisulpride as compared with Viloxazine in a group of patients diagnosed as dysthymic, according to the DSM-III-R criteria is presented. Study was a double-blind, randomized controlled trial: Subjects were assessed during an initial examination with informed consent, then entering a 4-week treatment trial. The Hamilton Depression Scale, the Widlocher Psychomotor Retardation Scale, and the Andreasen Negative Symptoms Scale were used for evaluating cases. Both the efficacy and safety of drugs were assessed. An analysis of results suggests a better therapeutic response among the Amisulpride group subjects.", "One hundred ninety-four nonmelancholic depressed outpatients with features of atypical depression took part in a 6-week randomized trial of imipramine hydrochloride, phenelzine sulfate, and placebo. Their courses of illness were also rated for chronicity. Significantly more patients responded to phenelzine (71%) than to imipramine (48%), which benefited significantly more patients than placebo (26%). Both chronicity and DMS-III diagnosis predicted response on several outcome measures. For example, patients with dysthymic disorder responded better to treatment than did those with major depression, suggesting that dysthymic disorder can be treated with medication. Placebo response correlated inversely with chronicity, regardless of DMS-III diagnosis. Atypical depression and longitudinal course of illness may add to the usefulness of DMS-III depressive diagnosis as a predictor of antidepressant response.", "Forty-two outpatients with major depressive disorder entered a double-blind, randomized trial of either desipramine or amitriptyline for a minimum of 6 weeks. Pretreatment polysomnographic and clinical measures were used to predict response. Response was defined as a 17-item Hamilton Rating Scale for Depression score less than or equal to 9 at the end of treatment. There was a 61.1% response rate for patients treated with amitriptyline and a 66.7% response rate for patients treated with desipramine. Reduced REM latency (2-night mean less than or equal to 65.0 min) predicted a positive response to these tricyclic antidepressants. REM latency did not differentiate between desipramine or amitriptyline responders. More patients with reduced REM latency (80%) responded to treatment compared with patients with nonreduced REM latency (50%). The 80% response rate in reduced REM latency depressed patients confirms our previous findings in a mixed inpatient and outpatient sample. Contrary to our hypothesis, in this sample, endogenous depression was not associated with a good response to tricyclic medication.", "The results of a double-blind trial of a tetracyclic antidepressant, maprotiline (Ludiomil) and a conventional tricyclic, amitriptyline (Elavil), in 67 ambulatory depressives are reported. Hamilton's Rating Scale for Depression was the main outcome criterion. No statistically significant differences were found between the drugs in onset of action, efficacy, side effects or predictors of response. Patients on either drug showed a significant reduction in symptoms after 1 week of treatment and at the end of the trial. Both drugs were tolerated well. A review of double-blind comparisons of maprotiline and tricyclic antidepressants, spanning 13 countries, and including over 900 patients, both ambulatory and inpatient, shows essentially similar results. The main outcome criterion in all these studies was manifest psychopathology assessed on the Hamilton Rating Scale for Depression by the treating physician. The absence of additional types of outcome criteria or assessment techniques, which may have detected differences in motor activity or drive as originally postulated, may have obscured results which were expected to be subtle.", "Outcomes of seven treatment trials comparing cognitive behavioral therapy to treatment with tricyclic antidepressant medication in major depressive disorder have been quite similar to one another. This led us to question whether treatment outcome in time-limited studies reflected a unique effect of cognitive behavioral therapy. To test the uniqueness hypothesis, relaxation training, a nonpharmacologic, noncognitive treatment, was chosen as a comparison for cognitive behavioral therapy as well as drug therapy. Treatment duration was 16 weeks. The sample of 37 patients treated for major depressive disorder was less depressed than those previously studied. For both cognitive behavioral therapy and relaxation training, outcome of depression was superior to that of tricyclic antidepressant medication by endpoint analysis. The posttreatment scores on the Beck Depression Inventory of 82% of the group receiving cognitive behavioral therapy improved to a Beck Depression Inventory score < or = 9 which was not significantly greater than that for the group receiving relaxation training (73%), so a unique effect was not demonstrated for cognitive behavioral therapy. The outcome for tricyclic antidepressant medication (29% improved to criteria) was significantly worse than that for cognitive behavioral therapy. The patient's pretreatment initial expectancy was not predictive.", "Many claims have been made for superior compliance with selective serotonin reuptake inhibitors (SSRIs) compared with tricyclic antidepressants, but to date meta-analyses have not confirmed reduced dropouts in randomized controlled trials. The authors used a randomized study design to evaluate differential compliance with antidepressant medications in a primary care setting.\n A total of 152 patients treated in 10 primary care practices in the United Kingdom were included in a randomized, open-label, parallel-group study of fluoxetine and dothiepin at therapeutic doses for 12 weeks. Compliance was assessed by using pill count, patient questionnaires, and the Medication Event Monitoring System.\n The level of compliance with fluoxetine was numerically higher than the level of compliance with dothiepin on all three primary outcome measures, although the differences were not significant. In a secondary analysis using data from the Medication Event Monitoring System, both a survival analysis for length of time without a gap in medicine taking and a derived compliance index showed a significant advantage to fluoxetine. Patients in the fluoxetine group reported superior response on the health transition scale of the 36-item Short-Form Health Survey Questionnaire and numerically greater improvement on the Hamilton Depression Rating Scale. In both treatment arms patients with a superior compliance index were more likely to have improved in Hamilton depression scale scores by the last study visit.\n This study supports recent meta-analyses of SSRIs versus tricyclic antidepressants in finding no significant differences in crude indices of compliance between fluoxetine and dothiepin, despite marked differences in side effect profile and dose regimen. However, both a survival analysis and a new measure that takes account of prolonged periods of noncompliance distinguished between the treatments and was associated with improvement in both groups.", "To assess whether tricyclic antidepressants are useful in patients with a serious physical disorder who develop symptoms of major depression, 42 medically ill outpatients who met RDC criteria for endogenous major depression and had a Raskin depression score of at least 7 were studied. The patients were randomly assigned to a 6-week trial of trimipramine or placebo under double-blind conditions. In the placebo group, depressive symptoms improved when the physical disorder improved; in the trimipramine group, improvement was seen in the depressive symptoms even when there was no concomitant improvement in physical condition.", "Changes in appetite and weight were examined in a group of 47 carefully diagnosed primary depressives who were treated in a random design with either placebo (N = 17) or amitryptyline (N = 30) over a 35-day protocol. While the amitriptyline treated group as a whole showed a greater gain in weight than did the placebo group (4.5 vs. 0.5 lb, p less than 0.05), no differential effects could be demonstrated between drug responders and nonresponders. Likewise, while a consistent relationship between the self-report of decreased appetite and final weight change was noted in the placebo group, no simple relationship between final weight change and self-reported changes in appetite were apparent in the drug-treated patients. There was, however, a relationship between the report of decreased appetite and clinical severity of depression in the drug nonresponder subgroup despite significant weight gain during the protocol. Thus, weight change during this study period did not appear to show a simple relationship to corresponding clinical change. The clinical lore that has supported the notion that increased appetite and weight gain in patients being treated with tricyclic antidepressants are \"good\" signs cannot be confirmed by our findings.", "There have been very few controlled studies of antidepressants in dysthymia, particularly in samples diagnosed reliably and with an adequate length of follow-up. In this investigation, we measured the long-term outcome in a large group of patients meeting DSM-III-R criteria for dysthymia. This study was designed to investigate whether fluoxetine is effective in the treatment of dysthymia.\n This randomised study including 140 patients, compared fluoxetine (91 patients) and placebo (49 patients) on a double-blind basis in two distinct phases: a short-term end-point (3 months with 20 mg/day fluoxetine) and a medium-term end-point (6 months) where the initial responders continued double-blind treatment unchanged and non-responders received an additional treatment of 20 mg/day fluoxetine.\n After three months of treatment, response was seen more frequently in the fluoxetine group (42/72) than in the placebo group (14/39, P < 0.0001). Improved patients at 3 months were still improved at 6 months. Furthermore, 50% of the nonresponders at 3 months improved and rated as responders at 6 months, after fluoxetine was increased to 40 mg daily.\n This study showed the significant and persistent action of fluoxetine on dysthymia. The finding that 50% of the non-responders at 3 months were improved at 6 months, after fluoxetine dosage was increased to 40 mg daily, argues in favour of treating dysthymic patients for at least 6 months, and with a higher dosage if the initial doses are ineffective.", "The purpose of this study was to determine the effects of antidepressant pharmacotherapy on mood symptoms and psychosocial outcomes in dysthymia.\n In a multicenter, double-blind, parallel-group trial, 416 patients with a diagnosis of early-onset primary dysthymia (DSM-III-R) of at least 5 years' duration without concurrent major depression were randomly assigned to 12 weeks of acute-phase therapy with sertraline, imipramine, or placebo. The psychosocial outcome measures used in the study were the Global Assessment of Functioning Scale, the Social Adjustment Scale, the Longitudinal Interval Follow-up Evaluation psychosocial ratings, and the Quality of Life Enjoyment and Satisfaction Questionnaire.\n Sertraline and imipramine were significantly better than placebo in improving psychosocial outcomes as measured by the first three instruments. The Quality of Life Enjoyment and Satisfaction Questionnaire scores demonstrated significant improvements from baseline, and both active treatments produced significantly greater improvements than placebo. Significantly fewer patients discontinued sertraline (6.0%) than discontinued imipramine (18.4%) because of adverse events.\n Pharmacotherapy is an effective treatment for dysthymia in terms of psychosocial functioning as well as depressive symptoms, even when the dysthymia is long-standing.", "Patients with endogenous depression fulfilling Feighner's criteria were included in the trial. All had pretrial scores above 20 on Hamilton's depression rating scale.Drugs were divided into groups A and B. Group A comprised of placebo and d-amphetamine. It was found that all patients who improved with d-amphetamine also improved with tricyclics. Two who did not improve with d-amphetamine did not improve with tricyclics.", "The objectives of this study were (1) to develop an individualized tricyclic audiovisual education program and (2) to compare the program's effectiveness with that of traditional education. The program is designed to increase short-term and long-term knowledge about tricyclic antidepressants and depression. The patient's dose was stabilized, and then a pretest was given. If the patient was in the study group, he received the seven-minute slide-tape program and a posttest within 72 hours. The control group received the posttest within five days of the pretest. Both groups were given knowledge tests at approximately four weeks. Statistical analysis of the data from this small study group revealed significance at the 95% confidence level for the following statement: the study group showed a greater increase in factual short-term and long-term knowledge about its tricyclic therapy as shown by differences in pretest, posttest, and scores of tests at four weeks. This study demonstrates an effective standardized alternative to traditional education which can be used to educate the majority of patients about tricyclic antidepressants and depression with a minimum time investment.", "Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken.\n In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks.\n For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression.\n Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.", "Relapse of depression is associated with a criticising attitude of the patient's partner.\n To compare the relative efficacy and cost of couple therapy and antidepressant drugs for the treatment and maintenance of people with depression living with a critical partner.\n A randomised controlled trial of antidepressant drugs v. couple therapy. The subjects were 77 people meeting criteria for depression living with a critical partner.\n Drop-outs were 56.8% [corrected] from drug treatment and 15% from couple therapy. Subjects' depression improved in both groups, but couple therapy showed a significant advantage, according to the Beck Depression Inventory, both at the end of treatment and after a second year off treatment. Adding the costs of the interventions to the costs of services used showed there was no appreciable difference between the two treatments.\n For this group couple therapy is much more acceptable than antidepressant drugs and is at least as efficacious, if not more so, both in the treatment and maintenance phases. It is no more expensive overall.", "The purpose of this study was to assess the efficacy of fluoxetine, a selective serotonergic antidepressant, in the treatment of dysthymia.\n Thirty-five patients who met criteria for dysthymia, but not major depression, began randomized, double-blind 8-week trials of fluoxetine or placebo.\n Of 32 patients who completed the study, 10 (62.5%) of the 16 patients given fluoxetine and three (18.8%) of the 16 given placebo responded to treatment. Response was defined as 1) 50% or greater decrease in Hamilton Rating Scale for Depression score and 2) a score of 1 or 2 on the Clinical Global Impression (CGI) improvement subscale. Fluoxetine subjects showed significantly greater improvement at week 8 than placebo subjects on the Hamilton depression and CGI scales, but not on the Hopkins Symptom Check-list (58-item) or the Cornell Dysthymia Rating Scale.\n When compared to placebo, fluoxetine showed short-term effectiveness in treating dysthymic symptoms.", "Previous research on the treatment of outpatients with bulimia nervosa has focused on two treatment strategies: (1) drug therapy, primarily using tricyclic antidepressants, and (2) psychotherapy, often employing behavioral and cognitive behavioral techniques. We report here the short-term treatment outcome of a 12-week comparison trial of bulimic outpatients who were randomly assigned to one of four treatment cells: (1) imipramine hydrochloride treatment, (2) placebo treatment, (3) imipramine treatment combined with intensive group psychotherapy, and (4) placebo treatment combined with intensive group psychotherapy. All three active treatment cells resulted in significant reductions in target-eating behaviors and in a significant improvement in mood relative to placebo treatment. However, the results also suggested that the amount of improvement obtained with the intensive group psychotherapy component was superior to that obtained with antidepressant treatment alone. The addition of antidepressant treatment to the intensive group psychotherapy component did not significantly improve outcome over intensive group psychotherapy combined with placebo treatment in terms of eating behavior, but did result in more improvement in the symptoms of depression and anxiety.", "Insufficient evidence exists for recommendation of specific effective treatments for older primary care patients with minor depression or dysthymia.\n To compare the effectiveness of pharmacotherapy and psychotherapy in primary care settings among older persons with minor depression or dysthymia.\n Randomized, placebo-controlled trial (November 1995-August 1998).\n Four geographically and clinically diverse primary care practices.\n A total of 415 primary care patients (mean age, 71 years) with minor depression (n = 204) or dysthymia (n = 211) and a Hamilton Depression Rating Scale (HDRS) score of at least 10 were randomized; 311 (74.9%) completed all study visits.\n Patients were randomly assigned to receive paroxetine (n = 137) or placebo (n = 140), starting at 10 mg/d and titrated to a maximum of 40 mg/d, or problem-solving treatment-primary care (PST-PC; n = 138). For the paroxetine and placebo groups, the 6 visits over 11 weeks included general support and symptom and adverse effects monitoring; for the PST-PC group, visits were for psychotherapy.\n Depressive symptoms, by the 20-item Hopkins Symptom Checklist Depression Scale (HSCL-D-20) and the HDRS; and functional status, by the Medical Outcomes Study Short-Form 36 (SF-36) physical and mental components.\n Paroxetine patients showed greater (difference in mean [SE] 11-week change in HSCL-D-20 scores, 0.21 [0. 07]; P =.004) symptom resolution than placebo patients. Patients treated with PST-PC did not show more improvement than placebo (difference in mean [SE] change in HSCL-D-20 scores, 0.11 [0.13]; P =.13), but their symptoms improved more rapidly than those of placebo patients during the latter treatment weeks (P =.01). For dysthymia, paroxetine improved mental health functioning vs placebo among patients whose baseline functioning was high (difference in mean [SE] change in SF-36 mental component scores, 5.8 [2.02]; P =. 01) or intermediate (difference in mean [SE] change in SF-36 mental component scores, 4.4 [1.74]; P =.03). Mental health functioning in dysthymia patients was not significantly improved by PST-PC compared with placebo (P>/=.12 for low-, intermediate-, and high-functioning groups). For minor depression, both paroxetine and PST-PC improved mental health functioning in patients in the lowest tertile of baseline functioning (difference vs placebo in mean [SE] change in SF-36 mental component scores, 4.7 [2.03] for those taking paroxetine; 4.7 [1.96] for the PST-PC treatment; P =.02 vs placebo).\n Paroxetine showed moderate benefit for depressive symptoms and mental health function in elderly patients with dysthymia and more severely impaired elderly patients with minor depression. The benefits of PST-PC were smaller, had slower onset, and were more subject to site differences than those of paroxetine.", "In a multicentre, double blind, parallel group study 281 patients with DSM III-R diagnosis of dysthymia or a single episode of major depression in partial remission were randomised to 3 months of treatment with amisulpride 50 mg/day or fluoxetine 20 mg/day. The baseline Montgomery and Asberg Depression Rating Scale (MADRS) total score was reduced by at least 50% in 74.1% of patients (103/139) with amisulpride and 67.4% (87/129) with fluoxetine (P =0.230). No significant differences between treatment groups were found in the reductions in mean total score with the MADRS, Widlöcher psychomotor retardation scale, Sheehan disability scale, and CGI. Anxiety measured by HAM-A total mean score decreased significantly more with amisulpride (63%) than with fluoxetine (54%; P = 0.021). There were 13 dropouts due to adverse events with amisulpride and ten with fluoxetine. The number of patients reporting at least one adverse event was similar in the two groups (amisulpride 47.5%; fluoxetine 40.9%). As expected, in the amisulpride group endocrine-like adverse events in female patients were the most common, while nausea, dyspepsia, anorexia and insomnia occurred more frequently with fluoxetine.", "To evaluate two different methods of improving adherence to antidepressant drugs.\n Factorial randomised controlled single blind trial of treatment leaflet, drug counselling, both, or treatment as usual.\n Primary care in Wessex\n 250 patients starting treatment with tricyclic antidepressants.\n Adherence to drug treatment (by confidential self report and electronic monitor); depressive symptoms and health status.\n 66 (63%) patients continued with drugs to 12 weeks in the counselled group compared with 42 (39%) of those who did not receiving counselling (odds ratio 2.7, 95% confidence interval 1.6 to 4.8; number needed to treat=4). Treatment leaflets had no significant effect on adherence. No differences in depressive symptoms were found between treatment groups overall, although a significant improvement was found in patients with major depressive disorder receiving drug doses of at least 75 mg (depression score 4 (SD 3.7) counselling v 5.9 (SD 5.0) no counselling, P=0.038).\n Counselling about drug treatment significantly improved adherence, but clinical benefit was seen only in patients with major depressive disorder receiving doses >/=75 mg. Further research is required to evaluate the effect of this approach in combination with appropriate targeting of treatment and advice about dosage.", "Depression is an international public health problem. Impairment in social and occupational functioning, increased comorbidity with other psychiatric and medical conditions, and an increased risk of mortality are a few of its consequences. Some psychiatrists have the impression that selective serotonin re-uptake inhibitors may not work as well as tricyclic anti-depressants in severe depression and/or melancholia. On the contrary, there is a general belief that selective serotonin re-uptake inhibitors are superior to the tricyclic anti-depressants in having fewer side-effects, particularly cardiovascular effects. The objective of this double-blind study was to compare the efficacy and safety of fluoxetine and nortriptyline in patients with moderate to severe major depression.\n A total of 48 adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM IV), forth edition for major depression, based on the structured clinical interview for DSM IV participated in the trial. Patients had a baseline Hamilton Rating Scale for Depression score of at least 20. In this double-blind, single-center trial, patients were randomly assigned to receive nortriptyline 150 mg/day (group 1) or fluoxetine 60 mg/day (group 2) for 6-weeks. The outcome of the two groups was assessed using Hamilton Depression Rating Scale, a side-effect checklist and a regular ECG assessment.\n The results suggest that the efficacy of nortriptyline is superior to fluoxetine in this group of major depressed patients. No significant differences were observed between dropout rates in the two groups but anti-cholinergic side-effects were significantly more frequent with nortriptyline than with fluoxetine but there was no significant difference in cardiovascular effects in particular QTc prolongation.\n The results of the current study suggest that nortriptyline was more effective than fluoxetine in the treatment of moderate to severe depression. A larger study is warranted." ]	Drugs are effective in the treatment of dysthymia with no differences between and within drug classes. Tricyclic antidepressants are more likely to cause adverse events and dropouts. As dysthymia is a chronic condition, there remains little information on quality of life and medium or long-term outcome.
CD007752	[ "6366725", "15588235", "17284630", "16621910" ]	[ "Results of controlled double-blind study of thyroid replacement in very low-birth-weight premature infants with hypothyroxinemia.", "Effects of increased thyroxine dosage pre-conception on thyroid function during early pregnancy.", "The influence of selenium supplementation on postpartum thyroid status in pregnant women with thyroid peroxidase autoantibodies.", "Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications." ]	[ "The nature of hypothyroxinemia in sick very low-birth-weight (VLBW) infants was evaluated by assessment of the hypothalamic-pituitary axis and by the clinical response to thyroxine (T4) therapy. Twenty-three very low-birth-weight infants of gestational age 26 to 28 weeks, whose serum T4 concentrations were 4 micrograms/dL on two occasions, and thyrotropin less than 20 microU/mL, were included in a double-blind study. Following a thyrotropin-releasing hormone stimulation test, babies were given either T4 or placebo. Nine babies were thyrotropin-releasing hormone tested prior to therapy; four babies, two from each group, were tested 1 to 2 weeks after therapy. In 11 untreated babies, mean base line serum thyrotropin of 7.0 +/- 1.4 rose to 23.7 +/- 4.1 microU/mL in 30 minutes. This response was not significantly greater than the observed response in full-term babies, 23.7 +/- 4.1 v 16.6 +/- 0.97 microU/mL, respectively, P greater than .05. In two babies treated with T4 the thyrotropin response to thyrotropin-releasing hormone was completely suppressed. Serial serum T4 determinations showed normalization in both groups after a similar time interval. There was no beneficial effect of T4 therapy on growth of head circumference, length, or weight. Developmental data revealed no significant differences in the mental, motor, or gross neurologic outcome in the treated and nontreated infants after 1 year of follow-up. These observations imply that hypothyroxinemia in sick preterm infants is not a direct consequence of hypothyroidism. Despite the lack of demonstrable short-term beneficial effects of T4 therapy, follow-up studies are necessary to resolve the question of long-term benefits.", "To compare the effects of pregnancy on the serum free thyroxine (FT4) levels in two cohorts of primary hypothyroid women treated with different levothyroxine (L-T4) doses before gestation.\n Twenty-five women with compensated hypothyroidism of different aetiology (thyroidectomized and Hashimoto's thyroiditis) were enrolled in this prospective study. The women were receiving substitutive doses of L-T4 and were anticipating pregnancy. They were assigned to two groups: 14 patients (group I) were switched to partially suppressive treatment while 11 patients (group II) continued the same therapeutic regimen.\n Pre-conceptional thyroid function evaluation demonstrated significantly higher FT4 and lower TSH in group I (P<0.001, for both hormones) and comparable free 3,5,3'-triiodothyronine (FT3) levels. The first post-conception thyroid function evaluation occurred at a median time of 6 (5-8) and 7 (5-9) weeks of gestation, for groups I and II respectively (P<0.05); all women in group I showed adequate serum FT4 levels while three patients in group II showed low-normal FT4 levels and one case was below normal levels. Statistical analysis demonstrated significantly higher frequencies (0% vs 36.4%; P<0.05) of low-normal FT4 levels in patients receiving substitutive doses of L-T4. None of the Hashimoto's-affected patients showed low or low-normal serum FT4 levels regardless of their therapeutic regimen.\n Our results suggest that in hypothyroid women anticipating pregnancy (with serum TSH in the lower quartile of normal range), the pre-conception adjustment of L-T4 doses may result in adequate maternal thyroid function up to the first post-conception evaluation. The procedure seems safe and inexpensive; it may be a worthwhile treatment, at least in thyroidectomized women, in view of the well-known potential effects of even marginal maternal thyroid hypofunction on the subsequent IQ of the progeny.", "Pregnant women who are positive for thyroid peroxidase antibodies [TPOAb(+)] are prone to develop postpartum thyroid dysfunction (PPTD) and permanent hypothyroidism. Selenium (Se) decreases thyroid inflammatory activity in patients with autoimmune thyroiditis.\n We examined whether Se supplementation, during and after pregnancy, influences the thyroidal autoimmune pattern and function.\n This was a prospective, randomized, placebo-controlled study.\n The study was conducted in the Department of Obstetrics and Gynecology and Department of Endocrinology.\n A total of 2143 euthyroid pregnant women participated in the study; 7.9% were TPOAb(+).\n During pregnancy and the postpartum period, 77 TPOAb(+) women received selenomethionine 200 microg/d (group S1), 74 TPOAb(+) women received placebo (group S0), and 81 TPOAb(-) age-matched women were the control group (group C).\n We measured the prevalence of PPTD and hypothyroidism.\n PPTD and permanent hypothyroidism were significantly lower in group S1 compared with S0 (28.6 vs. 48.6%, P<0.01; and 11.7 vs. 20.3%, P<0.01).\n Se supplementation during pregnancy and in the postpartum period reduced thyroid inflammatory activity and the incidence of hypothyroidism.", "Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications.\n We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT(4)) treatment exerts beneficial effects.\n This was a prospective study.\n The study was conducted in the Department of Obstetrics and Gynecology.\n A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb(+)).\n TPOAb(+) patients were divided into two groups: group A (n = 57) was treated with LT(4), and group B (n = 58) was not treated. The 869 TPOAb(-) patients (group C) served as a normal population control group.\n Rates of obstetrical complications in treated and untreated groups were measured.\n At baseline, TPOAb(+) had higher TSH compared with TPOAb(-); TSH remained higher in group B compared with groups A and C throughout gestation. Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59-9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18-2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93-18.7).\n Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery." ]	This review found no difference between levothyroxine therapy and a control for treating pregnant euthyroid women with thyroid peroxidase antibodies for the outcome of pre-eclampsia, however a reduction in preterm birth and a trend towards reduced miscarriage with levothyroxine was shown. This review also showed no difference for pre-eclampsia or preterm birth when selenium was compared with placebo, however a promising reduction in postpartum thyroiditis was shown. Childhood neurodevelopmental delay was not assessed by any trial included in the review. Given that this review is based on four trials of moderate risk of bias, with only two trials contributing data (n = 284), there is insufficient evidence to recommend the use of one intervention for clinical or subclinical hypothyroidism pre-pregnancy or during pregnancy over another, for improving maternal, fetal, neonatal and childhood outcomes.
CD003730	[ "9892253", "11281957", "9836012", "14643092", "9892314", "11806864", "15364042", "10784481", "10553752", "10432468", "10071726", "8037263", "11356585", "7811160" ]	[ "Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.", "Double-blind, placebo-controlled, crossover trial of D-cycloserine adjuvant therapy for treatment-resistant schizophrenia.", "D-serine added to antipsychotics for the treatment of schizophrenia.", "Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial.", "Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia.", "Adjunctive high-dose glycine in the treatment of schizophrenia.", "Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia.", "Placebo-controlled trial of glycine added to clozapine in schizophrenia.", "D-serine added to clozapine for the treatment of schizophrenia.", "D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study.", "A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia.", "Amelioration of negative symptoms in schizophrenia by glycine.", "Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia.", "Pharmacotherapy of impaired affect in recovering schizophrenic patients." ]	[ "Disturbances of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may play an important role in the pathophysiology of negative symptoms of schizophrenia. Glycine, a small nonessential amino acid, functions as an obligatory coagonist at NMDA receptors through its action at a strychnine-insensitive binding site on the NMDA receptor complex. Glycine-induced augmentation of NMDA receptor-mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia.\n Twenty-two treatment-resistant schizophrenic patients participated in a double-blind, placebo-controlled, 6-week, crossover treatment trial with 0.8 g/kg per day of glycine added to their ongoing antipsychotic medication. Clinical assessments, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Simpson-Angus Scale for Extrapyramidal Symptoms, and the Abnormal Involuntary Movement Scale, were performed biweekly throughout the study. Clinical laboratory values and amino acid serum levels were monitored.\n Glycine treatment was well tolerated and induced increased glycine (P=.001) and serine (P=.001) serum levels. Glycine administration resulted in (1) a significant (P<.001) 30%+/-16% reduction in negative symptoms, as measured by the PANSS, and (2) a significant (P<.001) 30%+/-18% improvement in the BPRS total scores. The improvement in negative symptoms was unrelated to alterations in extrapyramidal effects or symptoms of depression. Low pretreatment glycine serum levels significantly predicted (r= 0.80) clinical response.\n These findings support hypoglutamatergic hypotheses of schizophrenia and suggest a novel approach for the pharmacotherapy of negative symptoms associated with this illness.", "Dysfunction of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may be relevant to the pathogenesis of negative symptoms in schizophrenia. The tuberculostatic compound D-cycloserine (DCS) acts as a partial agonist at the strychnine-insensitive glycine regulatory site on the NMDA receptor complex. Dose-finding trials suggest that DCS doses of 50-100 mg/d may be beneficial in the treatment of negative symptoms in schizophrenia. Nine treatment-resistant chronic schizophrenic patients participated in a double-blind, placebo-controlled, adjuvant treatment trial with 50 mg/d DCS. Between treatment-groups differences in symptom changes were not significant. However, a significant (p<0.05) reduction in negative symptoms was registered during treatment with DCS but not placebo. Greater reductions were registered in patients with lower baseline serum glycine levels (p<0.008). No side effects were registered. These preliminary findings indicate a potential role of DCS in the treatment of negative symptoms in schizophrenia. However, the degree of symptom reduction may be modest, at least among treatment-resistant inpatients.", "Hypofunction of N-methyl-D-aspartate (NMDA) subtype glutamate receptor has been implicated in the pathophysiology of schizophrenia. D-serine is a full agonist of the glycine site of NMDA receptor, an endogenous cotransmitter enriched in corticolimbic regions and distributed in parallel with NMDA receptor. Supplementation of D-serine may improve the symptoms of schizophrenia.\n Thirty-one Taiwanese schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-serine (30 mg/kg/day), which was added to their stable antipsychotic regimens. Of these, 28 completed the trial. Measures of clinical efficacy, side effects, and serum levels of amino acids and D-serine were determined every other week. Wisconsin Card Sorting Test (WCST) was performed at the beginning and end of the trial.\n Patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in WCST. D-serine levels at week 4 and 6 significantly predicted the improvements. D-serine was well tolerated and no significant side effects were noted.\n The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia. Given the effects of D-serine on positive symptoms, a trial of D-serine alone in schizophrenia should be considered.", "There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine.\n Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period.\n In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms.\n These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia.", "The focus of this study was the systematic evaluation of the clinical effects of glycine as an adjunct to the atypical antipsychotic clozapine in the treatment of schizophrenia.\n In a double-blind, placebo-controlled study, 19 patients with chronic, treatment-resistant schizophrenia who were maintained on optimal doses of clozapine (400-1200 mg/day) were administered either 30 g/day of glycine (N=9) or placebo (N=10) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Simpson-Angus movement scale were completed biweekly.\n The use of glycine as an adjunct to clozapine was not effective in decreasing positive or negative symptoms. In contrast, the patients treated with clozapine without glycine had a 35% reduction in positive symptoms.\n These preliminary data suggest that glycine may interfere with the antipsychotic efficacy of atypical neuroleptics such as clozapine.", "Glycine is an agonist at brain N-methyl-D-aspartate receptors and crosses the blood-brain barrier following high-dose oral administration. In a previous study, significant improvements in negative and cognitive symptoms were observed in a group of 21 schizophrenic patients receiving high-dose glycine in addition to antipsychotic treatment. This study evaluated the degree to which symptom improvements might be related to alterations in antipsychotic drug levels in an additional group of 12 subjects. Glycine treatment was associated with an 8-fold increase in serum glycine levels, similar to that observed previously. A significant 34% reduction in negative symptoms was observed during glycine treatment. Serum antipsychotic levels were not significantly altered. Significant clinical effects were observed despite the fact that the majority of subjects were receiving atypical antipsychotics (clozapine or olanzapine). As in earlier studies, improvement persisted following glycine discontinuation.", "Lamotrigine, a novel anticonvulsant drug having modulatory effects on glutamatergic neurotransmission, improves mood and cognition parameters in bipolar disorder. Recent studies suggest that when added to clozapine, lamotrigine treatment may result in significant positive symptoms reductions in schizophrenia. Similar effects were not observed in an open trial in which lamotrigine was used as adjuvant to nonclozapine antipsychotics.\n Thirty-eight treatment-resistant schizophrenia inpatients receiving conventional and atypical antipsychotics enrolled in a 10-week, double-blind, placebo-controlled study, in which they were randomized in a 2:1 ratio to receive adjuvant treatment with lamotrigine, gradually titrated to a 400 mg/day dose, or placebo. Of these, 31 completed the trial. Measures of clinical efficacy and side effects were determined every other week. Serum levels of amino acids were assessed at the beginning and end of the study.\n In primary last observation carried forward analysis, no statistically significant between-group differences were observed; however, the completers' analyses revealed that lamotrigine treatment resulted in significant (p < or = .05) reductions in positive and general psychopathology symptoms, as measured by the Positive and Negative Syndrome Scale. No significant differences in lamotrigine effects were noted between conventional versus atypical antipsychotics. Lamotrigine treatment was well tolerated, and glutamate serum levels remained stable throughout the study.\n These preliminary findings 1) support the hypothesis that lamotrigine adjuvant treatment may improve positive symptoms and general psychopathology in schizophrenia, 2) suggest that beneficial effects may be achieved when lamotrigine is added to both conventional and atypical antipsychotics, and 3) warrant additional, larger scale trials.", "The purpose of this study was to evaluate the effects of high-dose oral glycine on positive and negative symptoms and cognitive function when added to clozapine in adults with schizophrenia.\n The authors conducted a double-blind, placebo-controlled, parallel-group trial of 60 g/day of glycine added to clozapine for 8 weeks in 30 adults with schizophrenia. Clinical ratings were performed every 2 weeks.\n Twenty-seven patients completed the trial. Glycine augmentation of clozapine produced no statistically significant change in positive or negative symptoms or cognitive functioning. No subjects showed clinically significant worsening of clinical ratings.\n These data, combined with data from previous trials with D-cycloserine and glycine, suggest that agonists at the glycine site may be less effective when combined with clozapine than they are when combined with conventional antipsychotics.", "D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed.\n In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week.\n The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine.\n The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine.", "A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.", "D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, has previously been shown to improve negative symptoms when added to conventional antipsychotics and, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine.\n Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of D-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout.\n Eleven patients competed the 13-week study. D-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms.\n The differing effects of D-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site may play a role in clozapine's efficacy for negative symptoms.", "Phencyclidine induces a psychotomimetic state by blocking neurotransmission at N-methyl-D-aspartic acid (NMDA) receptors. In a double-blind, placebo-controlled fashion, 14 medicated patients with chronic schizophrenia were treated with glycine, a potentiator of NMDA-receptor-mediated neurotransmission. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia.", "Evidence that the metabolism of phospholipids and polyunsaturated fatty acids (PUFA) is abnormal in schizophrenia provided the rationale for intervention studies using PUFA supplementation. An initial open label study indicating efficacy for n-3 PUFA in schizophrenia led to two small double-blind pilot studies. The first study was designed to distinguish between the possible effects of two different n-3 PUFA: eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA). Forty-five schizophrenic patients on stable antipsychotic medication who were still symptomatic were treated with either EPA, DHA or placebo for 3 months. Improvement on EPA measured by the Positive and Negative Syndrome Scale (PANSS) was statistically superior to both DHA and placebo using changes in percentage scores on the total PANSS. EPA was significantly superior to DHA for positive symptoms using ANOVA for repeated measures. In the second placebo-controlled study, EPA was used as a sole treatment, though the use of antipsychotic drugs was still permitted if this was clinically imperative. By the end of the study, all 12 patients on placebo, but only eight out of 14 patients on EPA, were taking antipsychotic drugs. Despite this, patients taking EPA had significantly lower scores on the PANSS rating scale by the end of the study. It is concluded that EPA may represent a new treatment approach to schizophrenia, and this requires investigation by large-scale placebo-controlled trials.", "Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken.\n In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks.\n For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression.\n Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature." ]	In general, all glutamatergic drugs appeared to be ineffective in further reducing positive symptoms of the disease when added to the existing antipsychotic treatment. Glycine and D-serine may somewhat improve negative symptoms when added to regular antipsychotic medication, but the results were not fully consistent and data are too few to allow any firm conclusions. Many participants in the included trials were treatment-resistant which may have reduced treatment response. Additional research on glutamatergic mechanisms of schizophrenia is needed.
CD003553	[ "8334888", "20185226", "10427482", "15259280", "8749599", "8164925", "2686457", "10836195", "18226669", "2596365", "2289388", "16850671", "10382078", "2335101", "12568841", "11019950", "9773261", "2352250" ]	[ "A multicenter comparative trial of triphasic and monophasic, low-dose combined oral contraceptives.", "A comparison between monophasic levonorgestrel-ethinyl estradiol 150/30 and triphasic levonorgestrel-ethinyl estradiol 50-75-125/30-40-30 contraceptive pills for side effects and patient satisfaction: a study in Iran.", "A comparison of cycle control with monophasic levonorgestrel/ethinylestradiol 100 micrograms/20 micrograms versus triphasic norethindrone/ethinylestradiol 500-750-1000 micrograms/35 micrograms: a multicenter, randomized, open-label study.", "Endometrial safety and tolerability of triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate therapy regimen.", "Ovarian activity suppression by two different low-dose triphasic oral contraceptives.", "Multicenter randomized comparative trial of two low-dose triphasic combined oral contraceptives containing desogestrel or norethindrone.", "Triphasic Randomized Clinical Trial: comparative frequency of intermenstrual bleeding.", "A comparison of cycle control and effect on well-being of monophasic gestodene-, triphasic gestodene- and monophasic desogestrel-containing oral contraceptives. Gestodene Study Group.", "Comparison of a transdermal contraceptive patch vs. oral contraceptives on hemostasis variables.", "A study comparing a gestoden triphasic formulation with a fixed combination OC.", "Cycle control on low-dose oral contraceptives: a comparative trial.", "Comparison of low-dose monophasic oral contraceptive pills and expectant management in treatment of functional ovarian cysts.", "Clinical comparison of triphasic norgestimate/35 micrograms ethinyl estradiol and monophasic norethindrone acetate/20 micrograms ethinyl estradiol. Cycle control, lipid effects, and user satisfaction.", "Comparison of two triphasic contraceptives with different progestogens: effects on metabolism and coagulation proteins.", "Bleeding patterns after immediate vs. conventional oral contraceptive initiation: a randomized, controlled trial.", "Comparative study on the acceptability of two modern monophasic oral contraceptive preparations: 30 microgram ethinyl estradiol combined with 150 microgram desogestrel or 75 microgram gestodene.", "A randomized cross-over study on various hormonal parameters of two triphasic oral contraceptives.", "Initial selection of oral contraceptives." ]	[ "A comparative multicenter clinical trial of two combined oral contraceptives (OCs) was conducted at clinics located in the Sudan, Sri Lanka, Chile, the Dominican Republic and Ecuador. The trial was designed to determine if there were differences in efficacy, safety and acceptability between a triphasic and a low-dose monophasic OC. This report includes analysis of 1088 women. At each center, subjects were randomly allocated to one of the two OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. There were two accidental pregnancies attributed to user failure reported during the study period; one in the triphasic group and one in the monophasic group. Adverse experiences were mainly minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. Cycle control was good in both groups with women in the triphasic group reporting fewer complaints of intermenstrual bleeding. Both OCs were safe and effective.", "Oral contraceptive pills (OCPs) are one of the most effective reversible and accessible contraceptives, and patient acceptance for their use depends partly on the unfavorable adverse effects. The present study compared the two kinds of OCPs (monophasic; levonorgestrel (LNG)-ethinyl estradiol (EE) 150/30 versus triphasic; LNG-EE 50-75-125/30-40-30) for adverse effects and patient satisfaction.\n A randomized clinical trial was performed on 314 women who used OCPs for the first time, as their contraception, for 6 months. Overall, 1884 cycles were studied. In the monophasic group (n=159 who finally finished the study), monophasic pills LNG-EE 150/30mcg, and in the triphasic group (n=155 who finally finished the study), triphasic pills LNG-EE 50-75-125/30-40-30 mcg were used. Statistical analysis was performed using SPSS 10: Chi square test, Fisher exact test and Student's t-test were used.\n There were no significant differences between the two groups for common side effects, including nausea, headache, nervousness, facial hyperpigmentation (chloasma), and body weight (increase or decrease) but breakthrough bleeding and spotting (BTB/S) were less in the triphasic group, occurring in 30 cycles (18.86%) versus 10 cycles (6.45%), P=0.009*. Patient satisfaction for the two OCPs was similar and high. The rates of side effects were low.\n It seems that the monophasic and triphasic pills are similar according to patient satisfaction and side effects; therefore there is no benefit of one over the other except for BTB/S, for which triphasic is superior.\n Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.", "This multicenter, randomized, open-label study was undertaken to compare the effects on menstrual cycle control of two oral contraceptive regimens: monophasic levonorgestrel (LNG) 100 micrograms/ethinylestradiol (EE) 20 micrograms (Alesse or Loette) and triphasic norethindrone (NET) 500-750-1000 micrograms/EE 35 micrograms (OrthoNovum 7/7/7).\n Healthy women with normal menstrual cycles were enrolled and completed up to four cycles of study medication. A total of 384 cycles in the LNG/EE group and 400 cycles in the NET/EE group were evaluable for analysis of cycle control.\n For all treatment cycles, the percentage of cycles classified as normal was consistently higher in the LNG/EE group than in the NET/EE group. By cycle 4, 69.9% of cycles with LNG/EE and 54.4% with NET/EE (p < 0.05) were normal. In individual cycles, consistently lower occurrences of intermenstrual bleeding (total bleeding and/or spotting) were seen for the LNG/EE group, although these differences were not statistically significant. Withdrawal bleeding characteristics were comparable between the two groups, except for the length of the latent period, which was significantly longer in the LNG/EE group. The incidence of treatment-emergent adverse events was similar in the two groups.\n This study indicates that the monophasic LNG/EE 100 micrograms/20 micrograms provides better cycle control than the multiphasic NET/EE product, despite its lower EE dose.", "Two randomized comparative multicenter studies were conducted to establish the endometrial safety and tolerability of a triphasic sequential hormone replacement estradiol valerate/medroxyprogesterone acetate (E2V/MPA) therapy regimen.\n Study 1 was a randomized, double-blind, clinical phase III study in 399 postmenopausal women, following parallel-group design with two groups. The duration of study treatment was 12 or 13 cycles of 28 days. A double-dummy technique was used to ensure blinding in the study. The investigational drugs were E2V/MPA triphasic and E2V/MPA biphasic (Diviseq and Divina, respectively; Orion Pharma). In study 2, a total of 341 subjects were randomly allocated by computer into two parallel groups receiving either E2V/MPA or estradiol/norethisterone acetate triphasic (E2/NETA, Trisequens; Novo Nordisk A/S) for 12-13 cycles. The study was an open, clinical phase III trial with a randomized, parallel-group design. Endometrial biopsies combined with transvaginal ultrasound were undertaken before and at the end of treatment during the progestogen phase. Bleeding patterns and symptom control were assessed throughout both studies.\n E2V/MPA triphasic was found to have similar endometrial effects and bleeding patterns to those with E2V/MPA biphasic and E2/NETA triphasic. Climacteric symptoms were relieved as quickly and effectively as with the two comparator treatments. No adverse drug reactions specific to E2V/MPA triphasic were observed. At the end of the study, the proportions of secretory samples were 67.1% for the combined E2V/MPA triphasic groups, 65.6% for the E2V/MPA biphasic group and 71.6% for the E2/NETA triphasic group. One case of hyperplasia occurred in the E2V/MPA triphasic group. Thus the incidence of hyperplasia for the combined groups was 0.33%.\n The triphasic E2V/MPA regimen was well tolerated and produced endometrial effects similar to those of the two comparators. Extending estrogen during the so-called treatment-free week with a lower dose of estradiol was effective in controlling vasomotor symptoms.", "In an open, randomized study in an outpatient clinic of a large teaching hospital, thirty-one female volunteers with regular cycles and established ovulation by ultrasonography were given one of two triphasic oral contraceptives containing ethinylestradiol combined with levonorgestrel or desogestrel during six cycles of treatment. The main outcome measures were transvaginal ultrasonography and serum E2 and P measurements in pill cycles 1, 3 and 6. No ovarian activity was found in 10 subjects. Among the remaining 21 women who showed ovarian activity, most follicle-like structures developed in the pill-free week and decreased in size or disappeared in the first pill week. One women taking triphasic desogestrel had evidence of a luteinized unruptured follicle and one women taking triphasic levonorgestrel had a possible ovulation. The latter women also showed symptoms of lower abdominal pain. A statistically significant difference in ovarian activity between the two oral contraceptives could not be established. The two triphasic oral contraceptives suppressed ovarian activity to the same degree. A trend was seen towards increasing ovarian activity with duration of use in both treatment groups.", "To compare a new triphasic oral contraceptive (OC) containing desogestrel and ethinyl estradiol (DSG/EE) with triphasic norethindrone/ethinyl estradiol (NE/EE) regarding effects on clinical efficacy, cycle control, and safety indices.\n In an open-label, comparative multicenter study, 407 subjects were randomized to a triphasic preparation containing DSG/EE and 405 subjects to a triphasic preparation containing NE/EE. The women were observed during six cycles of OC use.\n The contraceptive efficacy of the triphasic DSG/EE OC was at least comparable to that of triphasic NE/EE. No pregnancies were reported with DSG/EE, whereas there were two pregnancies with NE/EE, both user failures. Cycle control with triphasic DSG/EE was statistically superior to that with triphasic NE/EE. Acceptability was excellent with both preparations as measured by the low discontinuation rates (particularly for adverse menstrual experiences). No thromboembolic or other serious drug-related adverse experiences were reported. The incidence of other drug-related adverse experiences was generally low and decreased with time in both groups. No adverse effects were seen in terms of blood pressure, body weight, laboratory indices, cervical cytology, and breast nodularity.\n Triphasic DSG/EE is an effective and safe OC with excellent acceptability and cycle control superior to that of triphasic NE/EE.", "Oral contraceptives have the highest theoretic efficacy of all reversible forms of contraception, yet in practice they have an actual failure rate equivalent to that of some barrier methods. The efficacy of oral contraceptives depends primarily on patient compliance. So-called \"nuisance\" side effects, such as intermenstrual bleeding (breakthrough bleeding or spotting), play a major role in their discontinuation. The Triphasic Randomized Clinical Trial compared the incidence of these side effects in three groups of subjects taking NET (A) (Ortho-Novum 7/7/7), LNG (Tri-Levlen), or NET (B) (Tri-Norinyl). Subjects taking NET (A) had the highest incidence of intermenstrual bleeding (63%) followed by NET (B) (44%) and LNG (33%). Only the difference between NET (A) and LNG attained statistical significance (p less than 0.030). Control subjects had no breakthrough bleeding and a 4% incidence of spotting. Further research is warranted to establish the cause of the disparity in the incidence of intermenstrual bleeding among patient groups assigned to the three oral triphasic contraceptives.", "This was an open-label multicenter study to compare the cycle control and effect on well-being of two oral contraceptives containing gestodene and one containing desogestrel. A total of 2419 healthy women < or = 41 years of age were randomized to receive oral contraceptives containing monophasic gestodene (Minulet; n = 806, mean age 24.5 years), triphasic gestodene (Tri-Minulet; n = 808, mean age 24.6 years) or monophasic desogestrel (Mercilon; n = 805, mean age 24.6 years). Subjects were to participate in the study for up to 13 treatment cycles. A modified Moos Menstrual Distress Questionnaire was used to evaluate menstrual symptoms and to assess overall well-being. A total of 698 women were withdrawn from the study, 154 due to adverse events. Cycle control with gestodene was superior to that with desogestrel at almost all time points, particularly for breakthrough bleeding and/or spotting, which occurred significantly less frequently with gestodene than with desogestrel at cycles 1-7 and 9-11 (p < 0.05). Generally, the proportion of subjects with breakthrough bleeding and/or spotting was almost twice as great with desogestrel as with gestodene. The duration of bleeding was not consistently different between the gestodene and desogestrel groups; however, the intensity of bleeding was greater with gestodene at all time points (p < 0.05). The latent period before withdrawal bleeding was significantly longer for monophasic gestodene at cycles 1-5 and 8-10 (p < 0.05). Treatment significantly improved overall well-being at cycles 6 and 9 with triphasic gestodene and at cycle 13 with desogestrel; however, no statistically significant differences among treatment groups in overall well-being scores or individual factors of well-being could be identified. All three treatments were well tolerated. The most common drug-related adverse events were headache (14.2%), breast pain (6.2%), nausea (4.1%), metrorrhagia (3.9%) and abdominal pain (3.5%). The incidence of adverse events in all treatment groups was similar, with the exception of metrorrhagia, which occurred in more patients in the desogestrel group than in the gestodene treatment groups (p < 0.05).", "The aim of this study was to compare effects of the transdermal contraceptive patch, a desogestrel/ethinyl estradiol (EE)-containing, monophasic combination oral contraceptive (COC) and a levonorgestrel/EE-containing, triphasic COC on hemostasis variables.\n This was a randomized, open-label study of 104 young women who received six cycles of treatment. Blood was collected at baseline and on treatment; changes by Day 20/Cycle 6 in baseline hemostasis markers [prothrombin fragment 1+2 (F 1+2), plasmin-plasmin inhibitor complex (PAP) and fibrin degradation products (D-dimer)] were assessed.\n All contraceptives induced similar increases in F 1+2 and D-dimer. Patch-induced PAP increases were less than with the monophasic and similar to the triphasic COC. Decreases in protein S and increases in sex hormone-binding globulin were greater with the patch than with either COC. Patch-induced increases in activated protein C resistance were greater than with the triphasic and similar to the monophasic COC.\n These contraceptives appeared to accelerate baseline procoagulation processes to a similar extent and to change coagulation potency variables differently.", "Metabolic parameters were studied in 30 patients over 12 treatment cycles in a double-blind randomized comparative trial of the new progestogen gestoden in a triphasic formulation against a fixed dose combination pill containing desogrestrel, in Bandung, Indonesia. The results of this laboratory experience affirm findings in similar previous metabolic studies that: (1) the changes induced by modern low-dose pills are clinically and statistically insignificant; (2) throughout the treatment cycles, the values of the various laboratory tests remain well within the normal range; and (3) the favorable balance between coagulation and fibrinolysis is maintained. Results of lipoprotein, coagulation, fibrinolytic and liver function tests in 27 patients are presented. Gestoden's pharmacologic profile and the worldwide clinical experience with the triphasic gestoden formulation in 4285 women are discussed.", "Cycle control was studied comparing the monophasic oral contraceptive Loestrin with three low-dose phasic preparations (Triphasil, Ortho 10/11 and Ortho 7/7/7) in 391 women of whom 300 completed 6 cycles. Loestrin subjects had a rate of occurrence (31% of cycles) for intermenstrual bleeding (IMB) comparable to the rates for subjects on the phasic preparations (36%, 37% and 37%, respectively). Triphasil subjects had lower rates than the Ortho 10/11 and Ortho 7/7/7 subjects (p less than 0.01) in cycle one when all subjects were analyzed and in pre-study users when continuing menstrual flow (CMF) episodes were not included as IMB. IMB was a cause for dropping out of the study in 7% of subjects who were evenly distributed between groups. There were no differences between groups for BTB when perceived by subjects as a side effect. Spotting was perceived as a side effect more often with Ortho 10/11 and Ortho 7/7/7 use than with Triphasil (p less than 0.01). Loestrin, Ortho 10/11 and Ortho 7/7/7 subjects were more likely to report amenorrhea (p less than 0.001) and less likely to report leg cramps (p less than 0.01) compared to those on Triphasil. Triphasil subjects were less likely to report acne than subjects on Ortho 7/7/7 (p less than 0.01).", "To compare the effectiveness of low-dose monophasic oral contraceptive pills in the treatment of spontaneously occurring functional ovarian cyst detected by ultrasonography compared with expectant management.\n A total of 70 women in their reproductive period with functional ovarian cysts detected by means of ultrasonography were randomized to low-dose monophasic Oral Contraceptive pills (OC) or to expectant management and followed up at one month with a second ultrasonography. If the ovarian cysts were still present, the women were followed for another month while on the same treatment.\n At the first month, the remission rates of ovarian cyst were 63.6% in low-dose monophasic OC and 52.9% in expectant groups. At the second month, the cumulative remission rates increased up to 72.7% in low-dose monophasic OC and 67.6% in expectant groups. There was no statistically significant difference between the two groups at both the first and second month of treatment. The most common side effect in women using OC was acne (18%).\n Low-dose monophasic OC were no more effective than expectant management in the treatment of spontaneously occurring functional ovarian cysts.", "This six-cycle, multicenter, open-label, randomized study compared the clinical experience of two low-dose oral contraceptives (OC): a triphasic OC containing norgestimate (NGM) and 35 micrograms ethinyl estradiol (EE) (Ortho Tri-Cyclen) and a monophasic OC containing norethindrone acetate (NETA) and 20 micrograms EE (Loestrin Fe 1/20). Cycle control, lipid and androgen profiles, and user satisfaction were studied in new-start OC users (i.e., no prior use within 60 days). Breakthrough bleeding or breakthrough spotting (BTB/BTS) occurred in a significantly smaller percentage of NGM/EE users than NETA/EE users during each of six cycles (p < or = 0.002). The incidence of BTB/BTS ranged from 3.7% to 13.5% for NGM/EE users and from 23.5% to 49.7% for NETA/EE users. Significantly fewer NGM/EE users than NETA/EE users experienced absence of menses at cycles 2 through 6 (p < or = 0.003). The percentages of women having no menses at each cycle ranged from 0.9% to 4.7% for NGM/EE users and from 10.3% to 21.3% for NETA/EE users. NGM/EE users reported a significantly (p < 0.001) higher level of satisfaction with their OC at the end of six cycles than did NETA/EE users, but there was no significant difference in compliance, discontinuation rates, or adverse events between the two groups. NGM/EE produced a significantly (p < or = 0.001) greater beneficial effect on HDL-C, HDL2, and apo A-I than did NETA/EE. No statistically significant treatment differences were found for total cholesterol, LDL-C, triglycerides, or apo-B. Both OC increased sex hormone binding globulin and decreased free testosterone, but NGM/EE had a significantly greater effect (p < 0.009).", "This study compared the effects of two triphasic oral contraceptives (OCs) taken for 6 pill cycles. One preparation contained levonorgestrel (EE/LN), the other a new progestagen, gestodene (SHG 415G). There were no effects on body weight, dietary habits, blood pressure, HDL-cholesterol or carbohydrate metabolism. Both OCs caused a small but statistically significant increase in plasma total cholesterol, LDL-cholesterol, LDL/HDL-cholesterol ratio and triglyceride concentration. Sex hormone binding globulin was increased by both preparations. Coagulation factor VII and fibrinogen were increased and antithrombin III levels reduced, indicating that both preparations had pro-coagulant activity. The gestodene triphasic preparation was associated with minor side effects similar to those experienced on EE/LN. The metabolic effects were similar despite the lower total steroid dose of the gestodene preparation.", "To compare bleeding patterns after immediate vs. conventional oral contraceptive (OC) initiation.\n Randomized controlled trial.\n University-based clinic.\n One hundred thirteen women initiating combination OCs.\n Participants received a 4-month supply of a monophasic 35-microg ethinyl E(2) (EE) OC and a bleeding diary, were randomized to immediate or conventional OC start, underwent monthly telephone follow-up, and after 90 days returned the diary and completed an exit interview.\n Total number of bleeding-spotting days, using the World Health Organization 90-day reference period method. Comparisons were made by trial assignment (immediate vs. conventional) and cycle day of OC initiation (day 8+ vs. days 1-7).\n There was no significant difference in the number of bleeding-spotting days (mean difference: -0.5 days; 95% CI: -3.4 to 2.3) or any other bleeding parameter between the immediate and conventional starters, or days 1-7 and day 8+ starters.\n Immediate start of OCs does not induce bleeding patterns different from conventional starting regimens. Concern about adverse bleeding patterns should not be considered a justification for instructing women to wait until menses before starting OCs.", "Cycle control and tolerability of two monophasic oral contraceptive pills containing 30 microg ethinyl estradiol (EE) with either 150 microg desogestrel (DSG) or 75 microg gestodene (GSD) were compared in women starting oral contraception. A minimum of 200 healthy women at risk for pregnancy were to be treated for a total of 6 cycles per patient in a prospective, randomized open parallel-group multicenter trial. Two hundred and forty-one subjects were randomized, 115 to DSG/EE and 126 to GSD/EE. Compliance to the study preparation was high (around 95%) in both groups and no pregnancies occurred during the study. Cycle control was excellent; there were no differences between the two groups with regard to incidence of spotting and breakthrough bleeding or duration and intensity of withdrawal bleeding. Side-effects were mild and in general comparable in the two groups. Both at baseline and during treatment, a higher proportion of women taking GSD/EE complained about breast tenderness. This resulted in more early withdrawals because of breast tenderness in the GSD/EE group. It was concluded that monophasic DSG/EE and GSD/EE are equally effective, have similar cycle control and both are generally well tolerated.", "The effect of two triphasic oral contraceptives (Triquilar [TRQ] and Trisiston [TRS]) containing ethinyl estradiol (EE) and levonorgestrel (LNG) on various hormonal parameters was investigated in 26 women during a cross-over study. TRS consisted of 0.03 mg EE + 0.05 mg LNG (six tablets), 0.04 mg EE + 0.075 mg LNG (six tablets), and 0.03 mg EE + 0.15 mg LNG (nine tablets), whereas TRQ was different in the second phase (five tablets) and third phase (10 tablets). Blood samples were taken on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. Both formulations inhibited ovulation reliably and decreased the serum levels of gonadotropins, free testosterone, and dehydroepiandosterone sulfate in a time-dependent manner, whereas estradiol and testosterone were already suppressed on day 6, indicating a direct suppressive effect on ovarian steroid synthesis. Prolactin, which rose sporadically in some women, was not significantly changed. In contrast, the levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the hormone-free interval of 7 days, all parameters returned at least partly to baseline. There was no significant difference between the effects of both formulations. The results suggest the possibility of a direct inhibitory effect of contraceptive steroids on ovarian steroid synthesis.", "A prospective, randomized trial compared client experiences with three popular oral contraceptives--Triphasil, Ortho-Novum 7/7/7 and Ortho-Novum 1/35. After one year, no significant relationship was found between the contraceptive prescribed and either breakthrough bleeding or satisfaction with the medication. The monophasic formulation, Ortho-Novum 1/35, was associated with amenorrhea more often." ]	The available evidence is insufficient to determine whether triphasic OCs differ from monophasic OCs in effectiveness, bleeding patterns or discontinuation rates. Therefore, we recommend monophasic pills as a first choice for women starting OC use. Large, high-quality RCTs that compare triphasic and monophasic OCs with identical progestogens are needed to determine whether triphasic pills differ from monophasic OCs. Future studies should follow the recommendations of Belsey or Mishell on recording menstrual bleeding patterns and the CONSORT reporting guidelines.
CD005593	[ "16083542", "15027039", "16260821", "11044775", "15590953", "18674411" ]	[ "Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period.", "Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease.", "Reality orientation therapy combined with cholinesterase inhibitors in Alzheimer's disease: randomised controlled trial.", "Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer's disease. A 24-week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group.", "Rivastigmine for dementia associated with Parkinson's disease.", "Efficacy, safety and tolerability of rivastigmine capsules in patients with probable vascular dementia: the VantagE study." ]	[ "Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period.\n Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs.\n In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment.\n Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.", "Cholinesterase (ChE) inhibitors are primarily used in the treatment of mild to moderate Alzheimer's disease (AD), but may also be effective in more severe disease.\n To evaluate the dual ChE inhibitor, rivastigmine, in more severe dementia.\n We retrospectively analysed pooled data from three randomised, placebo-controlled, double-blind, 6-month trials, involving 2126 AD subjects. Subjects were selected according to baseline Mini-Mental State Examination (MMSE) score to identify subjects with more severe cognitive impairment (10-12 MMSE points). One-hundred-and-seventeen subjects were included who had been treated with rivastigmine 6-12 mg/day or placebo. The AD Assessment Scale-Cognitive Subscale (ADAS-Cog), the MMSE, a six-item subscore of the Progressive Deterioration Scale (PDS) and the BEHAVE-AD assessed efficacy. Tolerability was assessed by recording adverse events (AEs) and the relative risk (RR) of discontinuation.\n This group of subjects responded well to rivastigmine. After 6 months, the mean ADAS-Cog score declined by 6.3 points in the placebo group and increased by 0.2 points in the rivastigmine group (observed cases; p<0.001). Clinical benefits were also observed with the MMSE, the six-item PDS score and items of the BEHAVE-AD. Rivastigmine showed the same pattern of AEs as in other studies, but the RR of dropping out due to AEs was lower than in subjects with milder AD.\n Current treatment guidelines do not recommend treating individuals with severe AD with ChE inhibitors. However, this retrospective analysis suggests that rivastigmine 6-12 mg/day may benefit subjects with more severe disease, as well as subjects with mild to moderate impairment.\n Copyright 2004 John Wiley & Sons, Ltd.", "Reality orientation therapy combined with cholinesterase inhibitors has not been evaluated in patients with Alzheimer's disease.\n To perform such an evaluation.\n We randomly assigned 79 of 156 patients treated with donepezil to receive a reality orientation programme. Caregivers of the treatment group were trained to offer the programme at home 3 days a week, 30 min/day, for 25 consecutive weeks, and were invited to stimulate and involve patients in reality-based communication.\n The treatment group showed a slight improvement in Mini-Mental State Examination (MMSE) scores (mean change +0.2, s.e.=0.4) compared with a decline in the control group (mean change -1.1, s.e.=0.4; P=0.02). Similarly for the Alzheimer's Disease Assessment Scale--Cognition (treatment group mean change +0.4, s.e.=0.8; control group -2.5, s.e.=0.8; P=0.01). The intervention had an equal effect on cognition in those with mild (MMSE score > or = 20) and moderate (score <20) dementia. No significant effect was observed for behavioural and functional outcomes.\n Reality orientation enhances the effects of donepezil on cognition in Alzheimer's disease.", "This study evaluated efficacy and safety of donepezil hydrochloride (donepezil) at 5 mg/day in patients with mild to moderately severe Alzheimer's disease for 24 weeks in a double-blind, placebo-controlled comparative trial. In this study, 268 patients were enrolled and 39 of these (15%) were withdrawn. In the evaluable population of efficacy, Protocol-Compatible (PC) analyzed patients (n = 228), better effects than that of placebo were confirmed using two primary efficacy measures: a cognitive performance test, the Japanese version of the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-J cog, p = 0.003) and a clinical global assessment, the Japanese version of the Clinical Global Impression of Change (J-CGIC, p = 0.000). The superiority of donepezil was also shown by secondary measures: the Sum of the Boxes of the Clinical Dementia Rating (CDR-SB), the Mental Function Impairment Scale (MENFIS) and the caregiver-rated modified Crichton scale (CMCS). The same results were obtained in the intention-to-treat (ITT) analysis (n = 263). The incidence of drug-related adverse events was 10% (14/136) in the donepezil and 8% (10/131) in the placebo group; no significant difference was seen between the two groups. The main adverse events were gastrointestinal symptoms, and these were almost all mild, and they all disappeared with continued administration or temporary discontinuation of donepezil. These results indicate that the donepezil appears to be effective and well tolerated in patients with mild to moderately severe Alzheimer's disease.\n Copyright 2000 S. Karger AG, Basel", "Cholinergic deficits are prominent in patients who have dementia associated with Parkinson's disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients.\n Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson's disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer's Disease Cooperative Study-Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini-Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test.\n A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer's disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01).\n In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson's disease but also with higher rates of nausea, vomiting, and tremor.\n Copyright 2004 Massachusetts Medical Society.", "The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD).\n VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects.\n NCT00099216.\n 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance.\n Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology." ]	The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. The evidence from one large trial shows fewer adverse events associated with donepezil compared with rivastigmine.
CD005390	[ "15199087", "15199089", "9765760", "15067028", "16823593", "7845115", "15933423", "1354275", "10749603", "11596588", "15108041", "9350242", "16332600", "11257395", "2202789", "9440756", "11720425", "20490797", "14752071", "20619634", "1900687", "8143995", "8665186", "3276901", "10623705", "1997835", "11955734", "2185340", "3286830", "7966789", "16155120", "18083404", "8412266", "7851558", "1333518", "3276900", "6749280", "6512582", "10334518", "8523058", "2276014", "17375049", "9345358" ]	[ "Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidence-based care's gastrointestinal cancer disease site group.", "American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer.", "Adjuvant therapy for stage II colon cancer after complete resection. Provincial Gastrointestinal Disease Site Group.", "Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?", "Randomized trial of the efficacy of adjuvant chemotherapy for colon cancer with combination therapy incorporating the oral pyrimidine 1-hexylcarbamoyl-5-fluorouracil.", "Long-term results of single course of adjuvant intraportal chemotherapy for colorectal cancer. Swiss Group for Clinical Cancer Research (SAKK)", "Adjuvant therapy with edrecolomab versus observation in stage II colon cancer: a multicenter randomized phase III study.", "Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma.", "Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: A multicenter phase III trial.", "A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients.", "Randomized controlled trial of the efficacy of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil and uracil/tegafur.", "[Prospective controlled study on the usefulness of Carmofur as a postoperative adjuvant chemotherapy for colorectal cancer].", "Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group.", "Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized phase III trials show promise.", "Adjuvant therapy of Dukes' A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: preliminary results of National Surgical Adjuvant Breast and Bowel Project Protocol C-02.", "Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer.", "Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III.", "Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC).", "Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials.", "Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.", "[Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report): five-year results. Cooperative Study Group of Surgical Adjuvant Chemotherapy for Colorectal Cancer in Japan].", "Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer.", "Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma.", "Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01.", "Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283.", "Effective surgical adjuvant therapy for high-risk rectal carcinoma.", "A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients.", "Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: a subset analysis of the Head and Neck Contracts Program.", "Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.", "Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited: long-term results of a controlled prospective study and further clinical experience.", "An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with curatively resected colon cancer.", "Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.", "Adjuvant chemotherapy for completely resected stage III non-small-cell lung cancer. Results of a randomized prospective study. The Japan Clinical Oncology Group.", "A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan).", "Adjuvant chemotherapy after radical surgery for non-small-cell lung cancer: a randomized study.", "Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01.", "Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung.", "Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas.", "Comparative efficacy of adjuvant chemotherapy in patients with Dukes' B versus Dukes' C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04)", "Intergroup study of fluorouracil plus levamisole as adjuvant therapy for stage II/Dukes' B2 colon cancer.", "Adjuvant chemotherapy with 5-fluorouracil, vincristine and CCNU for patients with Dukes' C colorectal cancer. The Swedish Gastrointestinal Tumour Adjuvant Therapy Group.", "An individual patient data meta-analysis of adjuvant therapy with uracil-tegafur (UFT) in patients with curatively resected rectal cancer.", "Long-term follow-up of the first randomized trial using neoadjuvant chemotherapy in stage Ib squamous carcinoma of the cervix: the final results." ]	[ "To develop a systematic review that would address the following question: Should patients with stage II colon cancer receive adjuvant therapy?\n A systematic review was undertaken to locate randomized controlled trials comparing adjuvant therapy to observation.\n Thirty-seven trials and 11 meta-analyses were included. The evidence for stage II colon cancer comes primarily from a trial of fluorouracil plus levamisole and a meta-analysis of 1,016 patients comparing fluorouracil plus folinic acid versus observation. Neither detected an improvement in disease-free or overall survival for adjuvant therapy. A recent pooled analysis of data from seven trials observed a benefit for adjuvant therapy in a multivariate analysis for both disease-free and overall survival. The disease-free survival benefits appeared to extend to stage II patients; however, no P values were provided. A meta-analysis of chemotherapy by portal vein infusion has also shown a benefit in disease-free and overall survival for stage II patients. A meta-analysis was conducted using data on stage II patients where data were available (n = 4,187). The mortality risk ratio was 0.87 (95% CI, 0.75 to 1.01; P =.07).\n There is preliminary evidence indicating that adjuvant therapy is associated with a disease-free survival benefit for patients with stage II colon cancer. These benefits are small and not necessarily associated with improved overall survival. Patients should be made aware of these results and encouraged to participate in active clinical trials. Additional investigation of newer therapies and more mature data from the presently available trials should be pursued.", "To address whether all medically fit patients with curatively resected stage II colon cancer should be offered adjuvant chemotherapy as part of routine clinical practice, to identify patients with poor prognosis characteristics, and to describe strategies for oncologists to use to discuss adjuvant chemotherapy in practice.\n An American Society of Clinical Oncology Panel, in collaboration with the Cancer Care Ontario Practice Guideline Initiative, reviewed pertinent information from the literature through May 2003.\n A literature-based meta-analysis found no evidence of a statistically significant survival benefit of adjuvant chemotherapy for stage II patients. Recommendations The routine use of adjuvant chemotherapy for medically fit patients with stage II colon cancer is not recommended. However, there are populations of patients with stage II disease that could be considered for adjuvant therapy, including patients with inadequately sampled nodes, T4 lesions, perforation, or poorly differentiated histology.\n Direct evidence from randomized controlled trials does not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer. Patients and oncologists who accept the relative benefit in stage III disease as adequate indirect evidence of benefit for stage II disease are justified in considering the use of adjuvant chemotherapy, particularly for those patients with high-risk stage II disease. The ultimate clinical decision should be based on discussions with the patient about the nature of the evidence supporting treatment, the anticipated morbidity of treatment, the presence of high-risk prognostic features on individual prognosis, and patient preferences. Patients with stage II disease should be encouraged to participate in randomized trials.", "Should patients with resected stage II colon cancer receive adjuvant therapy?\n To make recommendations regarding the use of adjuvant therapy in the treatment of resected stage II colon cancer.\n Overall survival is the primary outcome of interest. Secondary outcomes are disease-free survival and adverse effects of the treatment regimens.\n Evidence was selected and reviewed by 2 members of the Provincial Gastrointestinal Disease Site Group (GI DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The recommendations resulting from this review have been approved by the GI DSG, which comprise medical and radiation oncologists, surgeons and epidemiologists. Community representatives did not participate in the development of this practice guideline but will do so in future guidelines development.\n There are 25 published randomized controlled trials (RCTs) and 1 meta-analysis. The GI DSG pooled data from 11 of the 25 RCTs that provided adequate data.\n The 25 RCTs are grouped according to the type of therapy and whether the control patients received no treatment (observation) or other adjuvant therapy after resection. Because the trials usually included patients with stage II and III cancer, the complete trial results and those for a subset of patients with stage II disease were analysed. Although the overall trial results showed a survival benefit for adjuvant treatments, the benefit was not significant for stage II patients. A meta-analysis of 11 trials comparing adjuvant treatment with observation in patients with stage II cancer indicated no significant reduction in the odds ratio (OR) for death (OR 0.83; 95% confidence interval [CI] 0.62 to 1.10). The OR for death among patients receiving chemotherapy by portal vein infusion (PVI) was 0.62 (95% CI 0.35 to 1.11).\n The toxic effects of 5-fluorouracil (5-FU) with either levamisole or leucovorin, or both, were mild to moderate and consisted mostly of stomatitis, diarrhea and myelosuppression; 5% of patients required hospital admission. 5-FU plus levamisole was associated with transient neurotoxic effects in 18% of patients. Toxic effects associated with PVI were mild, rare and mostly consisted of leukopenia and diarrhea; 1% of patients experienced bowel perforation.\n Adjuvant therapy is not recommended at this time for the routine management of patients with resected stage II colon cancer. Patients with stage II disease and high-risk factors (bowel obstruction, tumour adhesion, invasion, perforation or aneuploidy) have a poorer prognosis, similar to that of patients with stage III colon cancer. For individual management, these patients should be made aware of their prognosis; treatment can be considered after the uncertainty of the value of adjuvant therapy has been explained to the patient. The enrolment of patients with high-risk stage II disease in clinical trials is encouraged. Trials comparing adjuvant therapy with observation are needed and are ethically acceptable in stage II colon cancer.", "Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain.\n Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets.\n Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients.\n Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.", "The purpose of the present trial was to clarify the efficacy of postoperative adjuvant chemotherapy including an oral fluoropyrimidine anticancer drug, the 1-hexylcarbamoyl-5-fluorouracil (HCFU), for the treatment of colon cancer.\n Patients with clinical stage Dukes' B and C colon cancer, who had been treated surgically, were assigned to a chemotherapy group treated with mitomycin C, 5-fluorouracil (5-FU), and HCFU and to a control group that received no postoperative adjuvant chemotherapy.\n Of the 1,001 patients registered for the study, 17 (1.7%) were ineligible. The incidence of toxicity was significantly higher in the chemotherapy group than in the control group. However, there were few severe side effects and no deaths related to the treatment. Overall survival showed no significant difference between the groups. The disease-free survival or the recurrence-free intervals was significantly higher in the chemotherapy group than in the control group. The incidence of hepatic recurrence was significantly (P=0.003) lower in the chemotherapy group than in the control group.\n The results of this study demonstrated the efficacy of adjuvant chemotherapy for colon cancer, i.e., combined chemotherapy that included the 5-FU oral anticancer drug HCFU.", "The efficacy of adjuvant chemotherapy after surgery for colorectal cancer remains unproven. We have investigated the efficacy of a perioperative intraportal cytotoxic regimen in a randomised trial of 533 patients with operable colorectal carcinoma. Patients were randomly assigned either a single course of portal infusion with mitomycin (10 mg/m2, one dose) plus fluorouracil (500 mg/m2 per 24 h for 7 days) starting immediately after surgery, or no adjuvant treatment. 505 (94%) were evaluable. At median follow-up of 8 years, adjuvant therapy reduced the risk of recurrence by 21% (hazard ratio 0.79 [95% CI 0.62-1.00], p = 0.051) and the risk of death by 26% (0.74 [0.57-0.97], p = 0.026). The lower risk of relapse was observed in all subgroups based on node status or localisation of the tumour; the risk reduction was greatest in patients with tumour-involved lymph nodes (Dukes' C; 0.67 [0.45-0.99], p = 0.045) and for those with colon cancer (0.78 [0.56-1.09], p = 0.151). Most of the difference in overall and disease-free survival could be attributed to a consistent reduction of all kinds of tumour recurrences (local relapses, liver metastases, and other distant metastases) in the treated group, rather than to a reduction of liver relapses only. We conclude that part of the benefit obtained with a single course of adjuvant chemotherapy via the portal vein for patients with operable colorectal carcinoma might be due to the systemic effects of the portal chemotherapy.", "In a phase III study recruiting patients with stage II colon cancer the effect of adjuvant therapy with edrecolomab, a murine monoclonal antibody to the cell-surface glycoprotein 17-1A, was compared to observation alone.\n From January 1997 until July 2000 a total of 377 patients were postoperatively stratified according to tumor stage (T3 vs. T4) and center, and randomly allocated to either treatment with edrecolomab (cohort A, n = 183) or observation (cohort B, n = 194). Patients in cohort A received a total of 900 mg edrecolomab. The study was terminated prematurely because of discontinuation of drug supply in Germany.\n 305 patients were eligible for the primary endpoint of overall survival and 282 patients for disease-free survival. After a median follow-up of 42 months overall survival and disease-free survival were not significantly different. Toxicity was mild.\n In the present study, postoperative adjuvant treatment with edrecolomab in patients with resected stage II colon cancer did not improve overall or disease-free survival.", "About half the patients treated with curative resection for colorectal cancer do not survive long-term. Adjuvant chemotherapy given during and after surgery may prevent hepatic metastases and improve patient survival. In patients with colorectal cancer, we have done a multicentre, randomised controlled trial comparing five-year survival after intraportal infusion of fluorouracil (1 g per day) plus heparin (10,000 U per day) (130 patients) or heparin alone (123) during curative resection and for 7 days thereafter, or after resection alone (145). There was no reduction in liver metastasis or increased overall survival advantage in either active-treatment arm of the study. However, patients who had stage III, Dukes' C (lymph-node-positive) tumours resected and were treated with fluorouracil plus heparin had a significant (p less than 0.03) survival advantage of about 16% compared with surgery-only controls. Further study of intraportal infusion of chemotherapeutic agent as adjuvant treatment to surgery in patients with colorectal cancer appears worthwhile.", "To evaluate the results of a prospective multicenter randomized study of adjuvant intraperitoneal 5-fluorouracil (5-FU) administered during 6 days shortly after resection of stages II and III colon cancers.\n Systemic adjuvant chemotherapy improves the survival of patients with stage III colon cancer receiving treatment for 6 months. Intraperitoneal chemotherapy theoretically combines peritoneal and hepatic effects.\n After resection, 267 patients were randomized into two groups. Patients in group 1 (n = 133) underwent resection followed by intraperitoneal administration of 5-FU (0.6 g/m2/day) for 6 days (day 4 to day 10). These patients also received intravenous 5-FU (1 g) during surgery. Patients in group 2 underwent resection alone (n = 134).\n In group 1, 103 patients received the total dose, 18 received a partial dose as a result of technical or tolerance problems, and 12 did not receive the chemotherapy. Rates of surgical death and complications were similar in both groups. Tolerance to treatment was excellent or fair in 97% of the patients and poor in 3%. After a median follow-up of 58 months, 5-year overall survival rates were 74% in group 1 and 69% in group 2; disease-free survival rates were 68% and 62%, respectively. Survival curves were superimposed until 3 years after treatment and began diverging thereafter. Among patients receiving the full treatment, the 5-year disease-free survival rate was improved in the treatment group in patients with stage II cancers but was unchanged in patients with stage III cancers.\n Chemotherapy with intraperitoneal 5-FU administered during a short period after surgery was well tolerated but was not sufficient to reduce the risk of death significantly. However, it reduced the risk of recurrence in stage II cancers. These results suggest that it should be associated with systemic chemotherapy to reduce both local and distant recurrences.", "Adjuvant chemotherapy is standard treatment for patients with resected colon cancer who are at high risk for recurrence, but the efficacy and toxicity of such treatment in patients more than 70 years of age are controversial.\n We performed a pooled analysis, based on the intention to treat, of individual patient data from seven phase 3 randomized trials (involving 3351 patients) in which the effects of postoperative fluorouracil plus leucovorin (five trials) or fluorouracil plus levamisole (two trials) were compared with the effects of surgery alone in patients with stage II or III colon cancer. The patients were grouped into four age categories of equal size, and analyses were repeated with 10-year age ranges (< or =50, 51 to 60, 61 to 70, and >70 years), with the same conclusions. The toxic effects measured in all trials were nausea or vomiting, diarrhea, stomatitis, and leukopenia. Patients in the fluorouracil-plus-leucovorin and fluorouracil-plus-levamisole groups were combined for the efficacy analysis but kept separate for toxicity analyses.\n Adjuvant treatment had a significant positive effect on both overall survival and time to tumor recurrence (P<0.001 for each, with hazard ratios of death and recurrence of 0.76 [95 percent confidence interval, 0.68 to 0.85] and 0.68 [95 percent confidence interval, 0.60 to 0.76], respectively). The five-year overall survival was 71 percent for those who received adjuvant therapy, as compared with 64 percent for those untreated. No significant interaction was observed between age and the efficacy of treatment. The incidence of toxic effects was not increased among the elderly (age >70 years), except for leukopenia in one study.\n Selected elderly patients with colon cancer can receive the same benefit from fluorouracil-based adjuvant therapy as their younger counterparts, without a significant increase in toxic effects.", "We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).\n Patients with stage II, III, or IV (Dukes' B, C) colorectal cancer were enrolled and randomly assigned to one of three groups: an immunochemotherapy group (mitomycin C [MMC] + 5-fluorouracil [5-FU] + HCFU + OK-432), a chemotherapy group (MMC + 5-FU + HCFU), and a control group (surgery alone) for those with colon cancer (study 1); and an immunochemotherapy group (MMC + 5-FU + UFT + OK-432), a chemotherapy group (MMC + 5-FU + UFT), and a control group (surgery alone) for those with rectal cancer (study 2).\n A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this randomized clinical trial (RCT). The incidence of side-effects was in the order of: immunochemotherapy group > chemotherapy group > control group in both the cohort of patients with colon cancer and the cohort with rectal cancer. In particular, the frequency of leucopenia and skin disorders was significantly higher than control groups. There were no severe adverse events such as death related to the adjuvant therapy. In both the colon cancer and rectal cancer cohorts, no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups.\n The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer, but that both combinations were well tolerated as adjuvant therapy. We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer, using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil (carmofur, HCFU) and uracil/tegafur (UFT).", "A prospective controlled study, the 7th cooperative study of the Japanese Foundation for Multidisciplinary Treatment, was conducted to evaluate the usefulness of concomitant therapy with MMC + HCFU as a postoperative adjuvant therapy in patients with colorectal cancer who had undergone curative resection for a period of 2 years and 11 months from February, 1986. The Dukes B and C patients with colorectal cancer classified by macroscopic examination who had an intravenous MMC 6 mg/m2 on the day of operation and followed by oral HCFU for 12 months from 2 weeks after operation (Group X) were compared with patients who had operation only (Group Y). Some 978 patients with colon cancer and 713 patients with rectal cancer were enrolled in the study, 85 (5.0%) of whom were not eligible. The 5-year survival rate of Group X in colon cancer was 79.3% and that of Group Y was 76.4%: thus the survival rate of Group X was slightly better than that of Group Y, but no significant difference was found between the two groups. Subset analysis revealed that the survival rate of Group X in advanced cancer of stage III b + IV, according to the General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus in Japan, was 62.4% and that of Group Y was 46.2%. Thus, the survival rate of Group X was significantly better than that of Group Y (logrank test: p = 0.035, generalized Wilcoxon test: p = 0.025). The disease-free survival rate was not significantly different between the groups with colon cancer and rectal cancer. The above results suggest that HCFU is useful for patients with a high risk of recurrence who had advanced colon cancer (stage III b + IV). However, additional prospective studies are required to verify them.", "Due to uncertainties regarding clinically meaningful gains from adjuvant chemotherapy after colorectal cancer surgery, several Nordic Groups in the early 1990s initiated randomised trials to prove or reject such gains. This report gives the joint analyses after a minimum 5-year follow-up. Between October 1991 and December 1997, 2 224 patients under 76 years of age with colorectal cancer stages II and III were randomised to surgery alone (n = 1 121) or adjuvant chemotherapy (n = 1 103) which varied between trials (5FU/levamisole for 12 months, n = 444; 5FU/leucovorin for 4-5 months according to either a modified Mayo Clinic schedule (n = 262) or the Nordic schedule (n = 397). Some centres also randomised patients treated with 5FU/leucovorin to+/-levamisole). A total of 812 patients had colon cancer stage II, 708 colon cancer stage III, 323 rectal cancer stage II and 368 rectal cancer stage III. All analyses were according to intention-to-treat. No statistically significant difference in overall survival, stratified for country or region, could be found in any group of patients according to stage or site. In colon cancer stage III, an absolute difference of 7% (p = 0.15), favouring chemotherapy, was seen. The present analyses corroborate a small but clinically meaningful survival gain from adjuvant chemotherapy in colon cancer stage III, but not in the other presentations.", "We performed three multi-institutional, prospectively randomized, controlled clinical trials, assessing the therapeutic effect of post-resection adjuvant active specific immunotherapy in patients with stage II and stage III colon cancer. In each study four outcomes were considered: time-to-disease recurrence, overall survival intervals, disease-free survival intervals, and recurrence-free survival intervals using the Kaplan-Meir method for generating curves and the log-rank test used to compare efficacy distributions. In addition, a meta-analysis of the three phase III trials was performed since the trials had proven homogeneity. Two main analyses were performed: (1) the intent-to-treat colon cancer patients from all three studies; and (2) analyzable colon cancer patients in all three studies. The conclusion of these analyses is that adjuvant active specific immunotherapy provided significant clinical benefits in patients with stage II colon cancer and appears to be an important new adjuvant treatment for these patients.", "Between March 1984 and July 1988, 1,158 patients with Dukes' A, B, and C carcinoma of the colon were entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-02. Patients were randomized to either no further treatment following curative resection or to postoperative fluorouracil (5-FU) and heparin administered via the portal vein. Therapy began on day of operation and consisted of constant infusion for 7 successive day. Average time on study was 41.8 months. A comparison between the two groups of patients indicated both an improvement in disease-free survival (74% v 64% at 4 years, overall P = .02) and a survival advantage (81% v 73% at 4 years, overall P = .07) in favor of the chemotherapy-treated group. When compared with the treated group, patients who received no further treatment had 1.26 times the risk of developing a treatment failure and 1.25 times the likelihood of dying after 4 years. Particularly significant was the failure to demonstrate an advantage from 5-FU in decreasing the incidence of hepatic metastases. The liver was the first site of treatment failure in 32.9% of 82 patients with documented recurrences in the control group and in 46.3% of 67 patients who received additional treatment. Therapy is administered via a regional route to affect the incidence of recurrence within the perfused anatomic boundary. Since, in this study, adjuvant portal-vein 5-FU infusion failed to reduce the incidence of hepatic metastases, it may be concluded that its use thus far is not justified. It may also be speculated that the disease-free survival and survival advantages (the latter of borderline significance) are a result of the systemic effects of 5-FU.", "This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy.\n Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups.\n Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01).\n There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.", "Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990, we conducted a prospective trial. 1029 patients were randomised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon (n = 730) or rectal cancer (n = 299). 45% were in stage II and 55% in stage III. With a median follow-up of 4 years and 9 months a significant reduction in odds of death (25%, SD 9%, P = 0.007) was observed for those with adjuvant treatment (65% at 5 year) compared to the observation group (55%). Improved relative survival was present in stage III (56% vs 44%), and in stage II patients (78% vs 70%). In rectal cancer a non-significant difference in disease-free or overall survival was observed. Distant metastases developed in 76%, while local recurrence alone occurred in 14%. An early start of adjuvant treatment (< 4 weeks) did not affect results. Compliance to 5FU plus levamisole was 69%. Severe toxicity did not occur. In conclusion, one year 5FU plus levamisole was of benefit in stage II and III colonic cancer; in rectal cancer a significant positive effect could not be demonstrated.", "In the latter 1990s, adjuvant chemotherapy for completely resected Stage III colorectal cancer remained controversial in Japan. We conducted two independent randomized controlled trials in patients with Stage III colon and rectal cancer.\n Patients were randomly assigned to receive surgery alone or surgery followed by treatment with UFT (400 mg/m²/day), given for five consecutive days per week for 1 year. The primary endpoint was relapse-free survival (RFS), and the secondary endpoint was overall survival (OS).\n A total of 334 patients with colon cancer and 276 with rectal cancer were enrolled. The patients' characteristics were similar between the UFT group and the Surgery-alone group. There was no significant difference in RFS or OS in colon cancer. In rectal cancer, however, RFS and OS were significantly better in the UFT group than in the Surgery-alone group. The only grade 4 toxicity in the UFT group was diarrhea, occurring in one patient with colon cancer and one patient with rectal cancer.\n Postoperative adjuvant chemotherapy with UFT is successfully tolerated and improves RFS and OS in patients with Stage III rectal cancer. In colon cancer, the expected benefits were not obtained (hazard ratio = 0.89).", "Adjuvant therapy of colorectal cancer with oral fluorinated pyrimidines is attractive because of its ease of administration and good tolerability. The purpose of this meta-analysis is to assess the survival and disease-free survival benefits of treating patients after surgical resection of a primary colorectal tumor with oral fluoropyrimidines for 1 year.\n This meta-analysis was performed on individual data from three randomized trials conducted by the Japanese Foundation for Multidisciplinary Treatment for Cancer involving a total of 5,233 patients with stages I to III colorectal cancer.\n The overall hazard ratio in favor of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P =.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <.001). Thus oral therapy reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumor stage (I, II, or III), tumor site (rectum or colon), patient age, or patient sex.\n Oral fluoropyrimidines improve disease-free survival and survival of patients after resection of early-stage colorectal cancer. These observations support the use of these agents alone after resection of early-stage disease, as well as further testing of oral agents in combination with new drugs that have recently shown antitumor activity in advanced colorectal cancer.", "Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled.\n Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy.\n In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01).\n Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.\n Copyright 2010 Elsevier Ltd. All rights reserved.", "A randomized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer. The schedules for drug administration were different in four districts: ACNU + Futraful (FT) group and FT alone group in the Hokkaido-Shikoku district; the same schedule groups plus untreated group in the Chubu-Kinki district; MMC+FT group, FT alone group in the Tohoku-Kanto district; and ADM+FT group and FT alone group in the Chugoku-Kyushu district. The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study. The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer, but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies. In n2 (+) or a2(s) rectal cancer in particular, combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate, and the rate of local recurrence was significantly lower with ADM+FT.", "Colon cancer is one of the major health problems in industrialized countries, and its incidence appears to be increasing. Surgical resectability is the most important prognostic determinant, although despite apparently curative surgery, recurrent tumors are common. Metastatic disease cannot be cured, and thus, there is a need for better adjuvant therapies.\n Two hundred and thirty-nine patients with surgically resected colon cancer in Dukes' stage B2 or C were randomly assigned to chemotherapy or observation alone to determine whether adjuvant chemotherapy could effectively reduce the rate of cancer recurrence. One hundred and twenty-one patients in stage B2 and 118 patients in stage C were enrolled in the study. Adjuvant treatment consisted of folinic acid 200 mg/m2, intravenously, plus 5-fluorouracil 400 mg/m2, intravenously, on days 1-5 every 4 weeks for 12 cycles.\n In stage B2, no significant difference between the adjuvant arm and the observation arm was noted. In stage C, adjuvant chemotherapy produced an advantage over observation in terms of a reduction in cancer recurrence rate with prolongation of a disease-free interval (P = 0.0016) and an improvement in overall survival (P = 0.0025).\n This study shows that folinic acid plus 5-fluorouracil adjuvant chemotherapy is effective in patients with surgically resected Dukes' stage C colon carcinoma.", "Adjuvant oral chemotherapy was studied in 67 patients with stage II hepatocellular carcinoma who underwent curative resection between May 1988 and December 1990. Patients were stratified into two groups according to preoperative liver dysfunction: 55 had stage I disease (mild dysfunction) and 12 had stage II (moderate dysfunction). A randomized controlled study of postoperative oral administration of 1-hexylcarbamoyl-5-fluorouracil (HCFU) was conducted in each group. From October 1994 HCFU administration was suspended because of side-effects in nine patients with stage I liver dysfunction and in three with stage II dysfunction who had received the drug for more than 4 weeks. Cumulative survival and recurrence-free survival rates of patients with stage I disease in the treatment group were higher (P = 0.08 and P = 0.04 respectively) than those in the control group. However, in patients with stage II disease no significant difference was observed (P = 0.77 and P = 1.0 respectively). This study suggests that the potential benefits of HCFU on tumour recurrence should be weighed against the risk of adverse reactions in patients with mild liver dysfunction.", "Data are presented from 1,166 patients with Dukes B and C carcinoma of the colon who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol C-01 between November 1977 and February 1983. Patients were randomized to one of three therapeutic categories: 1) no further treatment following curative resection (394 patients); 2) postoperative chemotherapy consisting of 5-fluorouracil, semustine, and vincristine (379 patients); or 3) postoperative BCG (393 patients). The average time on study was 77.3 months. A comparison between patients receiving postoperative adjuvant chemotherapy and those treated with surgery alone indicated that there was an overall improvement in disease-free survival (P = .02) and survival (P = .05) in favor of the chemotherapy-treated group. At 5 years of follow-up, patients treated with surgery alone were at 1.29 times the risk of developing a treatment failure and at 1.31 times the likelihood of dying as were similar patients treated with combination adjuvant chemotherapy. Comparison of the BCG-treated group with the group treated with surgery alone indicated that there was no statistically significant difference in disease-free survival (P = .09). There was, however, a survival advantage in favor of the BCG-treated group (P = .03). At 5 years of follow-up, patients randomized to the surgery-alone arm were at 1.28 times the risk of dying as were similar patients treated with BCG. Further investigation disclosed that this survival advantage in favor of BCG was a result of a diminution in deaths that were non-cancer related. When analyses were conducted on which events not related to cancer recurrence were eliminated, the survival difference between the BCG and control groups became nonsignificant (P = .40); the cumulative odds at 5 years decreased from 1.28 to 1.10. The findings from this study are the first from a randomized prospective clinical trial to demonstrate that a significant disease-free survival and survival benefit can be achieved with postoperative adjuvant chemotherapy in patients with Dukes B and C carcinoma of the colon who have undergone curative resection.", "A randomized phase III clinical trial of adjuvant active specific immunotherapy (ASI) with an autologous tumor cell-bacillus Calmette-Guérin (BCG) vaccine was conducted to determine whether surgical resection plus ASI was more beneficial than resection alone in stage II and III colon cancer patients.\n Patients (n = 412) with colon cancer (297 with stage II disease, 115 with stage III disease) were randomly allocated to an observation arm or to a treatment arm in which they received three weekly intradermal vaccine injections of 10(7) irradiated autologous tumor cells beginning approximately 4 weeks after surgery. The first two weekly injections also contained 10(7) BCG organisms. Patients were observed for determination of time to recurrence and disease-free and overall survival.\n This was a negative study in that after a 7.6-year median follow-up period, there were no statistically significant differences in clinical outcomes between the treatment arms. However, there were disease-free survival (P =.078) and overall survival (P =.12) trends in favor of ASI when treatment compliance was evaluated, ie, patients who received the intended treatment had a delayed cutaneous hypersensitivity (DCH) response to the third vaccination (induration >/=5 mm). Also, the magnitude of the DCH response correlated with improved prognosis. The 5-year survival proportion was 84.6% for those with indurations greater than 10 mm, compared with 45.0% for those with indurations less than 5 mm.\n When all randomized patients were evaluated, no significant clinical benefit was seen with ASI in surgically resected colon cancer patients with stage II or III colon cancer. However, there was an indication that treatment compliance with effective immunization results in disease-free and overall survival benefits.", "Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study, combined radiation and chemotherapy improved survival significantly as compared with surgery alone, but not as compared with adjuvant radiation, which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy, decrease recurrence, and improve survival as compared with adjuvant radiation alone.\n Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil, which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU).\n After a median follow-up of more than seven years, the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval, 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval, 2 to 70 percent), and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval, 9 to 57 percent). In addition, combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval, 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval, 7 to 45 percent). Its acute toxic effects included nausea, vomiting, diarrhea, leukopenia, and thrombocytopenia. These effects were seldom severe. Severe, delayed treatment-related reactions, usually small-bowel obstruction requiring surgery, occurred in 6.7 percent of all patients receiving radiation, and the frequencies of these complications were comparable in both treatment groups.\n The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis, as compared with postoperative radiation alone.", "To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC) patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant chemotherapy to RT alone in patients with advanced NPC.\n Between November 1994 and March 1999, 157 patients with Stage IV, M(0) (UICC/AJCC, 1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35-40 fractions, 1.8-2.0 Gy/fraction/day, 5 days/week, to a total dose 70-72 Gy with or without 9 weekly cycles of 24-h infusional chemotherapy (20 mg/m(2) cisplatin, 2,200 mg/m(2) 5-fluorouracil, and 120 mg/m(2) leucovorin) after RT. Of 157 patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis.\n With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were 60.5% vs. 54.5% (p = 0.5) and 49.5% vs. 54.4% (p = 0.38) for the radiotherapy-alone group and the combined radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates ratio of combined treatment to RT alone was 0.673 (p value = 0.232); the 95% confidence interval was 0.352 and 1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiotherapy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (>or= Grade 3) occurred in 17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (>or= Grade 3).\n We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit for overall survival or relapse-free survival.", "To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer, the Head and Neck Contracts Program conducted a three-arm study comparing standard surgery and radiation, induction chemotherapy (cisplatin and bleomycin) plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. As previously reported, this trial of 462 patients demonstrated no significant difference in disease-free survival or survival, but a significantly lower metastatic rate in the maintenance arm. To determine whether particular subgroups may have benefited from adjuvant therapy, we evaluated results based on primary site, and tumor (T) and node (N) stage. Of the 192 patients with oral cavity cancer, those on the maintenance arm had a significantly improved 3-year disease-free survival (67%) compared with the standard arm (49%) or induction arm (44%) (overall P = .05). For hypopharyngeal and laryngeal cancers there was no marked overall benefit. For the 106 patients with T1 plus T2 disease, there was marginal improvement in disease-free survival for the maintenance group (72%) compared with the standard group (47%) or induction group (43%) (overall P = .09). There was no advantage for patients with T3 and T4 disease. There was superior disease-free survival for patients with N1 disease on the maintenance arm (70%) compared with the standard arm (42%) (P = .024). The same was true for disease-free survival in 109 patients with N2 disease: standard (52%), induction (30%), maintenance (84%) (overall P less than .001). There was no benefit for N3 disease. A significant survival advantage with maintenance chemotherapy was only seen for N2 disease (overall P = .04). Since head and neck cancer patients are a heterogeneous group, there may be particular sites and stages for which adjuvant chemotherapy would be advantageous, and subset analysis can help indicate directions for new trials.", "The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.", "A total of 83 patients with nonorgan-confined bladder cancer with or without lymph node metastases (tumor stages pT3b, pT4a and/or pN1, pN2) was evaluated in November 1993 for relapse-free and overall survival. All patients underwent radical cystectomy between 1987 and 1991, 38 underwent adjuvant polychemotherapy with methotrexate, vinblastine and cisplatin plus doxorubicin (M-VAC) or epirubicin (M-VEC). Of the 83 patients 49 had entered a prospective randomized trial comparing adjuvant to no adjuvant treatment. The protocol was activated in May 1987. Patient recruitment was concluded in December 1990 because an interim analysis of the 49 randomized patients revealed a significant prognostic advantage in favor of the 26 patients randomized to the chemotherapy group compared to 23 in the control group (p = 0.0015, log-rank test for relapse-free survival curves). Preliminary data were published in 1992. Of the 26 patients randomized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC, 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function. The update of patient followup obtained in November 1993 continues to demonstrate a significant improvement in progression-free survival in favor of patients randomized for adjuvant chemotherapy (p = 0.0005). Followup of patients living free of disease ranged from 38 to 78 months. In a second analysis of actual treatment, the total collective of 83 patients treated from 1987 to 1991 was reviewed: 38 who had actually undergone adjuvant M-VAC/M-VEC (18 during the prospective trial and 20 in 1991 as the routinely recommended therapy) were compared with 45 without adjuvant M-VAC/M-VEC (7 refused to participate in the adjuvant trial, 8 randomized for but did not undergo adjuvant M-VAC/M-VEC, 23 belonged to the control group of the trial, and 7 underwent cystectomy in 1991 and remained without adjuvant treatment). This analysis again revealed a significant prognostic advantage in favor of the patients treated with adjuvant M-VAC/M-VEC. We conclude that adjuvant chemotherapy with M-VAC/M-VEC leads to a significant prolongation of relapse-free survival and to an improvement of the definitive cure rates after radical cystectomy for locally advanced transitional cell carcinoma of the bladder.", "Oral carmofur, either as a single or in combination with other chemotherapeutic agents, has been used as adjuvant chemotherapy for curatively resected colon cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with this cancer. The objective of this study was to perform a reappraisal of randomized clinical trials conducted in this regard.\n We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of oral carmofur for curatively resected colon cancer in terms of overall survival (OS) and disease-free survival (DFS).\n We analyzed individual patient data of three randomized clinical trials, which met the predetermined inclusion criteria. These three trials had a combined total of 2152 patients, carmofur as adjuvant chemotherapy compared with surgery-alone, 5 years follow-up, intention-to-treat-based analytic strategy and similar end points (OS and DFS). In a pooled analysis, 5 year OS rates were 80.4 and 76.4%, and 5 year DFS rates 76.9 and 71.0%, respectively, in carmofur and surgery-alone group. Oral carmofur had significant advantage over surgery-alone in terms of both OS [pooled hazard ratio, 0.82; 95% confidence interval (CI) = 0.68-0.99; P = 0.043] and DFS (pooled hazard ratio, 0.77; 95% CI = 0.65-0.91; P = 0.003).\n This individual patient-based meta-analysis demonstrated that oral carmofur significantly improves both OS and DFS in patients with curatively resected colon cancers.", "The aim of the QUASAR trial was to determine the size and duration of any survival benefit from adjuvant chemotherapy for patients with colorectal cancer at low risk of recurrence, for whom the indication for such treatment is unclear.\n After apparently curative resections of colon or rectal cancer, 3239 patients (2963 [91%] with stage II [node negative] disease, 2291 [71%] with colon cancer, median age 63 [IQR 56-68] years) enrolled between May, 1994, and December, 2003, from 150 centres in 19 countries were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617). Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid. Until 1997, levamisole (12 courses of 450 mg over 3 days repeated every 2 weeks) or placebo was added. After 1997, patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only. The primary outcome was all-cause mortality. Analyses were done by intention to treat. This trial is registered with the International Clinical Trial Registry, number ISRCTN82375386.\n At the time of analysis, 61 (3.8%) patients in the chemotherapy group and 50 (3.1%) in the observation group had missing follow-up. After a median follow-up of 5.5 (range 0-10.6) years, there were 311 deaths in the chemotherapy group and 370 in the observation group; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 (95% CI 0.70-0.95; p=0.008). There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001). Treatment efficacy did not differ significantly by tumour site, stage, sex, age, or chemotherapy schedule. Eight (0.5%) patients in the chemotherapy group and four (0.25%) in the observation group died from non-colorectal cancer causes within 30 weeks of randomisation; only one of these deaths was deemed to be possibly chemotherapy related.\n Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death seen here translates into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0).", "Two hundred nine patients with completely resected stage III non-small-cell lung cancer were randomized to receive postoperative cisplatin and vindesine chemotherapy or no further treatment. Before randomization, patients were stratified by the histologic characteristics of their tumors (squamous versus nonsquamous cell carcinoma). Prognostic variables such as histology, performance status, extent of operation, and tumor and nodal status of the eligible patients in chemotherapy (n = 90) and control groups (n = 91) were equally distributed. There was no statistically significant difference in disease-free and overall survival between the two groups. The 3-year disease-free survivals of the chemotherapy and control groups were 37% and 42%, respectively. The median survival times (5-year survival) were 31 months (35%) in the chemotherapy group and 37 months (41%) in the control group. These was no different pattern in the first site of recurrence (local versus systemic) between the two groups. This study failed to demonstrate the therapeutic benefits of postoperative cisplatin and vindesine chemotherapy.", "A prospective randomized trial (the second cooperative study) was conducted from July 1985 to December 1987 to investigate the benefits of postoperative adjuvant chemotherapy in patients for whom non-small cell lung cancer had been resected completely. Patients were randomly assigned either to a chemotherapy group (group A) treated postoperatively with CDDP (66 mg/m2 x 1), ADM (26 mg/m2 x 1) and UFT (8 mg/kg/day) during 6 months, or to a control group (group B) which had undergone surgery only. Three hundred and thirty-three resected cases were registered. Among them, 24 cases (7.2%) were excluded, because of incomplete resection (15), pathologically benign tumour (3), small cell lung cancer (2) and other factors (4). Three hundred and nine cases were eligible: 155 cases in group A (p-Stage I 93, II 19, III 43) and 154 in group B (I 109, II 10, III 35). The 5-year survival rate in group A was 61.8%, and that in group B 58.1%. The 5-year disease-free survival rate for each group was 61.8% and 57.4%, respectively. There were no significant differences in the 5-year survival between the two groups. However, since a significant difference was observed between the two groups regarding pathological lymph node metastasis (pN), the prognostic factors were adjusted using Cox's proportional hazard model. Thereafter the adjusted survival rate and disease-free survival rate for group A became significantly higher than for group B (P = 0.044 and P = 0.036, respectively). Thus, from these results, it is concluded that the role of surgery for non-small cell lung cancer still remains of primary importance, and postoperative adjuvant chemotherapy is effective to improve the results of surgery and prolong life of patients with non-small cell lung cancer.", "The aims of this study were to assess the effect of adjuvant chemotherapy on overall survival, disease-free survival, and relapse pattern, as well as its toxicity in patients who underwent radical surgery for non-small-cell lung cancer (NSCLC).\n One hundred ten patients with T1-3N0 (World Health Organization [WHO] 1981) NSCLC underwent radical surgery during the period of 1982 through 1987. After surgery, the patients were randomized to receive adjuvant chemotherapy (n = 54) (cyclophosphamide 400 mg/m2, doxorubicin 40 mg/m2, and cisplatin 40 mg/m2 [CAP] for six cycles) or no active treatment (n = 56).\n After 10 years from the start of the study, 61% of patients were alive in the chemotherapy group and 48% were alive in the control group (P = .050). Seventeen patients (31%) in the CAP group and 27 patients (48%) in the control group had a recurrence during the follow-up period (P = .01). The 5-year survival rate was 67% in the chemotherapy group and was 56% in the control group (P = .050). The patients in the chemotherapy group who completed the planned treatment had a slightly better 5-year survival than those whose chemotherapy was discontinued (72.5% v 50.3%; P = .15). Chemotherapy-related gastrointestinal toxicity grade 3 to 4 (WHO) occurred in 63% and was the main reason why patients refused further planned therapy.\n Our results suggest that patients with NSCLC at pathologic stage I who have undergone radical surgery benefit from adjuvant chemotherapy.", "Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-01 between November 1977 and October 1986. Their average time on study was 64.1 months. The patients were randomized to receive no further treatment (184 patients), postoperative adjuvant chemotherapy with 5-fluorouracil, semustine, and vincristine (MOF) (187 patients), or postoperative radiation therapy (184 patients). The chemotherapy group, when compared with the group treated by surgery alone, demonstrated an overall improvement in disease-free survival (P = .006) and in survival (P = .05). Employing the proportional hazards model, a global test was used to determine the presence of treatment interactions. Investigation of stratification variables employed in this study indicated that sex, and to a lesser extent age and Dukes stage, made individual contributions to the disease-free survival and the survival benefit from chemotherapy. When evaluated according to sex, the benefit for chemotherapy at 5 years, both in disease-free survival (29% vs. 47%; P less than .001; relative odds, 2.00) and in survival (37% vs. 60%; P = .001; relative odds, 1.93), was restricted to males. When males were tested for age trend with the use of a logistic regression analysis, chemotherapy was found to be more advantageous in younger patients. When the group receiving post-operative radiation (4,600-4,700 rad in 26-27 fractions; 5,100-5,300 rad maximum at the perineum) was compared to the group treated only by surgery, there was an overall reduction in local-regional recurrence from 25% to 16% (P = .06). No significant benefit in overall disease-free survival (P = .4) or survival (P = .7) from the use of radiation has been demonstrated. The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant. In conclusion, this investigation has demonstrated a benefit from adjuvant chemotherapy (MOF) for the management of rectal cancer. The observed advantage was restricted to males. Postoperative radiation therapy reduced the incidence of local-regional recurrence, but it failed to affect overall disease-free survival and survival.", "Eight hundred sixty-five patients with a microscopically curative resection for carcinoma of the lung were accepted for study, none of whom were excluded from analysis. Adjuvant therapy was randomly assigned about the tenth to 14th postoperative day; 432 patients (treated) were to receive CCNU and hydroxyurea for one year, while 433 patients (controls) were to receive no adjuvant therapy. Toxic reactions to therapy were reported, but only 1% were severe enough to require stopping therapy. No evidence of improved survival or delayed recurrence of disease was seen in treated patients as a whole or when examined by cell type and by postsurgical TNM category. On the contrary, survival beyond the second year of follow-up may have been impaired by the drugs when administered to patients without evidence of tumor spread to the lymph nodes.", "Between June 1975 and April 1981, 61 of the 177 eligible patients whose nonosseous sarcomas of extremity or trunk origin had been completely excised primarily or after local recurrences agreed to participate in a randomized study of adjuvant chemotherapy. Dermatofibrosarcoma, lymphomas, myeloma, Kaposi's sarcoma, and embryonal rhabdomyosarcoma were excluded as were patients with significant second primary cancers and those who received either preoperative or postoperative radiation therapy. After stratification by anatomic status of disease, site of origin, and histologic grade, a random one half of the 61 participants began alternating courses of vincristine/cyclophosphamide/dactinomycin, and vincristine/doxorubicin/dacarbazine at six-week intervals for one year. The control group was evaluated at six-week intervals without adjuvant chemotherapy, but these patients were offered this chemotherapy later if they had progressive disease excised. Although 30% of the 61 patients experienced local recurrence of disease within the first five years after randomization, and only 54% were continuously disease free for five or more years, 82% were surviving at five years (Kaplan-Meier calculations) with a median follow-up of 64.3 months. Partial suppression of distant metastasis by adjuvant chemotherapy was apparent in the overall study, in the extremity tumor category, and in the subgroup of patients who had received limb-sparing surgery; however, no survival advantage for chemotherapy-treated patients was demonstrated. The 30 adjuvant chemotherapy-treated patients received a total of three thoracotomies as compared with 17 salvage thoracotomies for the 31 control patients; however, salvage surgery for local recurrences has been similar in the two groups. Recent improvement in the survival of patients with soft-tissue sarcomas is not necessarily a result of adjuvant chemotherapy or radiation therapy.", "Although the benefit from adjuvant chemotherapy has been clearly established in patients with Dukes' C colon cancer, such benefit has been questioned in patients with Dukes' B disease. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, we examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment.\n The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU with operation alone. Protocol C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04 compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the combination of 5-FU, LV, and LEV.\n Forty-one percent of the patients included in these four trials had resected Dukes' B tumors. In all four studies, the overall, disease-free, and recurrence-free survival improvement noted for all patients was evident in both Dukes' B and Dukes' C patients. When the relative efficacy of chemotherapy was examined, there was always an observed reduction in mortality, recurrence, or disease-free survival event, irrespective of Dukes' stage, and in most instances, the reduction was as great or greater for Dukes' B patients as for Dukes' C patients. When data from all four trials were examined in a combined analysis, the mortality reduction was 30% for Dukes' B patients versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients occurred irrespective of the presence or absence of adverse prognostic factors.\n Patients with Dukes' B colon cancer benefit from adjuvant chemotherapy and should be presented with this treatment option. Regardless of the presence or absence of other clinical prognostic factors, Dukes' B patients seem to benefit from chemotherapy administration.", "To determine the effectiveness of fluorouracil plus levamisole administered postoperatively to patients with resected stage II (Dukes' B2) colon cancer.\n This randomized controlled clinical trial (INT-0035) was performed by National Cancer Institute-sponsored cancer clinical trials cooperative groups. Patients were assigned to observation only or to fluorouracil (450 mg/m2 intravenously [IV] daily for 5 days and, beginning at 28 days, weekly for 48 weeks) plus levamisole (50 mg orally three times daily for 3 days repeated every 2 weeks for 1 year). Cancer recurrence, survival, and treatment side effects were assessed.\n Three hundred eighteen eligible patients were analyzed with a median follow-up time of 7 years. Fluorouracil plus levamisole reduced the recurrence rate by 31%, although this trend was not statistically significant (P = .10). A total of 87 patients died: 43 on observation and 44 on fluorouracil plus levamisole. Disparity between effects on recurrence rate and overall survival is partially explained by a higher rate of non-colon cancer-related deaths on fluorouracil plus levamisole (15 v seven) and by the effects of salvage surgery with curative intent. Of seven patients with recurrence who were rendered disease-free by salvage surgery, six were on the observation arm. As was observed in patients treated with fluorouracil plus levamisole for stage III disease, toxicity was acceptable and compliance was excellent.\n Fluorouracil plus levamisole is tolerable and accepted as standard surgical adjuvant therapy for patients with stage III colon cancer, but the data from this study in stage II patients suggest a decreased relapse rate without a significant improvement in survival.", "A prospective controlled randomized trial testing adjuvant postoperative combination chemotherapy (5-fluorouracil, lomustine (CCNU) and vincristine) versus no adjuvant therapy in patients operated on for Dukes' C colorectal cancer is reported. In total 334 patients aged less than 70 years were recruited: 205 patients with colonic and 99 with rectal cancer, but there were three protocol violations and these cases are excluded from further consideration. Twenty-seven patients had a limited resection of their cancer. After 5 years' follow-up there was no significant difference in the tumour-free survival rate or in the survival rate between the treated and control groups. Twenty-nine of the 147 patients who started chemotherapy discontinued this treatment because of side-effects, mainly from the gastrointestinal tract. In 30 patients treatment was discontinued because of recurrent disease. The conclusion is that systemic administration of combination chemotherapy for colorectal cancer after operation is not worthwhile in routine clinical practice.", "Uracil-Tegafur (UFT), an oral fluorinated pyrimidine chemotherapeutic agent, has been used for adjuvant chemotherapy in curatively resected colorectal cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with rectal cancer. The objective of this study was to perform a reappraisal of randomised clinical trials conducted in this field. We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of UFT for curatively resected rectal cancer in terms of overall survival (OS), disease-free survival (DFS), and local relapse-free survival (LRFS). We analysed individual patient data of five adjuvant therapy randomised clinical trials for rectal cancer, which met the predetermined inclusion criteria. These five trials had a combined total of 2091 patients, UFT as adjuvant chemotherapy compared to surgery-alone, 5-year follow-up, intention-to-treat-based analytic strategy, and similar endpoints (OS and DFS). In a pooled analysis, UFT had significant advantage over surgery-alone in terms of both OS (hazard ratio, 0.82; 95% confidence interval (CI), 0.70-0.97; P=0.02) and DFS (hazard ratio, 0.73; 95%CI, 0.63-0.84; P<0.0001). This individual patient-based meta-analysis demonstrated that oral UFT significantly improves both OS and DFS in patients with curatively resected rectal cancer.", "To determine if three courses consisting of 50 mg/m2 cis-platinum, 1 mg/m2 vincristine, and 25 mg/m2 bleomycin (day 1-3) at 10-day intervals can improve survival before Wertheim-Meigs + radiotherapy.\n Two hundred five unselected stage Ib patients (having tumors > 2 cm in diameter) were divided into two groups at random: (1) The group control consisted of 103 patients (56 bulky, > 4 cm diameter) treated with Wertheim-Meigs (if the tumor was resectable with free surgical margins) + adjuvant radiotherapy to whole pelvis (extended field radiation was used only in patients with paraaortic lymph node metastases). When the tumor was unresectable, a surgical staging was performed and radiotherapy was the chosen treatment. (2) Neoadjuvant (102 patients, 61 bulky) had neoadjuvant chemotherapy and then the same treatment as the control patients.\n After 67 (31-102) months of follow-up, no difference was seen in tumors > 2 and < 4 cm in both groups (C = 77% vs N = 82%), but statistically significant differences were seen in survival and disease-free survival, in bulky tumors, and between patients with neoadjuvant chemotherapy + Wertheim-Meigs + radiotherapy (80%) and the control (61%). This was due to an increased operability that was substantially improved in bulky tumors in the neoadjuvant chemotherapy group (61/61, 100%) vs control (48/56, 85%; P < 0.01). After 7 years of follow-up, the outcome of the unresectable bulky control group of patients is significantly worse (14%) than that of the resectable group (69%; P < 0.001). With regard to recurrences, a significant decrease in pelvic failures in the neoadjuvant chemotherapy group was observed (P < 0.001). Survival was improved in bulky resectable cases (N = 81% vs C = 69%, P < 0.05). Pathological findings for the surgical specimens revealed differences between both groups because all the risk factors such as parametrial and lymph node metastases, tumor bulk, and vascular embolism had been decreased (P < 0.001).\n Neoadjuvant chemotherapy can improve survival because of increased operability with free survival margins and a decrease in pathologic risk factors in unselected, bulky (> 4 cm diameter) stage Ib patients." ]	: Although there was no improvement in overall survival in the pooled analysis, we did find that disease-free survival in patients with stage II colon cancer was signficantly better with the use of adjuvant therapy. It seems reasonable to discuss the benefits of adjuvant systemic chemotherapy with those stage II patients who have high risk features, including obstruction, perforation, inadequate lymph node sampling or T4 disease. The co-morbidities and likelihood of tolerating adjuvant systemic chemotherapy should be considered as well. There exists a need to further define which high-risk features in stage II colon cancer patients should be used to select patients for adjuvant therapy. Also, researchers must continue to search for other therapies which might be more effective, shorter in duration and less toxic than those available today.
CD006915	[ "16537867", "19450268", "16356437", "11008978", "8625677" ]	[ "Clinical effects of heliox administration for acute bronchiolitis in young infants.", "Heliox reduces respiratory system resistance in respiratory syncytial virus induced respiratory failure.", "Noninvasive therapy with helium-oxygen for severe bronchiolitis.", "Randomized trial of the use of heliox as a driving gas for updraft nebulization of bronchodilators in the emergent treatment of acute exacerbations of chronic obstructive pulmonary disease.", "Evaluation of heliox in children hospitalized with acute severe asthma. A randomized crossover trial." ]	[ "To assess the effect of heliox, a helium-oxygen mixture, on respiratory distress symptoms in young infants.\n Prospective, randomized, double-blind study.\n Pediatric ICU (PICU) of a university hospital.\n Twenty infants, all < 3 months old, admitted to the PICU with moderate-to-severe acute respiratory syncytial virus bronchiolitis.\n All infants were randomly and blindly assigned to inhale either heliox or an air-oxygen mixture (airox) for 1 h under an oxyhood.\n After 1 h, the respiratory distress score was significantly lower in the heliox group compared with the airox group (3.05 vs 5.5, p < 0.01), with a significant reduction in accessory muscles use (p < 0.05) and expiratory wheezing (p < 0.01). In contrast, inspiratory breath sounds and cyanosis did not significantly differ between groups. The ex-premature infants of the heliox group had a higher respiratory distress score at baseline compared with the term infants of this group (5.8 vs 5.2, p < 0.05) and a comparable decrease in the score at 60 min.\n In young infants, even those born prematurely, heliox breathing induced a rapid reduction in accessory muscles use and expiratory wheezing. Further studies are needed to confirm the decreased respiratory muscle work of breathing during heliox inhalation in this population.", "Respiratory syncytial virus (RSV) lower respiratory tract disease is characterised by narrowing of the airways resulting in increased airway resistance, air-trapping and respiratory acidosis. These problems might be overcome using helium-oxygen gas mixture. However, the effect of mechanical ventilation with heliox in these patients is unclear. The objective of this prospective cross-over study was to determine the effects of mechanical ventilation with heliox 60/40 versus conventional gas on respiratory system resistance, air-trapping and CO2 removal.\n Mechanically ventilated, sedated and paralyzed infants with proven RSV were enrolled within 24 hours after paediatric intensive care unit (PICU)admission. At T = 0, respiratory system mechanics including respiratory system compliance and resistance, and peak expiratory flow rate were measured with the AVEA ventilator. The measurements were repeated at each interval (after 30 minutes of ventilation with heliox, after 30 minutes of ventilation with nitrox and again after 30 minutes of ventilation with heliox). Indices of gas exchange (ventilation and oxygenation index) were calculated at each interval. Air-trapping (defined by relative change in end-expiratory lung volume) was determined by electrical impedance tomography (EIT) at each interval.\n Thirteen infants were enrolled. In nine, EIT measurements were performed. Mechanical ventilation with heliox significantly decreased respiratory system resistance. This was not accompanied by an improved CO2 elimination, decreased peak expiratory flow rate or decreased end-expiratory lung volume. Importantly, oxygenation remained unaltered throughout the experimental protocol.\n Respiratory system resistance is significantly decreased by mechanical ventilation with heliox (ISCRTN98152468).", "To determine whether noninvasive therapy using a helium-oxygen mixture reduces the use of positive-pressure ventilation in the treatment of respiratory failure caused by severe bronchiolitis.\n This was a multicenter, randomized, double-blind, placebo-controlled trial that recruited infants in 4 pediatric intensive care units (PICUs). A total of 39 nonintubated infants with severe bronchiolitis caused by respiratory syncytial virus (RSV) were randomly assigned within 8 hours of PICU admission to receive a helium-oxygen mixture (helium group) or an air-oxygen mixture (control group) through an inflatable head hood. The primary study outcome was the requirement for positive pressure mechanical ventilation. Results were compared using Fisher's exact test.\n No differences were noted between the control and helium groups with respect to age (1.0 vs 1.1 months), prematurity, or family history of asthma or smoking. Positive pressure ventilation was judged necessary for 4 of the 21 (19.0%) infants in the control group and in 4 of the 18 (22.2%) in the helium group (relative risk = 1.17; 95% confidence interval = 0.34 to 4.01).\n This study did not detect any differences between the patients in the helium group and the control group with respect to the rate of positive-pressure ventilation.", "To determine whether the bronchodilator effects of albuterol and ipratropium bromide are greater if updraft nebulization is driven by 80% helium and 20% oxygen (HELIOX) than if driven by compressed room air (AIR) during the treatment of an acute exacerbations of chronic obstructive pulmonary disease (COPD).\n The emergency department of a 750-bed inner-city community hospital.\n Over a 12-month period, a convenience sample of 50 normoxic patients presenting with signs and symptoms of an acute exacerbation of COPD were prospectively randomized to receive either HELIOX or AIR as the driving gas for updraft nebulization of a mixture of albuterol 2.5 mg and ipratropium bromide 0.5 mg. Additional aerosol treatments with albuterol 2.5 mg were given at 20, 40, and 120 mins after randomization using the assigned gas. Spirometry was obtained while breathing room air before the first treatment (baseline) and at 1 hr and 2 hrs after the initiation of treatment. The primary measure of efficacy was the change in percent of predicted forced expiratory volume in 1 sec (FEV1) over the treatment period. A secondary measure of efficacy was the change in percentage of predicted forced expiratory flow after 25% to 75% of vital capacity had been expelled (FEF25-75).\n Twenty-five patients were randomized to each treatment group. Three patients (1 HELIOX, 2 AIR) were unable to complete the study. The baseline FEV1was 44% (95% confidence interval, 35% to 52%) of predicted in the HELIOX group and 39 (31% to 46%) of predicted in the AIR group. There were no adverse outcomes observed in either the HELIOX group or the AIR group. There were no significant differences in the change of FEV1 between the two groups by either the 1 hr or 2 hr time point (1 hr, HELIOX + 10% [7% to 13%], AIR + 9% [5% to 13%]; 2 hr HELIOX + 10% [6% to 15%], AIR + 10% [6% to 14%]). The improvement in FEF25-75 was significantly greater in the HELIOX group than in the AIR group at both the 1 hr time point (HELIOX + 14% [7% to 22%] vs. AIR + 7% [3% to 10%], p = .05) and at the 2 hr time point (HELIOX + 15% [8% to 21%] vs. AIR + 7% [4% to 11%], p = .05).\n Use of HELIOX as a driving gas for the updraft nebulization of bronchodilators during the first 2 hrs of treatment of an acute COPD exacerbation failed to improve FEV1 faster than the use of AIR. The faster improvement in FEF25-75 during the first 2 hrs of treatment was small and of uncertain clinical significance.", "To determine whether breathing a blend of 70% helium:30% oxygen (heliox) would improve pulmonary function, decrease clinical score, and improve the sensation of dyspnea in children hospitalized with acute severe asthma.\n Prospective, randomized, double-blind, crossover study.\n The inpatient pediatric service of a military, tertiary care, teaching hospital.\n Children 5 to 18 years who required hospital admission for treatment of acute asthma.\n All patients received 5 mg of nebulized albuterol every 1 to 4 h, with a dose given within 30 min of the start of the study, and IV administered methylprednisolone. Patients breathed heliox and a 30% oxygen-enriched air mixture for 15 min each in random order.\n Clinical score, dyspnea score, oxygen saturation, heart rate, and respiratory rate, followed by FVC, FEV1, peak expiratory flow rate (PEFR), and, mean midexpiratory flow rate (FEF25-75) were obtained at study entry, 15 min after breathing the first gas mixture (heliox or air per randomization), 15 min after breathing the second mixture, and again 15 min after stopping the second gas mixture (study end values). Eleven children were enrolled, and all completed the study. There were no significant differences between study entry and study end spirometric values. Using the paired t test, we found no significant differences between mean values (SD) of FEV1 and FVC obtained while breathing heliox vs air; FEV1-heliox, 53% (18%) of the predicted value; FEV1-air, 52% (16%) of the predicted value (p = 0.36); FVC-heliox, 69% (22%) of the predicted value; and FVC-air, 70% (21%) of the predicted value (p = 0.50). The differences in values for PEFSR and FEF25-75 while breathing heliox vs air were small but did reach statistical significance in favor of heliox: PEFR-heliox, 56% (20%) of the predicted value; PEFR-air, 50% (16%) of the predicted value (p = 0.04); FEF25-75-heliox, 32% (13%) of the predicted value; and FEF25-75-heliox, 29% (11%) of the predicted value (p = 0.006). Heliox had no effect on either clinical or dyspnea scores.\n The short-term inhalation of heliox did not benefit this group of children hospitalized with acute, severe asthma." ]	Current evidence suggests that the addition of heliox therapy may significantly reduce a clinical score evaluating respiratory distress in the first hour after starting treatment in infants with acute RSV bronchiolitis. Nevertheless, there was no reduction in the rate of intubation, in the need for mechanical ventilation, or in the length of PICU stay. Further studies with homogeneous logistics in their heliox application are needed. Such studies would provide necessary information as to the appropriate place for heliox in the therapeutic schedule for severe bronchiolitis.
CD004768	[ "15476903", "15218558", "16494645", "12017395", "11299404", "20959428", "10423616", "14520769", "3421455", "19648310", "2044396", "15511762" ]	[ "Dose-ranging analgesic study of Prosorb diclofenac potassium in postsurgical dental pain.", "Analgesic safety and efficacy of diclofenac sodium softgels on postoperative third molar extraction pain.", "Efficacy and tolerability of diclofenac potassium sachets in acute postoperative dental pain: a placebo-controlled, randomised, comparative study vs. diclofenac potassium tablets.", "Comparison of the analgesic efficacy of rofecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: a randomized, placebo-controlled clinical trial.", "Comparative study of diclofenac sodium and paracetamol for treatment of pain after adenotonsillectomy in children.", "Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT).", "Onset and duration of analgesia of diclofenac potassium in the treatment of postepisiotomy pain.", "Analgesic efficacy of low-dose diclofenac versus paracetamol and placebo in postoperative dental pain.", "Diclofenac sodium for post-tonsillectomy pain in children.", "Diclofenac sodium gel in patients with primary hand osteoarthritis: a randomized, double-blind, placebo-controlled trial.", "A multi-centre comparative study of diclofenac sodium and a dipyrone/spasmolytic combination, and a single-centre comparative study of diclofenac sodium and pethidine in renal colic patients in India.", "The prophylactic use of diclofenac (Voltarol) suppositories in perineal pain after episiotomy. A random allocation double-blind study." ]	[ "ProSorb diclofenac potassium (K) is a novel, liquid-filled rapid-dispersion formulation of the nonsteroidal anti-inflammatory drug diclofenac, placed into soft gelatin capsules. Its time to maximal plasma drug concentration has been shown to be approximately half, and its maximal plasma drug concentration nearly twice, that of immediate-release diclofenac K tablets.\n This study compared the analgesic dose-response relationship and tolerability of 3 doses of ProSorb diclofenac K and placebo in the treatment of pain after dental impaction surgery.\n This randomized, double-blind, double-dummy, placebo-controlled parallel-group study was conducted at 6 centers across the United States. Patients aged 18 to 65 years with moderate or severe pain after the removal of > or =1 impacted mandibular third molar were randomly assigned to receive a single dose of ProSorb diclofenac K 25, 50, or 100 mg or placebo. Pain intensity and relief were assessed up to 6 hours after dosing. Rescue treatment was allowed after 1 hour. Efficacy end points included the summed pain intensity difference over 3 and 6 hours (SPID3 and 6); total pain relief at 3 and 6 hours (TOTPAR3 and 6); median times to onset of perceptible and meaningful relief (analgesic onset) and rescue medication use (analgesic duration); and cumulative percentage of patients using rescue medication. Tolerability was assessed using vital sign measurements and spontaneous reporting of adverse events.\n A total of 265 patients (154 women, 111 men; mean age, 23.3 years) were enrolled. All 3 ProSorb diclofenac K groups showed higher SPID6 and TOTPAR6 scores and longer median times to rescue medication use than the placebo group (all, P < 0.001). For these end points, a dose-response relationship was evident between the 100-mg dose and the 25- and 50-mg doses (P < or = 0.05); the 25- and 50-mg doses were similar. In the diclofenac groups, median onset times for first perceptible (< or =22.5 min) and meaningful (< or =53.0 min) relief were significantly more rapid than placebo (P < or = 0.01). Proportions of patients requiring rescue analgesic were < or =50.8% with diclofenac compared with 79.4% with placebo. Proportions of patients assigning a global evaluation of good or better was > or =68% with diclofenac compared with 21% for placebo. Tolerability was similar across all treatment groups.\n In this study of patients treated for pain following dental impaction surgery, single doses of ProSorb diclofenac K 25, 50, and 100 mg were more efficacious than placebo with respect to reduction of pain. All 3 doses provided a rapid analgesic onset and were well tolerated.", "The purpose of this single-blind, placebo-controlled, 3-arm parallel, randomized study was to compare the analgesic efficacy and tolerability of a single dose of 100 mg diclofenac potassium (Cataflam; Novartis, Stein, Switzerland), 100 mg diclofenac sodium softgel, and placebo in patients experiencing moderate to severe postoperative pain after third molar extraction.\n Seventy-five patients (67% female with a mean age of 23, age range 18 to 34.5 years) participated in the study following removal of at least 1 impacted mandibular third molar. Patients received a single dose of study medication when their postoperative pain reached a moderate or severe intensity. Analgesic efficacy measures included the time to meaningful pain relief measured using a stopwatch and time to rescue medication. Pain relief (PR) and Pain intensity (PI) ratings were recorded at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours postdosing. Summary analgesic measures, including Summed Pain Relief Score (TOTPAR) and Summed Pain Intensity Differences (SPID), were calculated from the 0.25- to 6-hour responses. The time between pain relief and rescue and a global evaluation for the effectiveness of the study medications were recorded at the end of the study. Seven scheduled blood samples were collected from each patient for determining plasma concentrations of diclofenac anion.\n Both diclofenac sodium softgel and Cataflam were significantly more effective than placebo (P <.0001) for all summary analgesic measures. The average overall pain relief was substantially better from diclofenac sodium softgel than from Cataflam, but the difference was not statistically significant (P =.14). In patients taking diclofenac sodium softgel, 50% of the patients experienced a time to onset of analgesic activity within 18 minutes and the median analgesic duration was 5 hours (302 minutes). Fifty percent of the patients taking Cataflam had a time to onset of action within 38 minutes, and the median duration of analgesia was 4.5 hours (272 minutes). At the time of rescue drug administration or 6 hours, whichever was earlier, 72% of the patients given diclofenac sodium softgel rated the medication as a very good or excellent pain reliever, whereas only 45% of the patients taking Cataflam gave these ratings. No serious adverse events were observed in this study. The mean concentrations of diclofenac from the diclofenac sodium softgel formulation were significantly different from the Cataflam formulation. The mean C(max) for the softgel was almost twice that of Cataflam and C(max) was reached an hour earlier, on average.\n More diclofenac anion was absorbed at a quicker rate using the formulation diclofenac sodium softgel 100 mg than Cataflam. The softgel provided a very rapid onset of analgesic activity, a prolonged analgesic duration, and an acceptable side-effect profile in the postoperative third molar surgery pain model. In an acute pain situation, the rapid absorption of nonsteroidal anti-inflammatory drugs from a formulation like the Softgel may positively affect the time of onset and duration of inflammatory pain compared with other commercially available nonsteroidal anti-inflammatory drug formulations.", "This double-blind, randomised, parallel-group trial compared the analgesic efficacy of single 50 mg doses of diclofenac potassium sachets and tablets with placebo in 184 patients with moderate/severe pain after third molar extraction. The primary efficacy variable was the average pain reduction from baseline during the first 2-h postdose, using a visual analogue scale (VAS). During the first 2-h postdose, sachets and tablets significantly reduced pain (p < 0.05) vs. placebo with an incremental benefit seen for sachets over tablets (p < 0.05). Onset of analgesic effect (VAS) was at 30 min for sachets and 45 min for tablets. Pain reduction vs. placebo (VAS) was maintained for 8 h for sachets and tablets (p < 0.05). VAS-findings were confirmed by pain relief and intensity verbal scale assessments. Fewer patients re-medicated vs. placebo. No safety issues were identified. This study demonstrates that both diclofenac potassium sachets and tablets offer patients suffering from acute pain conditions an effective treatment with incremental analgesic benefits seen for sachets.", "Rofecoxib is a selective cyclooxygenase-2 inhibitor indicated for the treatment of acute pain, with similar analgesic efficacy to ibuprofen and naproxen sodium. Diclofenac sodium is the most commonly prescribed nonsteroidal anti-inflammatory drug worldwide; it is effective for the treatment of pain as well as the signs and symptoms associated with the painful conditions of osteoarthritis and rheumatoid arthritis.\n The aim of this study was to compare the analgesic efficacy and tolerability of a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg, and placebo over 8-hour and 24-hour periods in patients with moderate to severe pain after oral surgery.\n In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate to severe pain after the surgical extraction of > or = 2 third molars were randomized to receive a single dose of rofecoxib 50 mg, 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg given every 8 hours), or placebo. Patients rated pain intensity, pain relief, and global assessments at prespecified times throughout the 24-hour period after initial dosing. Overall analgesic efficacy was determined by total pain relief over 8 hours (TOPAR8) and 24 hours (TOPAR24) and patient global assessments at 8 and 24 hours. Onset of analgesic effect was determined by using the 2-stopwatch method for confirmed perceptible pain relief. Peak analgesic effect was the maximum pain relief attained during the first 8 hours. The duration of analgesic effect was determined by median time to rescue analgesia use.\n A total of 305 patients were randomized to treatment: 121 received rofecoxib, 121 received diclofenac sodium, and 63 received placebo. The baseline demographics were similar among the groups. Overall, 61.3% experienced moderate pain and 38.7% experienced severe pain; 53.1% were female; and the mean age was 23.4 years. The overall analgesic efficacy, as assessed by TOPAR8, of a single dose of rofecoxib 50 mg was significantly greater than a single dose of enteric-coated diclofenac sodium 50 mg (20.5 vs 8.2) and placebo (20.5 vs 5.9). Patient global assessment at 8 hours was also significantly better for rofecoxib compared with enteric-coated diclofenac sodium and placebo. TOPAR24 was significantly greater for a single dose of rofecoxib 50 mg compared with 3 doses of enteric-coated diclofenac sodium 50 mg (64.1 vs 25.1) and placebo (64.1 vs 19.2). At 24 hours, the patient global assessment for rofecoxib was significantly better than that achieved with enteric-coated diclofenac sodium and placebo. The onset of analgesic effect was significantly more rapid for rofecoxib than for enteric-coated diclofenac sodium and placebo (median times: 31 minutes, >4 hours, and >4 hours, respectively). The peak analgesic effect was significantly greater for rofecoxib compared with enteric-coated diclofenac sodium (3.2 vs 1.5) and placebo (3.2 vs 1.1). The duration of analgesia was significantly longer for rofecoxib than enteric-coated diclofenac sodium (median times: >24 hours vs 1 hour and 37 minutes) and placebo (>24 hours vs 1 hour and 37 minutes). Enteric-coated diclofenac sodium was numerically greater than placebo for the key end points measuring overall efficacy (total pain relief and patient global assessment), but diclofenac sodium did not provide as much analgesic effect as expected for a drug effective for pain, osteoarthritis, and rheumatoid arthritis and did not differ significantly from placebo. Overall, both rofecoxib and enteric-coated diclofenac sodium were generally well tolerated, although the rofecoxib group had a significantly lower incidence of clinical and drug-related adverse events than the enteric-coated diclofenac sodium group.\n A single 50-mg dose of rofecoxib provided greater overall analgesic efficacy over 8 hours, more rapid onset of analgesia, greater maximum analgesic effect, and longer duration of effect than a single 50-mg dose of enteric-coated diclofenac sodium in patients with moderate to severe pain associated with oral surgery. Compared with 3 doses of enteric-coated diclofenac sodium 50 mg (50 mg every 8 hours), a single dose of rofecoxib 50 mg provided greater overall analgesic efficacy over 24 hours.", "To compare the analgesic efficacy of diclofenac sodium and paracetamol on post adenotonsillectomy postoperative pain and oral intake.\n Between January 1999 and July 2000, 80 children aged 3-14 years, underwent tonsillectomy and adenoidectomy for either recurrent tonsillitis or adenotonsillar hypertrophy in Prince Zeid Ben Al-Hussein Hospital and Prince Rashid Ben Al-Hussein Hospital. Forty-one children received diclofenac sodium suppositories (1-3mg/kg) postoperatively, whereas 39 children received only paracetamol syrup (10-15 mg/kg) in 4 divided doses. All children were observed for postoperative pain, oral intake, vomiting, temperature and complications.\n Children who received diclofenac sodium had significantly less pain, less elevation of temperature, more oral intake, and started drinking significantly sooner than the paracetamol group. Two children in the diclofenac group experienced nausea and vomiting compared to 12 children in the paracetamol group in the first day. The time to first solid intake was significantly earlier in the diclofenac sodium group (p < 0.0001). With regard to complications, one patient in each group developed secondary hemorrhage, one child developed otitis media in the 2nd group. Each group had one readmission, and 2 children from the paracetamol group had an emergency department visit for pain and dehydration.\n Diclofenac sodium has a significant effect on decreasing the pain associated with swallowing postoperatively and on the general condition of the patient. Improved oral intake resulted in a lower incidence of nausea and vomiting and allowed safer and earlier hospital discharge.", "This study assessed the efficacy of diclofenac potassium for oral solution, a novel water-soluble buffered powder formulation, versus placebo for the acute treatment of migraine. Diclofenac potassium for oral solution has a time to maximum plasma concentration (Tmax) of 15 minutes, suggesting the potential for a rapid onset of therapeutic effects.\n This was a randomized, double-blind, parallel-group, placebo-controlled study conducted in 23 US centers. Adult sufferers with an established migraine diagnosis according to the International Classification of Headache Disorders, second edition (ICHD-II), treated one moderate or severe attack with 50 mg diclofenac potassium for oral solution (dissolved in approximately 2 ounces of water; N=343) or matching placebo (N=347). Four co-primary endpoints included the percentage of subjects who at two hours post-treatment reported no headache pain, no nausea, no photophobia and/or no phonophobia.\n Significantly more subjects treated with diclofenac potassium for oral solution (N=343) achieved a two-hour pain-free response (25% vs. 10%, p<.001), no nausea (65% vs. 53%; p=.002), no photophobia (41% vs. 27%; p<.001) and no phonophobia (44% vs. 27%; p<.001) compared to placebo. Pain intensity differences between treatments were significantly lower in the diclofenac potassium oral solution group, starting at 30 minutes post-treatment (p=.013) with significant differences at all time points thereafter (p<.001). Twenty-four-hour sustained pain-free response favored diclofenac potassium oral solution treatment versus placebo (19% vs. 7%, p<.0001). The most common adverse event considered to be treatment related was nausea (diclofenac potassium for oral solution [4.6%]; placebo [4.3%]).\n This study shows that this formulation of diclofenac potassium for oral solution is effective in reducing pain intensity within 30 minutes, which may be related to the 15-minute T(max) associated with this formulation. The rapid-onset benefits were sustained through 24 hours post-treatment.", "A double-blind, placebo-controlled, parallel group study was performed to compare the analgesic efficacy of diclofenac potassium (25, 50, or 100 mg) with that of aspirin (650 mg), or placebo. Two hundred fifty-five inpatients with severe postepisiotomy pain were randomly assigned to receive a single oral dose of one of the four active treatments or placebo. Analgesia was assessed over an 8-hour period. Treatments were compared on the basis of standard scales for pain intensity and relief and a number of derived variables based on these data, as well as two global ratings of the study medication. All active treatments were effective analgesics statistically superior to placebo for many hourly and summary measures, including the global ratings. Diclofenac potassium (50 and 100 mg) was statistically significantly superior to aspirin at half-hour and for many other hourly scores from hour 3 on. The 4- and 8-hour sum of the pain intensity difference and total pain relief scores reflected the superiority of diclofenac potassium to aspirin. In addition, the 100-mg dose was significantly more efficacious than the 25-mg dose of diclofenac potassium. The probability of obtaining onset was significantly better for all active treatments than for placebo; however, the median onset times were similar for all treatments. The duration of effect, as measured by mean pain intensity difference and relief scores, was better for diclofenac potassium than aspirin, and these differences were significant for the 50- and 100-mg doses. The probability of pain returning to baseline was significantly less for the diclofenac groups than for placebo or aspirin groups. In addition, significantly fewer patients treated with diclofenac (25, 50, or 100 mg) or aspirin (650 mg) required remedication during the 8-hour study period as compared with those treated with placebo. Diclofenac potassium is an effective analgesic in the range of aspirin (650 mg) at the 25-mg dose and superior in efficacy and longer lasting than aspirin at the 50- and 100-mg doses. The onset of analgesia was similar for aspirin and diclofenac potassium.", "To compare the efficacy and safety of diclofenac-K (12.5 mg) vs paracetamol (500 mg) and placebo given in a flexible dosage regimen to treat pain resulting from extraction of impacted third molar teeth.\n This was a 2-day, double-blind, double-dummy, randomized, parallel-group, placebo-controlled study of diclofenac-K (12.5 mg) tablets vs paracetamol (500 mg) tablets and placebo in patients with moderate or severe pain within 8 hours of extraction of impacted third molars.\n After the first 2-tablet dose, patients took on average 2.5 additional tablets of diclofenac-K or 2.4 tablets of paracetamol, almost all as 1-tablet doses. Most placebo patients discontinued by taking rescue medication (ibuprofen 200 mg) on the first day. Pain relief after the initial dose of diclofenac-K (2 x 12.5 mg) was superior to placebo (P < .01 for all efficacy outcomes) and comparable to paracetamol (2 x 500 mg). About 30% of patients in each active treatment group took rescue medication during the study, compared to 78% on placebo. About 70% in each active treatment group considered the overall pain relief to be \"some,\" \"a lot,\" or \"complete\" compared to only 15% on placebo. The incidence of adverse events in each active treatment group was low and comparable between the treatments.\n An initial double-dose of diclofenac-K (2 x 12.5 mg) or paracetamol (2 x 500 mg) adequately relieved the most intense postoperative pain, and the flexible multiple dose regimen (1 or 2 tablets) maintained adequate pain relief thereafter. Most patients needed only 1-tablet doses following the initial 2-tablet dose.", "Diclofenac sodium was assessed as an analgesic for postoperative pain following paediatric tonsillectomy in a randomised double blind trial. In a comparison made with both a pethidine and a control group diclofenac was shown to be an effective analgesic. No significant difference in analgesic efficacy was demonstrated between the two drugs, although patients who received diclofenac tended to be less drowsy postoperatively than those who received pethidine. There were no significant differences between the two drugs in respect of time to awaken from anaesthesia or incidence of postoperative vomiting.", "To measure the efficacy and safety of diclofenac sodium gel in patients with primary hand osteoarthritis (OA).\n In a randomized, double-blind, placebo-controlled trial, men and women aged > or = 40 years diagnosed with primary OA in the dominant hand were randomly assigned to self-apply topical 1% diclofenac sodium gel (Voltaren Gel) (n = 198) or vehicle (n = 187) to both hands 4 times daily for 8 weeks. Primary outcome measures included OA pain intensity (100-mm visual analog scale), total Australian/Canadian Osteoarthritis Hand Index (AUSCAN) score, and global rating of disease activity at 4 and 6 weeks. Secondary outcomes included onset of efficacy in Weeks 1 and 2, durability of efficacy at 8 weeks, measures of disease activity in the dominant hand, pain intensity in the non-dominant hand, AUSCAN subindices, end of study rating of efficacy, and Osteoarthritis Research Society International response criteria.\n Diclofenac sodium gel decreased pain intensity scores by 42%-45%, total AUSCAN scores by 35%-40%, and global rating of disease by 36%-40%. Significant differences favoring diclofenac sodium gel over vehicle were observed at Week 4 for pain intensity and AUSCAN, with a trend for global rating of disease activity. At Week 6, diclofenac sodium gel treatment significantly improved each primary outcome measure compared with vehicle. Secondary outcomes generally supported the primary outcomes. The most common treatment-related adverse event (AE) was application-site paresthesia. Most AE were mild. No cardiac events, gastrointestinal bleeding, or ulcers were reported.\n Topical diclofenac sodium gel was generally well tolerated and effective in primary hand OA. (NCT ID: NCT00171665).", "A single-blind, randomized clinical trial was carried out to compare the analgesic effectiveness in patients with renal colic of single intramuscular doses of diclofenac sodium (75 mg) versus a dipyrone (1 g)/spasmolytics combination, and diclofenac sodium (75 mg) versus pethidine (75 mg). The first study involved three centres, the second study one centre. In total, 107 patients were treated with diclofenac sodium, 85 with dipyrone/spasmolytics, and 25 with pethidine. Assessments were made during the first hour after drug administration of the degree of pain relief, the severity of pain using a visual analogue scale, and the duration of analgesia. A global assessment of treatment efficacy was made by the participating physicians at the end of the study period. Patients treated with diclofenac sodium showed an earlier onset of analgesia and a higher incidence of total pain relief compared to those treated with dipyrone/spasmolytics or pethidine. Although the mean duration of analgesia was only slightly greater in the diclofenac sodium group than in the dipyrone/spasmolytics group, a significantly longer effect was seen when diclofenac sodium was compared with pethidine (p less than 0.01). Pain severity assessments revealed that diclofenac sodium caused a significantly greater improvement in pain after 60 minutes compared to dipyrone/spasmolytics (p less than 0.05) and after 30 minutes compared to pethidine (p less than 0.05). Global efficacy assessments by the physician rated diclofenac sodium as significantly superior to dipyrone/spasmolytics (p less than 0.01) and pethidine (p less than 0.001). Moreover, diclofenac sodium was better tolerated than either of the comparative treatments. The results indicate that intramuscular diclofenac sodium is a useful alternative to the drugs commonly used in India in the treatment of renal colic.", "One hundred and ten patients who had episiotomies to aid normal vaginal delivery without epidural analgesia were = allocated at random to receive either diclofenac (n = 56) or = placebo (n = 54) suppositories. Pain after episiotomy was assessed at 24 and 48 hours using a combination of a visual analogue scale, a modified pain score and a review of additional analgesia required. All patients in both groups were allowed routine hospital analgesia on request. Our data suggests that very few patients suffered severe pain, even in the placebo group. However, the prophylactic use of diclofenac suppositories significantly reduced perineal pain in the first 24 hours, although the difference was less marked by 48 hours. Overall additional analgesia requirement was correspondingly less in the diclofenac group." ]	Oral diclofenac is an effective single-dose treatment for moderate to severe postoperative pain. Significantly more participants experienced at least 50% pain relief over 4 to 6 hours with diclofenac potassium than with diclofenac sodium. There was no significant difference between diclofenac and placebo in the incidence of adverse events.
CD004156	[ "10421300" ]	[ "Intensity of leg and arm training after primary middle-cerebral-artery stroke: a randomised trial." ]	[ "We investigated the effects of different intensities of arm and leg rehabilitation training on the functional recovery of activities of daily living (ADL), walking ability, and dexterity of the paretic arm, in a single-blind randomised controlled trial.\n Within 14 days after stroke onset, 101 severely disabled patients with a primary middle-cerebral-artery stroke were randomly assigned to: a rehabilitation programme with emphasis on arm training; a rehabilitation programme with emphasis on leg training; or a control programme in which the arm and leg were immobilised with an inflatable pressure splint. Each treatment regimen was applied for 30 min, 5 days a week during the first 20 weeks after stroke. In addition, all patients underwent a basic rehabilitation programme. The main outcome measures were ability in ADL (Barthel index), walking ability (functional ambulation categories), and dexterity of the paretic arm (Action Research arm test) at 6, 12, 20, and 26 weeks. Analyses were by intention to treat.\n At week 20, the leg-training group (n=31) had higher scores than the control group (n=37) for ADL ability (median 19 [IQR 16-20] vs 16 [10-19], p<0.05), walking ability (4 [3-5] vs 3 [1-4], p<0.05), and dexterity (2 [0-56] vs 0 [0-2], p<0.01). The arm-training group (n=33) differed significantly from the control group only in dexterity (9 [0-39] vs 0 [0-2], p<0.01). There were no significant differences in these endpoints at 20 weeks between the arm-training and leg-training groups.\n Greater intensity of leg rehabilitation improves functional recovery and health-related functional status, whereas greater intensity of arm rehabilitation results in small improvements in dexterity, providing further evidence that exercise therapy primarily induces treatment effects on the abilities at which training is specifically aimed." ]	The single trial performed was too small to determine whether individualized moderate intensity endurance type exercises for the trunk and limbs are beneficial or harmful. No other medical, surgical or alternative treatment and therapy has been evaluated in a randomized fashion in this patient population. More research is needed.
CD003230	[ "19567452", "3324594", "6760969", "15357156", "17944738", "19936370" ]	[ "Early and short-term acenocumarine or dalteparin for the prevention of central vein catheter-related thrombosis in cancer patients: a randomized controlled study based on serial venographies.", "Single-dose v. short-term antibiotic therapy for prevention of wound infection in general surgery. A prospective, randomized double-blind trial.", "Short-term versus long-term cefuroxime prophylaxis in patients undergoing emergency cesarean section.", "Routine changing of intravenous administration sets does not reduce colonization or infection in central venous catheters.", "Clinical trial: randomized-controlled clinical study comparing the efficacy and safety of a low-volume vs. a high-volume mesalazine foam in active distal ulcerative colitis.", "Effective treatment of mild-to-moderate nasal polyposis with fluticasone delivered by a novel device." ]	[ "We evaluated efficacy and safety of early and short-term prophylaxis with acenocumarine or dalteparin in the prevention of non-occlusive or occlusive central vein catheter-related thrombosis (CVCrT).\n Consecutive cancer patients scheduled for chemotherapy randomly received: acenocumarine 1 mg/day for 3 days before and 8 days after central vein catheter (CVC) insertion; dalteparin 5000 IU 2 h before and daily for 8 days after CVC insertion; no anticoagulant treatment (NT). All patients underwent venography on days 8 and 30, some of them on days 90, 150 and 210 after CVC.\n A total of 450 patients were randomized, 348 underwent at least two venography. Both acenocumarine and dalteparin reduced venography-detected CVCrT rate [21.9% acenocumarine versus 52.6% NT, odds ratio (OR) 0.3, P < 0.01; 40% dalteparin versus 52.6% NT, OR 0.6, P = 0.05]. Acenocumarine was more effective than dalteparin (OR 0.4, P = 0.01). The rate of occlusive CVCrT was not different in the three groups (0.9% acenocumarine, 3.3% dalteparin, 1.8% NT; P = 0.40). Most CVCrTs (95.6%) were observed on day 8 after CVC insertion and were non-occlusive.\n In this study of early and short-term prophylaxis, acenocumarine was more effective than dalteparin on non-occlusive and asymptomatic CVCrT events. The first days following CVC insertion represent the highest risk for CVCrT.", "To investigate the effectiveness of a single-dose antibiotic regimen for preventing postoperative wound infection, a prospective, randomized double-blind trial was carried out in patients undergoing \"clean-contaminated\", \"contaminated\" or \"clean\" (vascular) surgery. Both elective and emergency operations were included. Single-dose (preoperative) prophylaxis was compared with short-term prophylaxis (1 dose preoperatively and 2 doses postoperatively). The antibiotics were penicillin, tobramycin and metronidazole in various combinations, and comparisons between single-dose and short-term prophylaxis were made with all the regimens. The incidence of wound infection was 5/277 (1.8%) in the short-term group and 9/287 (3.1%) in the single-dose group. The difference was not statistically significant. Nor was statistically significant difference found when the type of operation and the degree of contamination were considered. Single-dose antibiotic prophylaxis thus gave a low incidence of postoperative wound infection, even in \"clean-contaminated\" or \"contaminated\" cases.", "A prospective randomized clinical trial was conducted to test the effectiveness of long-term and short-term prophylaxis with cefuroxime in preventing morbidity after cesarean section. Sixty patients who required emergency cesarean section were randomly assigned to one of three treatment groups: a control group of 20 patients receiving no prophylactic antibiotics; a group of 20 patients receiving 24 hours of cefuroxime prophylaxis (0.75 gm 30 to 60 minutes before surgery and at 8 hours and 16 hours after surgery); and a group of 20 patients receiving five days of cefuroxime prophylaxis (0.75 gm three times a day, the first dose being given postoperatively). The short-term and long-term prophylaxes were equally effective in reducing morbidity, assessed by postoperative temperatures, presence or absence of endometritis, and duration of postoperative hospital stay.", "To determine the effect of routine intravenous (IV) administration set changes on central venous catheter (CVC) colonization and catheter-related bacteremia.\n Prospective, randomized, controlled trial.\n Eighteen-bed intensive care unit (ICU) in a large metropolitan hospital.\n Two hundred fifty-one patients with 404 chlorhexidine gluconate and silver sulfadiazine-coated multi-lumen CVCs.\n CVCs inserted in the ICU and in situ on day 4 were randomized to have their IV administration sets changed on day 4 (n = 203) or not at all (n = 201). Use of fluid containers and blood product administration sets was limited to 24 hours. CVCs were removed when not required, infection was suspected, or in place on day 7. Catheter cultures were performed on removal by blinded laboratory staff. Catheter-related bacteremia was diagnosed by a blinded intensivist using strict definitions. Data were collected regarding catheter duration, site, Acute Physiology and Chronic Health Evaluation (APACHE) II score, patient age, diagnosis, hyperglycemia, hypoalbuminemia, immune status, number of fluid containers and IV injections, and administration of propofol, blood, total parenteral nutrition, or lipid infusion.\n There were 10 colonized CVCs in the group receiving a set change and 19 in the group not receiving one. This difference was not statistically significant on Kaplan-Meier survival analysis. There were 3 cases of catheter-related bacteremia per group. Logistic regression found that burns diagnosis and increased ICU stay significantly predicted colonization.\n IV administration sets can be used for 7 days in patients with short-term, antiseptic-coated CVCs.", "Rectally administered mesalazine (mesalamine; 5-aminosalicylic acid) is the first-line therapy for treatment of distal ulcerative colitis. Recently, a high-volume 5-aminosalicylic acid foam has been shown to be as effective and safe as standard 5-aminosalicylic acid enema.\n To study the efficacy and safety of a low-volume vs. a high-volume 5-aminosalicylic acid foam.\n In this investigator-blinded study, patients with active distal ulcerative colitis [Clinical Activity Index (CAI) > 4, Endoscopic Index > or = 4] were randomized to receive 2 x 1 g/30 mL low-volume (n = 163) or 2 x 1 g/60 mL high-volume 5-aminosalicylic acid foam (n = 167) for 42 days. Primary end point was clinical remission (CAI < or = 4) at the final/withdrawal visit (per-protocol).\n 330 patients were evaluable for efficacy and safety by intention-to-treat, 290 for per-protocol analysis. Clinical remission rates at week 6 (per-protocol) were 77% on low-volume foam vs. 77% on high-volume foam (P = 0.00002 for non-inferiority). The low-volume foam was associated with a lower frequency of severe discomfort, pain and retention problems.\n Low-volume 5-aminosalicylic acid foam is as effective and safe as a high-volume 5-aminosalicylic acid foam in the treatment of active distal ulcerative colitis, but offers compliance advantages compared to the high-volume preparation.", "To assess the efficacy and safety of fluticasone propionate administered using OptiNose's novel delivery device (Opt-FP) in subjects with bilateral mild-to-moderate nasal polyposis.\n A prospective, multicentre, randomized, double-blind, placebo-controlled, parallel group study was conducted in adult subjects (n = 109) with mild-to-moderate bilateral nasal polyposis. Subjects received Opt-FP 400 microg or placebo twice daily for 12 weeks. Endpoints included endoscopic assessment of polyp size using Lildholdt's Scale, peak nasal inspiratory flow (PNIF), symptom scores and use of rescue medication.\n The proportion of subjects with improvement in summed polyp score >or= 1 (Lildholdt\\'s Scale) was significantly higher with Opt-FP compared with placebo at 4, 8 and 12 weeks (22% vs 7%, p = 0.011, 43% vs 7%, p < 0.001, 57% vs 9%, p < 0.001). After 12 weeks the summed polyp score was reduced by 35% (-0.98 vs +0.23, p < 0.001). PNIF increased progressively during Opt-FP treatment (p < 0.05). Combined symptom score, nasal blockage, discomfort, rhinitis symptoms and sense of smell were all significantly improved. Rescue medication use was lower (3.1% vs 22.4%, p < 0.001). Opt-FP was well tolerated.\n Fluticasone propionate (400 microg b.i.d.) administered using OptiNose's breath actuated bi-directional delivery device was an effective and well tolerated treatment for mild-to- moderate bilateral nasal polyposis." ]	The evidence presented suggests that HCSE is an efficacious and safe short-term treatment for CVI. However, several caveats exist and larger, definitive RCTs are required to confirm the efficacy of this treatment option.
CD002945	[ "11062788", "7648155", "12443589" ]	[ "Screening for abdominal aortic aneurysm: lessons from a population-based study.", "Influence of screening on the incidence of ruptured abdominal aortic aneurysm: 5-year results of a randomized controlled study.", "The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial." ]	[ "To test the acceptability of screening and to identify modifiable risk factors for abdominal aortic aneurysm (AAA) in men.\n A trial of ultrasound screening for AAA in a population-based random sample of men aged 65-83 years, and a cross-sectional case-control comparison of men in the same sample.\n 12,203 men who had an ultrasound examination of their abdominal aorta, and completed a questionnaire covering demographic, behavioural and medical factors.\n Prevalence of AAA, and independent associations of AAA with demographic, medical and lifestyle factors.\n Invitations to screening produced a corrected response of 70.5%. The prevalence of AAAs (> 30 mm) rose from 4.8% in men aged 65-69 years to 10.8% in those aged 80-83 years. The overall prevalence of large (> 50 mm) aneurysms was 0.69%. In a multivariate logistic model Mediterranean-born men had a 40% lower risk of AAA (> 30 mm) compared with men born in Australia (odds ratio [OR], 0.6; 95% CI, 0.4-0.8), while ex-smokers had a significantly increased risk of AAA (OR, 2.3; 95% CI, 1.9-2.8), and current smokers had even higher risks. AAA was significantly associated with established coronary and peripheral arterial disease and a waist:hip ratio greater than 0.9; men who regularly undertook vigorous exercise had a lower risk (OR, 0.8; 95% CI, 0.7-1.0).\n Ultrasound screening for AAA is acceptable to men in the likely target population. AAA shares some but not all of the risk factors for occlusive vascular disease, but the scope for primary prevention of AAA in later life is limited.", "From family medical practices 15775 men and women aged 65-80 years were identified and randomized into two groups: one group was invited for ultrasonographic screening for abdominal aortic aneurysm (AAA), and the other acted as age- and sex-matched controls. Of the 7887 invited for screening 5394 (68.4 per cent) accepted. AAA was detected in 218 (4.0 per cent overall and 7.6 per cent of men). Aortic surgery was offered to the screened group if certain criteria were met and no patient died from rupture who was fit for operation and accepted elective treatment. The incidence of rupture was reduced by 55 per cent in men in the group invited for screening, compared with controls. The incidence of rupture in women was low in both groups.", "Opposing views have been published on the importance of ultrasound screening for abdominal aortic aneurysms. The Multicentre Aneurysm Screening Study was designed to assess whether or not such screening is beneficial.\n A population-based sample of men (n=67800) aged 65-74 years was enrolled, and each individual randomly allocated to either receive an invitation for an abdominal ultrasound scan (invited group, n=33839) or not (control group, n=33961). Men in whom abdominal aortic aneurysms (> or =3 cm in diameter) were detected were followed-up with repeat ultrasound scans for a mean of 4.1 years. Surgery was considered on specific criteria (diameter > or =5.5 cm, expansion > or =1 cm per year, symptoms). Mortality data were obtained from the Office of National Statistics, and an intention-to-treat analysis was based on cause of death. Quality of life was assessed with four standardised scales. The primary outcome measure was mortality related to abdominal aortic aneurysm.\n 27147 of 33839 (80%) men in the invited group accepted the invitation to screening, and 1333 aneurysms were detected. There were 65 aneurysm-related deaths (absolute risk 0.19%) in the invited group, and 113 (0.33%) in the control group (risk reduction 42%, 95% CI 22-58; p=0.0002), with a 53% reduction (95% CI 30-64) in those who attended screening. 30-day mortality was 6% (24 of 414) after elective surgery for an aneurysm, and 37% (30 of 81) after emergency surgery.\n Our results provide reliable evidence of benefit from screening for abdominal aortic aneurysms." ]	There is evidence of a significant reduction in mortality from AAA in men aged 65 to 79 years who undergo ultrasound screening. There is insufficient evidence to demonstrate benefit in women. The cost effectiveness may be acceptable, but needs further expert analysis. These findings need careful consideration in judging whether a co-ordinated population-based screening programme should be introduced.
CD000434	[ "10905680", "11372943", "16452734", "20176167", "10813165", "12463661", "7263746", "3881447", "15795204", "15805203", "11514765", "10366909", "1592640", "11284567", "17931895", "16900354", "10622478", "11407040", "19181969", "16203881", "11154750", "7615598" ]	[ "Cannulated screws versus hemiarthroplasty for displaced intracapsular femoral neck fractures in demented patients.", "Extramedullary fixation of 569 unstable intertrochanteric fractures: a randomized multicenter trial of the Medoff sliding plate versus three other screw-plate systems.", "Randomized comparison of reduction and fixation, bipolar hemiarthroplasty, and total hip arthroplasty. Treatment of displaced intracapsular hip fractures in healthy older patients.", "Systematic effects of surgical treatment of hip fractures: gliding screw-plating vs intramedullary nailing.", "Fixation of fractures of the shaft of the humerus by dynamic compression plate or intramedullary nail. A prospective, randomised trial.", "Hemiarthroplasty versus internal fixation for displaced intracapsular hip fractures in the elderly. A randomised trial of 455 patients.", "Internal fixation versus hemiarthroplasty for the displaced subcapital fracture of the femur. A prospective randomised study.", "A prospective, randomized study of the management of severe ankle fractures.", "Internal fixation versus hemiarthroplasty for displaced fractures of the femoral neck in elderly patients with severe cognitive impairment.", "Dynamic hip screw compared with external fixation for treatment of osteoporotic pertrochanteric fractures. A prospective, randomized study.", "Prospective randomized controlled trial of an intramedullary nail versus dynamic screw and plate for intertrochanteric fractures of the femur.", "Trans-styloid fixation of fractures of the distal radius. A prospective randomized comparison between 6- and 1-week postoperative immobilization in 60 fractures.", "[The gamma-nail as a resilient alternative to the dynamic hip screw in unstable proximal femoral fractures in the elderly].", "Treatment for displaced intracapsular fracture of the proximal femur. A prospective, randomised trial in patients aged 65 to 79 years.", "Primary hemiarthroplasty in four-part fractures of the proximal humerus: randomized trial of two different implant systems.", "Comparison of the use of the humerus intramedullary nail and dynamic compression plate for the management of diaphyseal fractures of the humerus. A randomised controlled study.", "Extramedullary fixation of 107 subtrochanteric fractures: a randomized multicenter trial of the Medoff sliding plate versus 3 other screw-plate systems.", "[Osteosynthesis of per- and subtrochanteric fractures by blade plate versus gamma nail. A randomized prospective study].", "Treatment with and without initial stabilizing surgery for primary traumatic patellar dislocation. A prospective randomized study.", "Cementless calcar-replacement hemiarthroplasty compared with intramedullary fixation of unstable intertrochanteric fractures. A prospective, randomized study.", "Internal fixation versus hemiarthroplasty versus total hip arthroplasty for displaced subcapital fractures of femur--13 year results of a prospective randomised study.", "Fracture of the distal radius. A prospective comparison between trans-styloid and Kapandji fixations." ]	[ "There are no randomised trials comparing internal fixation and hemiarthroplasty for a displaced intracapsular femoral neck fracture in relation to mental state.\n To establish what should be the treatment of first choice, a prospective randomised clinical study was performed on 60 demented patients with displaced intracapsular femoral neck fractures, comparing internal fixation (n = 31) with hemiarthroplasty (n = 29).\n There was no significant difference in the mortality rate of both groups. Hemiarthroplasty was associated with significantly more loss of blood and more wound complications. Reoperation for secondary displacement of the fracture after internal fixation occurred in four patients. Although not-statistically significant, failure of internal fixation seemed to be higher after an inadequate osteosynthesis.\n Postoperative mortality is high and the chance of successful rehabilitation very small for both types of treatment in this group of patients. In our opinion, demented patients should not be treated with a major surgical procedure like hemiarthroplasty. Internal fixation should be considered the treatment of choice, because it is a smaller operation than prosthetic replacement, with less morbidity. If adequate reduction can not be achieved, a primary hemiarthroplasty should be performed.", "We compared the efficacy of the Medoff sliding plate (MSP) with 3 other screw-plate systems for fixation of unstable intertrochanteric fractures in a randomized multicenter trial of 569 elderly patients. The MSP has biaxial dynamic capacity along both the neck and the shaft of the femur unlike the other systems, which lack dynamic capacity along the shaft. 268 fractures were operated on with the MSP, and 301 with the dynamic hip screw (DHS), with or without a trochanteric stabilizing plate (DHS/TSP) or with the dynamic condylar screw (DCS). The MSP had recently been shown to the surgeons. The patients in the groups were similar as regards age, domestic situation, preinjury walking ability and type of fracture. We followed the patients clinically and radiographically for at least 1 year. There was no significant difference in walking ability at follow-up or rate of return to home. Fixation failure occurred in 18/268 fractures operated on with the MSP, in 8/238 with the DHS, in 3/49 with the DHS/TSP and in 1/14 with the DCS. The difference in the rate of fixation failure was not statistically significant when the MSP group was compared to the 3 other groups. In 14 of the 18 fixation failures in the MSP group, the biaxial dynamic capacity of the MSP had not been used due to technical errors by surgeons, unfamiliar with the new method. No selection bias was found regarding fracture types in the 2 subgroups of patients with correct or inadequate biaxial dynamization. Extramedullary fixation of unstable intertrochanteric fractures with these implants showed a low failure rate. When using the MSP, biaxial dynamization must be correctly performed.", "Orthopaedic surgeons vary in their management of displaced intracapsular fractures of the hip in healthy older patients. The aim of this investigation was to determine the functional, clinical, and resource consequences of three different types of surgical treatment.\n The study was a multicenter randomized controlled trial. Reduction and fixation was compared with bipolar hemiarthroplasty with cement and total hip replacement with cement. Participating surgeons elected to randomize their patients to be treated with either one of the three types of procedures or with either fixation or bipolar hemiarthroplasty. Functional outcomes were measured with a hip-rating questionnaire and the EuroQol health status measure. Clinical outcomes included mortality and complications. The direct health service costs were compared. Participants were followed up for two years.\n Two hundred and seven patients were randomized to be treated with one of the three operations, and ninety-one were randomized to be treated with either fixation or bipolar hemiarthroplasty. There were no differences in the mortality rates among the treatment groups. The rate of secondary surgery was highest in the fixation group (39% compared with 5% in the group treated with bipolar hemiarthroplasty and 9% in the group treated with total hip replacement). The fixation group had the worst hip-rating-questionnaire and EuroQol scores at four and twelve months. The total hip replacement group had significantly better functional outcome scores at twenty-four months than the other two groups. Although fixation was initially the least costly procedure, this short-term advantage was eroded by significantly higher costs for subsequent hip-related hospital admissions.\n Arthroplasty is more clinically effective and cost-effective than reduction and fixation in healthy older patients with a displaced intracapsular fracture of the hip. The long-term results of total hip replacement may be better than those of bipolar hemiarthroplasty.", "Numerous studies have been published regarding the comparison between intramedullary nail and the dynamic hip screw and plate for the fixation of intertrochanteric fractures in elderly patients. In this paper we present a comparative study of these two methods regarding their systemic effects on this group of patients.\n This is a randomized trial of 120 consecutive patients with an intertrochanteric fracture treated with either extramedullary fixation (dynamic hip screw and plate; DHS, Synthes-Stratec, Oberdorf, Switzerland) or intramedullary nail (Gamma nail, Stryker Howmedica, Freiburg, Germany and Endovis BA, Citieffe, Bologna, Italy). The parameters that we assessed pre-operatively, in addition to their demographics, included their mental state (MMSE), their nutritional and immune state and their pulmonary function. Intra-operatively we calculated the amount of radiation exposure, the amount of blood loss and the length of operative time for each procedure. Postoperatively we repeated the calculation of the mental and pulmonary state and the blood loss, during days 1, 3, and 10 and related them to the ease of the patient's mobilization.\n Decreased bleeding and post-operative pain, reduced post-operative morbidity and faster recovery of function were better but not significant in the group of intramedullary fixation (all p>0.05). However, in the same group there were slightly more patients in whom the MMSE was falling, together with their pulmonary function, suggesting that this method probably predisposes to higher chances of pulmonary dysfunction and the possibility of pulmonary embolism.\n We found no significant differences between the two methods of stabilization of these fractures regarding their systemic effects perioperatively. The classic dynamic hip screw can preserve its position as a safe and effective solution for these already vulnerable patients having sustained a trochanteric fracture against the novel intramedullary techniques.\n Copyright 2009. Published by Elsevier Ltd.", "We randomised prospectively 44 patients with fractures of the shaft of the humerus to open reduction and internal fixation by either an intramedullary nail (IMN) or a dynamic compression plate (DCP). Patients were followed up for a minimum of six months. There were no significant differences in the function of the shoulder and elbow, as determined by the American Shoulder and Elbow Surgeons' score, the visual analogue pain score, range of movement, or the time taken to return to normal activity. There was a single case of shoulder impingement in the DCP group and six in the IMN group. Of these six, five occurred after antegrade insertion of an IMN. In the DCP group three patients developed complications, compared with 13 in the IMN group. We had to perform secondary surgery on seven patients in the IMN group, but on only one in the DCP group (p = 0.016). Our findings suggest that open reduction and internal fixation with a DCP remains the best treatment for unstable fractures of the shaft of the humerus. Fixation by IMN may be indicated for specific situations, but is technically more demanding and has a higher rate of complications.", "A total of 455 patients aged over 70 years with a displaced intracapsular fracture of the proximal femur was randomised to be treated either by hemiarthroplasty or internal fixation. The preoperative characteristics of the patients in both groups were similar. Internal fixation has a shorter length of anaesthesia (36 minutes versus 57 minutes, p < 0.0001), lower operative blood loss (28 ml versus 177 ml, p < 0.0001) and lower transfusion requirements (0.04 units versus 0.39 units, p < 0.0001). In the internal fixation group 90 patients required 111 additional surgical procedures while only 15 additional operations on the hip were needed in 12 patients in the arthroplasty group. There was no statistically significant difference in mortality between the groups at one year (61/226 versus 63/229, p = 0.91), but there was a tendency for an improved survival in the older less mobile patients treated by internal fixation. For the survivors assessed at one, two and three years from injury there were no differences with regard to the outcome for pain and mobility. Limb shortening was more common after internal fixation (7.0 mm versus 3.6 mm, p = 0.004). We recommend that displaced intracapsular fractures in the elderly should generally be treated by arthroplasty but that internal fixation may be appropriate for those who are very frail.", "A prospective randomised trial of surgical treatment for the displaced subcapital femoral fracture in patients of 70 years or more is presented. Two hundred and eighteen patients were randomly allocated into one of three treatment groups: manipulative reduction and internal fixation using Garden screws; Thompson hemiarthroplasty through a posterior (Moore) approach; and Thompson hemiarthroplasty through an anterolateral (McKee) approach. There is no significant difference in the mortality of the internal fixation and posterior arthroplasty groups. Both groups showed a significantly higher mortality than patients operated on through the anterior approach. The technical results of operation were worse in the internally fixed group, with only 40 per cent being satisfactory. Mobilisation was best achieved after the posterior approach. It is concluded that Thompson hemiarthroplasty, using an anterolateral approach, is the safest operation in this group of patients.", "One hundred and thirty-eight patients with a closed grade-4 supination-external rotation or pronation-external rotation ankle fracture (Lauge-Hansen classification) who were seen in the emergency room of the University of Chicago Hospitals were entered into a randomized study of the results of various methods of treatment. Ninety-six patients with satisfactory initial closed reduction were randomized between continued closed treatment in a plaster cast and open reduction with rigid internal fixation according to the techniques of the Association for the Study of Internal Fixation (ASIF). Forty-two patients with unsatisfactory closed reduction were randomized between open reduction with internal fixation of only the medial malleolus and open reduction with rigid internal fixation according to the ASIF techniques. Of the 138 patients who were admitted to the study, only seventy-one (51 per cent) could be followed for an average of 3.5 years (a typical return rate of urban trauma centers). The outcomes were evaluated by a scoring system that included clinical, anatomical, and arthritis scores. Statistical analysis of the data showed that, of the patients with initial satisfactory closed reduction, the ones treated by open reduction and rigid internal fixation had significantly higher total scores, particularly the patients who were more than fifty years old and those with a medial malleolar fracture. The small number of patients with unsatisfactory closed reduction who were treated by one of the two types of open reduction and internal fixation and were available for follow-up precluded drawing any conclusions about the superiority of one method of internal fixation over the other in that group. The difference in the talocrural angle between the injured and normal sides was the only statistically significant radiographic indicator of a good prognosis.", "We studied 60 patients with an acute displaced fracture of the femoral neck and with a mean age of 84 years. They were randomly allocated to treatment by either internal fixation with cannulated screws or hemiarthroplasty using an uncemented Austin Moore prosthesis. All patients had severe cognitive impairment, but all were able to walk independently before the fracture. They were reviewed at four, 12 and 24 months after surgery. Outcome assessments included complications, revision surgery, the status of activities of daily living (ADL), hip function according to the Charnley score and the health-related quality of life (HRQOL) according to the Euroqol (EQ-5D) (proxy report). General complications and the rate of mortality at two years (42%) did not differ between the groups. The rate of hip complications was 30% in the internal fixation group and 23% in the hemiarthroplasty group; this was not significant. There was a trend towards an increased number of re-operated patients in the internal fixation group compared with the hemiarthroplasty group, 33% and 13%, respectively (p = 0.067), but the total number of surgical procedures which were required did not differ between the groups. Of the survivors at two years, 54% were totally dependent in ADL functions and 60% were bedridden or wheelchair-bound regardless of the surgical procedure. There was a trend towards decreased mobility in the hemiarthroplasty group (p = 0.066). All patients had a very low HRQOL even before the fracture. The EQ-5D(index) score was significantly worse in the hemiarthroplasty group compared with the internal fixation group at the final follow-up (p < 0.001). In our opinion, there is little to recommend hemiarthroplasty with an uncemented Austin Moore prosthesis compared with internal fixation, in patients with severe cognitive dysfunction.", "Although the use of a sliding hip screw is considered to be the preferred treatment for pertrochanteric femoral fractures, we theorized that external fixation could produce clinical outcomes equal to, if not better than, the outcomes obtained with conventional treatment. Furthermore, because external fixation is minimally invasive, we expected a lower rate of morbidity and a reduced need for blood transfusions. Therefore, we compared the two treatments in a clinical trial of elderly patients with pertrochanteric fracture.\n Forty consecutive elderly female patients who had a pertrochanteric fracture were randomized to be treated with either fixation with a 135 degrees four-hole sliding hip screw (Group A) or an external fixation device with hydroxyapatite-coated pins (Group B). The inclusion criteria were female gender, an age of at least sixty-five years, an AO/OTA type-A1 or A2 fracture, and a bone mineral density T-score of less than -2.5. There were no differences in patient age, fracture type, bone mineral density, comorbidities, length of hospital stay, or quality of reduction between the two groups.\n The average intraoperative time (and standard deviation) was 64 +/- 6 minutes in Group A and 34 +/- 5 minutes in Group B (p < 0.005). The average number of units of blood transfused postoperatively was 2.0 +/- 0.1 in Group A and none in Group B (p < 0.0001). Group B had less pain five days postoperatively (p < 0.05). Varus collapse of the fracture at six months averaged 6 degrees +/- 8 degrees in Group A and 2 degrees 1 degrees in Group B (p < 0.002). No pin-track infections occurred in Group B. The average Harris hip score at six months was 62 +/- 19 points in Group A and 63 +/- 17 points in Group B.\n This study showed that external fixation with hydroxyapatite-coated pins is an effective treatment for this fracture in this patient population. The operative time is brief, the blood loss is minimal, the fixation is adequate, and the reduction is maintained over time.", "To compare the surgical complications and functional outcome of the Gamma nail intramedullary fixation device versus the Richards sliding hip screw and plate device in intertrochanteric femoral fractures.\n A prospective, randomised controlled clinical trial with observer blinding.\n A regional teaching hospital in the United Kingdom.\n All patients admitted from the local population with intertrochanteric fractured femurs were included. There were 400 patients entered into the study and 399 followed-up to one year or death.\n The devices were assigned by randomization to either a short-type Gamma nail (203 patients) or a Richard's-type sliding hip screw and plate (197 patients).\n The main surgical outcome measurements were fixation failure and reoperation. A functional outcome of pain, mobility status, and range of movement were assessed until one year.\n The requirement for revision in the Gamma nail group was twelve (6%); for Richard's group, eight (4%). This was not statistically different (p = 0.29; odds ratio, 1.48 [0.59-3.7]). A subcapital femoral fracture occurred in the Richard's group. Femoral shaft fractures occurred with four in the Gamma nail group (2%) and none in the Richard's group (p = 0.13). Three required revision to another implant. Lag-screw cut-out occurred in eight patients in the gamma nail group (4%) and four in the Richard's group (2%). This was not statistically significant (p = 0.37; odds ratio, 2.29 [0.6-9.0]). The development of other postoperative complications was the same in both groups. There was no difference between the two groups in terms of early or long-term functional status at one year.\n The use of an intramedullary device in the treatment of intertrochanteric femoral fractures is still associated with a higher but nonsignificant risk of postoperative complications. Routine use of the Gamma nail in this type of fracture cannot be recommended over the current standard treatment of dynamic hip screw and plate.", "We performed a prospective randomized study on 60 patients with dorsally displaced extra-articular or noncomminuted intraarticular fractures of the distal radius. All 60 fractures were treated by closed reduction and Kirchner wire trans-styloid fixation. 30 patients had 1 weeks' postoperative immobilization and 30 patients had 6 weeks' immobilization. All patients had a clinical and radiographic review at 6 weeks and at 1 year after the operation. Pain, range of movement and grip strength were tested clinically, and changes in dorsal tilt, frontal radial deviation, ulnar variance, and radial shortening were assessed radiographically. Rates of complications were the same in both groups. At follow-up, pain was similar in both groups and range of motion and grip strength were somewhat better after early mobilization--in comparison with the opposite wrist--but this was statistically significant only for ulnar deviation. The postoperative radiographic reductions were similar in both groups, with no differences in loss of reduction after bone healing. Therefore, in Colles' fractures, trans-styloid fixation with two K-wires seems to give a stable osteosynthesis, which does not need additional immobilization with a plaster cast.", "In a prospective randomised trial between September 1989 and June 1990 one hundred patients with per- and subtrochanteric fractures were consecutively treated by gamma-nail or DHS. The average age of both groups was about 80 years. The operation time for gamma-nailing was longer than for DHS implantation and also the postoperative blood loss was higher in the gamma-nail group. We found no difference of intraoperative blood loss, of perioperative lethality and in duration of hospital care. 90% of gamma-nail patients and 80% of DHS patients were successfully able to walk four days after operation with full weight bearing on the operated limb. Three patients in the DHS group with unstable fractures got cranial perforation of the cephalic screw mobilisation. Five patients of the gamma-nail group were reoperated, one case because of missed distal locking, one because of cranial perforation of the cephalic screw after varus dislocation of the proximal fragment. One patient suffered intraoperatively a proximal femur shaft fracture which was corrected during operation. In one case a wound hematoma was evacuated, an other patient needed secondary wound closure. Despite technical imperfection of implant and instruments, we conclude that the gamma-nail allows a very high percentage early and full weight bearing immediately after operation. So we consider that in the treatment of unstable pertrochanteric fractures of geriatric patients, the gamma-nail has proven to be more efficient than the DHS.", "We performed a prospective, randomised trial comparing three treatments for displaced intracapsular fractures of the hip in 280 patients aged 65 to 79 years. The mean patient survival was significantly higher in the group undergoing reduction and internal fixation (79 months) compared with that with a cemented Thompson hemiarthroplasty or a cemented Monk bipolar hemiarthroplasty (61 months and 68 months, respectively). After three years, 32 of 93 patients (34.4%) who had undergone fixation had local complications, necessitating further intervention in 28 (30%). There were no significant differences in the functional outcome in survivors, who were reviewed annually to five years. Either reduction and internal fixation or cemented hemiarthroplasty may be offered as alternative treatments for a displaced intracapsular fracture in a mobile and mentally competent patient under the age of 80 years. The choice of procedure by the patient and the surgeon should be determined by the realisation that the use of internal fixation is associated with a 30% risk of failure requiring further surgery. If this is accepted, however, hemiarthroplasty is avoided, which, in our study has a significantly shorter mean survival time. The use of a bipolar prosthesis has no significant advantage.", "The objective of this study was to determine the effect of different prosthetic systems on the functional and radiographic outcomes after shoulder arthroplasty for fractures. This study comprised 35 patients (28 women and 7 men) with a mean age of 74 years (range, 56-88 years) who sustained 4-part fractures of the proximal humerus and were randomly allocated to 2 different groups regarding the type of prosthesis. The 2 systems used differ mainly in the type of fixation of the tuberosities. In group 1 (EPOCA), the fixation was achieved with wire cables through a medial and a lateral hole in the stem, whereas in group 2 (HAS), the fixation was performed by use of transosseous braided sutures. After a follow-up of 1 year, the functional and radiographic outcomes were evaluated. The retrieved data demonstrate that rigid fixation and anatomic positioning of the tuberosities (group 1) increase the rate of bony healing superior to all other factors. There was a statistically significant difference regarding the relative individual Constant score (P = .001) and the mean active range of motion (flexion, P < .001; abduction, P = .001; external rotation in adduction, P = .01; and external rotation in 90 degrees abduction, P = .001) when both groups were compared, showing a better outcome in the EPOCA group for all parameters. Radiologic findings, like heterotopic ossification, glenoid erosion, or subluxation, had no significant influence on the outcome in this study. Accurate placement of the tuberosities and healing at the bone-bone interface of the rotator cuff seem to be the most important factors influencing the outcome in prosthetic care of fractures.", "The aim of this study was to compare the results of the humerus intramedullary nail (IMN) and dynamic compression plate (DCP) for the management of diaphyseal fractures of the humerus. Forty-seven patients with diaphyseal fracture of the shaft of the humerus were randomised prospectively and treated by open reduction and internal fixation with IMN or DCP. The criteria for inclusion were grade 1 or 2a compound fractures, polytrauma, early failure of conservative treatment and unstable fractures. The patients with pathological fractures, grade 3 open fractures, refractures and old neglected fractures of the humerus were excluded from the study. Twenty-three patients underwent internal fixation by IMN and 24 by DCP. Reamed antegrade nailing was done in all cases. DCP was done through an anterolateral or posterior approach. The outcome was assessed in terms of the union time, union rate, functional outcome and the incidence of complications. Functional outcome was assessed using the American Shoulder and Elbow Surgeons' Score (ASES). On comparing the results by independent samples t test, there was no significant difference in ASES scores between the two groups (P>0.05). The average union time was found to be significantly lower for IMN as compared to DCP (P<0.05). The union rate was found to be similar in both groups. Complications such as infection were found to be higher with DCP as compared to IMN, while shortening of the arm (1.5-4 cm) and restriction of shoulder movements due to impingement by the nail were found to be higher with IMN as compared to DCP. However, this improved in all patients following the removal of the nail once the fracture had healed. This study proves that IMN can be considered a better surgical option for the management of diaphyseal fractures of the humerus as it offers a short union time and lower incidence of serious complications like infection. However, there appears to be no difference between the two groups in terms of the rate of union and functional outcome.", "We compared the efficacy of a load-sharing device, the Medoff sliding plate (MSP), with that of 3 other load-bearing screw-plate devices for the fixation of subtrochanteric fractures in a randomized multicenter trial of 107 elderly patients. 55 fractures were operated on with the MSP, and 52 with the dynamic hip screw (DHS) with or without a trochanteric stabilizing plate (TSP) or with the dynamic condylar screw (DCS). The patient material in the groups was similar regarding age, domestic situation, preinjury walking ability and fracture types. We followed the patients clinically and radiographically for a minimum of 1 year. There was no significant difference in walking ability or return rate to the home at follow-up. Fixation failure occurred in 1/55 fractures operated on with the MSP, in 3/32 with the DHS, in 3/12 with the DCS and in 2/8 with the DHS/TSR The difference in the rate of fixation failure was statistically significant, when the MSP group was compared to the 3 load-bearing devices in the other group (1 vs 8). On the basis of this experience, we think that the load-sharing principle of the MSP, which seems to facilitate fracture impaction and stability, appears to be a good alternative in extramedullary fixation of subtrochanteric fractures.", "To compare clinical and radiological results in per- and subtrochanteric fractures' management with 90 degrees blade plate or Gamma nail fixation; an implant allowing early weight-bearing and fracture healing in correct position remains still difficult.\n Between 1993 and 1995, 26 patients addressed to our Center for a Kyle IV [1] fracture were divided into 2 groups, one fixed with blade plate and the other with Gamma nail. The follow-up for all patients is 12 months.\n Gamma nail allows early weight-bearing in all patients, fracture healing is acquired at 4.2 months; an operative diaphyseal fracture needed conversion to a long Gamma nail. We observed a slight cut-out that didn't need reoperation. In the blade plate group, we noticed three femoral head necrosis without major flattening, two non-unions, one plate's breakage and two malunions; fracture healing is acquired at 6.3 months. The two non-unions and the plate's breakage didn't need reoperation because of low functional demand.\n We prefer Gamma nail in per- and subtrochanteric femoral fractures' management, it allows early and fast weight-bearing and fracture healing is acquired in all cases.", "There is no consensus about the management of acute primary traumatic patellar dislocation in young physically active adults. The objective of this study was to compare the clinical outcomes after treatment with and without initial stabilizing surgery for primary traumatic patellar dislocation in young adults.\n Forty young adults, thirty-seven men and three women with a median age of twenty years (range, nineteen to twenty-two years), who had an acute primary traumatic patellar dislocation were randomly allocated to be treated with initial surgical stabilization (eighteen patients, with each receiving one of two types of initial stabilizing procedures) or to be managed with an orthosis (twenty-two patients, including four who had osteochondral fragments removed arthroscopically). After a median of seven years, thirty-eight patients returned for a follow-up examination. Redislocations, subjective symptoms, and functional limitations were evaluated. Radiographs and magnetic resonance images were obtained at the time of randomization, and twenty-nine (76%) patients underwent magnetic resonance imaging at the time of final follow-up.\n A hemarthrosis as well as injuries of the medial retinaculum and the medial patellofemoral ligament were found on magnetic resonance imaging in all patients at the time of randomization. During the follow-up period, six of the twenty-one nonoperatively treated patients and none of the seventeen patients treated with surgical stabilization had a redislocation (p = 0.02). Four nonoperatively treated patients and two patients treated with surgical stabilization reported painful patellar subluxation. The median Kujala scores were 91 points for the surgically treated patients and 90 points for the nonoperatively treated patients. Thirteen patients in the surgically treated group and fifteen in the nonoperatively treated group regained their former physical activity level. At the time of follow-up, a full-thickness patellofemoral articular cartilage lesion was detected on magnetic resonance imaging in eleven patients; the lesions were considered to be unrelated to the form of treatment.\n In a study of young, mostly male adults with primary traumatic patellar dislocation, the rate of redislocation for those treated with surgical stabilization was significantly lower than the rate for those treated without surgical stabilization. However, no clear subjective benefits of initial stabilizing surgery were seen at the time of long-term follow-up.", "Unstable intertrochanteric fractures in elderly patients are associated with a high rate of complications. The purpose of this investigation was to compare the results of long-stem cementless calcar-replacement hemiarthroplasty with those of treatment with a proximal femoral nail for unstable intertrochanteric fractures in elderly patients.\n Fifty-eight elderly patients with an AO/OTA type 31-A2 intertrochanteric fracture of the femur were randomized into two treatment groups and were followed for a minimum of two years. The twenty-nine patients in Group I were treated with a long-stem cementless calcar-replacement prosthesis, and the twenty-nine patients in Group II were treated with a proximal femoral nail. The two treatment groups were comparable with regard to demographic and injury variables.\n There were no significant differences between the groups in terms of functional outcomes, hospital stay, time to weight-bearing, or general complications. Patients treated with a proximal femoral nail had a shorter operative time, less blood loss, fewer units of blood transfused, a lower mortality rate, and lower hospital costs compared with those treated with the long-stem cementless calcar-replacement prosthesis.\n In elderly patients with an unstable intertrochanteric femoral fracture, a proximal femoral nail provides superior clinical outcomes but no advantage with regard to functional outcome when compared with a long-stem cementless calcar-replacement arthroplasty.\n Therapeutic Level I.", "In this prospective randomised trial we compare the mortality, morbidity and functional results of patients following each of the three principal methods of treatment for displaced subcapital fractures of the femur. Two hundred and ninety patients over the age of 65 years were included and randomly allocated to undergo closed reduction and internal fixation with a sliding compression screw plate or uncemented Austin Moore hemiarthroplasty or cemented Howse II total hip arthroplasty (THA). Nineteen patients were subsequently excluded. The 13 year results show that there was no statistical difference in the mortality between the three groups (81, 85 and 91% respectively). Internal fixation and hemiarthroplasty groups fared poorly with a revision rate of 33 and 24%, respectively, compared with 6.75% in the THA group. The dislocation rate was 13% following hemiarthroplasty and 20% following THA. Average Harris hip scores were 62, 55 and 80, respectively, for the internal fixation, hemiarthroplasty and THA groups. In the long term, both internal fixation and hemiarthroplasty resulted in a poor outcome with respect to pain and mobility. Despite high early complications, THA resulted in least pain and most mobility both in the short and long-term and was encouraging with a revision rate of only 6.25%. THA should be seriously considered in physiologically active patients with a displaced subcapital fracture of the femur.", "We performed a prospective study on 96 patients with extra-articular or intra-articular fractures of the distal radius with a dorsally displaced posteromedial fragment. After closed reduction, we compared trans-styloid fixation and immobilisation with Kapandji fixation and early mobilisation. Forty-two patients of mean age 57.1 years +/- 18.1 (SD) were treated by trans-styloid K-wire fixation and 45 days of short-arm cast immobilisation. Fifty-four patients of mean age 57.7 years +/- 18.7 (SD) had Kapandji fixation and immediate mobilisation according to the originator. All the patients had clinical and radiological review at about six weeks and at 3, 6, 12 and 24 months after the operation. Pain, range of movement and grip strength were tested clinically, and changes in dorsal tilt, radial tilt, ulnar variance, and radial shortening were assessed radiologically. Statistical analysis was applied to comparisons with the normal opposite wrist. Pain and reflex sympathetic dystrophy were more frequent after Kapandji fixation and early mobilisation, but the range of motion was better although this became statistically insignificant after six weeks. The radiological reduction was better soon after Kapandji fixation, but there was some loss of reduction and increased radial shortening during the first three postoperative months. The clinical result at two years was similar in both groups." ]	There is insufficient evidence to inform the management of these fractures. Early physiotherapy, without immobilisation, may be sufficient for some types of undisplaced fractures. It remains unclear whether surgery, even for specific fracture types, will produce consistently better long term outcomes but it is likely to be associated with a higher risk of surgery-related complications and requirement for further surgery. There is insufficient evidence to establish what is the best method of surgical treatment, either in terms of the use of different categories of surgical intervention (such as plate versus nail fixation, or hemiarthroplasty versus tension-wire fixation) or different methods of performing an intervention in the same category (such as different methods of plate fixation). There is insufficient evidence to say when to start mobilisation after either surgical fixation or hemiarthroplasty.
CD001933	[ "2194417", "12067168", "7044724", "3063043" ]	[ "Antibiotics in elective colon surgery. A randomized trial of oral, systemic, and oral/systemic antibiotics for prophylaxis.", "Oral versus systemic antibiotic prophylaxis in elective colon surgery: a randomized study and meta-analysis send a message from the 1990s.", "Comparison between oral and systemic antibiotics and their combined use for the prevention of complications in colorectal surgery.", "Failure of topically applied antibiotics, added to systemic prophylaxis, to reduce perineal wound infection in abdominoperineal excision of the rectum." ]	[ "A prospective, randomized double-blind study was undertaken to compare the efficacy of three prophylactic regimens (oral neomycin and erythromycin, intravenous cefoxitin, and a combination of both oral and intravenous antibiotics) in patients undergoing elective colorectal surgery. One hundred sixty-nine patients were randomized and 146 patients were evaluable. Septic complications occurred in 11.4 per cent of patients receiving oral antibiotics only, in 11.7 per cent of patients receiving intravenous cefoxitin alone, and in 7.8 per cent of patients receiving both oral and intravenous antibiotics. These differences were not statistically different. The greatest number of septic complications occurred in those patients with anastomotic disruptions. Two patients died (1.3%), both of whom had major anastomotic failures. There was no advantage between any of the groups in the incidence of wound infection (3.9-6.8%). Thus, no advantage could be identified in this study in the combination of oral and intravenous antibiotics in elective colorectal surgery.", "To compare the efficacy of combined oral and systemic antibiotics (combined) versus systemic antibiotics (systemic) alone in preventing surgical site infection in elective surgery of the colon, and to perform a meta-analysis of randomized studies comparing combined versus systemic antibiotics in elective colon surgery.\n A double-blind, placebo-controlled, randomized clinical trial.\n The Queen Elizabeth Hospital, Montreal, a university-affiliated community hospital.\n Two hundred and fifteen patients scheduled to undergo elective surgery of the colon.\n Patients were randomized to receive neomycin and metronidazole orally (109 patients) or identical placebos (106 patients) on the final preoperative day. All were given amikacin and metronidazole intravenously just before operation. Thirteen randomized series comparing combined and systemic antibiotic prophylaxis in elective colon surgery were identified for meta-analysis.\n Rates of postoperative surgical site infections: risk differences, risk ratios (RRs) and 95% confidence intervals (CIs); organisms found in the colon and wound fat at surgery, and in infected wounds.\n Three patients in the systemic group, and 5 in the combined group were excluded. Wound infections occurred in 5 patients in the combined group but in 17 in the systemic group (p < 0.01, RR = 0.29, 95% CI 0.11-0.75). Bacteria isolated from wound infections and wound fat were similar to those found in the colon. They were more frequent in the colon in the systemic group (p < 0.001) and occurred in wound fat in the systemic group twice as often as in the combined group (p < 0.001). By stepwise logistic regression, the presence of bacteria in wound fat at surgery was the strongest predictor of postoperative wound infection (p < 0.002). In the meta-analysis, the summary weighted risk difference in surgical site infections between groups (d(w)) and the summary RR both favoured combined prophylaxis (d(w) = 0.56, 95% CI 0.26-0.86; RR = 0.51, 95% CI 0.24-0.78; p < 0.001).\n In elective surgery of the colon combined oral and systemic antibiotics are superior to systemic antibiotics in preventing surgical site infections. Orally administered antibiotics add value by reducing bacterial loading of the colon and wound fat contamination, both associated with postoperative wound infection. Meta-analysis of randomized clinical trials reported from 1975 to 1995 supports these conclusions.", "Ninety patients were included in this prospective randomized trial. Each required electric colorectal surgery and was prepared for operation with oral preoperative antibiotic therapy, systemic peroperative therapy, or by a combination of both. The number of each type of septic postoperative complication and their total did not differ between the group treated by oral antibiotics prior to operation and the group treated peroperatively with systemic antibiotic therapy. The total number of septic complications (wall abscesses, fistulas, subdiaphragmatic abscesses, septicemia, peritonitis), however, was significantly less (P less than 0.05) in the group treated by both preoperative oral antibiotics and peroperative systemic antibiotic therapy (3.3 per cent) than in either groups treated only orally preoperatively (30 per cent) or by systemic antibiotic therapy during the operation (23 per cent). The combination of oral antibiotic therapy prior to operation and of systemic peroperative antibiotic therapy, therefore, presents the most effective prophylactic effectiveness.", "In a prospective, randomized trial, prophylactic use of topical antibiotics in addition to systemic prophylaxis was studied in patients undergoing abdominoperineal amputation of the rectum. All patients received gentamicin 80 mg and metronidazole 500 mg intravenously at induction of anesthesia, followed by the same dose 8 hourly for 48 hours. In accordance with the randomization, half of the patients were additionally given gentamicin 160 mg + metronidazole 400 mg topically into the perineal wound at closure. Perineal wound infection appeared in 19 of the 41 patients who received both systemic and topical prophylaxis, and in 18 of the 38 with only systemic antibiotics. Cell-mediated immunity was preoperatively assessed with a skin test (Multitest) in all but three patients. Impairment of cell-mediated immunity was associated with significantly heightened rate of wound infection, and these patients did not benefit from topical antibiotics." ]	The authors of this review have been unable to identify the most effective intervention or to assess the associated risks. Research is urgently needed into the effectiveness of oral versus topical antibiotics in this group of patients. Clinicians considering antibiotic treatment need to balance any potential benefit against the risks of side effects and antibiotic resistance.
CD004171	[ "16959690", "7633976", "17414601", "14560228", "11679600", "15541982", "17085137", "15544076", "10477639", "10565650", "11333096", "14649578", "9725389", "9447855", "16914772", "7519132", "16220761", "17898365", "8748919", "15531229", "11413430", "16136287", "12575787", "8442983", "7928148" ]	[ "A pilot study of the effects of Vivostat patient-derived fibrin sealant in reducing blood loss in primary hip arthroplasty.", "Fibrin sealant reduces suture line bleeding during carotid endarterectomy: a randomised trial.", "Application of fibrin glue sealant after hepatectomy does not seem justified: results of a randomized study in 300 patients.", "Prospective randomized multicenter trial of fibrin sealant versus thrombin-soaked gelatin sponge for suture- or needle-hole bleeding from polytetrafluoroethylene femoral artery grafts.", "Use of fibrin sealant to reduce bloody drainage and hemoglobin loss after total knee arthroplasty: a brief note on a randomized prospective trial.", "The effect of autologous fibrin sealant (Vivostat) on morbidity after pulmonary lobectomy: a prospective randomised, blinded study.", "A prospective, randomized trial evaluating the safety and efficacy of fibrin sealant in tubeless percutaneous nephrolithotomy.", "The effect of fibrin sealant combined with fibrinolysis inhibitor on reducing the amount of lymphatic leakage after axillary evacuation in breast cancer. A prospective randomized clinical trial.", "Hemostatic efficacy of fibrin sealant (human) on expanded poly-tetrafluoroethylene carotid patch angioplasty: a randomized clinical trial.", "The use of fibrin tissue adhesive to reduce blood loss and the need for blood transfusion after total knee arthroplasty. A prospective, randomized, multicenter study.", "Fibrin sealant reduces the duration and amount of fluid drainage after axillary dissection: a randomized prospective clinical trial.", "Fibrin sealant reduces perioperative blood loss in total hip replacement.", "Vivostat system autologous fibrin sealant: preliminary study in elective coronary bypass grafting.", "Aprotinin decreases blood loss and homologous transfusions in patients undergoing major orthopedic surgery.", "Effectiveness of autologous fibrin tissue adhesive in reducing postoperative blood loss during total hip arthroplasty: a prospective randomised study of 100 cases.", "Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery.", "Adhesion-prevention effects of fibrin sealants after laparoscopic myomectomy as determined by second-look laparoscopy: a prospective, randomized, controlled study.", "Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.", "The use of fibrin sealant in in vitro fertilization and embryo transfer.", "Does fibrin glue sealant decrease the rate of pancreatic fistula after pancreaticoduodenectomy? Results of a prospective randomized trial.", "The efficacy of antifibrinolytics in the reduction of blood loss during complex adult reconstructive spine surgery.", "Randomized trial comparing Quixil surgical sealant with Kaltostat hemostatic dressing to control suture line bleeding after carotid endarterectomy with ePTFE patch reconstruction.", "Does fibrin sealant reduce drain output and allow earlier removal of drainage catheters in women undergoing operation for breast cancer?", "The effect of fibrin glueing to seal bronchial and alveolar leakages after pulmonary resections and decortications.", "Prevention of pleural effusion after hepatectomy using fibrin sealant." ]	[ "A pilot study evaluated the effectiveness of Vivostat patient-derived fibrin sealant in reducing blood loss in patients who underwent primary hip arthroplasty. Eighty adult patients undergoing elective surgery were randomized to receive either Vivostat sealant or control (no additional hemostatic treatment). Patients allocated Vivostat sealant donated 120 mL of blood, which was then processed perioperatively to produce a fibrin sealant that was applied to the bleeding wound surfaces just before closure. Transfusion requirements, blood loss during surgery, drain volumes, and daily hematocrit and hemoglobin levels were measured. Hospitalization times, adverse events, and postoperative wound complications were also monitored. Blood loss during surgery and wound drainage volume was lower in the Vivostat group than in the control group, although the differences were not significantly different. Transfusion requirements (median, 270 mL of packed red blood cells) and hospitalization times (both median 7 days) were the same for both groups. No adverse events related to the use of Vivostat occurred. There were indications of a possible reduction in the incidence of postoperative wound oozing (15% vs 25%) and hematomas (6% vs 11%) with the use of Vivostat compared with the control group, although differences were not statistically significant. In conclusion, in this pilot study, use of Vivostat patient-derived fibrin in hip arthroplasty was not associated with a significant reduction in blood loss. Further studies, with larger numbers of patients, may be warranted to investigate a possible benefit of Vivostat in reducing postoperative wound complications.", "To determine whether topical fibrin sealant reduced suture line bleeding during carotid endarterectomy with polytetrafluoroethylene (PTFE) patch closure.\n Prospective randomised non-blinded control trial.\n Regional vascular surgery unit.\n Seventeen patients undergoing carotid endarterectomy were randomised either to receive fibrin sealant as a topical haemostatic agent at the arteriotomy suture line or to act as control.\n Time taken to achieve haemostasis at the suture line. Intraoperative blood loss. Total operative time.\n The median time to achieve haemostasis was 5.5 min (range 4-31 min) in the treatment group and 19 min (range 10-47 min) in the control group. This difference was statistically significant p < 0.005 by Mann-Whitney test. There was no statistical difference in total operative time. Operative blood loss was lower in the treatment group (median 420ml, range 300-500ml) than in the control group (median 550ml, range 350-1200ml) but this difference was not statistically significant. One patient in the control group suffered a perioperative thrombo-embolic event.\n Fibrin sealant is an effective topical haemostatic agent for arteriotomy suture lines involving PTFE material.", "To evaluate the efficacy, amount of hemorrhage, biliary leakage, complications, and postoperative evolution after fibrin glue sealant application in patients undergoing liver resection.\n Fibrin sealants have become popular as a means of improving perioperative hemostasis and reducing biliary leakage after liver surgery. However, trials regarding its use in liver surgery remain limited and of poor methodologic quality.\n A total of 300 patients undergoing hepatic resection were randomly assigned to fibrin glue application or control groups. Characteristics and debit of drainage and postoperative complications were evaluated. The amount of blood loss, measurements of hematologic parameters liver test, and postoperative evolution (particularly involving biliary fistula and morbidity) was also recorded.\n Postoperatively, no differences were observed in the amount of transfusion (0.15 +/- 0.66 vs. 0.17 +/- 0.63 PRCU; P = 0.7234) or in the patients that required transfusion (18% vs. 12%; P = 0.2), respectively, for the fibrin glue or control group. There were no differences in overall drainage volumes (1180 +/- 2528 vs. 960 +/- 1253 mL) or in days of postoperative drainage (7.9 +/- 5 vs. 7.1 +/- 4.7). Incidence of biliary fistula was similar in the fibrin glue and control groups, (10% vs. 11%). There were no differences regarding postoperative morbidity between groups (23% vs. 23%; P = 1).\n Application of fibrin sealant in the raw surface of the liver does not seem justified. Blood loss, transfusion, incidence of biliary fistula, and outcome are comparable to patients without fibrin glue. Therefore, discontinuation of routine use of fibrin sealant would result in significant cost saving.", "We evaluated the safety and efficacy of the fibrin sealant Beriplast P (FSBP; Aventis-Behring) for hemostasis in anastomosis of polytetrafluoroethylene (PTFE) grafts to the femoral artery.\n In a single-blinded randomized prospective multicenter clinical trial, FSBP was compared with thrombin-soaked gelatin sponge (TSG) for efficacy in stopping bleeding from needle or suture holes in PTFE grafts after anastomosis to the femoral artery. Patients were randomized to FSBP application, which requires a 3-minute period of arterial clamping to enable the fibrin clot to adhere, or to TSG application, which requires pressure from gauze sponges, after completion of the femoral artery anastomosis. The primary end point was hemostasis, defined as absence of any detectable bleeding as judged by the operating surgeon, by 4 minutes after randomization. Secondary end points included actual time from randomization to hemostasis, time to beginning of wound closure, measured blood loss (weighed sponges), incidence of recurrent bleeding, stay in the intensive care unit, and hospital length of stay. Data were analyzed with the intention-to-treat method.\n Two hundred thirty-five subjects were enrolled at 26 medical centers; 34 were subsequently excluded from the study. Of the 201 randomized subjects, 100 received FSBP and 99 received TSG. Hemostasis was achieved by 4 minutes in 64 subjects (63%) in the FSBP group and 40 subjects (40%) in the TSG group (P =.0018). In the FSBP group, compared with the TSG group, time to hemostasis was shorter (median, 4.0 minutes; 95% confidence interval [CI], 3.8-4.18 minutes vs median, 5.6 minutes, 95% CI, 4.5-7.0; P =.008), blood loss was less (mean, 4.0 +/- 29.7 g vs mean, 15.6 +/- 28.4 g; P <.0001), and time to wound closure was shorter (median, 15 minutes; 95% CI, 10.47-18.67 minutes vs median, 22.8 minutes; 95% CI, 18.67-30.67; P =.005). There were no differences in recurrent bleeding or any other adverse events. There was no significant difference in ICU stay, but hospital length of stay was shorter in the FSBP group compared with the TSG group, and the difference approached significance (median, 6.5 days; 95% CI, 5.00-7.00 days vs median, 7.0 days; 95% CI,. 6.00-8.00 days; P =.0565).\n FSBP is more effective than TSG for achieving hemostasis of needle or suture hole bleeding from PTFE femoral artery grafts.", "A phase-III trial that included fifty-three patients undergoing unilateral primary total knee arthroplasty with cement was conducted to investigate the hemostatic efficacy of fibrin sealant.\n Following cementing of the joint, 10 mL of fibrin sealant was sprayed onto the wound before tourniquet deflation and wound closure. No placebo was used in the control group. All patients received drains.\n Within twelve hours after the surgery, the amount of bloody drainage was 184.5 +/- 28.9 mL (mean and standard error) in the fibrin-sealant group (information available for twenty-three patients) and 408.3 +/- 54.6 mL in the control group (information available for twenty-three patients) (p = 0.002, after adjustment for variance in the time that the drainage was measured). On the first postoperative day, the hemoglobin level had decreased by 20.1 +/- 2.1 g/L in the fibrin-sealant group (information available for twenty-two patients) and by 27.3 +/- 2.1 g/L in the control group (information available for twenty-four patients). After adjustment for baseline values, the decrease in the hemoglobin level was 28.9% less in the fibrin-sealant group than in the control group (p = 0.005, 95% confidence limits = 10.2, 43.7). There were no seroconversions in the fibrin-sealant group.\n These results suggest that fibrin sealant can safely reduce bloody drainage following total knee arthroplasty while maintaining higher hemoglobin levels.", "Postoperative air leakage is the most frequent complication after pulmonary surgery. The development of modern surgical techniques has been influenced strongly by the need to manage air leakage effectively during pulmonary resection. This study evaluated the effect of using an autologous fibrin sealant (Vivostat) during lobectomy on morbidity following surgery.\n This was a prospective, blinded, randomised clinical study. Patients undergoing lobectomy were enrolled into two groups (Vivostat or non-treatment control, 20 per group). Air leakage was measured over a 1-h period (using a mechanical suction pump) on the day of operation, and both air leakage and bleeding/exudation (drainage volume) were recorded every morning postoperatively until the chest tubes were removed. Personnel recording these parameters were blinded to the intervention received. Results: Compared with the control group, mean bleeding/exudate volumes were significantly reduced in the Vivostat group (day 1,370 vs. 525 ml; total, 424 vs. 782 ml; both P<0.001), and drains were inserted for a shorter time (medians, 1 vs. 2 days, P=0.07). Significantly fewer patients had air leakage at any time in the Vivostat group (40 vs. 80%, P=0.02), and air leakage volumes were significantly lower compared with the control group (median differences: day of surgery: 0.6l/min, P=0.01; total 0.8l/min, P=0.03). Postoperative hospitalisation time was shorter in the Vivostat group than in the control group but the difference was not significant (0.5 days, P=0.12).\n Vivostat fibrin sealant significantly reduces post-surgical air leakage and drainage volumes following lobectomy in pulmonary surgery and is suitable for routine use in this procedure.", "We performed a prospective, randomized trial to assess the safety and efficacy of fibrin sealant in tubeless percutaneous nephrolithotomy.\n A total of 63 patients undergoing tubeless percutaneous nephrolithotomy were randomized to receive Tisseel vapor heated sealant at the end of the procedure. Fibrin sealant was instilled under direct vision in the nephrostomy tract at the end of the procedure. Patients younger than 14 years and those undergoing staged percutaneous nephrolithotomy or bilateral simultaneous percutaneous nephrolithotomy were excluded from study. Patients needing greater than 2 percutaneous tracts, those with significant bleeding or associated pyonephrosis and those with a residual stone burden were also excluded from study. The perioperative outcome in these patients (experimental group) was compared with the outcome in those undergoing tubeless percutaneous nephrolithotomy without fibrin sealant (control group).\n Fibrin sealant was instilled in 32 patients. There was no difference in the hematocrit decrease and blood transfusion requirement in the 2 groups. Patients in the experimental group experienced less postoperative pain and required less analgesia. They were discharged home 5 hours earlier than patients in the control group. However, this difference was not statistically significant. Complete stone clearance was achieved in 87.5% of patients in the experimental group and in 90.32% of controls.\n The instillation of Tisseel fibrin glue is safe for tubeless percutaneous nephrolithotomy. It is associated with less postoperative pain and a lower analgesic requirement. Additional prospective, randomized studies are required to better define its clinical role in the future.", "One third of women undergoing mastectomy with axillary evacuation for primary breast cancer suffer from postoperative seromas leading to unnecessary costs and complications such as infections and new operations. Different methods to prevent seroma formation have been tried without permanent success. The aim of this prospective randomised study was to examine the effect of fibrin sealant with fibrinolysis inhibitor firstly on the reduction of the amount of lymphatic leakage after axillary evacuation and secondly on the reduction of days with drains and postoperative seroma punctures.\n 40 patients with primary breast cancer were prospectively randomised to the treatment group (n = 19) getting fibrin glue combined with fibrinolysis inhibitor (aprotinin) sprayed into the axillary fossa and to the control group (n = 21).\n There were no differences in the incidence of postoperative seromas between the groups. However, the seromas were easier to treat if fibrin clue was used. Total quantity (mean+/-SD) of lymphorrhea and total number of aspirations (mean+/-SD) were almost twice as high in the patients of the control group compared to those having fibrin sealant. In the treatment group seromas resolved after one or occasionally after two aspirations in 71 % of patients, while in the control group 90 % of patients needed three or more aspirations.\n Potentially, fibrin sealant combined with fibrinolysis inhibitor might be used for the treatment of post- axillary evacuation lymphorrhea and seroma.", "The efficacy of solvent-detergent-treated fibrin sealant (human [FSH]) for controlling anastomotic bleeding from expanded polytetrafluoroethylene (ePTFE) patch angioplasty during carotid endarterectomy was evaluated, and FSH was compared with thrombin-soaked gelatin sponge (Gelfoam; TSG).\n The study was of a randomized, open-label, single-site, single-treatment, parallel design that took place in a referral center with hospitalized patients. Forty-seven adult patients (33 men, 14 women) underwent elective carotid endarterectomy. Patients were randomized to receive either FSH (N = 24) or TSG (N = 23). FSH was obtained as an investigational new drug. FSH was applied as a liquid by means of a dual-syringe technique. Heparin anticoagulation, patch thickness, and suture type were standardized. Two different needle sizes were used (CV-6, PT-13: N = 21 [FSH: N = 10, TSG: N = 11]; CV-6, PT-9: N = 26 [FSH: N = 14, TSG: N = 13]). The FSH or TSG was applied to the ePTFE patch, and then blood flow was restored through the carotid artery. Degree of anticoagulation was assessed by anti-factor Xa activity. The time from restoration of carotid blood flow until achieving hemostasis was recorded. The blood loss from patch suture hole bleeding was measured. Completion intraoperative duplex ultrasound scanning was performed in all cases. Heparin was reversed with protamine sulfate. The primary end point was successful hemostasis within 15 minutes of restoration of carotid blood flow. The secondary end points were the amount of blood loss caused by suture line bleeding and the time to achieve hemostasis.\n There was no difference in the number of patients with complete hemostasis at 15 minutes (TSG, 13 of 23; FSH, 12 of 24; P =.77). The measured blood loss was 99.0 +/- 119.9 (SD) mL for TSG, and 105.0 +/- 107.9 mL for FSH (P =.86). The time to hemostasis was the same for both groups (TSG, 16.5 +/- 16.5 minutes; FSH, 16.6 +/- 14.2 minutes; P =.97). Within both treatment groups, the use of larger needles (PT-13) was associated with greater blood loss (FSH, 169.7 +/- 124.2 mL; TSG, 172.7 +/- 151.5 mL) than was the use of smaller needles (PT-9; FSH, 58.8 +/- 66.3 mL; TSG, 34.1 +/- 25.6 mL; P =.036, P =.001, respectively). There were no postoperative strokes or bleeding complications in either group. No abnormalities were shown in either group by means of completion carotid duplex ultrasound scanning.\n FSH was equivalent, but not superior to, TSG in achieving hemostasis during carotid endarterectomy performed with ePTFE patch angioplasty. Adhesion properties of FSH to ePTFE are possibly different than those to native tissue and warrant additional investigation.", "Total knee arthroplasty is associated with major postoperative blood loss of approximately 800 to 1200 milliliters, and blood transfusion is frequently required. With the increased concern about the risks of blood transfusion, various methods of blood conservation in orthopaedic surgery have been studied. The most appropriate solution, however, is to reduce the loss of blood during and after an operation. The present prospective, controlled, randomized study was designed to evaluate the hemostatic efficacy of the use of fibrin tissue adhesive in patients managed with total knee arthroplasty.\n Fifty-eight patients who were scheduled to have a total knee arthroplasty were randomly divided into two groups: a control group, in which the standard means of hemostasis were applied, and a treatment group, in which the standard means to control local bleeding were applied and a fibrin tissue adhesive was sprayed on the internal aspects of the operative field before skin closure. All operations were performed in a bloodless field with use of a pneumatic tourniquet. All patients received low-molecular-weight heparin as thromboprophylaxis twelve hours before the operation and every twelve hours postoperatively. Blood loss during the operation was evaluated by measuring the volume in the suction apparatus and by estimating the amount of lost blood in the swabs at the end of the operation. The apparent postoperative lost blood was determined by measuring the volume in the suction-drain bottles. All blood transfusions were recorded.\n The mean apparent postoperative blood loss (and standard deviation) in the fibrin-tissue-adhesive group was 360+/-287.7 milliliters compared with 878+/-403.0 milliliters in the control group, with a mean difference of 518 milliliters (p<0.001). The decrease in the level of hemoglobin was 25+/-10 grams per liter in the treatment group compared with 37+/-12 grams per liter in the control group (p<0.001). Sixteen patients (55 percent) in the control group required a blood transfusion and eight (28 percent) required two units of blood, whereas only five (17 percent) of the patients in the fibrin-tissue-adhesive group required a blood transfusion and only one (3 percent) required two units (p = 0.004). The number of adverse events was comparable between the two groups. None of the adverse events were considered to be related to the use of fibrin tissue adhesive. One death, which was due to massive pulmonary embolism, was reported in the control group. No seroconversion was reported at three and six months after the operation.\n The use of fibrin tissue adhesive in total knee arthroplasty seems to be an effective and safe means with which to reduce blood loss and blood-transfusion requirements. Furthermore, the importance of these findings was enhanced by a significant reduction in blood loss, in the postoperative decrease in the level of hemoglobin, and in blood-transfusion requirements despite preoperative thromboprophylaxis with low-molecular-weight heparin.", "Patients who have axillary dissections during lumpectomy or modified radical mastectomy for breast carcinoma accumulate serosanguinous fluid, potentially resulting in a seroma. Currently accepted practice includes insertion of one or more drains for fluid evacuation. This multicenter, randomized, controlled, phase II study was undertaken to evaluate whether a virally inactivated, investigational fibrin sealant is safe and effective when used as a sealing agent to reduce the duration and volume of serosanguinous fluid drainage and to determine the dose response of this effect.\n Patients undergoing lumpectomy or modified radical mastectomy were randomized to treatment with 4, 8, or 16 mL of fibrin sealant or control (no agent) at the axillary dissections site. Patients undergoing modified radical mastectomy also received an additional 4 or 8 mL of fibrin sealant at the skin flap site. Efficacy was evaluated by the number of days required for wound drainage and the volume of fluid drainage compared with control. Safety was confirmed by clinical course, the absence of viral seroconversion, and no major complications attributable to the sealant.\n The 4-mL axillary dissection dose of fibrin sealant significantly reduced the duration and quantity of fluid drainage from the axilla following lumpectomy (p < or = 0.05). In the modified radical mastectomy patients, a 16-mL axillary dissection dose combined with an 8-mL skin flap dose was significantly effective in reducing the number of days to drain removal (p < or = 0.05) and fluid drainage (p < or = 0.01). There were no fibrin sealant patient viral seroconversions and no major complications attributable to the sealant. A number of wound infections were noted, although this may represent a center-specific effect.\n Application of fibrin sealant following axillary dissection at the time of lumpectomy or modified radical mastectomy can significantly decrease the duration and quantity of serosanguinous drainage. The viral safety of the product was also supported.", "Patients (n = 81) undergoing total hip replacement (THR) were randomized to receive either standard of care plus fibrin sealant (FS) (10 mL total) or standard of care alone to evaluate the efficacy of FS for reducing blood loss in THR. Considering the 81 intent-to-treat patients, adjusted perioperative blood loss was reduced significantly in the FS group, by 197 mL [95% CI: 45 mL, 319 mL] or 23.5% [95% CI: 5.4%, 38.1%] (p = 0.014). When protocol violators were eliminated, leaving 73 patients, the adjusted FS group perioperative bleeding was reduced by 221 mL [95% CI: 63 mL, 351 mL] or 27.1% [95% CI: 7.6%, 42.5%] (p = 0.0098).", "The Vivostat System is a medical device for the preparation of an autologous fibrin sealant from 120 mL of the patient's blood in the operating room. The system is fully automated and microprocessor controlled and is made up of three components: an automated processor unit, an automated applicator unit, and a disposable, single-patient-use unit, which includes a preparation set and a Spraypen applicator. The biochemical process is initiated by batroxobin, which acts upon the fibrinogen in the patient's plasma. The completion of the process depends entirely on endogenous thrombin in producing the sealant.\n Twenty-four volunteer patients undergoing elective primary coronary artery bypass grafting were randomized to either conventional hemostasis (control group) or the use of Vivostat fibrin sealant as an adjunct to conventional hemostasis. The patients were followed up at 1 month and 1 year.\n The preparation process was completed in 30 minutes. No safety issues associated with the use of the sealant were identified. From 120 mL of the patient's blood the yield of fibrin sealant was 4.5 mL (range, 3.9 to 4.8 mL). There was a favorable trend toward lower amounts of chest tube drainage in the Vivostat group. In the Vivostat group, 1 of 11 patients (9%) required a perioperative transfusion and in the control group 3 of 12 patients (25%) required a perioperative transfusion.\n It is possible to prepare autologous fibrin sealant with the Vivostat system in 30 minutes. No exogenous thrombin is required. The sealant has no known adverse effects and may prove to be a useful adjunct to hemostasis in cardiothoracic surgery.", "Major orthopedic surgery can be associated with dramatic blood loss, thereby requiring high-volume homologous transfusions in patients unable to benefit from blood salvage techniques. The effect of aprotinin on blood loss and transfusion requirements during orthopedic surgery for either the resection of malignancies of the removal of infected hardware was prospectively studied.\n Twenty-three patients scheduled for orthopedic surgery of the hip, femur, or pelvis for sepsis or malignant tumors, all under general anesthesia, were randomly allocated to receive during operation, in a blinded manner, either aprotinin administered as a bolus of 1.106 kallikrein inactivation units (KIU) followed by an infusion of 5 x 10(5) KIU/h, or the equivalent volume of saline. The anesthesia and perioperative management, as well as the designated transfusion criteria, were standardized. The total blood loss of each patient was evaluated using intraoperative suction losses, sponge weights, and postoperative volumetric drainage. Homologous transfusion requirements were noted. Hemoglobin and hematocrit measures, as well as coagulation and fibrinolytic pathway explorations, were performed before and after surgery. Deep venous thrombosis prophylaxis was applied, and the incidence of this complication was assessed.\n Twelve patients received aprotinin. Aprotinin reduced the total blood loss from a median of 5,305 ml (range, 3,000-9,770 ml) to a median of 1,783 ml (range, 1,140-4,955 ml; P < 0.05). A blood loss reduction of 56% during surgery and 68% on discharge from the postanesthesia care unit was observed. Seven units (range, 4-16) of packed erythrocytes were transfused per patient in the placebo group, and 3 (range, 2-5) were transfused in the aprotinin group (P < 0.05). In the aprotinin group, platelet counts were higher, and postoperative prothrombin times and D. Dimer values were lower. The activated partial thromboplastin time values showed no significant difference between the two groups. No side effects were observed in the aprotinin group. A deep venous thrombosis developed in one patient in the placebo group.\n Aprotinin treatment during major orthopedic surgery significantly reduces both blood loss and consequent homologous blood transfusion requirements.", "To evaluate the effectiveness of autologous fibrin tissue adhesive (auto-FTA) in reducing blood loss during cementless total hip arthroplasty (THA).\n From September 2000 to August 2001, 100 patients who predonated 400 ml of autologous blood were randomised to undergo either standard treatment with auto-FTA (auto-FTA group) or standard treatment alone (control group). The volume of postoperative blood loss and the decrease in haemoglobin level were measured. All patients were followed up for 3 years to evaluate the rate of bone ingrowth and heterotopic ossification.\n The mean postoperative blood loss was 580 ml (standard deviation [SD], 240 ml) in the auto-FTA group and 810 ml (SD, 341 ml) in the control group; the difference was significant (230 ml, p<0.001). The decrease in haemoglobin concentration was 17 g/l (SD, 11 g/l) in the auto-FTA group and 22 g/l (SD, 12 g/l) in the control group. The difference was significant (5 g/l, p=0.03). The percentage of total blood loss of >1200 ml in any single patient was significantly lower in the auto-FTA group (4%) than in the control group (20%) [p=0.01].\n Auto-FTA is a safe and effective means of reducing perioperative blood loss in THA.", "Patients on cardiopulmonary bypass (CPB) have an increased susceptibility to postoperative bleeding. Previous reports using desmopressin acetate (DDAVP) for the prevention of postoperative bleeding have given contradictory results, whereas the protease inhibitor aprotinin has been shown to reduce blood loss after this type of surgery. This randomized study was performed to assess the efficacy of DDAVP versus aprotinin in the prevention of bleeding after CPB.\n One hundred nine of 122 eligible patients were randomized to four different groups: Group A (n = 28) received aprotinin starting with a bolus of 2 x 10(6) KIU followed by a continuous infusion of 0.5 x 10(6) KIU/h until the end of surgery; group B (n = 25) received of DDAVP 0.3 micrograms/kg i.v. on completion of CPB; group C (n = 28) received two doses of DDAVP, the first as in group B and an additional dose 6 hours after surgery; group D (n = 28) received no treatment. There was a marked reduction of postoperative blood loss either at 12 hours (P < .01) or 72 hours (P < .02) in the aprotinin group compared with all other groups, whereas no significant effect was observed in either of the two DDAVP regimens. A significant reduction in the amount of blood used was observed only in the aprotinin group (P < .01). Of the plasma fibrinolytic components assayed, there was a significant reduction of the fibrin degradation product generation in the aprotinin group (P < .001), whereas a significant systemic hyperfibrinolysis was observed in both DDAVP-treated groups and the control group. No side effects related to the study drugs were observed in any patient.\n Aprotinin inhibited fibrinolysis; this correlated with a significant reduction of postoperative blood loss and need for blood replacement after CPB. Neither one nor two doses of DDAVP had a beneficial effect. Aprotinin offers a better alternative than DDAVP in the prevention of bleeding after CPB.", "To examine the adhesion prevention effects of 2 types of fibrin sealant after laparoscopic myomectomy (LM).\n A prospective, randomized study (Canadian Task Force I) was conducted at a University-affiliated hospital. A total of 91 patients showing a minimal myoma > 5 cm, excluding pedunculated myomas, underwent LM alone: 32 patients in the control group, 29 in the fibrin gel group and 30 patients in the fibrin sheet group. After LM, postoperative adhesions were evaluated by second-look laparoscopy. The frequency of postoperative adhesions was the main outcome.\n The frequency of postoperative adhesions of the uterus was significantly lower (p < 0.05) in the fibrin gel group, with 20/32 (62.5%) in the control group, 10/29 (34.5%) in the fibrin gel group and 20/30 (67.7%) in the fibrin sheet group. Although no significant differences were found in the incidence of de novo adnexal adhesions, the lowest rate was found in the fibrin gel group, with 4/32 patients (12.5%) in the control group, 2/29 patients (6.8%) in the fibrin gel group and 5/30 patients (16.7%) in the fibrin sheet group. No bilateral adnexal adhesions were observed in the 3 groups.\n After LM for myomas as large as > or = 5 cm, postoperative adhesions were observed in > or = 50% of patients. The use of fibrin gel after LM is recommended.", "To explore whether disturbed fibrin polymerization is the main problem underlying dilutional coagulopathy and can be reversed by fibrinogen administration, we conducted a prospective study using modified thrombelastography (ROTEM).\n Sixty-six orthopedic patients randomly received modified gelatin solution, hydroxyethyl starch 130/0.4, or exclusively Ringer lactate solution. ROTEM analysis was performed, concentrations of coagulation factors and markers of thrombin generation were measured. Fibrinogen concentrate (Hemocomplettan) was administered (30 mg/kg) when thrombelastographically measured fibrinogen polymerization was critically decreased.\n The alpha angle, clot firmness, and fibrinogen polymerization (median [min to max]) significantly decreased in the patients receiving hydroxyethyl starch (area under the curve minus baseline (-5 [-9 to -2]), followed by gelatin solution (-3 [-8 to 0]), with the least reductions seen for Ringer lactate solution (-2 [- 4 to 1]) (colloids versus Ringer lactate P < 0.0001). Thirteen patients in the colloid groups but none in the Ringer lactate group needed fibrinogen concentrate to maintain borderline clot firmness. Activity of FVII, FVIII, FIX, and von Willebrand ristocetin activity decreased significantly with colloids. Thrombelastographically measured coagulation time, molecular markers of thrombin generation, and activity of all other coagulation factors were comparable in all groups.\n Disturbance of fibrinogen/fibrin polymerization is the primary problem triggering dilutional coagulopathy during major orthopedic surgery. The magnitude of clot firmness reduction is determined by the type of fluid used, with hydroxyethyl starch showing the most pronounced effects. These undesirable effects of intravascular volume therapy can be reversed by increasing fibrinogen concentration by administering fibrinogen concentrate, even during continuing blood loss and intravascular volume replacement.", "To evaluate the role of fibrin sealant for embryo transfer (ET) and the effect of patient mobilization after ET on pregnancy rates.\n A prospective, randomized, controlled study.\n Two hundred eleven patients who were admitted to the IVF Unit over a period of 6 months participated in the study. Patients who had three or more embryos were randomly divided into two groups: group 1 (study group), in which ET was performed using fibrin sealant, and group 2, who served as the controls. Ovulation induction was carried out using the long GnRH-a suppression protocol.\n Comparison of the results regarding the implantation and pregnancy rates and ectopic pregnancy rate revealed a nonsignificant difference between the two groups. However, analysis of the results according to the patients' age revealed a significant increase in pregnancy (P < .05) and implantation (P < .01) rate in elderly patients (aged 39-42) using fibrin sealant for ET as compared with controls. Furthermore, we found that bed rest has no advantage over patient mobilization after ET.\n The use of fibrin sealant for ET is advantageous in elderly women, but has no apparent effect on the success rate or ectopic pregnancy rate in younger patients. Immediate mobilization does not jeopardize the results of IVF-ET.", "Despite substantial improvements in perioperative mortality, complications, and specifically the development of a pancreatic fistula, remain a common occurrence after pancreaticoduodenectomy. It was the objective of this study to evaluate the role of fibrin glue sealant as an adjunct to decrease the rate of pancreatic fistula after pancreaticoduodenectomy. One hundred twenty-five patients were randomized after pancreaticoduodenal resection only if, in the opinion of the surgeon, the pancreaticojejunal anastomosis was at high risk for development of a pancreatic anastomotic leak. After completion of the pancreaticojejunal anastomosis, the patients were randomized to topical application of fibrin glue sealant to the surface of the anastomosis or no such application. The primary postoperative end points in this study were pancreatic fistula, total complications, death, and length of hospital stay. A total of 59 patients were randomized to the fibrin glue arm, whereas 66 patients were randomized to the control arm and did not receive fibrin glue application. The pancreatic fistula rate in the fibrin glue arm of the study was 26% vs. 30% in the control group (p = not significant [NS]). The mean length of postoperative stay for all patients randomized was similar (fibrin glue = 12.2 days, control = 13.6 days) and the mean length of stay for patients in whom pancreatic fistula developed was also not different (fibrin glue = 18.9 days, control = 21.7 days). There were no differences with respect to total complications or specific complications such as postoperative bleeding, infection, or delayed gastric emptying. These data demonstrate that the topical application of fibrin glue sealant to the surface of the pancreatic anastomosis in this patient population undergoing high-risk pancreaticojejunal anastomosis did not reduce the incidence of pancreatic fistula or total complications after pancreaticodudodenectomy. There seems to be no benefit regarding the use of this substance in this setting.", "Controlled study to assess the efficacy of aprotinin and Amicar in reducing blood loss during complex spinal fusions.\n To compare blood loss and the clotting profile with a thromboelastogram in patients with spinal deformities undergoing sequential anterior and posterior spinal fusions treated intraoperatively with either aprotinin or Amicar.\n Spinal fusion for correction of adult spinal deformities is associated with large blood losses despite the implementation of multiple factors to reduce this blood loss. The antifibrinolytics aprotinin and Amicar have both been shown to reduce blood loss in other surgical procedures with the potential for large blood loss. Hence, we compared their efficacy for reducing blood loss in complex spinal fusions.\n Sixty patients for elective sequential anteroposterior thoracolumbosacral fusions were randomly assigned to three groups: control, aprotinin, and Amicar. Patients were assessed for blood loss, transfusion requirements, postoperative complications, and coagulation profile using a thromboelastogram.\n The study demonstrated a significant reduction in total blood loss (aprotinin 3628 mL, Amicar 4056 mL, control 5181 mL) and transfusion requirements using the half-dose aprotinin regimen compared with Amicar or control. Aprotinin also preserved the thromboelastogram mean clot formation time, clot strength, and clotting index compared with Amicar or control.\n For complex spinal operations with large blood losses, the half-dose aprotinin regimen will reduce blood loss and the need for blood components and may have a role in reducing postoperative lung injury.", "Following carotid endarterectomy (CEA), patch angioplasty provides a significant reduction in the risk of perioperative complications. The expanded polytetrafluoroethylene (ePTFE) patch is strong, is resistant to infection, and has low thrombogenicity; but it remains unpopular because of its tendency of prolonged bleeding at the suture line. We aimed to investigate whether the application of Quixil sealant to the suture line could improve the time to achieve hemostasis and reduce local blood loss when compared to a standard topical hemostat Kaltostat. A prospective, randomized trial of 20 patients undergoing CEA was undertaken. Patients were randomized to receive either Quixil sealant (treatment group) or topical Kaltostat (controls) as a hemostatic agent to the patch suture line. Hemostasis was defined as no bleeding at the suture line for 1 minute. Statistical analysis was performed using the Mann-Whitney test. The two groups had a similar age and sex distribution. The mean age was 71 years, and there were seven men and three women in each group. The time to achieve hemostasis was significantly lower in the Quixil group (median 2.5 minutes, range 1-4 minutes) compared to the controls (median 17 minutes, range 7-59 minutes) (p < 0.001). Blood loss after clamp release was also significantly reduced in the Quixil group; median 24.5 ml (range 5.5-105.0 ml) versus 203 ml (range 54.5-817.0 ml) (p < 0.001). This study has demonstrated that Quixil human surgical sealant is an effective sealant of ePTFE patch suture holes and does not compromise the patch repair. It could be used during other vascular procedures involving ePTFE.", "Serosanguinous drainage after mastectomy and axillary lymph node dissection has traditionally been treated with the temporary use of closed suction drainage catheters. Use of drainage catheters is associated with wound infection, discomfort, nerve injury, and impaired arm movement. Commercially produced fibrin sealant has been proposed to reduce postoperative serosanguinous collections. We hypothesized that the intraoperative application of low-dose (2-5 cm3) fibrin sealant would reduce serosanguinous drainage and allow earlier removal of closed suction drainage catheters after operation for breast cancer. Fifty-five women with known breast cancer underwent either total mastectomy, modified radical mastectomy, or isolated level I and II axillary lymph node dissection. Twenty-six patients were treated with fibrin sealant and 29 served as control subjects. The application of fibrin sealant resulted in a significant reduction in overall duration catheters were needed (7 vs 8.3 days; P = 0.05). More importantly fibrin sealant reduced the time until 24-hour drain output was less than 30 cm3 (4.9 vs 6.2 days). Additionally fibrin sealant application resulted in a 60 per cent reduction in overall drainage amount after total mastectomy and a 32 per cent reduction after modified radical mastectomy. The application of fibrin sealant after axillary lymph node dissection did not decrease overall drainage amount. In conclusion fibrin sealant reduces serosanguinous drainage after total mastectomy and modified radical mastectomy and may allow earlier removal of closed suction drainage catheters.", "In order to investigate the effect of fibrin glueing on the treatment or prevention of air leakages, 114 patients undergoing pulmonary resections and pneumonectomies were studied in two treatment groups: surgery alone (59 patients) or analogous surgical treatment followed by the application of fibrin glue (55 patients). The patients were randomly assigned to treatment groups within two strata: pulmonary resections (63 patients) and pneumonectomies (51 patients). Intraoperatively, 81% of the patients undergoing pulmonary resection who suffered from air leakages after conventional suturing showed improved results of the airway-tolerance-pressure test after the application of fibrin glue (one-sided P value < 0.01; 95% confidence interval: 58-95%). Treatment with fibrin glue reduced the incidence of postoperative leakages significantly from 66% in the control group to 39% in the treatment group (one-sided P-value < 0.02; estimated risk reduction 41%; 95% confidence interval 2-65%). An additional reduction of the duration of post-operative air leakages by the treatment with fibrin glue could not be shown. In terms of minor response criteria, slight trends for an advantage of treatment with fibrin glue could be observed for the duration of stay in hospital and the number of patients with complications. There were no obvious trends concerning fever, intraoperative and postoperative intubation times, the amount of secretion from thoracic tubes and the general condition of the patients. No adverse drug event related to fibrin glueing was observed.", "Retention of pleural effusion after hepatectomy is an important complication that may affect the postoperative course. However, there are few reports on its pathogenesis or preventive measures. We evaluated the mechanism of the development of this complication and preventive measures against it. During the past 4-year period, hepatectomy was performed in 77 patients, of whom 64 underwent liver mobilization by transecting the hepatic ligaments. A fibrin sealant was sprayed on the cut surface of the hepatic ligaments in randomly selected 25 of the 64 patients to determine whether this application can prevent postoperative retention of pleural effusion. Post-operative pleural effusion was not observed in any patient treated by fibrin sealant spraying but was observed in 13 (30%) of the other 39 patients treated with this sealant (p < 0.05). In addition, none of the 23 patients in whom the liver was not mobilized during hepatectomy showed postoperative pleural effusion. These results suggest that severance of the hepatic ligaments is a major cause of pleural effusion, and application of a fibrin sealant to the undersurface of the diaphragm around the insertion of the liver ligaments is useful for preventing this complication." ]	Overall, the results suggest that fibrin sealants are efficacious in reducing both post-operative blood loss and peri-operative exposure to allogeneic RBC transfusion. Although treatment-effect heterogeneity was observed for these primary efficacy outcomes, heterogeneity was generally in terms of the size of effect rather than the direction of effect. Fibrin sealants appeared to demonstrate their greatest beneficial effects in the context of orthopaedic surgery, where blood loss is often substantial. Trials not involving orthopaedic surgery generally showed a trend toward decreased post-operative blood loss but the observed reductions were not clinically significant. The majority of trials included in this review were small, which raises concerns about the potential effects of publication bias. Funnel plot assessment indicates that there is some evidence of publication bias in the form of a missing population of small negative trials. We believe that large, methodologically rigorous, randomised controlled trials of fibrin sealants are needed.
CD002834	[ "15006907", "8719151", "16417695", "9678615", "8768414", "2495337", "15155598", "11983755", "7786943", "9889451", "2025672", "14588129", "12781927", "9294390", "8790508", "7646664", "12883063", "18090130", "1958248", "2073774", "2504359", "14528540", "1790034", "15782877", "9734786", "1479324", "12590989", "12244644", "18308500", "9402779", "11291370", "8347386", "17329652", "9388791", "16091137" ]	[ "A large population-based randomized controlled trial to increase attendance at screening for cervical cancer.", "A randomised controlled trial of strategies to prompt attendance for a Pap smear.", "Improving uptake of cervical cancer screening in women with prolonged history of non-attendance for screening: a randomized trial of enhanced invitation methods.", "Promoting participation in a population screening program for breast and cervical cancer: a randomized trial of different invitation strategies.", "Mass mailing campaigns to promote screening for cervical cancer: do they work, and do they continue to work?", "Computerized reminders to encourage cervical screening in family practice.", "Media interventions to increase cervical screening uptake in South Africa: an evaluation study of effectiveness.", "A randomized controlled trial of interventions to promote cervical cancer screening among Chinese women in North America.", "Cervical screening in general practice.", "Do personalised letters in Vietnamese increase cervical cancer screening among Vietnamese women?", "A randomised trial of invitations to attend for screening mammography.", "The safety net: a cost-effective approach to improving breast and cervical cancer screening.", "Tailored messages for breast and cervical cancer screening of low-income and minority women using medical records data.", "Effectiveness of a call/recall system in improving compliance with cervical cancer screening: a randomized controlled trial.", "Effectiveness of three community based strategies to promote screening for cervical cancer.", "Breast and cervical cancer screening in a low-income managed care sample: the efficacy of physician letters and phone calls.", "Randomised controlled trial of the effect of evidence based information on women's willingness to participate in cervical cancer screening.", "Promotion of cervical screening among nonattendees: a partial cost-effectiveness analysis.", "Can health education increase uptake of cervical smear testing among Asian women?", "A randomised trial of general practitioner-written invitations to encourage attendance at screening mammography.", "Prospective randomised controlled trial of methods of call and recall for cervical cytology screening.", "The impact of tailored interventions on a community health center population.", "Increasing women's compliance with opportunistic cervical cancer screening: a randomized trial.", "How much does a reminder letter increase cervical screening among under-screened women in NSW?", "Using an office system intervention to increase breast cancer screening.", "Does the offer of cervical screening with breast screening encourage older women to have a cervical smear test?", "Comparison of tailored interventions to increase mammography screening in nonadherent older women.", "Message framing and mammography screening: a theory-driven intervention.", "A randomized trial of two print interventions to increase colon cancer screening among first-degree relatives.", "Improving uptake of breast screening in multiethnic populations: a randomised controlled trial using practice reception staff to contact non-attenders.", "Promoting breast and cervical cancer screening at the workplace: results from the Woman to Woman Study.", "Does feedback improve the quality of cervical smears? A randomized controlled trial.", "Effective lay health worker outreach and media-based education for promoting cervical cancer screening among Vietnamese American women.", "Encouraging underscreened women to have cervical cancer screening: the effectiveness of a computer strategy.", "Effect on survey response rate of hand written versus printed signature on a covering letter: randomised controlled trial [ISRCTN67566265]." ]	[ "Although cervical cancer is one of the potentially most preventable malignancies, it is still fairly common. In settings with established screening programs, increased compliance is important for future reduction in cervical cancer incidence, but it is presently unclear how this can be effectively achieved.\n We conducted a randomized controlled trial including all 12,240 women invited to organized screening in Sweden. To increase compliance, three successive interventions were tested: (a) modified invitation versus the standard invitation letter, (b) reminder letter to nonattenders after the first intervention versus no reminder letter, and (c) phone reminder to nonattenders after the reminder letter versus no phone reminder. We analyzed the proportion of women attending screening after each intervention and the cumulative proportion after the interventions as well as the cumulative proportions of cytologic abnormalities.\n The modified invitation did not increase attendance compared with the standard invitation letter [difference 1.3% 95% confidence interval (CI) -0.3 to 2.9]. In contrast, a reminder letter increased the proportion of women attending with 9.2% (95% CI 7.9-10.5) compared with women who did not receive a reminder letter, and a phone reminder increased the proportion of women attending with 31.4% (95% CI 26.9-35.9). Combinations of modified invitation, written reminder, and phone reminder almost doubled attendance within 12 months, and the number of detected cytologic abnormalities was more than tripled.\n Simple reminders by mail and phone can drastically increase women's participation in Papanicolaou smear screening and increase the number of detected precursor lesions and thereby save lives.", "To assess the comparative efficacy, by randomised controlled trial, of three interventions designed to encourage \"at risk\" women to have a Pap smear: an educational pamphlet; letters inviting attendance at a women's health clinic; and letters from physicians.\n Subjects at risk for cervical cancer who had not been adequately screened were identified by a random community survey and randomly allocated to one of the intervention groups or a control group. Six months after intervention implementation, a follow up survey assessed subsequent screening attendance. Self report was validated by comparison with a national screening data base.\n A significantly greater proportion of women (36.9%) within the group receiving a physician letter reported screening at follow up than in any other group (P = 0.012). The variables most strongly predicting screening attendance were: age, perceived frequency of screening required, use of oral contraceptives, and allocation to receive the physician letter intervention.\n The relative efficacy of the GP letter in prompting screening attendance shows that this strategy is worthy of further investigation. There remains a need to examine the barriers to screening for older women, and to develop tailored strategies for this population.", "To compare the effectiveness and cost-effectiveness of three methods of inviting women with a long history of non-attendance to undergo cervical screening.\n Randomized controlled trial and cost-effectiveness analysis. In all, 1140 women were identified from routine NHS screening records as having no smear for at least 15 years and randomly allocated to receive a telephone call from a nurse, a letter from a well-known celebrity (Claire Rayner) or letter from the local NHS Cervical Screening Commissioner. Uptake of screening was measured using routine data and attributed to interventions if occurring within three months. Uptake was compared with a control group. Costs of carrying out the interventions were noted from the perspective of the NHS and cost-effectiveness, as cost per additional attender, calculated.\n Uptake following all interventions was low: telephone call (1.4, 95% confidence interval [CI] 0.38-3.6%); celebrity letter (1.8, 95% CI 0.57-4.0%); commissioner letter (4.6, 95% CI 2.5-7.7%); control group (1.8, 95% CI 0.57-4.0%). There were no significant differences between groups. Telephone intervention was not possible in a quarter of women whose numbers were unlisted. Telephone intervention was the most expensive and least effective of the interventions. The commissioner letter yielded an additional attender within three months at an incremental cost of 23.21 pounds compared with taking no action.\n Neither a telephone call from a nurse nor a letter from a celebrity to encourage attendance for cervical screening were effective or cost-effective in women with a prolonged history of non-participation in the screening programme. A letter from the local cervical screening programme commissioner resulted in a small, non-significant increase in uptake. The low cost and ease of implementation of this intervention supports further research into its use in routine practice.", "Attendance level has been identified as a major determinant of cost-effectiveness of organized screening programs. We tested the effectiveness of 4 different invitation systems in the context of an organized population screening program for cervical and breast cancer.\n Women eligible for invitation--8385 for cervical and 8069 for breast cancer screening--listed in the rosters of 43 and 105 general practitioners (GP), respectively, who had accepted to collaborate in the program, were randomized to 4 invitation groups: Group A--letter signed by the GP, with a prefixed appointment; Group B--open-ended invitation, signed by the GP, prompting women to contact the screening center to arrange an appointment; Group C--letter (same as for group A), signed by the program coordinator, with a prefixed appointment; Group D--extended letter (highlighting the benefits of early cancer detection) signed by the GP, with a prefixed appointment. Assignment to the interventions was based on a randomized block design (block=GP).\n Assuming Group A as the reference, the overall compliance with cervical cancer screening was reduced by 39% in Group B (RR=0.61; 95% CI, 0.56-0.68) and by 14% in Group C (RR=0.86; 95% CI, 0.78-0.93); no difference was observed for Group D (RR=1.03; 95% CI, 0.95-1.1). The response pattern was similar for breast screening (Group B: RR=0.71; 95% CI, 0.65-0.76; Group C: RR=0.87; 95% CI, 0.81-0.94; Group D: RR=1.01; 95% CI, 0.94-1.08).\n Personal invitation letters signed by the woman's GP, with preallocated appointments, induce a significant increase in compliance with screening. Efficiency can be ensured through the adoption of overbooking, provided that attendance levels are regularly monitored.", "Campaigns involving sending personally addressed letters to encourage women to have Pap smears increase Pap smear rates. The aim of this study was to assess whether this effect is maintained when campaigns are repeated regularly. In October 1992, a letter reminding women of the importance of screening was mailed to all women in three New South Wales postcode regions where a similar letter had been sent three years previously. The response was compared to the response in three regions receiving no earlier letter. The number of women attending for cervical screening during the three months after distribution of the letters was assessed from Health Insurance Commission claims for cervical cytology. These attendances were compared with expected attendances based on the attendance patterns over 28 pre-intervention quarters. Significant postintervention increases in attendance were observed in all three regions receiving an initial letter. However, in one region, the increase in attendances, around 1 per cent of eligible women, was not significantly greater than the increase in the control region (z = 0.15, P = 0.88). The second letter campaign had no measurable effect on attendances. No significant increase in screenings was observed in two of the towns. A significant increase was observed in one region, but this was not significantly greater than the increase in the control region (z = -0.05, P = 0.96). These results suggest that repeated direct-mail campaigns to promote screening for cervical cancer may be of no benefit. A one-off campaign may result in an increase in screenings in the short term.", "In a randomized trial three ways of increasing rates of cervical screening were compared for women attending a family medicine center. Working from computerized medical records, 1,587 women aged 18 to 35 years who were overdue for a screening test were included in the study. In a control group, no formal method was used to encourage patients to attend for screening, and 13.7 percent obtained a test within the trial year. In one intervention group the physician was issued a message identifying those women visiting the center for a routine appointment who were due for screening; 16.1 percent were screened. Sending a letter to patients in a second group yielded a 25.9 percent compliance rate. In a third group the practice nurse called patients on the telephone to advise them to obtain the test, and 20.0 percent complied. Reminders issued to the physician provide a low-cost, opportunistic approach to reach women who happen to visit the practice, but this approach should be supplemented by telephoning or sending a letter to those women who do not attend regularly.", "Successful cervical cancer prevention depends on reaching, screening and treating women with pre-invasive disease. We aimed to evaluate the effectiveness of two media interventions-a photo-comic and a radio-drama-in increasing cervical screening uptake. A randomized controlled trial compared a photo-comic on cervical cancer screening with a placebo comic. One month after the comics were distributed a radio-drama paralleling the photo-comic was broadcast on the community radio station and a retrospective evaluation was carried out. The trial was set in Khayelitsha, a peri-urban squatter community near Cape Town, South Africa. A random sample consisted of 658 women between the ages of 35 and 65 years, from a stratified sample of census areas. The main outcome measure was self-reported cervical screening uptake 6 months after distribution of the comics. Seven percent (18 of 269) of women who received the intervention photo-comic reported cervical screening during the 6 months follow-up, compared with 6% (25 of 389) of controls (P = 0.89). Women who recalled hearing the radio-drama were more likely to report attending screening (nine of 53, 17%) than those who did not (19 of 429, 4%; P < 0.001). We conclude that the photo-comic was ineffective in increasing cervical screening uptake in this population. The radio-drama may have had more impact, but only a minority of women recalled being exposed to it. Future research must concentrate not only on achieving high level of exposure to health messages, but also on investigating the links between exposure and action.", "North American Chinese women have lower levels of Papanicolaou (Pap) testing than other population subgroups. We conducted a randomized controlled trial to evaluate the effectiveness of two alternative cervical cancer screening interventions for Chinese women living in North America.\n Four hundred and eighty-two Pap testing underutilizers were identified from community-based surveys of Chinese women conducted in Seattle, Washington, and Vancouver, British Columbia. These women were randomly assigned to one of two experimental arms or control status. Several Chinese-language materials were used in both experimental arms: an education-entertainment video, a motivational pamphlet, an educational brochure, and a fact sheet. Women in the first experimental group (outreach worker intervention) received the materials, as well as tailored counseling and logistic assistance, during home visits by trilingual, bicultural outreach workers. Those in the second experimental group (direct mail intervention) received the materials by mail. The control group received usual care. Follow-up surveys were completed 6 months after randomization to ascertain participants' Pap testing behavior. All statistical tests were two-sided.\n A total of 402 women responded to the follow-up survey (83% response rate). Of these women, 50 (39%) of the 129 women in the outreach group, 35 (25%) of the 139 women in the direct mail group, and 20 (15%) of the 134 women in the control group reported Pap testing in the interval between randomization and follow-up data collection (P<.001 for outreach worker versus control, P =.03 for direct mail versus control, and P =.02 for outreach worker versus direct mail). Intervention effects were greater in Vancouver than in Seattle.\n Culturally and linguistically appropriate interventions may improve Pap testing levels among Chinese women in North America.", "This study examined the effect of three interventions for encouraging women to have a Pap smear in a general practice: tagging the medical record to remind the doctor to offer a Pap smear, sending an invitation to make an appointment for a Pap smear, and sending an invitation with an appointment to attend for a Pap smear at a special screening clinic staffed by women. The study took place in a university general practice at Lockridge, near Perth. A computerised practice age-sex register provided 2139 women in the age range 36 to 69 inclusive. Of these, 757 were eligible for inclusion in the study and were allocated randomly to one of three intervention groups or a control group. In total, 177 women had a Pap smear during the study. Significantly more Pap smears were taken for the appointment-letter and letter-only groups than the control group (odds ratio (OR) 2.13, 95% confidence interval (CI) 1.34 to 3.57, and OR 1.67, CI 1.01 to 2.77 respectively), but there was no significant difference between the tagged-notes and the control groups. Women who attended the screening clinic rated the experience positively. Attendance, however, was inadequate for the clinic's viability in a private practice.", "In Australia, Vietnamese women are at greater risk of cervical cancer than other Australian women. To increase their participation in cervical screening, the Vietnamese community was exposed to a media campaign about the advantages of cervical smear screening which was delivered in Vietnamese through Vietnamese newspapers and radio. In addition, 689 Vietnamese (18-67 years) were selected from the electoral roll. They were randomly assigned to either receive a personal letter written in Vietnamese promoting cervical screening, or not. We report on the effect of the letter on smear rates. Being randomised to be sent such a letter was not associated with any increase in screening (relative rate of appropriate screening in the intervention versus the control group was 0.85, 95% CI 0.55-1.3). It is important to carefully evaluate untested health promotion interventions.", "The aim of this study was to evaluate the effectiveness of invitations for mammographic screening. Women aged 45 to 69 who had not attended for screening at the mobile Breast X-Ray Programme of the Central Sydney Area Health Service were randomly selected from the 1989 electoral listing. In the geographical area in which the study was conducted (Drummoyne local government area), 36 per cent of women had attended for screening before the intervention, indicating that the invitations were aimed at the reluctant participant. Women were randomly allocated to a control group who did not receive invitations (n = 80), and an intervention group who received letters from the Program inviting them to attend at a specified time (n = 163). Overall 33 per cent of women (53 of 163) who were sent invitations attended for screening compared to 9 per cent of those not invited (7 of 80) (P less than 0.001). Older women responded at least as well as younger women. In addition, the distribution of language spoken at home was similar for electoral listing attenders and the community as a whole, suggesting that this intervention works as well for women of English- and non-English-speaking backgrounds. The results suggest that the response to an invitation for screening from a source not personally known to women achieves comparable attendance to an invitation from their general practitioner, as assessed in a previous study.", "The purposes of the study were (1). to assess the cost-effectiveness of three interventions to deliver breast and cervical cancer screening to women unscreened for >or=3 years and (2). to determine the relation of an invasive cervical cancer diagnosis to the interval since the last true screening test.\n In a randomized trial, women were randomly assigned to (1). usual care, (2). letter plus follow-up letter, (3). letter plus follow-up phone call, (4). phone call plus follow-up phone call. Screening within 12 weeks was the outcome. A 5-year retrospective review of cervical cancer cases and screening histories was done.\n The 8% of women not screened for >or=5 years had 62% of the invasive cervical cancer cases. Mammography outreach led to screening in 10%, 24%, 51%, and 50% of controls, letter/letter, letter/phone, and phone/phone interventions groups, respectively. Cervical cancer screening outreach led to screening in 17%, 22%, 54%, and 50% of the respective groups. Letter reminders alone produced fewer tests at substantially higher costs than did personalized telephone notification.\n For cervical cancer, only 1 person in 12 was not screened in the preceding 5 years, but these accounted for nearly two thirds of invasive cancers. Aggressive outreach to the rarely screened is an important part of screening programs. Letter reminder, followed by a telephone appointment call, was the most cost-effective approach to screening rarely screened women. Lack of accurate information on prior hysterectomy adds substantial unnecessary costs to a screening reminder program.", "Barriers to screening and early detection often result in cancers in low-income and minority women diagnosed at stages too advanced for optimal treatment. This randomized controlled trial examined whether a personalized form (PF) letter containing generic cancer information and a personalized tailored (PT) letter containing minimally tailored individualized risk factor information based on medical records data affected breast and cervical cancer screening among 1574 urban low-income and minority women. The personalized form-letter group was significantly more likely to schedule a screening appointment and to have undergone a Pap test and mammography within 1 year after the intervention than were the tailored letter and control groups (P<0.001 for all comparisons). Personalized tailored letters that contain individualized cancer risk factor information may decrease the likelihood of receiving cancer screening among medically underserved low-income and minority women, but personalized form letters that contain generic cancer information may improve these rates in this disadvantaged population.", "To determine the effectiveness of a simple call/recall system in improving compliance with cervical cancer screening among women not screened in the previous 3 years.\n Prospective randomized controlled study.\n Two family medicine clinics (1 urban, 1 rural) affiliated with Memorial University of Newfoundland, St. John's.\n A sample of women aged 18-69 years who were listed as patients of the clinics but who had not had a Papanicolaou test (Pap test) within the 3 years before the start of the study. Of 9071 women listed as patients 1360 (15.0%) had not undergone screening in the previous 3 years. A random sample of 650 were selected, 209 of whom were excluded because they had had a hysterectomy, had had a recent Pap test, had moved or had records containing clerical errors. This left 441 women for the study.\n The 221 women in the intervention group were sent a letter asking them to seek a Pap test and a reminder letter 4 weeks later. The 220 in the control group were sent no letters.\n Number of women who had a Pap test within 2 months and 6 months after the first letter was sent.\n Within 2 months, more women in the intervention group than in the control group had been screened (2.8% [5/178] and 1.9% (4/208] respectively). There was also a difference between the overall proportions at 6 months (10.7% [19/178] and 6.3% [13/208] respectively). None of the differences was statistically significant.\n A letter of invitation is not sufficient to encourage women who have never or have infrequently undergone a Pap test to come in for cervical cancer screening. The effectiveness of added recruitment methods such as opportunistic screening by physicians, follow-up by telephone and the offer of a specific appointment should be evaluated.", "Evaluation of three potential methods for increasing Pap smear use: television media, television media combined with letter based recruitment, and television media combined with general practitioner based (GP based) recruitment.\n A trial of each intervention was carried out in three postal regions in New South Wales, Australia-a rural locality (containing about 1000 women), a country town (about 3000 women), and a major rural centre (about 10,000 women). Three control regions were selected to be demographically similar to the corresponding intervention regions.\n Outcome data on regional Pap smear rates were obtained from government health insurance claims for cervical screening, and from pathology service records. Expected Pap smear rates for the three months after the intervention were predicted from 45 pre-intervention months and were compared with observed rates for this period.\n Television media alone was associated with a significant increase in attendances for screening in one of the three regions where a trial was carried out: 13.3% in the rural centre. The media/letter based campaign was associated with a significant increase in attendances in two out of three regions: 52.7% in the rural locality, 43.2% in the rural centre. The media/GP based campaign was associated with significant increases in attendances in all three regions: 50.2% in the rural locality, 80.8% in the country town, 15.7% in the rural centre. All three interventions were associated with significant increases in the number of women attending for cervical screening above those observed in the control regions. Furthermore, these increases were not restricted to women at low risk. They were also found for older women (aged 50-69 years) and women who had not had a Pap smear within the past three years.", "A randomized trial was conducted to evaluate the combined impact of a physician reminder letter and a telephone contact on the use of Pap tests and mammograms in a low-income managed care program. Women 40 to 79 years of age who were past due for cancer screening were randomly assigned to an intervention or control group. Medical claims were reviewed after 6 months to determine intervention effectiveness. The odds of receiving all needed cancer screening tests during follow-up were four times higher in the intervention group. Women who reported having to take time off from work to see a doctor had lower odds of getting screened.", "To assess whether providing women with additional information on the pros and cons of screening, compared with information currently offered by the NHS, affects their intention to attend for screening.\n Randomised controlled trial. Participants were randomly assigned to receive either the control, (based on an NHS Cervical Screening Programme leaflet currently used), or the intervention leaflet (containing additional information on risks and uncertainties).\n Three general practices in Birmingham.\n 300 women aged 20 to 64 attending the practices during a one month period.\n Intention to attend for screening. Main results: 283 women (94.3%) completed the study. Fewer women in the intervention (79%) than the control group (88%) expressed intention to have screening after reading the information leaflet (difference between groups 9.2%, 95% confidence intervals (CI) 3.2% to 21.7%). The crude odds ratio (OR) and 95% CI was 0.50 (0.26 to 0.97). After adjusting for other factors, the trend persisted (OR 0.60, 95% CI 0.28 to 1.29). Having a previous Pap smear was the only significant predictor of intention to have screening (adjusted OR 2.54, 95% CI 1.03 to 6.21). Subgroup analysis showed no intervention effect in intended uptake between women at higher and lower risk of cervical cancer (p=0.59).\n Providing women with evidence based information on the risks, uncertainties, and the benefits of screening, is likely to deter some, but not differentially those at higher risk.", "Measures to increase attendance rate in cervical screening programmes have been suggested, but few have been evaluated in terms of value for money. The aim of this study was to describe the cost-effectiveness of a resource-intensive intervention to promote attendance at cervical screening among women with no registered cervical smear during the last 5 years. Among all 56 644 women (28-65 years) in Kalmar County, January 2004, a total of 6565 women had no registered cervical smear during the last 5 years. From this population, 400 women were randomly selected to a study group and another 400 women to a control group. The intervention was composed of a variety of efforts intended to promote attendance at cervical screening. We included, for example, all costs for identifying the women, sending out invitation letters, making phone calls and helping to make arrangements. Data on registered cervical smears at follow-up were collected from a data register within 1 year. In the study group, 118 women had a registered cervical smear compared with 74 in the control group (P=0.000). In the study group, the cost per cervical smear taken was 66.87 euro compared with 16.63 euro in the ordinary screening programme. The incremental cost per additional registered cervical smear was calculated at 151.36 euro in an area with high coverage, efforts to promote attendance at cervical screening were related to high costs per extra cervical smear gained and is not considered as reasonable from a cost-effectiveness perspective.", "To determine the effects of three different methods of providing health education on the uptake of cervical smear testing among Asian women, and to evaluate the acceptability of different health education materials.\n Prospective cohort study over one year of effects of written materials by post, personal visit to give written materials, and personal visit to show a video on the uptake of smear testing. Techniques included a personally administered questionnaire.\n Leicester, a city with a large Asian population.\n 737 randomly selected Asian women aged 18 to 52 who were not recorded on the central cytology laboratory's computer as ever having had a cervical smear test. 159 declined to participate or were not contactable.\n Women were randomised into four groups: visited and shown a video (263), visited and shown a leaflet and fact sheet (219), posted a leaflet and fact sheet (131), not contacted at all (124).\n Cervical smear test recorded on computer within four months after intervention.\n 57 (37%, 26% of group) of the women visited and given leaflets and 80 (47%, 30% of group) shown the video attended for cervical smears. Only six (5%) of those who were not contacted and 14 (11%) of those sent leaflets had a smear test during the study.\n Health education interventions increased the uptake of cervical cytology among Asian women in Leicester who had never been tested. Personal visits were most effective irrespective of the health education materials used, but there was some evidence that home viewed videos may be particularly effective in one of the most hard to reach groups: Urdu speaking, Pakistani Moslems. Written translated materials sent by post were ineffective.", "The aim of this study was to examine the effectiveness of general practitioner-written invitations to the Breast X-Ray Programme of the Central Sydney Area Health Service. Five out of six randomly selected general practices in Drummoyne participated. Within each practice, women aged 45 to 70 were individually randomised to receive or not receive a letter from their general practitioner (GP). Thirty-two per cent of women attended if invited compared to 7 per cent if they were not sent an invitation. An attendance of 38 per cent was obtained for women whose GP chose to send a letter with an appointment compared to 24 per cent for women whose GP chose to send a general invitation without an appointment. Combining all practices, women who consulted their GP within the previous 6 months were more likely to attend in response to the invitation (38 per cent) than women whose last consultation was more remote, dropping to 15 per cent in those who last attended that GP over 2 years earlier. Women aged 65 to 70 years old were at least as likely to respond to the invitation as women aged 45 to 64. Reminder letters were subsequently sent to a random half of nonrespondents who had attended the practice in the previous 12 months. A further 18 per cent of women attended after the reminder letter was sent (8/45), compared with 2 per cent in the control group (1/48). Twenty-seven per cent of women in Drummoyne had already attended for screening mammography before the trial.(ABSTRACT TRUNCATED AT 250 WORDS)", "To discover whether systematic methods of call and recall are more effective than a non-systematic method and to see which of the two systematic methods was more effective.\n Prospective randomised controlled trial over a year.\n One group general practice.\n 416 Women over 35 eligible for a smear test who had never had a cervical smear test or in whom a smear test was overdue (previous test more than five years before).\n One group received written invitations to have a smear taken. The second group had their notes tagged so that the doctor would remind them (when they attended for another reason) to have a smear test. No special intervention was made in the third group.\n Performance of a cervical smear test during the year of the study.\n 32% (45/140) of the screened group, 27% (39/142) of the tagged group, and 15% (20/134) of the control group had a smear test during the year. The percentage of women having a smear test in the screened group was not significantly different from that in the tagged group, but the percentages in the two groups were significantly different from that in the control group. Whether a woman had had a previous smear test significantly affected the uptake of the invitation to have a smear test independently of the method of invitation.\n The systematic methods of call and recall were more effective than a non-systematic method. There was no significant difference between the two systematic methods (sending letters or tagging the notes) at one year.", "We conducted a 4-year randomized study in a community health center that serves primarily low income Blacks in Durham, North Carolina. Patients (1318 at baseline) were assigned randomly to one of three study groups: provider prompting intervention alone, provider prompting and tailored print materials or the previous group and tailored telephone counseling. The purpose of the study was to determine whether increasingly intensive, tailored print and telephone interventions also were increasingly effective in promoting adherence to mammograms, Pap tests and overall cancer screening compliance. Thus, the combination of tailored print interventions (print and telephone) should have been more effective than the provider prompting intervention alone, or the print intervention and prompting combination. This is one of the few studies to examine a measure of overall cancer screening compliance and to assess the benefit of combinations of tailored interventions in promoting adherence to cancer screening. Patients gave extremely high ratings to the interventions. At the bivariate level, we found a significant effect of the most intensive group (provider prompting intervention, tailored print communications and tailored telephone counseling) on Pap test compliance (P = 0.05) and borderline significance at the multivariate level (P = 0.06) as well on overall screening compliance (P = 0.06). There was not a significant effect on mammography, probably because a majority of the patients were receiving regular mammograms. We also found some important subgroup differences. For example, a larger proportion of women reported Pap tests in the tailored print and counseling group when they believed the materials were 'meant for me.' These results show that a combination of tailored interventions may have potential for reaching the women who have too often been labeled the 'hard to reach.'", "Our objective was to evaluate the efficacy and acceptability of two interventions designed to increase opportunistic cervical cancer screening. We designed a randomized trial of two interventions additional to usual care. We recruited 17 male general practitioners selected at random from the inner metropolitan region of Sydney, Australia. The patients were 202 women, between 20 and 65 years of age, eligible for a Pap smear. We allocated minimal and maximal interactional interventions to obtain consent for a Pap smear. Our main outcome measure was women's having a Pap smear during the consultation or within one month. We also measured acceptability of interventions to practitioners and women. These were our results: minimal: 55% of women had a Pap smear; maximal: 67% of women had a Pap smear; total when both approaches are combined: 61%. We conclude that brief advice is as effective as maximal persuasion in increasing women's compliance with opportunistic screening in routine consultations. Both interventions were acceptable to women. Practitioners preferred the minimal intervention. We demonstrate opportunistic screening is an effective and acceptable way to encourage women at risk to have a Pap smear.", "To evaluate a direct mail-out campaign to increase Pap screening rates in women who have not had a test in 48 months.\n Ninety thousand under-screened women were randomised to be mailed a 48-month reminder letter to have a Pap test (n=60,000), or not to be mailed a letter (n=30,000). Differences in Pap test rates were assessed by Kaplan-Meier survival analysis, by chi2 tests of significance between Pap test rates in letter versus no-letter groups, and by proportional hazards regression modelling of predictors of a Pap test with letter versus no-letter as the main study variable. T-tests were conducted on mean time to Pap test to assess whether time to Pap test was significantly different between the intervention and control groups.\n After 90 days following each mail-out, Pap test rates in the letter group were significantly higher than in the non-letter group, by approximately two percentage points. After controlling for potential confounders, the hazard ratio of a Pap test within 90 days of a mail-out in the letter group was 1.5 compared with 1.0 in the no-letter group. Hazard ratios of having a Pap test within 90 days decreased significantly with time since last Pap test (p<0.0001); were significantly higher than 1.0 for most non-metropolitan areas of NSW compared with metropolitan areas; and increased significantly with age (p<0.0001). Pap test hazard ratios were not associated with socio-economic status of area of residence, but the hazard ratio was significantly higher than 1.0 if the reminder letter was sent after the Christmas/New Year break. No significant differences in mean time to Pap test were found between the letter and no-letter groups.\n Being sent a reminder letter is associated with higher Pap testing rates in under-screened women.", "To evaluate an innovative approach to continuing medical education, an outreach intervention designed to improve performance rates of breast cancer screening through implementation of office systems in community primary care practices.\n Randomized, controlled trial with primary care practices assigned to either the intervention group or control group, with the practice as the unit of analysis.\n Twenty mostly rural counties in North Carolina.\n Physicians and staff of 62 randomly selected family medicine and general internal medicine practices, primarily fee-for-service, half group practices and half solo practitioners.\n Physician investigators and facilitators met with practice physicians and staff over a period of 12 to 18 months to provide feedback on breast cancer screening performance, and to assist these primary care practices in developing office systems tailored to increase breast cancer screening.\n Physician questionnaires were obtained at baseline and follow-up to assess the presence of five indicators of an office system. Three of the five indicators of office systems increased significantly more in intervention practices than in control practices, but the mean number of indicators in intervention practices at followup was only 2.8 out of 5. Cross-sectional reviews of randomly chosen medical records of eligible women patients aged 50 years and over were done at baseline (n = 2,887) and follow-up (n = 2,874) to determine whether clinical breast examinations and mammography, were performed. Results for mammography were recorded in two ways, mention of the test in the visit note and actual report of the test in the medical record. These reviews showed an increase from 39% to 51% in mention of mammography in intervention practices, compared with an increase from 41% to 44% in control practices (p = .01). There was no significant difference, however, between the two groups in change in mammograms reported (intervention group increased from 28% to 32.7%; control group increased from 30.6% to 34.0%, p = .56). There was a nonsignificant trend (p = .06) toward a greater increase in performance of clinical breast examination in intervention versus control practices.\n A moderately intensive outreach intervention to increase rates of breast cancer screening through the development of office systems was modestly successful in increasing indicators of office systems and in documenting mention of mammography, but had little impact on actual performance of breast cancer screening. At follow-up, few practices had a complete office system for breast cancer screening. Outreach approaches to assist primary care practices implement office systems are promising but need further development.", "The aim was to determine what effect the offer of a cervical smear test when attending for breast screening has on the uptake of cervical and breast screening.\n The study involved randomisation to compare uptake in those women invited for cervical screening in advance with their breast screening invitation (group 1) with those invited for breast screening only and then offered a smear test upon arrival for breast screening (group 2). The main outcome measure was improvement in the uptake of cervical screening among older women without detriment to the breast screening service.\n The study took place at the Northern Hospital in North Manchester.\n Participants were 2131 women aged 50-64 years invited for breast screening at the Northern Hospital in the summer of 1990.\n Overall, 54% of the women who were eligible attended for breast screening, 52% attended from group 1 and 55% from group 2. Of those attending for breast screening, 957 were eligible for cervical screening and 193 (20%) had a smear test. There was a difference in the proportion tested from each group (p < 0.001), 28% had a smear test from group 1 and 13% from group 2. Forty five percent of the 193 had not had a cervical smear for at least five years.\n The cervical screening facility did attract some women who were overdue for a smear test and who might not normally have attended for cervical screening, and there was no evidence to suggest that it had a detrimental effect on the breast screening uptake. An advanced cervical screening invitation seemed preferable to an invitation upon arrival at the breast screening unit.", "Recent increases in mammography use have led to a decrease in mortality from breast cancer.\n Building on the Health Belief Model, the Transtheoretical Model, and past effectiveness of tailored interventions, we conducted a prospective randomized trial (n = 773) to test the efficacy on mammography adherence of tailored interventions delivered by five different methods, i.e., telephone counseling, in-person counseling, physician letter, and combinations of telephone with letter and in-person with letter.\n All five interventions increased mammography adherence significantly relative to usual care (odds ratios, 1.93 to 3.55) at 6 months post intervention. The combination of in-person with physician letter was significantly more effective than telephone alone or letter alone. Women thinking about getting a mammogram at baseline were more likely to be adherent by 6 months; even those in usual care achieved 48% adherence compared with 50-70% in the intervention groups. In contrast, women not thinking about getting a mammogram needed the interventions to increase their adherence from 13% to over 30%.\n All five interventions were effective at increasing mammography adherence. Women not thinking about getting a mammogram were most likely to benefit from these tailored interventions while other women might need less intensive interventions.", "Although the rising incidence of breast cancer has prompted a surge of intervention strategies aimed at increasing women's use of mammography screening, the majority of patient-directed interventions have not been driven by relevant theoretical work on persuasive health communication. The authors evaluated an intervention derived from prospect theory that was designed to increase women's adherence to recommendations for annual mammography screening. They sent 1 of 3 reminder letters (positive frame, negative frame, or standard hospital prompt) to 929 randomly selected women who were due for mammography screening and had been identified as having either a positive or negative family history of breast cancer. The primary hypothesis that women with a positive history would be more responsive to negatively framed messages, whereas women with a negative history would be more responsive to positively framed letters, was not confirmed. The lack of support for predictions derived from prospect theory raises important questions about the generalizability of laboratory research to natural settings.", "First-degree relatives (FDRs) of people diagnosed with colorectal cancer (CRC) have a two- to threefold increased risk of developing the same disease. Tailored print interventions based on behavior change theories have demonstrated considerable promise in facilitating health-promoting behaviors. This study compared the impact of two mailed print interventions on CRC screening outcomes among FDRs.\n This randomized trial compared effects of two mailed print interventions--one tailored and one nontailored--on participation in CRC screening among FDRs of CRC survivors. Data collected via phone interviews from 140 FDRs at baseline, 1 week post-intervention, and 3 months post-intervention.\n At 3 months, both the tailored and nontailored interventions yielded modest but statistically insignificant increases in adherence to any CRC screening test (14% vs. 21%, respectively; p=0.30). While there were no main effects for tailored versus nontailored interventions, there were significant interactions that showed that the tailored print intervention had significantly greater effects on forward stage movement for CRC screening depending on stage of adoption at baseline, race, and objective CRC risk. Receipt of the tailored intervention was 2.5 times more likely to move baseline precontemplators and contemplators forward in stage of adoption for colonoscopy (95% CI: 1.10-5.68) and was three times more likely to move Caucasians forward in stage of adoption for FOBT (95% CI: 1.00-9.07). In addition, the tailored intervention was 7.7 times more likely to move people at average risk forward in stage of adoption for colonoscopy (95% CI: 1.25-47.75).\n The tailored print intervention was more effective at moving Caucasians, those in precontemplation and contemplation at baseline, and those at average risk forward in their stage of adoption for CRC screening.\n Both tailored and nontailored print interventions showed moderate effects for increasing CRC screening participation. Tailored print interventions may be more effective for certain subgroups.", "To determine whether a two hour training programme for general practice reception staff could improve uptake in patients who had failed to attend for breast screening, and whether women from different ethnic groups benefited equally.\n Controlled trial, randomised by general practice.\n Inner London borough of Newham.\n 2064 women aged 50-64 years who had failed to attend for breast screening. Women came from 26 of 37 eligible practices, 31% were white, 17% were Indian, 10% Pakistani, 14% black, 6% Bangladeshi, 1% Chinese, 4% were from other ethnic groups, and in 16% the ethnic group was not reported.\n Attendance for breast screening in relation to ethnic group in women who had not taken up their original invitation.\n Attendance in the intervention group was significantly better than in the control group (9% v 4%). The response was best in Indian women--it was 19% in the intervention group and 5% in the control group.\n This simple, low cost intervention improved breast screening rates modestly. Improvement was greatest in Indian women--probably because many practice staff shared their cultural and linguistic background. This intervention could be effective as part of a multifaceted strategy to improve uptake in areas with low rates.", "This article reports findings from a peer-delivered intervention designed to increase use of breast and cervical cancer screening.\n Twenty-six worksites were randomly assigned to the intervention or comparison group. The 16-month intervention consisted of group discussions, outreach, and educational campaigns. Data were collected from a random sample of women employees stratified by age (baseline n = 2943; final n = 2747). Cross-sectional analyses were conducted to evaluate the impact of the intervention on screening behaviors.\n Relative to comparison worksites, the intervention group experienced greater increases in the percentage of women who reported a recent mammogram (7.2% vs 5.6%), clinical breast examination (5.8% vs 2.1%), and Papanicolaou (Pap) test (4.7% vs 1.9%). After worksite cluster and age strata were controlled for, the observed increase in Pap tests was significantly greater in the intervention group (odds ratio [OR] = 1.28; 95% confidence interval [CI] = 1.01, 1.62); however, differences in mammography screening rates (OR = 1.14; 95% CI = 0.90, 1.44) and clinical breast examination (OR = 1.19; 95% CI = 0.96, 1.49) were not statistically significant.\n Intervention activities produced a modest increase in cervical cancer screening, but they did not accelerate breast cancer screening rates above the observed secular trend.", "In a randomized controlled trial three methods of feedback of increasing intensity, directed at 183 doctors taking cervical smears, were compared with respect to their effects on the sampling quality of smears. Overall, feedback was found to have no influence on quality criteria in the crude data analysis. However, a significantly larger decrease in the percentage of smears lacking endocervical cells was found in the groups receiving monthly overviews of their results with peer comparison, when compared with the groups not receiving this type of feedback (odds ratio 0.75). Moreover, feedback appeared to have a clear effect on the presence of endocervical cells among doctors submitting a substantial number of smears in the intervention period, as opposed to those who submitted fewer smears. A positive correlation was also observed between the increase in the group mean of the proportions of smears containing pathological cells and the intensity of the feedback. However, this increase did not reach statistical significance. This study suggests that monthly feedback with peer comparison may have a positive relationship with some aspects of quality improvement in cervical screening.", "We sought to promote cervical cancer screening among Vietnamese American women in Santa Clara County, Calif.\n In 2001-2004, we recruited and randomized 1005 Vietnamese American women into 2 groups: lay health worker outreach plus media-based education (combined intervention) or media-based education only. Lay health workers met with the combined intervention group twice over 3 to 4 months to promote Papanicolaou (Pap) testing. We used questionnaires to measure changes in awareness, knowledge, and Pap testing.\n Testing increased among women in both the combined intervention (65.8% to 81.8%; P<.001) and media-only (70.1% to 75.5%; P<.001) groups, but significantly more in the combined intervention group (P=.001). Among women never previously screened, significantly more women in the combined intervention group (46.0%) than in the media-only group (27.1%) obtained tests (P<.001). Significantly more women in the combined intervention group obtained their first Pap test or obtained one after an interval of more than 1 year (became up-to-date; 45.7% to 67.3%, respectively; P<.001) than did those in the media-only group (50.9% to 55.7%, respectively; P=.035).\n Combined intervention motivated more Vietnamese American women to obtain their first Pap tests and to become up-to-date than did media education alone.", "Computers that collect data from patients and provide both patients and practitioners with printed feedback on a range of health risks are a tool for assisting general practitioners with preventive care. This study assessed the impact of computer-generated printed feedback on cervical screening among women who were underscreened for cervical cancer.\n Female attenders at two Australian general practices were randomly allocated to Experimental or Control groups. Women in both groups completed a health risk survey on a touch screen computer prior to their consultation. Those in the Experimental group received printed pages summarizing their results, including their eligibility for cervical screening and last Pap test, for themselves and their doctor. The number and proportion of underscreened women who had a Pap test in the 6 months after completing the computer survey, as determined by pathology records, were examined.\n Of the 679 participants, 139 were classified as underscreened on the basis of self-report (74 Experimental, 65 Control) and 272 on the basis of their pathology records (148 Experimental, 124 Control). Overall about one-third of women had a test in the 6-month period, and the differences between the groups were not significant for women overall (18-70 years) or for women 18-49 years. Among women 50-70 who were underscreened based on self-report, those receiving the printout were more likely to have a Pap test in the next 6 months (P < 0.05). This pattern was also evident, but did not reach statistical significance, for older women who were underscreened based on pathology records.\n We are unable to draw conclusions regarding the effectiveness of the computer system due to the modest proportions of women screened, the small numbers, and the fact that the computer survey may have created an intervention effect in the Control group. As the study suggests the computer system is acceptable to women and may be effective for encouraging screening among older women, further exploration of the system is desirable.", "It is important that response rates to postal surveys are as high as possible to ensure that the results are representative and to maximise statistical power. Previous research has suggested that any personalisation of approach helps to improve the response rate. This experiment tested whether personalising questionnaires by hand signing the covering letter improved the response rate compared with a non-personalised group where the investigator's signature on the covering letter was scanned into the document and printed.\n Randomised controlled trial. Questionnaires about surgical techniques of caesarean section were mailed to 3,799 Members and Fellows of the Royal College of Obstetricians and Gynaecologists resident in the UK. Individuals were randomly allocated to receive a covering letter with either a computer printed signature or a hand written signature. Two reminders were sent to non-respondents. The outcome measures were the proportion of questionnaires returned and their time to return.\n The response rate was 79.1% (1506/1905) in the hand-signed group and 78.4% (1484/1894) in the scanned and printed signature group. There was no detectable difference between the groups in response rate or time taken to respond.\n No advantage was detected to hand signing the covering letter accompanying a postal questionnaire to health professionals." ]	There is evidence to support the use of invitation letters to increase the uptake of cervical screening. There is limited evidence to support educational interventions but it is unclear what format is most effective. The majority of the studies are from developed countries and so the relevance to developing countries is unclear.
CD008225	[ "17076751", "8847377", "19794200", "12456542", "11473908", "2504794", "19076262", "14560166", "18244958", "17350966" ]	[ "Randomised controlled trial of a parenting intervention in the voluntary sector for reducing child conduct problems: outcomes and mechanisms of change.", "Large group community-based parenting programs for families of preschoolers at risk for disruptive behaviour disorders: utilization, cost effectiveness, and outcome.", "Long-term effectiveness of a parenting intervention for children at risk of developing conduct disorder.", "Improving mental health through parenting programmes: block randomised controlled trial.", "Multicentre controlled trial of parenting groups for childhood antisocial behaviour in clinical practice.", "The long-term effectiveness and clinical significance of three cost-effective training programs for families with conduct-problem children.", "Immediate and short-term outcomes of the 'COPEing with Toddler Behaviour' parent group.", "Brief psychoeducational parenting program: an evaluation and 1-year follow-up.", "Universal parenting programme to prevent early childhood behavioural problems: cluster randomised trial.", "Parenting intervention in Sure Start services for children at risk of developing conduct disorder: pragmatic randomised controlled trial." ]	[ "To test effectiveness of a parenting intervention, delivered in a community-based voluntary-sector organisation, for reducing conduct problems in clinically-referred children.\n Randomised controlled trial, follow-up at 6, 18 months, assessors blind to treatment status. Participants--76 children referred for conduct problems, aged 2-9, primarily low-income families, randomised to treatment vs. 6-month wait-list group. Retention was 93% at 6 months, 90% at 18 months. Interventions--Webster-Stratton Incredible Years video-based 14-week group programme, teaches cognitive-behavioural principles for managing behaviour, using a collaborative, practical, problem-solving approach. Primary outcomes--child problem behaviour by parent-report (Eyberg) and home-based direct observation; secondary outcomes--observed positive and negative parenting; parent-reported parenting skill, confidence and depression.\n Post-treatment improvements were found in child problem behaviour, by parent-report (effect size (ES) .48, p = .05) and direct observation (ES .78, p = .02); child independent play (ES .77, p = .003); observed negative (ES .74, p = .003) and positive (ES .38, p = .04) parenting; parent-reported confidence (ES .40, p = .03) and skill (ES .65, p =.01), using ANCOVA to control for baseline scores. Maternal depression did not change. Consumer satisfaction was high. At 18-month follow-up, although no randomised comparison was possible, changes appeared to maintain, with no significant change toward baseline level on any measure. Change in observed positive parenting appeared to mediate change in child problem behaviour (p < .025).\n Findings suggest that a group-based cognitive-behavioural parenting programme, delivered by well-trained and supervised staff, can be effective in a community voluntary-sector setting, for reducing conduct problems and enhancing parenting skills. Change in parenting skill appears to be a key mechanism for change in child behaviour. Findings have implications for feasibility of translating evidence-based programmes, even for clinically-referred conduct problems, into less specialised community settings, likely to have lower costs and be more accessible for families.", "A significant percentage of children with disruptive behavior disorders do not receive mental health assistance. Utilization is lowest among groups whose children are at greatest risk. To increase the availability, accessibility, and cost efficacy of parent training programs, this prospective randomized trial compared a large group community-based parent training program to a clinic-based individual parent training (PT) programs. All families of junior kindergartners in the Hamilton public and separate school boards were sent a checklist regarding problems at home. Those returning questionnaires above the 90th percentile were block randomly assigned to: (1) a 12-week clinic-based individual parent training (Clinic/Individual), (2) a 12-week community-based large group parent training (Community/Group), or (3) a waiting list control condition. Immigrant families, those using English as a second language, and parents of children with severe behaviour problems were significantly more likely to enroll in Community/Groups than Clinic/Individual PT. Parents in Community/Groups reported greater improvements in behaviour problems at home and better maintenance of these gains at 6-month follow-up. A cost analysis showed that, with groups of 18 families, Community/Groups are more than six times as cost effective as Clinic/Individual programs.", "The typical pattern for intervention outcome studies for conduct problems has been for effect sizes to dissipate over time with decreasing effects across subsequent follow-ups.\n To establish whether the short-term positive effects of a parenting programme are sustained longer term. To observe trends, and costs, in health and social service use after intervention.\n Parents with children aged 36-59 months at risk of developing conduct disorder (n = 104) received intervention between baseline and first follow-up (6 months after baseline n = 86) in 11 Sure Start areas in North Wales. Follow-ups two (n = 82) and three (n = 79) occurred 12 and 18 months after baseline. Child problem behaviour and parenting skills were assessed via parent self-report and direct observation in the home.\n The significant parent-reported improvements in primary measures of child behaviour, parent behaviour, parental stress and depression gained at follow-up one were maintained to follow-up three, as were improved observed child and parent behaviours. Overall, 63% of children made a minimum significant change (0.3 standard deviations) on the Eyberg Child Behavior Inventory problem scale between baseline and follow-up (using intention-to-treat data), 54% made a large change (0.8 standard deviations) and 39% made a very large change (1.5 standard deviations). Child contact with health and social services had reduced at follow-up three.\n Early parent-based intervention reduced child antisocial behaviour and benefits were maintained, with reduced reliance on health and social service provision, over time.", "To assess the effectiveness of a parenting programme, delivered by health visitors in primary care, in improving the mental health of children and their parents among a representative general practice population.\n Parents of children aged 2-8 years who scored in the upper 50% on a behaviour inventory were randomised to the Webster-Stratton 10 week parenting programme delivered by trained health visitors, or no intervention. Main outcome measures were the Eyberg Child Behaviour Inventory and the Goodman Strengths and Difficulties Questionnaire to measure child behaviour, and the General Health Questionnaire, Abidin's Parenting Stress Index, and Rosenberg's Self Esteem Scale to measure parents' mental health. These outcomes were measured before and immediately after the intervention, and at six months follow up.\n The intervention was more effective at improving some aspects of the children's mental health, notably conduct problems, than the no intervention control condition. The Goodman conduct problem score was reduced at immediate and six month follow up, and the Eyberg Child Behaviour Inventory was reduced at six months. The intervention also had a short term impact on social dysfunction among parents. These benefits were seen among families with children scoring in the clinical range for behaviour problems and also among children scoring in the non-clinical (normal) range.\n This intervention could make a useful contribution to the prevention of child behaviour problems and to mental health promotion in primary care.", "To see whether a behaviourally based group parenting programme, delivered in regular clinical practice, is an effective treatment for antisocial behaviour in children.\n Controlled trial with permuted block design with allocation by date of referral.\n Four local child and adolescent mental health services.\n 141 children aged 3-8 years referred with antisocial behaviour and allocated to parenting groups (90) or waiting list control (51).\n Webster-Stratton basic videotape programme administered to parents of six to eight children over 13-16 weeks. This programme emphasises engagement with parental emotions, rehearsal of behavioural strategies, and parental understanding of its scientific rationale.\n Semistructured parent interview and questionnaires about antisocial behaviour in children administered 5-7 months after entering trial; direct observation of parent-child interaction.\n Referred children were highly antisocial (above the 97th centile on interview measure). Children in the intervention group showed a large reduction in antisocial behaviour; those in the waiting list group did not change (effect size between groups 1.06 SD (95% confidence interval 0.71 to 1.41), P<0.001). Parents in the intervention group increased the proportion of praise to ineffective commands they gave their children threefold, while control parents reduced it by a third (effect size between groups 0.76 (0.16 to 1.36), P=0.018). If the 31 children lost to follow up were included in an intention to treat analysis the effect size on antisocial behaviour was reduced by 16%.\n Parenting groups effectively reduce serious antisocial behaviour in children in real life conditions. Follow up is needed to see if the children's poor prognosis is improved and criminality prevented.", "We evaluated the long-term effectiveness of three cost-effective parent training programs for conduct-problem children. One year posttreatment, 93.1% of families (94 mothers and 60 fathers) were assessed on the basis of teacher and parent reports and home observations. Results indicated that all the significant improvement reported immediately posttreatment were maintained one year later. Moreover, approximately two thirds of the entire sample showed \"clinically significant\" improvements. There were very few differences between the three treatment conditions except for the \"consumer satisfaction\" measure indicating that the treatment combining group discussion and video-tape modeling was superior to treatments without both components.", "Controlling, uninvolved, and rejecting parenting in early childhood are strong predictors of later disruptive behavior disorders. However, there have been no evaluations of non-targeted groups for parents of very young children, despite their potential advantages.\n We randomly assigned 79 mothers of 12- to 36-month-olds to an 8-session parent training program (called 'COPEing with Toddler Behaviour') or to a waiting list control condition. We investigated the immediate and short-term impact on parent-reported child behavior problems, observed parent-child interaction, and self-reported parenting behavior and parent functioning.\n In an intent-to-treat design, the program yielded significant effects on child behavior problems, positive parent-child interaction, and parental overreactivity and depression but not observed negative child behavior or parental laxness. Most effects were significant at both post-test and 1-month follow-up and effects sizes were small to medium for the intervention group and inverse to small for the control group.\n The potential of the program to prevent later behavior problems is supported by improvements in six of the eight outcomes. As part of a community strategy, groups such as COPEing with Toddler Behaviour may promote positive parent-child interaction and children's mental health.", "Despite recognition of the need for parenting interventions to prevent childhood behavioral problems, few community programs have been evaluated. This report describes the randomized controlled evaluation of a four-session psychoeducational group for parents of preschoolers with behavior problems, delivered in community agencies.\n In 1998, 222 primary caregivers, recruited through community ads, filled out questionnaires on parenting practices and child behavior. Parents were randomly assigned to immediate intervention or a wait-list control. The intervention comprised three weekly group sessions and a 1-month booster, the focus being to support effective discipline (using the video 1-2-3 Magic) and to reduce parent-child conflict.\n Using an intent-to-treat analysis, repeated-measures analyses of variance indicated that the parents who received the intervention reported significantly greater improvement in parenting practices and a significantly greater reduction in child problem behavior than the control group. The gains in positive parenting behaviors were maintained at 1-year follow-up in a subset of the experimental group.\n This brief intervention program may be a useful first intervention for parents of young children with behavior problems, as it seems both acceptable and reasonably effective.", "To determine whether a parenting programme, offered universally in primary care, can prevent behavioural problems in children and improve parenting and maternal mental health.\n Cluster randomised trial.\n 40 primary care nursing centres (clusters) in Victoria, Australia.\n 733 English speaking mothers of 8 month old children sequentially recruited from well child appointments; 656 retained at 24 months.\n Structured three session programme at age 8-15 months, co-led by well child providers and a parenting expert. The programme covered normal development and behaviour, strategies to increase desired behaviour, and strategies to reduce unwanted behaviour.\n Maternal report of child externalising behaviour (child behavior checklist 1(1/2)-5 year old), parenting (parent behavior checklist), and maternal mental health (depression anxiety stress scales) at 18 and 24 months.\n At 18 months, child behaviour and parenting scores were similar in the two groups. At 24 months, externalising scores in the intervention and control groups were similar (mean 11.9 (SD 7.2) v 12.9 (7.4)); however, on the parent behavior checklist subscale scores, intervention group parents were less likely to report harsh/abusive parenting (mean 38.9 (SD 7.7) v 40.5 (8.8); adjusted mean difference -1.83, 95% confidence interval -3.12 to -0.55) and unreasonable expectations of child development (40.9 (9.9) v 42.7 (9.6); -2.18, -3.74 to -0.62). Mean scores for nurturing parenting and maternal mental health were similar in the two groups at both times.\n A universal parenting programme resulted in modest improvement in parenting factors that predict behavioural problems in children but did not reduce externalising behavioural problems or affect maternal mental health at 2 years. Trial registration ISRCTN 77531789.", "To evaluate the effectiveness of a parenting programme as a preventive intervention with parents of preschool children considered to be at risk of developing conduct disorder.\n Pragmatic randomised controlled trial using a block design with allocation by area.\n Eleven Sure Start areas in north and mid-Wales.\n 153 parents from socially disadvantaged areas, with children aged 36-59 months at risk of conduct disorder defined by scoring over the clinical cut off on the Eyberg child behaviour inventory. Participants were randomised on a 2:1 basis, 104 to intervention and 49 to remaining on the wait listing (control). Twenty (13%) were lost to follow-up six months later, 18 from the intervention group.\n The Webster-Stratton Incredible Years basic parenting programme, a 12 week group based intervention.\n Problem behaviour in children and parenting skills assessed by self reports from parents and by direct observation in the home. Parents' self reported parenting competence, stress, and depression. Standardised and well validated instruments were used throughout.\n At follow-up, most of the measures of parenting and problem behaviour in children showed significant improvement in the intervention group. The intention to treat analysis for the primary outcome measure, the Eyberg child behaviour inventory, showed a mean difference between groups of 4.4 points (95% confidence interval 2.0 to 6.9, P<0.001) on the problem scale with an effect size of 0.63, and a mean difference of 25.1 (14.9 to 35.2, P<0.001) on the intensity scale with an effect size of 0.89.\n This community based study showed the effectiveness of an evidence based parenting intervention delivered with fidelity by regular Sure Start staff. It has influenced policy within Wales and provides lessons for England where, to date, Sure Start programmes have not been effective.\n ISRCTN46984318." ]	Behavioural and cognitive-behavioural group-based parenting interventions are effective and cost-effective for improving child conduct problems, parental mental health and parenting skills in the short term. The cost of programme delivery was modest when compared with the long-term health, social, educational and legal costs associated with childhood conduct problems. Further research is needed on the long-term assessment of outcomes.
CD007687	[ "19389793", "10966997", "17138770" ]	[ "Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial.", "Once a month administration of mifepristone improves bleeding patterns in women using subdermal contraceptive implants releasing levonorgestrel.", "Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial." ]	[ "Uterine leiomyomas are widely prevalent and frequently cause menorrhagia. The major therapeutic option today is hysterectomy. Medical options are of highest interest.\n A total of 30 women with uterine leiomyomas scheduled for surgical intervention were randomized to receive either 50 mg mifepristone or placebo every other day during 3 months prior to surgery. Uterine blood flow and leiomyoma volume were evaluated once a month until surgery. Endometrial biopsies were obtained prior to and at end of treatment. Relevant biochemistry, symptoms and bleeding were recorded. Primary outcome was reduction in uterine leiomyoma size.\n There was a significant percentual decrease (P = 0.021) in the total leiomyoma volume in the mifepristone-treated group, -28 (-48, -8) % (mean +/- 0, 95 confidence interval), compared with the control group values 6 (-13, 25) %. Mifepristone treatment significantly reduced the bleeding days (P = 0.001) and increased serum haemoglobin values (P = 0.046). Serum cortisol levels remained unchanged, while a mild increase in serum androgens was noted. Endometrial biopsies showed no premalignant changes or changes in mitotic indices.\n Mifepristone may offer an effective treatment option for women with uterine leiomyoma and the associated pronounced uterovaginal bleeding. Clinical Trials identifier: www.clinicaltrials.gov: NCT00579475.", "It has been suggested that the administration of an anti-progesterone might improve bleeding patterns in women with irregular bleeding while using low-dose progestin-only contraception. We report the findings of a double-blind, randomized, placebo-controlled trial of mifepristone 50 mg taken once every 4 weeks in 100 Chinese women (50 subjects and 50 controls) complaining of frequent and irregular bleeding while using a levonorgestrel-releasing subdermal contraceptive implant. In all women, regardless of treatment, the frequency of bleeding decreased significantly over 360 days of observation. Women recorded significantly shorter episodes of bleeding (P: < 0.0002) during mifepristone treatment than during the 90 days before treatment started. In contrast, the duration of bleeding episodes fell more gradually in placebo-treated controls. Women using mifepristone were more likely to find treatment acceptable than women receiving a placebo tablet (P: < 0.01). Despite concern that anti-progestogenic effects may jeopardize contraception, there were no pregnancies. This approach may offer a useful strategy to improve continuation rates by alleviating unwanted side-effects until bleeding patterns improve spontaneously with time.", "To assess the effect of low-dose mifepristone on quality of life, pain, bleeding, and uterine size among women with symptomatic leiomyomata.\n Forty-two women with symptomatic uterine leiomyomata and uterine volume of 160 mL or more were randomized to mifepristone, 5 mg daily, or placebo for 26 weeks. Quality of life (Uterine Fibroid Symptoms Quality of Life Questionnaire and Medical Outcomes Study 36-Item Short Form survey) and uterine and leiomyoma size (ultrasonography) were assessed at baseline, and at 1 month, 3 months, and 6 months of treatment. Bleeding (daily logs and pictorial charts) and pain (McGill Pain Questionnaire) were assessed monthly. Endometrial pathology was assessed at baseline and 6 months.\n Forty-two women were randomized; 37 women completed all 6 months. Women randomized to mifepristone showed an improvement in leiomyoma-specific quality of life. Forty-one percent became amenorrheic, rates of anemia improved, and adjusted uterine size was reduced by 47%. Compared with the placebo group, improvements in these outcomes in the treatment group were significantly greater (P<.05 to .001). There were no significant differences in adverse effects between the groups. No endometrial hyperplasia was noted in any participant.\n Low-dose mifepristone improves leiomyoma-specific quality of life and reduces leiomyoma size among women with symptomatic leiomyomata.\n ClinicalTrials.gov www.clinicaltrials.gov NCT00133705\n I." ]	Mifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.
CD006585	[ "11493843", "22151496", "15048740" ]	[ "A randomized controlled trial to prevent patient lift and transfer injuries of health care workers.", "A pilot study to investigate the effects of electrical stimulation on recovery of hand function and sensation in subacute stroke patients.", "Randomized clinical trial of hand-assisted laparoscopic versus open Roux-en-Y gastric bypass for the treatment of morbid obesity." ]	[ "Randomized controlled trial (RCT).\n To compare the effectiveness of training and equipment to reduce musculoskeletal injuries, increase comfort, and reduce physical demands on staff performing patient lifts and transfers at a large acute care hospital.\n Back injury to nursing staff during patient handling tasks is a major issue in health care. The value of mechanical assistive devices in reducing injuries to these workers is unclear.\n This three-armed RCT consisted of a \"control arm,\" a \"safe lifting\" arm, and a \"no strenuous lifting\" arm. A medical, surgical, and rehabilitation ward were each randomly assigned to each arm. Both intervention arms received intensive training in back care, patient assessment, and handling techniques. Hence, the \"safe lifting\" arm used improved patient handling techniques using manual equipment, whereas the \"no strenuous lifting\" arm aimed to eliminate manual patient handling through use of additional mechanical and other assistive equipment.\n Frequency of manual patient handling tasks was significantly decreased on the \"no strenuous lifting\" arm. Self-perceived work fatigue, back and shoulder pain, safety, and frequency and intensity of physical discomfort associated with patient handling tasks were improved on both intervention arms, but staff on the mechanical equipment arm showed greater improvements. Musculoskeletal injury rates were not significantly altered.\n The \"no strenuous lifting\" program, which combined training with assured availability of mechanical and other assistive patient handling equipment, most effectively improved comfort with patient handling, decreased staff fatigue, and decreased physical demands. The fact that injury rates were not statistically significantly reduced may reflect the less sensitive nature of this indicator compared with the subjective indicators.", "Objectives. 1) To compare the effect of cyclic neuromuscular electrical stimulation (NMES) of the forearm and elbow extensor muscles with passive stretching exercises on hand function and sensation following stroke. 2) To inform sample size for a larger randomized controlled trial (RCT). Materials and Methods. Twenty-two subjects with hemiplegia resulting from a stroke during the previous 12 months were randomly allocated into stimulation (treatment) and exercise (control) groups. Stimulation was applied to the elbow, and forearm extensor muscle groups of the hemiplegic arm for 12 weeks. Subjects in the control group were taught passive stretching exercises for the same period. The primary outcome measure was the Action Research Arm test (ARAT). Sensation was tested using two-point discrimination. Statistical analysis applied nonparametric analysis of covariance (ancova). Results. Statistically significant between-group differences in change in ARAT scores were shown between the two groups after 12 weeks of treatment (p = 0.003) and following 12 further weeks without intervention (p = 0.012). There were no significant differences in sensation. Conclusions. 1) A significant treatment effect of electrical stimulation over passive exercise has been demonstrated in a group of 22 subacute stroke patients, randomized into two equal groups and further work identified which may help to improve recovery of hand function and sensation following stroke. 2) A sample size of 24 subjects in each group has been estimated assuming a two-sided test significance level of 5% with 80% power, primary outcome variability SD = 6.75, a minimum difference of ten ARAT score units, and a 10% dropout rate.", ": Roux-en-Y gastric bypass (RYGBP) has increased in popularity since the introduction of the laparoscopic procedure, but this approach requires extensive surgical skill and the learning curve is steep. The present study examined the suitability of hand-assisted laparoscopy for RYGBP.\n In a prospective trial, 50 patients (median age 38 years, body mass index 45 kg/m(2)) were randomized to either hand-assisted (n = 25) or open (n = 25) RYGBP. The hand-assisted device was introduced through a right subcostal incision. Laparoscopic staplers were also used in the open group, allowing a short upper midline incision. The gastrojejunostomy was made by means of a circular stapler and the Roux limb placed behind the colon and excluded stomach.\n The postoperative outcome, with respect to morphine consumption, complications, hospital stay (6 days) and weight loss, was similar in the two groups. The operating time was significantly longer in the hand-assisted group (150 versus 85 min; P < 0.001) but there was no conversion to open operation. One patient in the hand-assisted group was reoperated owing to leakage and one patient developed an incisional hernia after open RYGBP.\n The hand-assisted technique was feasible and allowed good working conditions in all patients. However, the postoperative outcome was excellent in both groups and there was no advantage to the hand-assisted technique.\n Copyright 2004 British Journal of Surgery Society Ltd." ]	Despite the limited number of trials performed, meta-analysis demonstrated a statistically significant decrease in conversion rates among the hand assisted group. There was no difference in operating time or perioperative complication rates. Additional adequately powered and methodologically sound trials are needed to determine if there is a clinically important difference in perioperative outcomes. Due to significant costs associated with the use of hand-assist devices, economic analyses are also warranted.
CD007219	[ "10362181" ]	[ "The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes." ]	[ "The purpose of this study was to assess safety and efficacy of enhanced external counterpulsation (EECP).\n Case series have shown that EECP can improve exercise tolerance, symptoms and myocardial perfusion in stable angina pectoris.\n A multicenter, prospective, randomized, blinded, controlled trial was conducted in seven university hospitals in 139 outpatients with angina, documented coronary artery disease (CAD) and positive exercise treadmill test. Patients were given 35 h of active counterpulsation (active CP) or inactive counterpulsation (inactive CP) over a four- to seven-week period. Outcome measures were exercise duration and time to > or =1-mm ST-segment depression, average daily anginal attack count and nitroglycerin usage.\n Exercise duration increased in both groups, but the between-group difference was not significant (p > 0.3). Time to > or =1-mm ST-segment depression increased significantly from baseline in active CP compared with inactive CP (p = 0.01). More active-CP patients saw a decrease and fewer experienced an increase in angina episodes as compared with inactive-CP patients (p < 0.05). Nitroglycerin usage decreased in active CP but did not change in the inactive-CP group. The between-group difference was not significant (p > 0.7).\n Enhanced external counterpulsation reduces angina and extends time to exercise-induced ischemia in patients with symptomatic CAD. Treatment was relatively well tolerated and free of limiting side effects in most patients." ]	We found one relevant trial which failed to address the characteristics of interest satisfactorily, in terms of severity of angina, for the participants in this review. Participants with the most severe symptoms of angina were excluded, therefore the results of this study represent only a subsection of the broader population with the disorder, are not generalizable and provide inconclusive evidence for the effectiveness of enhanced external counterpulsation therapy for chronic angina pectoris.
CD009194	[ "11029326", "3889259", "8774514" ]	[ "Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis.", "Exogenous human surfactant for treatment of severe respiratory distress syndrome: a randomized prospective clinical trial.", "A multicenter randomized, masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome." ]	[ "Infants with respiratory syncytial virus (RSV) bronchiolitis are deficient in surfactant, both in quantity and ability to reduce surface tension. New evidence suggests surfactant has a role in maintaining the patency of conducting airways, which has implications for RSV bronchiolitis. A randomized, controlled pilot study was undertaken to assess the effects of exogenous surfactant supplementation to RSV-positive infants on pulmonary mechanics, indices of gas exchange, and the phospholipid composition of bronchoalveolar lavage fluid (BALF). Nineteen ventilated infants (median corrected age 4 wk) received either two doses of surfactant (Survanta, 100 mg/kg) within 24 and 48 h of mechanical ventilation (n = 9), or air placebo (n = 10). Static lung compliance and resistance of infants in the placebo but not in the surfactant-treated group became progressively worse over the first 30 h following enrollment. Although no significant acute changes in gas exchange parameters were seen following surfactant, infants in the surfactant group showed a more rapid improvement in oxygenation and ventilation indices over the first 60 h of ventilation. Surfactant status was assessed from the concentration ratio in BALF of the disaturated phospholipid species dipalmitoylphosphatidylcholine to that of the monounsaturated species palmitoyloleoylphosphatidylcholine. This ratio correlated with both lung compliance (positively) and resistance (negatively), and over time increased in the treated group and declined in placebo infants. The data from this pilot study suggest that functional surfactant has a role in maintaining small airway patency as well as lung compliance in infants infected with RSV and an outcome study is now warranted.", "We performed a randomized, prospective clinical trial comparing intratracheal administration of human surfactant with conventional treatment with intermittent mandatory mechanical ventilation alone for treatment of severe respiratory distress syndrome in preterm infants of less than 30 weeks gestation. Twenty-two infants (mean gestational age 27.0 weeks, mean birth weight 987 gm) were given surfactant, and 23 infants (mean gestational age 27.2 week, mean birth weight 1055 gm) received intermittent mandatory ventilation. Infants given surfactant required less FiO2 during the first week, had lower mean airway pressure during the first 48 hours, and had improved ventilatory index and a/A PO2 ratio. Death or the occurrence of bronchopulmonary dysplasia was significantly less among infants given surfactant (P = 0.019). Pneumothorax, pulmonary interstitial emphysema, and need for FiO2 greater than or equal to 0.3 for greater than 30 days was significantly less in the surfactant group. This trial confirms the efficacy of treatment with human surfactant in preterm infants with severe respiratory distress syndrome.", "To compare the efficacy and safety of two surfactant preparations in the treatment of respiratory distress syndrome (RDS).\n We conducted a randomized, masked comparison trial at 21 centers. Infants with RDS who were undergoing mechanical ventilation were eligible for treatment with two doses of either a synthetic (Exosurf) or natural (Infasurf) surfactant if the ratio of arterial to alveolar partial pressure of oxygen was less than or equal to 0.22. Crossover treatment was allowed within 96 hours of age if severe respiratory failure (defined as two consecutive arterial/alveolar oxygen tension ratios < or = 0.10) persisted after two doses of the randomly assigned surfactant. Four primary outcome measures of efficacy (the incidence of pulmonary air leak (< or = 7 days); the severity of RDS; the incidence of death from RDS; and the incidence of survival without bronchopulmonary dysplasia (BPD) at 28 days after birth) were compared by means of linear regression techniques.\n The primary analysis of efficacy was performed in 1033 eligible infants and an analysis of safety outcomes in the 1126 infants who received study surfactant. Preentry demographic characteristics and respiratory status were similar for the two treatment groups, except for a small but significant difference in mean gestational age (0.5 week) that favored the infasurf treatment group. Pulmonary air leak (< or = 7 days) occurred in 21% of Exosurf- and 11% of infasurf-treated infants (adjusted relative risk, 0.53; 95% confidence interval, 0.40 to 0.71; p < or = 0.0001). During the 72 hours after the initial surfactant treatment, the average fraction of inspired oxygen (+/-SEM) was 0.47 +/- 0.01 for Exosurf- and 0.39 +/- 0.01 for infasurf-treated infants (difference, 0.08; 95% confidence interval, 0.06 to 0.10; p < 0.0001); the average mean airway pressure (+/-SEM) was 8.6 +/- 0.1 cm H2O; for Exosurf- and 7.2 +/- 0.1 cm H2O for Infasurf-treated infants (difference, 1.4 cm H2O; 95% confidence interval, 1.0 to 1.8 cm H2O; p < 0.0001). The incidences of RDS-related death, total respiratory death, death to discharge, and survival without bronchopulmonary dysplasia at 28 days after birth did not differ. The number of days of more than 30% inspired oxygen and of assisted ventilation, but not the duration of hospitalization, were significantly lower in Infasurf-treated infants.\n Compared with Exosurf, Infasurf provided more effective therapy for RDS as assessed by significant reductions in the severity of respiratory disease and in the incidence of air leak complications." ]	The available evidence is insufficient to establish the effectiveness of surfactant therapy for bronchiolitis in critically ill infants who require mechanical ventilation. There is a need for larger trials with adequate power and a cost-effectiveness analysis to evaluate the effectiveness of exogenous surfactant therapy for infants with bronchiolitis who require intensive care management.
CD009306	[ "21051731", "19028741", "16085942" ]	[ "Internal limiting membrane peeling versus no peeling for idiopathic full-thickness macular hole: a pragmatic randomized controlled trial.", "Value of internal limiting membrane peeling in surgery for idiopathic macular hole stage 2 and 3: a randomised clinical trial.", "Idiopathic macular hole surgery in Chinese patients: a randomised study to compare indocyanine green-assisted internal limiting membrane peeling with no internal limiting membrane peeling." ]	[ "To determine whether internal limiting membrane (ILM) peeling is effective and cost effective compared with no peeling in patients with idiopathic stage 2 or 3 full-thickness maculay hole (FTMH).\n This was a pragmatic multicenter randomized controlled trial. Eligible participants from nine centers were randomized to ILM peeling or no peeling (1:1 ratio) in addition to phacovitrectomy, including detachment and removal of the posterior hyaloid and gas tamponade. The primary outcome was distance visual acuity (VA) at 6 months after surgery. Secondary outcomes included hole closure, distance VA at other time points, near VA, contrast sensitivity, reading speed, reoperations, complications, resource use, and participant-reported health status, visual function, and costs.\n Of 141 participants randomized in nine centers, 127 (90%) completed the 6-month follow-up. Nonstatistically significant differences in distance visual acuity at 6 months were found between groups (mean difference, 4.8; 95% confidence interval [CI], -0.3 to 9.8; P = 0.063). There was a significantly higher rate of hole closure in the ILM-peel group (56 [84%] vs. 31 [48%]) at 1 month (odds ratio [OR], 6.23; 95% CI, 2.64-14.73; P < 0.001) with fewer reoperations (8 [12%] vs. 31 [48%]) performed by 6 months (OR, 0.14; 95% CI, 0.05-0.34; P < 0.001). Peeling the ILM is likely to be cost effective.\n There was no evidence of a difference in distance VA after the ILM peeling and no-ILM peeling techniques. An important benefit in favor of no ILM peeling was ruled out. Given the higher anatomic closure and lower reoperation rates in the ILM-peel group, ILM peeling seems to be the treatment of choice for idiopathic stage 2 to 3 FTMH. (Clinical Trials.gov number, NCT00286507.).", "To determine the effect of internal limiting membrane (ILM) peeling on anatomical and functional success rates in stage 2 and 3 idiopathic macular hole surgery (MHS).\n Randomised clinical trial of stage 2 and 3 idiopathic macular hole without visible epiretinal fibrosis and with less than 1 year's duration of symptoms. Eyes were randomised to (1) vitrectomy alone without retinal surface manipulation, (2) vitrectomy plus 0.05% isotonic Indocyanine Green (ICG)-assisted ILM peeling or (3) vitrectomy plus 0.15% Trypan Blue (TB)-assisted ILM peeling. Main outcomes were hole closure after 3 and 12 months and best-corrected visual acuity after 12 months.\n 78 eyes were enrolled. Primary closure rates were significantly higher with ILM peeling than without peeling for both stage 2 holes (ICG peeling 100%, non-peeling 55%, p = 0.014) and for stage 3 holes (ICG peeling 91%, TB peeling 89%, non-peeling 36%, p<0.001). Visual outcomes in eyes with primary hole closure were not significantly different between the groups.\n Dye-assisted ILM peeling was associated with significantly higher closure rates than non-peeling in both stage 2 and 3 MHS. Intraoperative ILM staining with 0.05% isotonic ICG was not associated with a significantly different visual outcome than non-peeling or TB peeling in eyes with primary hole closure. Trial registration number: NCT00302328.", "To compare the anatomical and visual outcomes of primary idiopathic macular hole surgery using indocyanine green-assisted internal limiting membrane peeling versus no internal limiting membrane peeling.\n Prospective randomised controlled clinical trial.\n University teaching hospital, Hong Kong.\n Fifty-one eyes of 49 Chinese patients with primary idiopathic macular hole were studied.\n Patients were randomised to undergo pars plana vitrectomy with indocyanine green-assisted internal limiting membrane peeling (26 eyes) or surgery without internal limiting membrane peeling (25 eyes). Perfluorocarbon gas was used in all cases as internal tamponade.\n Primary macular hole closure rate and best-corrected visual acuity.\n The mean follow-up duration was 12 months (range, 6-23 months). Respectively to the indocyanine green-assisted internal limiting membrane peeling group and non-internal limiting membrane peeling group, the primary anatomical closure rate was 92.3% and 32.0% (P<0.001), whereas improvement in best-corrected visual acuity was 3.7 and 1.5 lines (P=0.002). More eyes in the first group (84.6%) had improvement of 2 or more lines of best-corrected visual acuity after surgery than in the second group (32.0%) [P<0.001]. Multivariate logistic regression showed indocyanine green-assisted internal limiting membrane peeling was the only significant predictor for primary closure of the macular hole (adjusted odds ratio=30.8).\n Indocyanine green-assisted internal limiting membrane peeling in idiopathic macular hole surgery results in significantly better anatomical and visual outcomes compared with non-internal limiting membrane peeling in Chinese patients." ]	Although we found no evidence of a benefit of ILM peeling in terms of the primary outcome (visual acuity at six months), ILM peeling appears to be superior to its no-peeling counterpart as it offers more favourable cost effectiveness by increasing the likelihood of primary anatomical closure and subsequently decreasing the likelihood of further surgery, with no differences in unwanted side-effects compared with no peeling.
CD004760	[ "10891977", "15159476", "17471547", "12529796", "10802796", "12578937", "15984021", "9390662", "11790236", "14694498", "16881064", "15804248", "12707981", "11113239" ]	[ "Creatine therapy in myophosphorylase deficiency (McArdle disease): a placebo-controlled crossover trial.", "Creatine monohydrate enhances strength and body composition in Duchenne muscular dystrophy.", "Creatine supplements in patients with idiopathic inflammatory myopathies who are clinically weak after conventional pharmacologic treatment: Six-month, double-blind, randomized, placebo-controlled trial.", "Creatine monohydrate in myotonic dystrophy: a double-blind, placebo-controlled clinical study.", "Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.", "Creatine monohydrate in DM2/PROMM: a double-blind placebo-controlled clinical study. Proximal myotonic myopathy.", "CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy.", "A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies.", "Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle disease: double-blind, placebo-controlled crossover study.", "Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1.", "Effects of exercise and creatine on myosin heavy chain isoform composition in patients with Charcot-Marie-Tooth disease.", "Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study.", "Beneficial effects of creatine supplementation in dystrophic patients.", "A placebo-controlled crossover trial of creatine in mitochondrial diseases." ]	[ "To determine whether treatment with creatine can improve exercise intolerance in myophosphorylase deficiency (McArdle disease).\n Double-blind, placebo-controlled crossover study with oral creatine monohydrate supplementation.\n Nine patients with biochemically and genetically proven McArdle disease were treated.\n Five days of daily high-dose creatine intake (150 mg/kg body weight) were followed by daily low-dose creatine intake (60 mg/kg). Each treatment phase with creatine or placebo lasted 5 weeks.\n The effect of treatment was estimated at the end of each treatment phase by recording clinical scores, ergometer exercise test results, phosphorus 31 nuclear magnetic resonance spectroscopy, and surface electromyography.\n Of 9 patients, 5 reported improvement of muscle complaints with creatine. Force-time integrals (P =.03) and depletion of phosphocreatine (P =.04) increased significantly during ischemic exercise with creatine. Phosphocreatine depletion also increased significantly during aerobic exercise (P =.006). The decrease of median frequency in surface electromyograms during contraction was significantly larger (P =.03) with creatine.\n This is the first controlled study indicating that creatine supplementation improves skeletal muscle function in McArdle disease.", "To determine whether creatine monohydrate (CrM) supplementation increases strength and fat-free mass (FFM) in boys with Duchenne muscular dystrophy (DD).\n Thirty boys with DD (50% were taking corticosteroids) completed a double-blind, randomized, cross-over trial with 4 months of CrM (about 0.10 g/kg/day), 6-week wash-out, and 4 months of placebo. Measurements were completed of pulmonary function, compound manual muscle and handgrip strength, functional tasks, activity of daily living, body composition, serum creatine kinase and gamma-glutamyl transferase activity and creatinine, urinary markers of myofibrillar protein breakdown (3-methylhistidine), DNA oxidative stress (8-hydroxy-2-deoxyguanosine [8-OH-2-dG]), and bone degradation (N-telopeptides).\n During the CrM treatment phase, there was an increase in handgrip strength in the dominant hand and FFM (p < 0.05), with a trend toward a loss of global muscle strength (p = 0.056) only for the placebo phase, with no improvements in functional tasks or activities of daily living. Corticosteroid use, but not CrM treatment, was associated with a lower 8-OH-2-dG/creatinine (p < 0.05), and CrM treatment was associated with a reduction in N-telopeptides (p < 0.05).\n Four months of CrM supplementation led to increases in FFM and handgrip strength in the dominant hand and a reduction in a marker of bone breakdown and was well tolerated in children with DD.", "To test the hypothesis that oral creatine supplements with exercise are more effective than exercise alone in improving muscle function in patients with established dermatomyositis or polymyositis receiving chronic medical therapies who are clinically weak yet stable.\n In a 6-month, 2-center, double-blind, randomized controlled trial, patients were randomized to receive oral creatine supplements (8 days, 20 gm/day then 3 gm/day) or placebo. All patients followed a home exercise program. The primary outcome was aggregate functional performance time (AFPT), reflecting the ability to undertake high-intensity exercise. Secondary outcomes included a functional index measuring endurance and muscle bioenergetics on (31)P magnetic resonance spectroscopy ((31)P MRS). Patients were receiving stable immunosuppressive treatment and/or corticosteroids.\n A total of 37 patients with polymyositis or dermatomyositis were randomized (19 to creatine, 18 to placebo); 29 completed 6 months. Intent-to-treat analyses demonstrated that AFPT improved significantly at 6 months with creatine (median decrease 13%, range -32-8%) compared with placebo (median decrease 3%, range -13-16%; P = 0.029 by Mann-Whitney U test). A completer analysis also showed significant benefits from creatine (P = 0.014). The functional index improved significantly with both creatine and placebo (P < 0.05 by paired Wilcoxon's rank sum test), with a significant benefit between groups in the completer analysis only. Phosphocreatine/beta-nucleoside triphosphate ratios using MRS increased significantly in the creatine group (P < 0.05) but not in the control group. No clinically relevant adverse events were associated with creatine.\n Oral creatine supplements combined with home exercises improve functional performance without significant adverse effects in patients with polymyositis or dermatomyositis. They appear safe, effective, and inexpensive.", "We assessed safety and efficacy of creatine monohydrate (Cr) in myotonic dystrophy (DM1) in a double-blind, cross-over trial. Thirty-four patients with defined DM1 were randomized to receive Cr and placebo for eight weeks (10.6 g day 1-10, 5.3 g day 11-56) in one of 2 treatment sequences. There was no significant improvement using manual and quantitative muscle strength, daily-life activities, and patients' own global assessment comparing verum with placebo administration. Cr supplementation was well tolerated without clinically relevant side effects, but did not result in significant improvement of muscle strength or daily-life activities.", "The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period.", "The efficacy and safety of creatine monohydrate (Cr) in patients with myotonic dystrophy type 2/proximal myotonic myopathy were studied in a small placebo-controlled double-blind trial. Twenty patients received either Cr or placebo for 3 months. After 3 months, there were no significant differences of muscle strength as assessed by hand-held dynamometry, testing of maximum grip strength, Medical Research Council scoring, and the Neuromuscular Symptom Score between the two groups. Some measures indicated trends toward mild improvement with Cr. Myalgia improved in two patients.", "We tested the efficacy and safety of glutamine (0.6 gm/kg/day) and creatine (5 gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6-month, double-blind, placebo-controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease-modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated.", "Fatigue in patients with mitochondrial cytopathies is associated with decreased basal and postactivity muscle phosphocreatine (PCr). Creatine monohydrate supplementation has been shown to increase muscle PCr and high-intensity power output in healthy subjects. We studied the effects of creatine monohydrate administration (5 g PO b.i.d. x 14 days --> 2 g PO b.i.d. x 7 days) in 7 mitochondrial cytopathy patients using a randomized, crossover design. Measurements included: activities of daily living (visual analog scale); ischemic isometric handgrip strength (1 min); basal and postischemic exercise lactate; evoked and voluntary contraction strength of the dorsiflexors; nonischemic, isometric, dorsiflexion torque (NIDFT, 2 min); and aerobic cycle ergometry with pre- and post-lactate measurements. Creatine treatment resulted in significantly (P < 0.05) increased handgrip strength, NIDFT, and postexercise lactate, with no changes in the other measured variables. We concluded that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities.", "In a recent study, we showed that administration of low-dose creatine (Cr) (60 mg/kg daily) improved work capacity in patients with McArdle disease.\n To assess the efficacy of high-dose Cr therapy in McArdle disease.\n Randomized, double-blind, placebo-controlled crossover study.\n Nineteen patients with McArdle disease.\n Treatment with Cr, 150 mg/kg daily. Each treatment phase with Cr or placebo lasted 5 weeks.\n The patient's daily rating of symptoms of exercise intolerance. At the end of each treatment phase, serum creatine and serum creatine kinase levels, phosphorus 31 magnetic resonance spectroscopy, and surface electromyograms were assessed.\n Clinical end points revealed increases in the intensity of exercise-induced pain in working muscles (mean treatment-induced difference [d], 0.30 in log(score); 95% confidence interval [CI], 0.05-0.55; P =.02), the limitation of daily activities (d, 0.59; 95% CI, 0.22-0.97;P =.005), and body mass index (d, 0.33 kg/m2, 95% CI, 0.10-0.56 kg/m2; P =.008) with Cr use. Surface electromyograms revealed a smaller increase in the electromyographic amplitude over time during muscle contraction with Cr use (d, -13.52%/min; 95% CI, -23.71%/min to -3.34%/min; P =.01). There were no significant changes in phosphorus 31 magnetic resonance spectroscopy variables.\n Administration of high-dose Cr worsened the main clinical symptoms of exercise intolerance in McArdle disease. These neurologic adverse effects represent a major dose-limiting factor in Cr therapy for McArdle disease. Taken together with results of a previous study, the indication for symptomatic therapy with Cr needs to be clarified. An effective Cr dosage without adverse effects may be between 60 and 150 mg/kg daily.", "Creatine monohydrate (CrM) supplementation may increase strength in some types of muscular dystrophy. A recent study in myotonic muscular dystrophy type 1 (DM1) did not find a significant treatment effect, but measurements of muscle phosphocreatine (PCr) were not performed. We completed a randomized, double-blind, cross-over trial using 34 genetically confirmed adult DM1 patients without significant cognitive impairment. Participants received CrM (5 g, approximately 0.074 g/kg daily) and a placebo for each 4-month phase with a 6-week wash-out. Spirometry, manual muscle testing, quantitative isometric strength testing of handgrip, foot dorsiflexion, and knee extension, handgrip and foot dorsiflexion endurance, functional tasks, activity of daily living scales, body composition (total, bone, and fat-free mass), serum creatine kinase activity, serum creatinine concentration and clearance, and liver function tests were completed before and after each intervention, and muscle PCr/beta-adenosine triphosphate (ATP) ratios of the forearm flexor muscles were completed at the end of each phase. CrM supplementation did not increase any of the outcome measurements except for plasma creatinine concentration (but not creatinine clearance). Thus, CrM supplementation at 5 g daily does not have any effects on muscle strength, body composition, or activities of daily living in patients with DM1, perhaps because of a failure of the supplementation to increase muscle PCr/beta-ATP content.", "It is not known whether myosin heavy chain (MHC) content changes in response to exercise training or creatine supplementation in subjects with Charcot-Marie-Tooth disease (CMT). Based on previous data, we hypothesized that resistance exercise and creatine would increase the percentage of type I MHC composition in the vastus lateralis muscle and that myosin isoform changes would correlate with improved chair rise-time in CMT subjects. To test this hypothesis, 18 CMT subjects were randomly assigned to either a placebo or creatine group. All subjects performed a 12-week, home-based, moderate-intensity resistance training program. Chair rise-time was measured before and after the training program. Muscle biopsies were obtained from the vastus lateralis before and after the 12-week program. Gel electrophoresis showed a significant decrease (approximately 30%) in MHC type I in CMT subjects given creatine supplementation when compared with placebo. There was a nonsignificant increase in both MHC type IIa (approximately 23%) and MHC type IIx (approximately 7%) in CMT subjects given creatine. Reduced MHC type I content and increased MHC type IIa content correlated with faster chair rise-times (i.e., improved muscle performance). The training-induced change in MHC IIa content was inversely correlated with chair rise-time in CMT subjects given creatine. When the two subject groups were combined, there was a linear, negative relationship between the change in MHC type IIa content and chair rise-time after training and a positive relationship between the training-induced change in MHC type I content and chair rise-time. These data suggest that improved function (chair rise-time) was associated with a lower level of MHC type I and increased MHC type IIa composition. Furthermore, the data are consistent with the hypothesis that creatine supplementation alters MHC composition in CMT patients undergoing resistance training and that MHC changes associated with creatine supplementation can improve muscle function.", "The purpose of our randomized, double-blind, placebo-controlled crossover study in 15 patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) because of single large-scale mitochondrial (mt) DNA deletions was to determine whether oral creatine (Cr) monohydrate can improve skeletal muscle energy metabolism in vivo. Each treatment phase with Cr in a dosage of 150 mg/kg body weight/day or placebo lasted 6 weeks. The effect of Cr was estimated by phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS), clinical and laboratory tests. (31)P-MRS analysis prior to treatment showed clear evidence of severe mitochondrial dysfunction. However, there were no relevant changes in (31)P-MRS parameters under Cr. In particular, phosphocreatine (PCr)/ATP at rest did not increase, and there was no facilitation of post-exercise PCr recovery. Clinical scores and laboratory tests did not alter significantly under Cr, which was tolerated without major side-effects in all patients. Cr supplementation did not improve skeletal muscle oxidative phosphorylation in our series of patients. However, one explanation for our negative findings may be the short study duration or the limited number of patients included.", "The effect of creatine (Cr) supplementation on muscle function and body composition of 12 boys with Duchenne muscular dystrophy and three with Becker dystrophy was evaluated by a randomized double-blind cross-over study (3 g Cr or maltodextrin daily for 3 months, with wash-out period of 2 months). After placebo, no change was observed in maximal voluntary contraction (MVC) and resistance to fatigue, whereas total joint stiffness (TJS) was increased by approximately 25% (P < 0.05). The patients receiving Cr did not show any change in TJS, improved MVC by 15% (P = 0.02), and almost doubled their resistance to fatigue (P < 0.001). In patients still independent of a wheelchair (n = 5), bone mineral density increased by 3% (P < 0.05), and urinary excretion of collagen type I cross-linking N-telopeptide declined to about one third (P < 0.001) after Cr. No adverse effect was observed. Thus, Cr may provide some symptomatic benefit in these patients.", "To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks. Cr was well tolerated, but there were no significant effects with regard to exercise performance, eye movements, or activities of daily life. The power of this pilot study was limited and future multicenter trials are needed." ]	High quality evidence from RCTs shows that short- and medium-term creatine treatment increases muscle strength in muscular dystrophies. There is also evidence that creatine improves functional performance in muscular dystrophy and idiopathic inflammatory myopathy. Creatine is well tolerated in these people. High quality but limited evidence from RCTs does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine treatment impaired activities of daily living and increased muscle pain in McArdle disease.
CD008310	[ "11965714" ]	[ "[Administration of exogenous surfactant in premature very low birth weight infants with RDS]." ]	[ "A retrospective study is carried out with the aim of establishing the effect from surfactant therapy on pulmonary function, survival and complication from intensive therapy on VLBWI with RDS. 67 premature infants below 1500 grams are included in the study divided in 3 groups: I gr.--27 babies treated with Corosurf; II gr.--16 babies treated with Exosurf; III gr.--24 control babies without surfactant. The results show that in spite of relatively lower gestational age and higher incidence of inborn infection in group I, Curosurf treated babies spend shortest time on mechanical ventilation and oxygen therapy showing lower incidence of BPD, IVH and mortality rate." ]	There are insufficient data to support or refute the use of nebulised surfactant in clinical practice. Adequately powered trials are required to determine the effect of nebulised surfactant administration for prevention or early treatment of RDS in preterm infants. Nebulised surfactant administration should be limited to clinical trials.
CD002194	[ "7792546", "20148940" ]	[ "The role of the psychologist in multidisciplinary treatments for chronic neck and shoulder pain: a controlled cost-effectiveness study.", "An exploratory trial of preventative rehabilitation on shoulder disability and quality of life in patients following neck dissection surgery." ]	[ "This study was designed to determine a cost-effective use of psychologist resources in multimodal cognitive-behavioural treatments (MMCBT) for chronic neck/shoulder pain. A randomised controlled trial was conducted with 66 patients divided in two groups. The first group (A) was treated following the approach of MMCBT with the clinical psychologist only functioning as a \"coach\" to the other health professionals. In this group, the psychologist had on average 5 hours of input per patients. The second group (B) was treated with the same inpatient MMCBT but with the behavioural component administered by the clinical psychologist directly to the patients. In this second group the psychologist had on average 17 hours of input per patient in the entire intervention. The outcome variables included physical, emotional and social factors, and sick-leave. Both groups showed significant improvements over time. The improvements were evident only in sub-groups, specifically in women. The only significant difference between the groups was in \"perceived helplessness\" favouring the \"psychologist contact\" setting. It is concluded that in terms of input of clinical psychology, the treatment setting with the \"coaching\" technique proved to be the most cost-effective use of the psychologist in the two treatment settings investigated.", "Patients commonly develop shoulder disability and reduction in quality of life (QOL) following neck dissection surgery. There is a lack of studies investigating the impact of preventative rehabilitation to prevent shoulder disability in this population. An exploratory trial was undertaken to investigate this gap in the head and neck cancer literature. Thirty-two subjects were randomly assigned to either one of two groups: early physiotherapy for a period of 3 months following surgery and current routine inpatient care and advice. Blinded measurement of shoulder function and QOL were recorded pre-operatively and at 1 year following surgery. No difference was found using between-group analysis (Mann-Whitney U-Test) for any outcome measures observed. Descriptive data analysis suggests that subjects receiving early physiotherapy had a perception of increased physical well-being when compared with subjects receiving routine care. There may be some clinical significance that subjects receiving a course of physiotherapy did appear to rate their physical well-being higher than those subjects not undergoing rehabilitation. Further research to investigate the preventative effects of physiotherapy on this population should consider the use of head and neck cancer-specific outcome measurement of both shoulder disability and QOL.\n © 2010 Blackwell Publishing Ltd." ]	We conclude that there appears to be little scientific evidence for the effectiveness of multidisciplinary biopsychosocial rehabilitation compared with other rehabilitation facilities for neck and shoulder pain. Multidisciplinary rehabilitation is a commonly used intervention for chronic neck and shoulder complaints, therefore we see an urgent need for high quality trials in this field.
CD003758	[ "400290", "1560482", "11939303", "5308697", "11791989", "9481098", "1296947", "5301383", "8059918", "10107821", "9713544", "11930093", "18955525", "11529382", "3555385" ]	[ "[Follow-up survey on the long-term effects of DEC medicated salt in the control of filariasis bancrofti (author's transl)].", "Mass treatment of filariasis using DEC-medicated salt.", "Efficacy of mass single-dose diethylcarbamazine and DEC-fortified salt against bancroftian filariasis in Papua New Guinea six months after treatment.", "The effect of salt medicated with diethylcarbamazine in bancroftian filariasis.", "A community-based trial for the control of lymphatic filariasis and iodine deficiency using salt fortified with diethylcarbamazine and iodine.", "Efficacy of diethylcarbamazine-medicated salt for microfilaraemia of Brugia malayi.", "Efficacy of diethylcarbamazine medicated salt in interrupting Brugia malayi transmission in hill tribe settlements in Kerala State.", "Control of Bancroftian filariasis by cooking salt medicated with diethylcarbamazine.", "Efficacy of 28-day and 40-day regimens of sodium stibogluconate (Pentostam) in the treatment of mucosal leishmaniasis.", "Metronidazole cost containment: a two-stage intervention.", "The efficacy, tolerability and safety of diethylcarbamazine-fortified salt in the treatment of the microfilaraemias of brugian filariasis: an open, hospital-based study.", "Treatment of childhood encopresis: a randomized trial comparing three treatment protocols.", "Clinical outcomes, safety, and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection.", "Oral ceftibuten switch therapy for acute pyelonephritis in children.", "Low- and conventional-dose maintenance therapy with fluphenazine decanoate. Two-year outcome." ]	[ "nan", "Diethylcarbamazine (DEC)-medicated salt was used to control bancroftian filariasis in 20 endemic counties and cities of Fujian Province in China. The population was 5,189,126 and the microfilaria (mf) rates were between 1.56 and 11.81%. The total dose of DEC was 6-10.5 g per person over a period of 2-4 months. Six to 9 months after treatment the mf rate was reduced to 0-0.57% with a mean of 0.07% (621/823,796). In 184 villages sampled one year post treatment the mf rate was 0.22% (371/171,067) and in 29 villages 2-4 years after treatment the mf rate was 0.05% (31/56,459). In a region of endemic Malayan filariasis, with a population of 67,778 and mf rate of 3.82-4.36%, treatment with DEC-medicated salt to a dosage of 3.2 g DEC per person was administered for 2 months. Six months after treatment the mean mf rate was reduced from 4.08 to 0.26% (10/3841). Filariasis in all the villages controlled with DEC-medicated salt reached the basic criteria of elimination (mf rate below 1%).", "The efficacy of two diethylcarbamazine (DEC) treatment strategies to control bancroftian filariasis, diethylcarbamazine-fortified salt (DEC-FS) and a single DEC dose on mass administration, was evaluated in two communities in Papua New Guinea with pretreatment antigen prevalence of 55% and 71%. In the first community 0.2% w/w diethylcarbamazine-fortified salt was distributed monthly to accepting households at no cost for 12 months. In the second community a single DEC dose based on body size but designed to give about 6 mg/kg was administered to eligible acceptors. Despite wide variation in antigen prevalence among study villages there were marked reductions in prevalences under both treatment strategies. Among individuals antigenaemic on day 0, DEC-FS and a single DEC dose gave filaria antigen clearance rates of 43% and 13%, respectively. In the salt-treated community the incidence of antigenaemia after 6 months in acceptors from households that received 5 kg or more of DEC-FS was 14% whereas in those receiving less than 5 kg salt was 4%. The incidence rates in the second community in those that received < 2.5 and > or = 2.5 tablets were 16% and 8%, respectively. The two treatment strategies were simple to manage and appropriate for developing countries and were widely accepted. DEC-FS was more efficacious than single-dose DEC tablets but a single administration of DEC tablets is easier to administer.", "The paper describes a trial conducted in Tanzania of the effect on bancroftian microfilaraemia of common salt medicated with diethylcarbamazine at a 0.1% (w/w) concentration, when given to a closed population of 600-700 with a known salt intake.After good observer agreement in microfilarial counting had been demonstrated, quantitative blood surveys were performed monthly on known carriers. Paired pretreatment microfilarial counts from the same patients at an interval of 4 months suggested a natural fluctuation in microfilarial densities and emphasized the need for parallel concurrent controls during treatment.During the trial the mean microfilarial densities fell steadily, being reduced by 73% at 3 months and 90% after 6 months. Tolerance to the drug-salt mixture was extremely good.Problems of planning, salt preparation and assessment of results are discussed and the importance of correct experimental design in future trials is stressed. The authors suggest that a trial of salt containing 0.2% (w/w) diethylcarbamazine may achieve optimum results. They point out that, while the use of diethylcarbamazine-medicated salt may prove useful in reducing transmission in closed communities or in endemic areas with no alternative source of salt, its extension to national populations as a sole means of bancroftian filariasis control would be of problematical value.", "To evaluate the effectiveness of salt fortified with diethylcarbamazine (DEC) and iodine for elimination of Bancroftian filariasis and iodine deficiency, all consenting residents of Miton, Haiti (n = 1,932) were given salt fortified with 0.25% diethylcarbamazine and 25 ppm of iodine for one year. Wuchereria bancrofti microfilaria prevalence and intensity, antigenemia, and urinary iodine were measured before and one year after salt distribution began. To measure the effect of DEC-fortified salt on adult worm motility, 15 microfilaria-positive men were examined by ultrasound of the scrotal area. Entomologic surveys were conducted to determine the proportion of W. bancrofti-infected Culex quinquefasciatus. After one year of treatment, the prevalence and intensity of microfilaremia were both reduced by more than 95%, while antigenemia levels were reduced by 60%. The motility of adult worms, as detected by ultrasound, was decreased, but not significantly, by DEC-fortified salt. The proportion of vector mosquitoes carrying infective stage larvae decreased significantly from 2.3% in the nine months before the intervention to 0.2% in the last three-month follow-up period. Iodine deficiency, which had been moderate to severe, was eliminated after one year of iodized salt consumption. The DEC-fortified salt was well accepted by the community and reduced microfilaremia and transmission to low levels in the absence of reported side effects. Based on these results, salt cofortified with DEC and iodine should be considered as a concurrent intervention for lymphatic filariasis and iodine deficiency elimination programs.", "Pilot studies in India and abroad have demonstrated the benefit of cooking salt fortified with diethylcarbamazine citrate (DEC) for the control of lymphatic filariasis. In India, DEC-medicated salt has been introduced on a commercial basis in the Cherthala region of Kerala, which is endemic for Brugia malayi (B. malayi). We studied the efficacy of DEC-medicated salt in the clearance of microfilaraemia of B. malayi.\n Eighteen cases of microfilaraemia (11 men; 7 women) were selected; 14 in the experimental group (i.e. treated with 0.2% w/w DEC-medicated salt) and the rest as the control group who were given a placebo. The consumption of salt and the status of parasitaemia were monitored till all the microfilaria carriers became negative.\n There was a significant reduction in the density of microfilariae (intensity) among the treated individuals over a period of time. The duration required for the clearance of microfilariae ranged from 9 to 30 [mean (SD) 19.4 (1.7)] weeks. All microfilaraemics except one reported side-effects which were mild-to-moderate and persisted for a maximum period of one month.\n DEC-medicated salt effectively clears microfilariae within 30 weeks in parasitaemic individuals. No 'endemic normals' reported any side-effects, though these were common among the microfilaria carriers.", "A filariasis survey carried out about eight years after achieving zero microfilaria (mf) rates following administration of diethylcarbamazine (DEC) medicated salt in the Kani hill tribe settlements in Quilon and Thiruvananthapuram districts of Kerala State revealed that there was no reappearance of Brugia malayi infection in the experimental areas. Mf rates were maintained at zero level in the experimental villages, while in the control villages, 2.9 per cent mf positives were observed. Mansonia (Mansonioides) uniformis dissected did not reveal filarial infection. It is concluded that DEC medicated salt regime in the experimental areas of Kani hill tribe settlements has been successful in effectively interrupting B. malayi transmission. Pilot studies in other B. malayi endemic areas of India using DEC medicated salt regime with the objective of eliminating B. malayi transmission are advocated, since the parasite has a restricted distribution in India and is already showing a declining trend.", "In small-scale pilot trials, filarial infection can usually be reduced to low levels by oral administration of diethylcarbamazine to all the persons concerned; but in mass campaigns it is often difficult to persuade large numbers of people to swallow the tablets. In order to overcome this difficulty the authors propose that the compound be incorporated into cooking salt, as has been done with chloroquine to control malaria. There are many reasons why this method of medication should be more effective against filariasis than it has often been against malaria.Laboratory trials showed that cooking the compound in food did not make it toxic for rats or diminish its antifilarial activity. A pilot trial was carried out at Recife, Brazil, in which 1000 adults received salt containing 0.4% diethylcarbamazine (corresponding to a daily intake of 100 mg/day) for 40 days, and then salt containing 0.1% compound for a year. This medication was simple to administer; it was quite acceptable to the subjects; it caused no untoward effects; and it removed almost all the microfilariae from the blood. Administration of medicated salt (0.3%) for 18 days to another group of 1300 adults was well tolerated and produced a considerable reduction of the microfilarial load; but this short period was insufficient to remove all the microfilariae.The authors recommend that this method of administering diethylcarbamazine to large numbers of people should be investigated further to see if it could be used for mass campaigns to control filariasis.", "The efficacy and toxicity of two regimens of antimony, 28 and 40 days of 20 mg of antimony/kg/day, were compared in the treatment of culture-positive mucosal leishmaniasis involving more than one anatomic site. Forty consecutive eligible Peruvians with infiltrative or ulcerative mucosal disease of the lips, nose, palate-uvula-pharynx, or larynx-epiglottis were randomized to receive either 28 days (P28) or 40 days (P40) of sodium stibogluconate (Pentostam). Treatment was prematurely terminated due to thrombocytopenia in three patients and two patients did not complete six months of follow-up. At one month post-treatment, 13% (2 of 16) of the P28 patients and 16% (3 of 19) of the P40 patients no longer had infiltrates or ulcers and were initially considered cured. During a further 11 months of follow-up, infiltrated lesions healed in eight more P28 patients and in 10 more P40 patients. The cure rate after 12 months of follow-up was therefore 63% for both groups (10 of 16 in the P28 group and 12 of 19 in the P40 group). The total of 13 patients who had infiltrates or ulcers at the 9-12-month follow-up were considered failures. All seven patients (three in the P28 group and four in the P40 group) whose lesions were culture-positive for Leishmania at some point in the 12 months after treatment, and who were thereby parasitologic failures, were also clinical failures.(ABSTRACT TRUNCATED AT 250 WORDS)", "A two-stage intervention was undertaken to extend the dosing interval of metronidazole--from the typically prescribed q6h or q8h regimen to a q12h dosing interval. Following an 2-week informational period, all prescriptions for parenteral metronidazole specifying a dosage interval of 8 hours or less were modified to 12-hour dosage intervals, unless overridden by the prescriber. Prescriptions for the 6-month periods prior to and following the intervention were reviewed to assess its impact on prescribing patterns and cost containment. The incidence of regimens involving 12-hour intervals increased from 5 to 95% following the intervention. A 2-year general hospital/drug utilization health record screen found no drug substitution effect, nor any change in postoperative infection rate or death among metronidazole recipients. Overall, the two-stage intervention was a well-accepted and effective means of cost containment, resulting in an estimated yearly cost savings of $28,000.", "Cooking salt fortified with diethylcarbamazine (DEC) has been successfully used to control lymphatic filariasis in several parts of the world. The kinetics and efficacy of DEC-fortified salt in clearing microfilaraemias of Brugia malayi and the salt's tolerability and safety are examined in this study. Twenty individuals with B. malayi microfilaraemias (pre-treatment levels of 108-6358 microfilariae/ml; median = 309/ml) consumed DEC-fortified salt (0.2%, w/w) with their food for 1 year, initially in hospital (for 1 week) and later at home. The mean daily intake of DEC was 21.4 mg (range = 9.0-39.4 mg). Even on the first day of consuming the salt, there was a decrease in the microfilarial levels of 14 patients and a sharp increase in six patients. Microfilarial levels tended to fluctuate thereafter but there was a progressive, general decline. At the end of the study year, eight patients were amicrofilaraemic and microfilarial clearance was > 95% in 58% of the patients. Eight patients did not develop any adverse reactions. Lymph-node tenderness and enlargement were seen in eight patients (40%), and dilated, inflamed lymphatic channels standing out as cords ('string sign') were seen in another five patients. These reactions were transient and did not require any specific treatment. The DEC-fortified salt was well accepted by the study population. The DEC content of fortified salt and the duration of its use for the control of brugian filariasis need to be re-examined. Health education should include messages that mild, self-limiting, adverse reactions are likely to occur even with the use of such salt.", "To compare short- and long-term effectiveness of three additive treatment protocols in children experiencing chronic encopresis.\n Children, 6 to 15 years of age, who experienced at least weekly fecal soiling for 6 months or longer were eligible for the study. Children were randomly assigned to a group that received intensive medical therapy (IMT), a group that received intensive medical therapy plus a behavior management program called enhanced toilet training (ETT), or a group that received intensive medical therapy with enhanced toilet training and external anal sphincter electromyographic biofeedback (BF). Data concerning toileting habits were collected for 14 consecutive days before an initial visit, and at 3, 6, and 12 months after initiation of therapy. All data were collected using a computerized voice-mail system that telephoned the families each day. At 12 months, children were classified as significantly improved (reduction in soiling, P < 0.001) or cured (<one fecal accident in 2 weeks).\n Eighty-seven children participated in the study, 72 boys and 15 girls. Mean age at enrollment was 8.6 +/- 2.0 years, and mean duration of symptoms was 58.2 +/- 38.5 months. At 12 months, the cure rates for the IMM, ETT, and BF groups were 36, 48, and 39, respectively (not significant). The improvement rates for these three groups were 45, 78, and 54, respectively (P < 0.05). These results were very stable over time (r > 0.90, P < 0.001 in each case). Response to treatment during the first 2 weeks of therapy was highly predictive of outcome at 3, 6, and 12 months (P < 0.0001). Children in the ETT group used less laxative medication (P < 0.04) and required fewer treatment contacts (P = 0.08) than children in the IMM group. All three treatments resulted in significant increases in daily bowel movements passed in the toilet and self-initiated toileting, and resulted in decreases in average daily soiling at 3, 6, and 12 months (P < 0.05).\n Enhanced toilet training is somewhat more effective in treating childhood encopresis than either intensive medical therapy or anal sphincter biofeedback therapy. Although similar total cure rates at 1 year can be expected with these three forms of therapy, enhanced toilet training results in statistically significant decreases in the daily frequency of soiling for the greatest number of children.", "OPT-80, a novel, minimally absorbed macrocycle, is a candidate treatment option for Clostridium difficile infection (CDI) based on cure without recurrence of CDI in the hamster challenge model, good in vitro activity against C. difficile, and relative sparing of commensal gram-negative anaerobes. In this open-label, dose-ranging clinical trial, 48 evaluable subjects were randomized to receive either 50, 100, or 200 mg of OPT-80 orally every 12 h for 10 days as treatment for mild to moderately severe CDI. OPT-80 was well tolerated by all subjects. Plasma concentrations were below the lower limit of quantitation in almost one-half of patients and typically <or=20 ng/ml across the dose range; the mean fecal concentrations exceeded the MIC at which 90% of the isolates tested are inhibited by 2,000- to 10,000-fold with increasing dosages. Resolution of diarrhea within 10 days was achieved in 10/14 patients (71%), 12/15 patients (80%), and 15/16 patients (94%), and the median time to resolution of diarrhea was reduced from 5.5 to 3.0 days with increasing dosages. Across all groups, the clinical cure rate, which was defined as resolution of diarrheal disease without the need for further treatment, was 41/45 patients (91%). Recurrence of CDI at approximately 1 month after treatment was observed in two (5%) patients, one each in the 100-mg and 400-mg groups. The apparent high clinical response, good tolerance, low recurrence rate, and more-complete and rapid symptom control with the highest dosage support the selection of the 200-mg twice-daily dose for further clinical development of OPT-80 for treatment of CDI.", "The available oral third generation of cephalosporin, \"ceftibuten\" was used to substitute the intravenous drug after defervescence in acute pyelonephritis in children. This randomized controlled study compared the efficacy of an oral ceftibuten switch therapy with a ceftriaxone in both short-term and long-term outcomes. 36 99mTc-dimercaptosuccinic acid (DMSA) scan proved pyelonephritis patients were randomized into the study group, \"ceftibuten\" (N=18) and the control group, \"ceftriaxone\" (N=18). Ceftriaxone (75 mg/kg/day) was the initial antibiotic in both groups. After defervescence for 24-48 hours, oral ceftibuten (9 mg/kg/day) was substituted in the study group and continued for 10 days. The subject characteristics and laboratory data were not different between the two groups. The urine culture at D14 was sterilized in both groups. The incidence of renal scarring was 66.6 per cent and 61.1 per cent in the study group and the control group respectively. The rate of recurrent infection showed no statistical significance. The duration of hospitalization was shorter in the study group than in the control. In conclusion, oral ceftibuten switch therapy can be recommended as a safe and effective treatment for acute pyelonephritis in children. The use of oral therapy may result in a significant reduction of health care expenditure.", "We evaluated the effectiveness and the side effects of what we defined as low (5-mg) and conventional (25-mg) doses of fluphenazine decanoate administered every two weeks in a double-blind comparison. Subjects were 66 patients who fulfilled DSM-III criteria for schizophrenic disorder. Evaluation of the survival with each dose revealed no significant difference at one year, but significantly better survival was seen with the 25-mg dose (64%) than the 5-mg dose (31%) at two years. There was no significant difference in survival when the clinician was permitted to make a dosage adjustment up to 10 mg in the low-dose group and 50 mg in the higher-dose group when the patient demonstrated evidence of a symptomatic exacerbation. Patients assigned to the higher dose appeared to feel more uncomfortable during the early months of the study, as indicated by significantly higher scores on subscales of the Hopkins Symptom Checklist-90R and higher side effect scores for retardation and akathisia. Implications for clinical practice are discussed." ]	DEC-medicated salt is an effective intervention when maintained with levels of coverage of at least 90% for at least six months. Further studies are required to assess the effects of continuous low-dose, DEC-medicated salt on adult worms, disease prevalence, and development of drug resistance.
CD005113	[ "15146409", "15228184", "18635256", "17029087" ]	[ "Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.", "Rapid alleviation of signs and symptoms of rheumatoid arthritis with intravenous or subcutaneous administration of adalimumab in combination with methotrexate.", "Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial.", "Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study." ]	[ "Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX).\n In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]).\n At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week.\n In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.", "This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite previous MTX therapy.\n Fifty-four patients were randomized to two injections of i.v. or s.c. adalimumab (1 mg/kg) or placebo while continuing on MTX (mean dose, 15.7 mg/week). Dosing intervals were determined by the European League Against Rheumatism (EULAR) response criteria, and were allowed to range from 1 to 3 months. Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology (ACR) response criteria.\n Moderate EULAR response was achieved at least once within 29 days after the first injection in 83% and 61% of patients receiving i.v. and s.c. adalimumab respectively, compared with 44% for placebo [probability (p) < or = 0.05 for i.v. adalimumab versus placebo]. A 20% improvement in disease activity according to the ACR criteria (ACR20 response) was achieved by 72% and 67% of patients receiving i.v. and s.c. adalimumab respectively, compared with 28% for placebo (p < or = 0.01 and p < or = 0.05, respectively, versus placebo). By Day 15 after the first and second injections, statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v. or s.c. adalimumab compared with placebo (p < or = 0.05). The mean times to second injection for i.v. adalimumab, s.c. adalimumab, and placebo were 42.2 days (range: 27-84 days), 38.3 days (range: 26-85 days), and 28.4 days (range: 26-32 days), respectively (minimum time allowed by the protocol between the first and second injections was 4 weeks). Adalimumab in combination with MTX was well tolerated, with no patients being withdrawn because of adverse events.\n Either i.v. or s.c. adalimumab added to MTX significantly improved the signs and symptoms of RA compared with MTX alone. Subcutaneously administered adalimumab appeared to provide a response that was as great, as rapid, and as enduring as that with i.v. adalimumab.", "Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept.\n 542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3-24 months were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494).\n 274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44-56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23-33%) taking methotrexate alone (effect difference 22.05%, 95%CI 13.96-30.15%, p<0.0001). 487 evaluable patients had severe disease (DAS28>5.1). 196 of 246 (80%, 75-85%) and 135 of 230 (59%, 53-65%), respectively, achieved radiographic non-progression (20.98%, 12.97-29.09%, p<0.0001). Serious adverse events were similar between groups.\n Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate.\n Wyeth Research.", "Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 +/- 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 +/- 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies." ]	On the basis of the studies reviewed here, adalimumab in combination with methotrexate is efficacious and safe in the treatment of the rheumatoid arthritis. Adalimumab 40 mg sc e.o.w. and 20 mg e.w. slows the radiographic progression at 52 weeks. Adalimumab in combination with DMARDs other than methotrexate is also efficacious and safe, even though data from one only study are available and the number of patients in each group is low. Adalimumab in monotherapy is efficacious and safe in the treatment of the rheumatoid arthritis but the effect size is lower than with combined therapy.
CD005647	[ "15172774", "18505387", "9636863", "9203426" ]	[ "Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial.", "High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial.", "Combination therapy with fluconazole and flucytosine for cryptococcal meningitis in Ugandan patients with AIDS.", "Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group." ]	[ "It frequently takes more than 2 weeks for drug treatments for cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis.\n 64 patients with a first episode of HIV-associated cryptococcal meningitis were randomised to initial treatment with: amphotericin B (0.7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment.\n Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0.0006), amphotericin B plus fluconazole ( p=0.02), or triple therapy (p=0.02).\n At these doses, amphotericin B plus flucytosine is the most rapidly fungicidal regimen. Quantification of CSF cultures provides a powerful new means to accurately assess the fungicidal activity of new treatment regimens for cryptococcal meningitis.", "The standard therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis of amphotericin B (AmB; 0.7 mg/kg per day) plus flucytosine frequently takes >2 weeks to sterilize the cerebral spinal fluid, and acute mortality remains high. A dosage range for AmB of 0.7-1 mg/kg per day is noted in current guidelines, but there are no data comparing 0.7 mg/kg per day with 1 mg/kg per day.\n Sixty-four HIV-seropositive, antiretroviral therapy-naive patients in Cape Town, South Africa, who experienced their first episode of cryptococcal meningitis during the period May 2005-June 2006 were randomized to receive either (1) AmB, 0.7 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 1; 30 patients); or (2) AmB, 1 mg/kg per day, plus flucytosine, 25 mg/kg 4 times per day (group 2; 34 patients). Regimens were given for 2 weeks, followed by treatment with oral fluconazole. The primary outcome measure was early fungicidal activity, as determined by results of serial, quantitative cerebral spinal fluid cryptococcal cultures. Secondary outcome measures were safety and mortality. The median duration of follow-up was 1 year.\n Early fungicidal activity was significantly greater for group 2 than for group 1 (mean +/- SD, -0.56 +/- 0.24 vs. -0.45 +/- 0.16 log cfu/mL of cerebral spinal fluid per day; P = .02). The incidence of renal impairment did not significantly differ between the 2 groups. Anemia was associated with female sex and, less strongly, with membership in group 2. Renal impairment and anemia reversed after the regimen was switched to fluconazole. Two- and 10-week mortality rates were 6% and 24%, respectively, with no difference between groups.\n AmB, 1 mg/kg per day, plus flucytosine is more rapidly fungicidal than is standard-dose AmB plus flucytosine. Because of its size, this study provides limited data on any difference in toxicity between the regimens, but toxicities were manageable and reversible.\n ISRCTN68133435 (http://www.controlled-trials.com).", "We performed a randomized trial in which combination therapy with fluconazole and short-term flucytosine was compared with fluconazole monotherapy in 58 patients with AIDS-associated cryptococcal meningitis (CM). Thirty of these patients were randomized to receive combination therapy with fluconazole, 200 mg once a day for 2 months, and flucytosine, 150 mg/(kg.d) for the first 2 weeks, and 28 were randomized to receive monotherapy with fluconazole at the same dose for 2 months. Patients in both groups who survived for 2 months received fluconazole as maintenance therapy at a dose of 200 mg three times per week for 4 months. The combination therapy prevented death within 2 weeks and significantly increased the survival rate among these patients (32%) at 6 months over that among patients receiving monotherapy (12%) (P = .022). The combination therapy also resulted in a significant decrease in the severity of headache after 1 month of treatment, compared with monotherapy (P = .005). No serious adverse reactions were observed in patients receiving either regimen. These data indicate that treatment with fluconazole and short-term flucytosine is a cost-effective and safe regimen that improves the quality of life for patients with AIDS-associated CM in developing countries where human immunodeficiency virus is endemic.", "Treatment with low-dose amphotericin B (0.4 mg per kilogram of body weight per day) or oral azole therapy in patients with the acquired immunodeficiency syndrome (AIDS) and cryptococcal meningitis has been associated with high mortality and low rates of cerebrospinal fluid sterilization.\n In a double-blind multicenter trial we randomly assigned patients with a first episode of AIDS-associated cryptococcal meningitis to treatment with higher-dose amphotericin B (0.7 mg per kilogram per day) with or without flucytosine (100 mg per kilogram per day) for two weeks (step one), followed by eight weeks of treatment with itraconazole (400 mg per day) or fluconazole (400 mg per day) (step two). Treatment was considered successful if cerebrospinal fluid cultures were negative at 2 and 10 weeks or if the patient was clinically stable at 2 weeks and asymptomatic at 10 weeks.\n At two weeks, the cerebrospinal fluid cultures were negative in 60 percent of the 202 patients receiving amphotericin B plus flucytosine and in 51 percent of the 179 receiving amphotericin B alone (P=0.06). Elevated intracranial pressure was associated with death in 13 of 14 patients during step one. The clinical outcome did not differ significantly between the two groups. Seventy-two percent of the 151 fluconazole recipients and 60 percent of the 155 itraconazole recipients had negative cultures at 10 weeks (95 percent confidence interval for the difference in percentages, -100 to 21). The proportion of patients who had clinical responses was similar with fluconazole (68 percent) and itraconazole (70 percent). Overall mortality was 5.5 percent in the first two weeks and 3.9 percent in the next eight weeks, with no significant difference between the groups. In a multivariate analysis, the addition of flucytosine during the initial two weeks and treatment with fluconazole for the next eight weeks were independently associated with cerebrospinal fluid sterilization.\n For the initial treatment of AIDS-associated cryptococcal meningitis, the use of higher-dose amphotericin B plus flucytosine is associated with an increased rate of cerebrospinal fluid sterilization and decreased mortality at two weeks, as compared with regimens used in previous studies. Although consolidation therapy with fluconazole is associated with a higher rate of cerebrospinal fluid sterilization, itraconazole may be a suitable alternative for patients unable to take fluconazole." ]	The main aim of this review was to determine the best treatment for cryptococcal meningitis in resource-limited settings. In these settings usually only AmB and fluconazole are available. No studies suitable for inclusion in the review were found that compared these two drugs. Therefore we are unable to recommend either treatment as superior to the other. The recommended treatment for CM is a combination of AmB and flucytosine. The optimal dosing of AmB remains unclear. Liposomal AmB is associated with less adverse events than AmB and may be useful in selected patients where resources allow.Future research into the management of cryptococcal meningitis in resource-limited settings should focus on the most effective use of medications that are available in these settings.Flucytosine in combination with AmB leads to faster and increased sterilisation of CSF compared to using AmB alone. As Flucytosine is often not available in developing countries, policy makers and national departments of heath should consider procuring this drug for HIV treatment programmes.
CD005504	[ "10617168", "17274039", "11248591", "15164191", "10894991", "16641323", "16211594", "11575866" ]	[ "Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial.", "Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi-center, randomized, active controlled trial.", "Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study.", "Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid.", "Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group.", "Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures.", "Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.", "Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa." ]	[ "To investigate the efficacy and safety of levodopa plus benserazide in the treatment of restless legs syndrome (RLS), in terms of the frequency of periodic limb movements (PLMs), objective and subjective criteria of sleep, onset of action, and withdrawal effects.\n A randomized, double-blind, placebo-controlled, multicenter, crossover trial, with two 4-week treatment periods.\n Outpatient units of three specialist centers in Germany.\n Eligible patients had to fulfill the diagnostic criteria of the International RLS Study Group and have sleep disturbances and PLMs during sleep shown on polysomnography at screening. Thirty-five patients were recruited, of whom 32 (13 men, 19 women) completed the study.\n Patients received a single dose of standard-release levodopa/benserazide 100/25 mg or placebo at bedtime each night for 4 weeks, before crossing over to receive the alternative treatment for a further 4 weeks; the dose could be doubled if required. The average dosages were 159 +/- 31 mg of levodopa and 1.56 +/- 0.29 capsules of placebo.\n Levodopa/benserazide significantly reduced the number of PLMs per hour (p<0.0001), increased the time in bed without limb movements (p<0.0001), and improved subjective quality of sleep (p=0.0004). The onset of action was rapid after the first dose, and full efficacy was achieved within the first few days of therapy; these improvements disappeared immediately when treatment was discontinued. Levodopa/benserazide treatment was well tolerated and safe.\n Levodopa/benserazide is effective and safe in the treatment of RLS. Objective and subjective measures of sleep improved rapidly after the first dose. RLS symptoms recurred immediately after treatment was discontinued.", "We report the first large-scale double-blind, randomly assigned study to compare two active dopaminergic therapies for Restless Legs Syndrome (RLS), the dopamine agonist cabergoline (CAB) and levodopa/benserazide (levodopa). Patients with idiopathic RLS were treated with fixed daily doses of 2 or 3 mg CAB or 200 or 300 mg levodopa for 30 weeks. Efficacy was assessed by changes in the IRLS (International RLS Severity Scale) and by time to discontinuation of treatment due to loss of efficacy or augmentation. 361 of 418 screened patients (age 58 +/- 12 years, 71% females) were randomly assigned and treated (CAB: n = 178; levodopa: n = 183) in 51 centers of four European countries. Baseline IRLS total score was 25.7 +/- 6.8. The baseline-adjusted mean change from baseline to week 6 in IRLS sum score was d = -16.1 in the CAB group and d = -9.5 in the levodopa group (d = -6.6, P < 0.0001). More patients in the levodopa group (24.0%) than in the CAB group (11.9%, P = 0.0029, log-rank test) discontinued because of loss of efficacy (14.2% vs. 7.9%, P = 0.0290) or augmentation (9.8% vs. 4.0%, P = 0.0412). Adverse events (AEs) occurred in 83.1% of the CAB group and in 77.6% of the levodopa group. In both groups, most frequent AEs were gastrointestinal symptoms (CAB: 55.6%, levodopa: 30.6%, P < 0.0001). This first large-scale active controlled study in RLS showed superior efficacy of cabergoline versus levodopa after a 30-week long-term therapy. Tolerability was found more favorable with levodopa than with cabergoline.", "Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.", "We aimed to compare the efficacy of valproic acid (VPA) on paresthesias and sleep in RLS to that of levodopa (LD). Twenty patients with idiopathic restless legs syndrome (RLS) were treated with 600 mg slow-release VPA and 200 mg slow-release LD+50mg benserazid in a randomized, placebo-controlled, cross-over, double-blind setting with polysomography (PSG) at the end of each 3-week treatment periods. There was no major difference between the efficacy of valproic acid or LD. Periodic leg movements in sleep (PLMS) and PLM arousal index (PLMAI) significantly decreased with LD (p < or= 0.005). However, LD, but not VPA, significantly increased arousals not associated with PLMS (p = 0.002). Decrease of intensity and duration of RLS symptoms were more pronounced with VPA (p < or= 0.022) than with LD (NS). We conclude that slow-release VPA provides a treatment alternative for RLS.", "The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.\n Copyright 2000 S. Karger AG, Basel", "To evaluate the efficacy and tolerability of levetiracetam (LEV) as adjunctive therapy in children (4 to 16 years) with treatment-resistant partial-onset seizures.\n This multicenter, randomized, placebo-controlled trial consisted of an 8-week baseline period followed by a 14-week double-blind treatment period. During the treatment period, patients received either placebo or LEV add-on therapy and were up-titrated to a target dose of 60 mg/kg/day.\n One hundred ninety-eight patients (intent-to-treat population) provided evaluable data. The reduction in partial-onset seizure frequency per week for LEV adjunctive therapy over placebo adjunctive therapy was significant (26.8%; p = 0.0002; 95% CI 14.0% to 37.6%). A 50% or greater reduction of partial seizure frequency per week was attained in 44.6% of the LEV group (45/101 patients), compared with 19.6% (19/97 patients) receiving placebo (p = 0.0002). Seven (6.9%) LEV-treated patients were seizure-free during the entire double-blind treatment period, compared with one (1.0%) placebo-treated patient. One or more adverse events were reported by 88.1% of LEV-treated patients and 91.8% of placebo patients. The most common treatment-emergent adverse events were somnolence, accidental injury, vomiting, anorexia, hostility, nervousness, rhinitis, cough, and pharyngitis. A similar number of patients in each group required a dose reduction or withdrew from the study as a result of an adverse event.\n Levetiracetam adjunctive therapy administered at 60 mg/kg/day is efficacious and well tolerated in children with treatment-resistant partial seizures.", "Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing \"rescue\" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa \"rescue\" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.\n (c) 2005 Movement Disorder Society.", "Rasagiline mesylate (TVP-1012) is a potent, selective, non-reversible MAO-B inhibitor, without the tyramine-potentiating effect and with neuroprotective activities. The benefit of rasagiline as monotherapy in patients with early Parkinson's disease (PD) has already been reported. To evaluate the safety, tolerability, and clinical effect of rasagiline as adjunctive therapy to levodopa, a multicenter, double-blind, randomized, placebo-controlled, parallel-group study (0.5, 1, and 2 mg/d) was conducted for 12 weeks in 70 patients with PD (mean age, 57.4 y; mean disease duration, 5.7 y; 32 patients had motor fluctuations). A beneficial clinical effect was observed in fluctuating patients treated with rasagiline (all doses), expressed as a decrease in total Unified Parkinson's Disease Rating Scale (UPDRS) score (23.0% vs 8.5% in the placebo group). The treatment effect was still evident 6 weeks after drug discontinuation (in all doses). The safety and tolerability of rasagiline were good. Adverse events were no different than those of patients taking placebo. Almost complete platelet MAO-B inhibition was obtained at all rasagiline doses. This study has demonstrated that rasagiline (up to 2 mg/day) has a good safety profile and a beneficial clinical effect in fluctuating patients with PD when given as an add-on to chronic levodopa therapy." ]	Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently.
CD004659	[ "2858710", "9509950", "8475955", "16158479", "14746947", "8608096", "8413387", "12742332", "8758317", "9494145", "8532271", "9532989", "2664522", "1622907", "9322987", "9163613", "9532988", "2035557", "11368138", "2664523", "3051530", "10476618", "12632426", "8904056", "12220757", "16769056", "12742333", "112475", "9219700", "9065133", "10523401", "7930659", "15037402", "11197445" ]	[ "Prevention of pre-eclampsia by early antiplatelet therapy.", "A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia.", "Low-dose aspirin therapy to prevent preeclampsia.", "Usefulness of aspirin therapy in high-risk pregnant women with abnormal uterine artery Doppler ultrasound at 14-16 weeks pregnancy: randomized controlled clinical trial.", "A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia.", "ECPPA: randomised trial of low dose aspirin for the prevention of maternal and fetal complications in high risk pregnant women. ECPPA (Estudo Colaborativo para Prevenção da Pré-eclampsia com Aspirina) Collaborative Group.", "Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.", "Aspirin (100 mg) used for prevention of pre-eclampsia in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 1).", "A prospective randomized placebo-controlled trial of low-dose aspirin for prevention of intra-uterine growth retardation.", "Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.", "A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow.", "A randomised trial of low dose aspirin for primiparae in pregnancy. The Jamaica Low Dose Aspirin Study Group.", "The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies.", "A randomized placebo-controlled study of the effect of low dose aspirin on platelet reactivity and serum thromboxane B2 production in non-pregnant women, in normal pregnancy, and in gestational hypertension.", "Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women.", "Low-dose aspirin in polycythaemia vera: a pilot study. Gruppo Italiano Studio Policitemia (GISP).", "Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications.", "Effect of low-dose aspirin on vascular refractoriness in angiotensin-sensitive primigravid women.", "Screening with a uterine Doppler in low risk pregnant women followed by low dose aspirin in women with abnormal results: a multicenter randomised controlled trial.", "Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension.", "Danish very-low-dose aspirin after carotid endarterectomy trial.", "Calcium and low-dose aspirin prophylaxis in women at high risk of pregnancy-induced hypertension.", "Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies.", "Low dose aspirin in prevention of pregnancy-induced hypertension in primigravidae at the Muhimbili Medical Center, Dar es Salaam.", "Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.", "A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages.", "Randomised comparison of uterine artery Doppler and aspirin (100 mg) with placebo in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 2).", "Prevention of thrombosis in patients on hemodialysis by low-dose aspirin.", "Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss.", "Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.", "Administration time-dependent effects of aspirin in women at differing risk for preeclampsia.", "A study of use of low dose aspirin in prevention of pregnancy induced hypertension.", "Adjuvant low-dose aspirin therapy in poor responders undergoing in vitro fertilization: a prospective, randomized, double-blind, placebo-controlled trial.", "Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project." ]	[ "102 patients at high risk of pre-eclampsia and/or fetal growth retardation were randomly allocated to treatment with 300 mg dipyridamole and 150 mg aspirin daily from 3 months' gestation onwards (group A) or to the control group (group B, no treatment). Group A was twice as likely as group B to have a normal pregnancy. Pre-eclampsia occurred in 6 patients in group B and none in group A. Major complications (fetal death or severe growth retardation) occurred in 9 patients in group B and none in group A. Platelet count and plasma volume were significantly higher in group A than in group B throughout pregnancy. The treatment did not produce serious adverse effects. Antiplatelet therapy given early in pregnancy to high-risk patients may thus protect against pre-eclampsia and fetal growth retardation.", "To determine whether low-dose aspirin reduces the incidence of pre-eclampsia, reduces perinatal mortality and improves birth weights in pregnant women considered at high risk of developing pre-eclampsia.\n Two-hundred fifty subjects were recruited from the antenatal clinics at Harare Central Hospital with either a previous history of pregnancy-induced hypertension or pre-existing chronic hypertension and were randomized to receive either 75 mg of aspirin (ASA) or placebo (PLA).\n Two-hundred thirty subjects (ASA, n = 113; PLA, n = 117) completed the trial. The odds of developing pre-eclampsia for those on aspirin was 0.72 times those on placebo (95% CI, 0.34-1.52). The mean birth weight was 2774 g for those on aspirin and 2694 g for those on placebo (P = 0.80). No difference was noted in the perinatal deaths (OR = 0.38; 95% CI, 0.10-1.20).\n Prophylactic use of aspirin was not associated with a significant effect on the major pregnancy outcomes assessed in this study.", "Our aim was to test the hypothesis that acetylsalicylate (aspirin) treatment reduces the incidence or severity of pregnancy-associated hypertension.\n Patients were nulliparous, healthy, and with a singleton gestation at between 20 and 22 weeks' gestation. A sample size of 600 patients was calculated on the basis of p < or = 0.05 and 90% power of observation. A 2-week placebo-controlled \"run-in\" was used to select compliant patients. Randomization occurred at 24 weeks, with 60 mg of aspirin or placebo treatment from randomization to delivery.\n Follow-up was maintained on 99% of the patients. The randomized patients had a 94% pill compliance index. At randomization, serum thromboxane medians were similar in both groups. Thromboxane B2 levels in the aspirin group decreased significantly from baseline at 29 to 31 weeks, 34 to 36 weeks, and at delivery as compared with an overall increase in the placebo group. Preeclampsia developed in five of 302 women (1.7%) who received aspirin versus 17 of 302 (5.6%) who received the placebo (p = 0.009). Preeclampsia was severe in one aspirin and in six placebo recipients (p = 0.06).\n Daily ingestion of 60 mg of aspirin beginning at 24 weeks' gestation significantly reduced the occurrence of preeclampsia.", "To assess the effectiveness of low-dose aspirin in the prevention of preeclampsia and intrauterine growth restriction (IUGR) in high-risk pregnant women with abnormal findings at uterine artery Doppler velocimetry performed at 14-16 weeks.\n Randomized controlled clinical trial.\n Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Egypt.\n The trial enrolled 139 women at risk of preeclampsia or IUGR, with abnormal uterine artery Doppler findings that included the presence of unilateral or bilateral diastolic notch, high resistance index (RI), or high pulsatility index (PI) at 14-16 weeks of gestation. The women were randomly allocated into two groups, one receiving aspirin since admission to hospital (n=74) and the other serving as control (n=65). All women were followed up until delivery to assess maternal and perinatal outcomes. T-test was used for comparison of quantitative variables, and categorical variables were compared by chi2 test. OUTCOME CRITERIA: Development of mild or severe preeclampsia, time of onset of preeclampsia, preterm delivery, and the development of IUGR.\n Preeclampsia developed in 35% of women receiving aspirin and 62% of women in the control group (P=0.003), with severe preeclampsia developing in 8% and 23% of women (P=0.215), respectively. Preeclampsia before 37 weeks of gestation was recorded in only 4% of women receiving aspirin as opposed to 83% of controls (P<0.001). In the group of women receiving aspirin, 19% of newborns suffered from IUGR as opposed to 32%of newborns in the control group (P=0.106). There was no significant difference between the two groups in the rate of preterm delivery (P=0.080), mode of delivery (P=0.971), Apgar score <5 after one minute (P=0.273) and after 5 minutes (P=0.941), maternal or neonatal bleeding (P=0.948), and neonatal birth weight (P=0.399).\n Low-dose aspirin administered as early as 14-16 weeks of gestation to pregnant women at high risk of preeclampsia with abnormal uterine Doppler findings may reduce or modify the course of severe preeclampsia. Its effects on the prevention of IUGR need further evaluation.", "To determine if aspirin (ASA) therapy reduces the incidence of pre-eclampsia in women at high risk of this condition.\n Randomised clinical trial. We recruited pregnant women with gestational age at randomisation <14 weeks, who satisfied the following criteria: chronic hypertension, history of severe pre-eclampsia or eclampsia or intrauterine growth retardation (IUGR) or intrauterine foetal death. Nineteen women in the no-treatment group and 16 in the ASA group were successfully followed up.\n The mean birthweight was higher in the ASA group than in the no-treatment group (2790 g (S.D. 340 g) versus 2616 g (S.D. 779 g)), but the difference was not statistically significant. We found no statistically significant differences between the groups in the proportion of infants with birthweight below 2500 g (13.3% versus 29.4%) and the number of cases with pregnancy-induced hypertension (PIH)/pre-eclampsia (31.3% versus 36.8%).\n These limited data give some support to the potential favourable effect of early treatment with ASA in pregnant women at risk of PIH and IUGR.", "To determine the effectiveness of low dose aspirin in women at high risk of adverse outcomes associated with pre-eclampsia.\n A collaborative randomised trial comparing the effects of low dose aspirin (60 mg) with placebo on pre-eclampsia and other materno-fetal complications associated with hypertension.\n Twelve teaching maternity hospitals and 182 obstetricians' offices in Brazil.\n One thousand and nine women considered to be at high risk for the development of pre-eclampsia, or its complications, entered the study between 12 and 32 weeks of gestation. They were randomly allocated to receive aspirin (498 women) or placebo (511 women) until delivery, and follow up was obtained for 96%.\n There were no significant differences between the treatment groups in the incidence of proteinuric pre-eclampsia (6.7% aspirin-allocated compared with 6.0% placebo-allocated women), of preterm delivery (22.3% compared with 26.1%), of intrauterine growth retardation (8.5% compared with 10.1%), or of stillbirth and neonatal death (7.3% compared with 6.0%), nor were there significant differences in the incidence of proteinuric pre-eclampsia in any subgroup of women studied, including those who had systolic blood pressures of 120 mmHg or above at entry (8.5% compared with 7.3%) or those who were chronically hypertensive (10.0% compared with 7.1%). Aspirin was not associated with a significant excess of maternal or fetal bleeding.\n The results of this study do not support the routine prophylactic administration of low dose aspirin in pregnancy to any category of high risk women (even those who have chronic hypertension or who are considered to be especially liable to early onset pre-eclampsia).", "Although low-dose aspirin has been reported to reduce the incidence of preeclampsia among women at high risk for this complication, its efficacy and safety in healthy, nulliparous pregnant women are not known.\n We studied 3135 normotensive nulliparous women who were 13 to 26 weeks pregnant to determine whether treatment with aspirin reduced the incidence of preeclampsia. Of this group, 1570 women received 60 mg of aspirin per day and 1565 received placebo for the remainder of their pregnancies. We also evaluated the effect of aspirin on maternal and neonatal morbidity.\n Of the original group of 3135 women, 2985 (95 percent) were followed throughout pregnancy and the immediate puerperium. The incidence of preeclampsia was lower in the aspirin group (69 of 1485 women [4.6 percent]) than in the placebo group (94 of 1500 women [6.3 percent]) (relative risk, 0.7; 95 percent confidence interval, 0.6 to 1.0; P = 0.05), whereas the incidence of gestational hypertension was 6.7 and 5.9 percent, respectively. There were no significant differences in the infants' birth weight or in the incidence of fetal growth retardation, postpartum hemorrhage, or neonatal bleeding problems between the two groups. Subgroup analysis showed that preeclampsia occurred primarily in women whose initial systolic blood pressure was 120 to 134 mm Hg (incidence among such women, 5.6 percent in the aspirin group vs. 11.9 percent in the placebo group; P = 0.01). The incidence of abruptio placentae was greater among the women who received aspirin (11 women, vs. 2 in the placebo group; P = 0.01).\n Low-dose aspirin decreases the incidence of preeclampsia among nulliparous women, primarily through its effect in those who have elevated systolic blood pressure initially. This treatment does not decrease perinatal morbidity but increases the risk of abruptio placentae.", "To reduce the incidence of pre-eclampsia in nulliparous women, in accordance with the suggestion of a recent meta-analysis that low dose aspirin might decrease this incidence by more than half if used early enough in and at a sufficient dose during pregnancy (more than 75 mg).\n Multicentre randomised double-blinded placebo-controlled trial.\n Twenty eight centres in Northern of France and one in Belgium.\n Three thousand and two hundred ninety-four nulliparous women recruited between 14 and 20 weeks.\n Randomisation to either 100 mg aspirin or placebo daily from inclusion through 34 weeks.\n Preeclampsia was defined as hypertension (> or =140 and or 90 mmHg) associated with proteinuria (> or =0.5 g/L).\n The aspirin (n = 1644) and placebo (n = 1650) groups did not differ significantly in the mothers' incidence of pre-eclampsia (28 of 1632 [1.7%] vs 26 of 1637 [1.6%]; relative risk, RR, 1.08, 95% CI 0.64-1.83), hypertension, HELLP syndrome or placental abruption, or in the children's incidence of perinatal deaths or birthweight below the 10th centile. The incidence of babies with birthweight below the third centile was significantly higher in the aspirin group, with no explanation. The incidence of maternal side effects was higher in the aspirin group, principally because of a significantly higher rate of haemorrhage.\n Aspirin at a dose of 100 mg does not reduce the incidence of pre-eclampsia in nulliparous women. Aspirin (100 mg) is associated with an increase in bleeding complications.", "To evaluate the effects of low-dose aspirin on placental circulation and on the prevention of intrauterine growth retardation (IUGR).\n We conducted a prospective randomized, double blind, controlled clinical trial in 84 pregnant women (mainly nulliparous women) at high risk of IUGR. From the 28th-30th week of gestation onward, low dose aspirin (75 mg daily, study group, n = 40) or placebo (control group, n = 44) was given consecutively for 6 to 8 weeks. Pulse-wave umbilical artery Doppler velocimetry was measured before and after drug use.\n The mean value of systolic/diastolic ratio of umbilical artery flow velocity waveforms in the study group was significantly lower than that in the control group after drug use, but there was no difference between the two groups before drug use. The incidences of IRGR and preeclampsia in the study group (7.5% and 10.0% respectively) were significantly lower than those in the control group (27.3% of both). No adverse effects of low dose aspirin on both mother and fetus were observed.\n Low dose aspirin administration (75 mg daily) beginning at the early stage of third trimester may improve the fetoplacental circulation, and thus prevent IUGR and/or preeclampsia effectively.", "Whether low-dose aspirin prevents preeclampsia is unclear. It is not recommended as prophylaxis in women at low risk for preeclampsia but may reduce the incidence of the disease in women at high risk.\n We conducted a double-blind, randomized, placebo-controlled trial in four groups of pregnant women at high risk for preeclampsia, including 471 women with pregestational insulin-treated diabetes mellitus, 774 women with chronic hypertension, 688 women with multifetal gestations, and 606 women who had had preeclampsia during a previous pregnancy. The women were enrolled between gestational weeks 13 and 26 and received either 60 mg of aspirin or placebo daily.\n Outcome data were obtained on all but 36 of the 2539 women who entered the study. The incidence of preeclampsia was similar in the 1254 women in the aspirin group and the 1249 women in the placebo group (aspirin, 18 percent; placebo, 20 percent; P=0.23). The incidences in the aspirin and placebo groups for each of the four high-risk categories were also similar: for women with pregestational diabetes mellitus, the incidence was 18 percent in the aspirin group and 22 percent in the placebo group (P=0.38); for women with chronic hypertension, 26 percent and 25 percent (P= 0.66); for those with multifetal gestations, 12 percent and 16 percent (P=0.10); and for those with preeclampsia during a previous pregnancy, 17 percent and 19 percent (P=0.47). In addition, the incidences of perinatal death, preterm birth, and infants small for gestational age were similar in the aspirin and placebo groups.\n In our study, low-dose aspirin did not reduce the incidence of preeclampsia significantly or improve perinatal outcomes in pregnant women at high risk for preeclampsia.", "To evaluate color Doppler imaging of the uterine arteries as a screening test in nulliparous women, and to examine the role of low-dose aspirin therapy in pregnancies with abnormal uteroplacental resistance.\n At the routine 18-week fetal morphology ultrasound scan, 955 nulliparous women underwent color Doppler imaging of the uterine arteries. Abnormal uteroplacental vascular resistance was defined with respect to both the systolic-diastolic ratio of the flow velocity waveform and the presence of an ipsilateral early diastolic notch. Those with abnormal uterine artery waveforms were asked to participate in a randomized controlled trial of aspirin therapy. Pregnancy outcomes were compared in women with normal or abnormal flow velocity waveforms, as well as in the two arms of the intervention study.\n Of 186 women with abnormal uteroplacental resistance according to criteria defined previously, 102 agreed to randomization to either low-dose aspirin (100 mg/day) or placebo for the remainder of the pregnancy. Abnormal uterine artery flow velocity waveforms were associated with statistically significant increases in preeclampsia (11 versus 4%), birth weight below the tenth percentile (28 versus 11%), and adverse pregnancy outcome (45 versus 28%). Prophylactic aspirin therapy did not result in a significant reduction in pregnancy complications.\n Abnormal uteroplacental resistance at 18 weeks' gestation was associated with a significant increase in adverse pregnancy outcome. Low-dose aspirin did not reduce pregnancy complications in women with uteroplacental insufficiency.", "To investigate whether low dose aspirin medication given to primiparous women provides benefit in preventing pre-eclampsia or intrauterine growth retardation.\n Randomised double-blind controlled trial of low dose aspirin and placebo in pregnancy.\n Residents of the parishes of Kingston and St Andrew, Jamaica; 6275 primiparae enrolled between 12 and 32 weeks of gestation.\n Hypertensive disorders of pregnancy (including pre-eclampsia and eclampsia), preterm delivery, and low birthweight. In addition, to assess whether enrollment early, rather than late had more beneficial effect. Possible adverse effects on the woman and her infant were monitored.\n Of enrolled primiparae, 97% were followed throughout pregnancy. There were no differences between those on aspirin and those on placebo in the development of hypertensive disorders (e.g. for a rise in diastolic pressure of 25 mmHg the odds ratio [OR] was 1.02 [95% CI 0.86-1.21]; for proteinuric pre-eclampsia OR 1.15 [95% CI 0.92-1.44]; eclampsia OR 0.82 [95% CI 0.44-1.53]); except for oedema which was significantly less prevalent in those on aspirin (OR 0.85 [95% CI 0.75-0.96]). Women on aspirin were no significantly less likely to deliver preterm (OR 0.93 [95% CI 0.79-1.09]) or have a larger fetus (mean birthweight difference 18 g [95% CI -9 to 45]). They were, however, significantly more likely to suffer from bleeding disorders antenatally, intrapartum and postpartum; for postpartum haemorrhage OR 1.40 (95% CI 1.13-1.73).\n This trial shows that low dose aspirin has no consistent beneficial effect in primiparae.", "We carried out a prospective, randomized, double-blind, placebo-controlled study to investigate the capacity of aspirin to prevent pregnancy-induced hypertension and to alter prostaglandin metabolism. A total of 791 pregnant women with various risk factors for pre-eclamptic toxemia were screened with use of the rollover test (a comparison of blood pressure before and after the woman rolls from her left side to her back) during week 28 or 29 of gestation. Of 69 women with abnormal results (an increase in blood pressure during the rollover test), 65 entered the study and were treated with a daily dose of either aspirin (100 mg; 34 women) or placebo (31 women) during the third trimester of pregnancy. The number of women in whom pregnancy-induced hypertension developed was significantly lower among the aspirin-treated than among the placebo-treated women (4 [11.8 percent] vs. 11 [35.5 percent]; P = 0.024); the same was true for the incidence of preeclamptic toxemia (1 [2.9 percent] vs 7 [22.6 percent]; P = 0.019). The mean ratio of serum levels of thromboxane A2 to serum levels of prostacyclin metabolites after three weeks of treatment decreased by 34.7 percent in the aspirin-treated group but increased by 51.2 percent in the placebo-treated group. No serious maternal or neonatal side effects of treatment occurred in either group. We conclude that low daily doses of aspirin taken during the third trimester of pregnancy significantly reduce the incidence of pregnancy-induced hypertension and pre-eclamptic toxemia in women at high risk for these disorders, possibly through the correction of an imbalance between levels of thromboxane and prostacyclin.", "To investigate the effect of 60 mg aspirin daily on platelet reactivity and prostaglandin production in various groups of patients. Similar regimens, which are thought to act through inhibition of platelet thromboxane production, are currently undergoing clinical assessment for the prevention of pre-eclampsia and intrauterine growth retardation.\n A prospective randomized placebo controlled study.\n University Hospital, Nottingham.\n 12 non-pregnant female volunteers, 18 normal primigravidae before 16 weeks gestation and 16 pregnant women admitted with gestational hypertension (GH) at a mean gestation of 38 weeks.\n In the non-pregnant women blood samples were taken before and after a 10-day course of 60 mg aspirin daily. The primigravidae had blood samples taken at 16 weeks and then they were randomized to receive either 60 mg aspirin daily or a matched placebo. Further blood samples were obtained at 28, 32 and 36 weeks.\n Changes in platelet reactivity and release reaction, and serum thromboxane production, were estimated in whole blood.\n 60 mg aspirin daily significantly inhibited cyclo-oxygenase dependent platelet aggregation, release reaction and serum thromboxane production in non-pregnant and pregnant women, and in women with GH (P less than 0.01). When adrenaline was used as the aggregating agent, the cyclo-oxygenase pathway was recruited in the increased reactivity seen in the third trimester of normal pregnancy, and was sensitive to inhibition by low dose aspirin.\n Low dose aspirin would appear to be an appropriate agent for the inhibition of platelet reactivity associated with hypertensive pregnancy.", "This study investigated the effects of low-dose acetylsalicylic acid (aspirin) on blood pressure in pregnant women who were at risk of developing gestational hypertension or preeclampsia and who received aspirin at different times of the day according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 100 pregnant women. Blood pressure for each subject was automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery. Women were randomly assigned to one of six groups according to treatment (placebo, 50 subjects or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Results indicated that there was (1) no effect on blood pressure from placebo at any time (P>.212) and (2) a highly statistically significant (P<.001) time-dependent effect on blood pressure from aspirin. There was no effect of aspirin on blood pressure at time 1 (compared with placebo), but the blood pressure reduction was highly statistically significant after time 2 and, to a greater extent, after time 3 (mean reduction of 12 and 8 mm Hg in 24 hours for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). These time-dependent effects of aspirin on blood pressure should be taken into account for the optimization of long-term aspirin administration at low doses for prevention of preeclampsia. In any meta-analysis of aspirin effects, inquiries about the time when the subjects took the drug are indicated and may account for discrepancies in the literature.", "In this pilot study, aimed at exploring the feasibility of a large-scale trial of low-dose aspirin in polycythaemia vera (PV), 112 PV patients (42 females, 70 males. aged 17-80 years) were selected for not having a clear indication for, or contraindication to, aspirin treatment and randomized to receive oral aspirin (40 mg/d) or placebo. Follow-up duration was 16 +/- 6 months. Measurements of thromboxane A2 production during whole blood clotting demonstrated complete inhibition of platelet cyclooxygenase activity in patients receiving aspirin. Aspirin administration was not associated with any bleeding complication. Within the limitations of the small sample size, this study indicates that a biochemically effective regimen of antiplatelet therapy is well tolerated in patients with polycythaemia vera and that a large-scale placebo-controlled trial is feasible.", "To determine whether prophylactic, low dose controlled-release aspirin improves outcome for pregnant women and their babies in Barbados.\n Randomised placebo-controlled trial.\n The Queen Elizabeth Hospital, Barbados.\n All women attending antenatal clinics between 12 and 32 weeks of gestation were eligible, if without specific contraindications to aspirin and unlikely to deliver immediately.\n Randomisation was computer-generated in the antenatal clinic; 1822 women were allocated to receive 75 mg controlled-release aspirin and 1825 matching placebo.\n Proteinuric pre-eclampsia, other pregnancy-induced hypertension, pregnancy duration, birthweight, stillbirths and neonatal deaths, major neonatal events.\n All but three women from each group were followed up successfully. Forty-four percent were primigravid, and 8% had previous obstetric complications. There were no significant differences between the allocated treatment groups in the incidence of proteinuric pre-eclampsia (40 [2.2%] of those allocated aspirin, compared with 46 [2.5%] allocated placebo), of preterm delivery (255 [14.0%] vs 270 [14.8%]), of birthweight < 1500 g (32 [1.7%] vs 33 [1.8%]) or of stillbirth and neonatal death (44 [2.4%] vs 38 [2.1%]). Aspirin was not associated with excess risk of maternal or fetal bleeding.\n The results of this study in Barbados do not support the routine use of low dose aspirin for prevention of pre-eclampsia or its complications, confirming results of previous large trials in other settings.", "The hypothesis that an enhanced vasopressor response to angiotensin II in pregnancy may be corrected by suppressing production of platelet thromboxane A2 with low-dose aspirin was tested in a randomized, placebo-controlled, double-blind trial. We studied 36 normotensive primigravid women with an elevated blood pressure response to intravenously infused angiotensin II at 28 weeks' gestation; 18 women received 60 mg of aspirin daily and the same number received matched placebo until 34 weeks' gestation, when angiotensin-sensitivity was again determined. In women taking aspirin, values of thrombin-induced platelet malondialdehyde production were approximately 10% of those determined in the placebo group, indicating marked suppression of thromboxane A2 synthesis. In the aspirin group vascular refractoriness to angiotensin II was restored in 14 of 17 treated women, by comparison with 5 of 15 women in the placebo group who had remained normotensive. These results support the hypothesis that prostacyclin/thromboxane imbalance is an important pathophysiologic factor in the development of the enhanced angiotensin-sensitivity associated with pregnancy-induced hypertensive disorders.", "To assess whether systematic screening with an uterine artery Doppler in low risk pregnant women followed by the prescription of low dose aspirin in cases with abnormal results reduced the incidence of intrauterine growth restriction and pre-eclampsia.\n A multicentre randomised trial.\n 3,317 low risk pregnant women. In the Doppler group, the uterine artery Doppler was performed between 20 and 24 weeks. Women with abnormal results received 100 mg of aspirin daily until the 35th week.\n Intrauterine growth restriction was defined as birthweight below the tenth and the third centile according to gestational age. Pre-eclampsia was defined as hypertension associated with proteinuria > 0.5g/L.\n Intrauterine growth restriction, whether defined by the third or tenth centile, did not differ significantly between the two groups (RR = 1.22 [0.73 - 2.04] and 1.18 [0.93 - 1.51] respectively). Screening with uterine artery Doppler did not affect birthweight or any of the criteria of perinatal morbidity. There was no effect on the incidence of pre-eclampsia (RR = 1.99 [0.97 - 4.09]) or hypertensive disorders. These results were the same for nulliparae and multiparae.\n There is no justification for screening with uterine artery Doppler in a low risk population, even if abnormal results are followed by aspirin treatment and increased prenatal surveillance. Future studies must assess predictive tests that can be performed early in pregnancy and can identify populations at very high risk of pre-eclampsia and intrauterine growth restriction. Only when all of these conditions are fulfilled, aspirin or other treatments may prove its efficacy.", "There is evidence that aspirin in low doses favorably influences the course of pregnancy-induced hypertension, but the mechanism, although assumed to involve suppression of the production of thromboxane by platelets, has not been established. We performed a randomized study of the effect of the long-term daily administration of 60 mg of aspirin (n = 17) or placebo (n = 16) on platelet thromboxane A2 and vascular prostacyclin in women at risk for pregnancy-induced hypertension. Low doses of aspirin were associated with a longer pregnancy and increased weight of newborns. Serum levels of thromboxane B2, a stable product of thromboxane A2, were almost completely (greater than 90 percent) inhibited by low doses of aspirin. The urinary excretion of immunoreactive thromboxane B2 was significantly reduced without changes in the level of 6-keto-prostaglandin F1 alpha, a product of prostacyclin. Mass spectrometric analysis showed that aspirin reduced the excretion of the 2,3-dinor-thromboxane B2 metabolite--mainly of platelet origin--by 81 percent and of thromboxane B2, probably chiefly of renal origin, by 59 percent. The urinary excretion of 6-keto-prostaglandin F1 alpha and of its metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha was not affected. Low doses of aspirin only partially (63 percent) reduced neonatal serum thromboxane B2. No hemorrhagic complications were observed in the newborns. Thus, in women at risk for pregnancy-induced hypertension, low doses of aspirin selectively suppressed maternal platelet thromboxane B2 while sparing vascular prostacyclin, but only partially suppressed neonatal platelet thromboxane B2, allowing hemostatic competence in the fetus and newborn.", "The effect of very-low-dose aspirin as an antithrombotic agent was evaluated blindly in 301 patients who had recently undergone carotid endarterectomy. After randomization, 150 patients received aspirin and 151 received placebo. The two groups were comparable with regard to age, sex, blood pressure, previous cerebrovascular events, and smoking habits. The effect of the study medication on platelet aggregation was measured twice in each patient during the first 2 months and at each follow-up visit; the dose was individually adjusted. In 76% of the patients receiving aspirin, 50 mg/day gave satisfactory platelet inhibition, 13% needed 60 mg/day, 8% needed 70 mg/day, and 3% needed 100 mg/day. Platelet aggregation was found to be inhibited in only 1.2% of the measurements in the patients receiving placebo. Observation during treatment averaged 21 months; total intention-to-treat follow-up averaged 25 months. For the combined outcome events of transient ischemic attack, stroke, acute myocardial infarction, and vascular death, aspirin reduced risk by 11% (95% confidence limits: -38% to 48%, p greater than 0.1). Thus, there was no significant effect of very-low-dose aspirin in our trial.", "The objectives of the study were to confirm the validity of using oscillometric measurement of MAP in the left lateral position to identify those at high risk for developing pregnancy-induced hypertension (PIH), and to assess and compare the efficacy of prophylaxis with low-dose aspirin or calcium supplementation in high-risk patients.\n A prospective study in pregnancy; 500 normotensive, primigravid Chinese women were recruited in the second trimester of pregnancy on the basis of 80 mm Hg > or = MAP < 106 mm Hg in the antenatal clinic. They were then screened by Dinamap in a research setting, measuring MAP in the left lateral position after rest and using a cutoff value of 60 mm Hg for inclusion in the randomized study. Randomization was divided into three groups: control, low-dose aspirin, and calcium supplementation. After delivery, patients were classified as either having remained normotensive or having developed PIH, with or without proteinuria.\n The incidence of both proteinuric and nonproteinuric PIH was significantly lower in patients screened out as low risk than in those selected as high risk using a critical value of 60 mm Hg for left lateral MAP (p < 0.05). The incidence of proteinuric PIH was significantly lower in patients given low-dose aspirin than in the control group (p < 0.05). However, the confidence intervals for the effect were wide, comparable with aspirin having no effect or leading to a 16-fold reduction in the risk of preeclampsia. For those given calcium supplementation, the reduction was not significant. There was no significant difference in the incidence of nonproteinuric PIH between the control group and the two groups receiving prophylaxis.\n Oscillometric measurement of second-trimester left lateral MAP is a valid predictor of proteinuric PIH. Low-dose aspirin may offer a degree of protection from proteinuric PIH in these high-risk women. Calcium supplementation was not shown to significantly reduce the incidence of PIH.", "To compare the 2 most efficacious therapeutic regimens, intravenous immunoglobulin (IVIG) and anticoagulation with low molecular weight (LMW) heparin plus low-dose aspirin, in women with recurrent pregnancy loss associated with antiphospholipid antibodies (aPL).\n We examined 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant. The subjects were randomly assigned to treatment with IVIG or LMW heparin plus low-dose aspirin. Both therapies were started when the women were pregnant as documented by a positive urine test. IVIG was stopped at the thirty-first week of gestation, aspirin at the thirty-fourth week, and heparin at the thirty-seventh week. The primary outcome of interest was the rate of live births with the 2 treatments.\n The characteristics of the 2 groups were similar at the time of randomization. The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%).\n Treatment with LMW heparin plus low-dose aspirin should be considered as the standard therapy for recurrent pregnancy loss due to aPL.", "There is evidence that aspirin in low doses favourably influences the course and outcome of pregnancy in women at risk of developing pregnancy-induced hypertension. We conducted a double blind prospective randomized study to investigate the effect of low dose aspirin in preventing pregnancy-induced hypertension. Two hundred and one primigravidae from twenty weeks of pregnancy and above were screened using the roll-over test. Of the 127 women with an increase in blood pressure during the roll-over test, 126 women entered the study and were treated with a daily dose of either aspirin (80 mg) or placebo up to 10 days before the expected date of delivery. Samples of urine were collected for detection of aspirin. The incidence of pregnancy-induced hypertension in the aspirin treated group was significantly lower than in the placebo treated group; 3.17% versus 15.9% with a p value of 0.02. It is concluded that low daily doses of aspirin taken from twenty weeks of pregnancy significantly reduce the incidence of pregnancy-induced hypertension, possibly through the correction of an imbalance in levels of thromboxane and prostacyclin.", "To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss.\n From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic.\n Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group.\n A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome.", "To compare the effect of aspirin and enoxaparin on live births in women with unexplained recurrent miscarriages, as well as secondary outcomes including birth weight, uterine and umbilical blood flows, and congenital malformations.\n Multicenter randomized comparative cohort study.\n Four centers including two university hospitals, a peripheral general hospital, and a community health clinic.\n One hundred seven patients were randomized, 104 were available for analysis; 54 were randomized to enoxaparin and 50 to aspirin.\n Treatment with enoxaparin or aspirin in subsequent pregnancy.\n Subsequent live births or miscarriage, and the incidence of obstetric complications.\n Both groups had a similar live birth rate (relative risk = 0.92, 95% confidence interval: 0.58-1.46). In primary aborters, live births occurred in 17 of 18 (94%) enoxaparin-treated pregnancies compared to 18 of 22 (81%) aspirin-treated pregnancies. In the aspirin group, two pregnancies were terminated: for tricuspid insufficiency and for hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome. One enoxaparin-treated infant was growth restricted (2,020 g) at 36 weeks. Preeclampsia was found in three aspirin-treated patients. Preterm delivery, placental Doppler blood flow, apgar scores, and mean birth weights were similar in both groups. In the aspirin group, one infant underwent orchidectomy after testicular torsion in utero, and one infant had hypoglycemia and convulsions.\n Both regimens were associated with a high live birth rate and few late pregnancy complications.", "To assess the effectiveness of a pre-eclampsia prevention strategy based on routine uterine artery Doppler flow velocity waveform examination during the second trimester of pregnancy, followed by a prescription for 100 mg aspirin in the case of abnormal Doppler findings.\n Multicentre randomised controlled trial.\n Eleven centres in the north of France and one in Belgium.\n One thousand and eight hundred and fifty-three nulliparous women recruited between 14 and 20 weeks of gestation.\n Randomisation either to undergo a uterine Doppler examination between 22 and 24 week of gestation or to take a placebo. Women with abnormal Doppler waveforms received 100 mg of aspirin daily from Doppler examination through 36 weeks.\n Pre-eclampsia was defined as hypertension (> or = 140 and/or 90 mmHg) associated with proteinuria (> or = 0.5 g/L).\n One thousand two hundred and fifty-three women (67%) were randomised into the systematic Doppler group and 617 (33%) into the placebo group. Of the 1175 patients in the Doppler group who underwent this examination, 239 (20.3%) had abnormal uterine artery Doppler and received a prescription for aspirin. Despite the aspirin prescription, the frequency of pre-eclampsia did not differ between the systematic Doppler group and the placebo group (28 of 1237 [2.3%] vs 9 of 616 [1.5%]; RR = 1.55, 95% CI 0.7-3.3). Furthermore, the groups did not differ in the frequency of children who were very small for their gestational age (< or =3rd centile) or for perinatal deaths. Compared with patients with normal Doppler findings, those with abnormal Doppler were at high risk of pre-eclampsia (RR = 5.5, 95% CI 2.5-12.2) and of giving birth to a small-for-gestational-age child (RR = 3.6, 95% CI 1.6-8.1).\n Despite its sensitivity in screening for pre-eclampsia, routine uterine Doppler in the second trimester cannot be recommended for nulliparous patients.", "Since platelet cyclo-oxygenase is much more sensitive to inactivation by aspirin than is the enzyme in the arterial wall and low doses of aspirin may prevent thrombosis by blocking thromboxane synthesis, we conducted a randomized, double-blind trial of aspirin (160 mg per day) vs. placebo in 44 patients on chronic hemodialysis. The study was continued until there were 24 patients with thrombi and both groups had been under observation for a mean of nearly five months. Thrombi occurred in 18 of 25 (72 per cent) of patients given placebo and 16 of 19 (32 per cent) of those given aspirin (P less than 0.01). The incidence of thrombosis was reduced from 0.46 thrombi per patient month in the placebo group to 0.16 thrombi per patient month in the aspirin group (p less than 0.005). A dose of 160 mg of aspirin per day is an effective, nontoxic antithrombotic regimen in patients on hemodialysis.", "Recurrent fetal loss has been well described in women with antiphospholipid antibodies. Such women also often have other autoantibodies commonly found in patients with systemic lupus erythematosus. Treating them with prednisone and aspirin may reduce the risk of fetal loss.\n We screened 773 nonpregnant women who had the unexplained loss of at least two fetuses for antinuclear, anti-DNA, antilymphocyte, and anticardiolipin antibodies and for the lupus anticoagulant. Of 385 women with at least one autoantibody, 202 who later became pregnant were randomly assigned in equal numbers to receive either prednisone (0.5 to 0.8 mg per kilogram of body weight per day) and aspirin (100 mg per day) or placebo for the duration of the pregnancy. The women were stratified according to age (18 to 34 years or 35 to 39 years) and the week of gestation at which the previous fetal losses had occurred (< or = 12 or > 12 weeks). The primary outcome measure was a successful pregnancy.\n Live infants were born to 66 women in the treatment group (65 percent) and 57 women in the placebo group (56 percent, P=0.19). More infants were born prematurely in the treatment group than in the placebo group (62 percent vs. 12 percent, P<0.001). The major side effects of therapy in the mothers were hypertension (treatment group, 13 percent; placebo group, 5 percent; P=0.05) and diabetes mellitus (15 percent and 5 percent, P=0.02).\n Treating women who have autoantibodies and recurrent fetal loss with prednisone and aspirin is not effective in promoting live birth, and it increases the risk of prematurity.", "The purpose of this study was to compare the use of low-dose aspirin alone with heparin and low-dose aspirin in the treatment of the antiphospholipid antibody syndrome.\n A prospective, single-center trial included 50 patients who were alternately assigned to treatment. Each patient had at least three consecutive spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared by chi(2) analysis and Fisher's exact test.\n Viable infants were delivered of 11 of 25 (44%) women treated with aspirin and 20 of 25 (80%) women treated with heparin and aspirin (p < 0.05). There were no significant differences between the low-dose aspirin and the heparin plus low-dose aspirin groups with respect to gestational age at delivery (37.8 +/- 2.1 vs 37.2 +/- 3.4 weeks), number of cesarean sections (18% vs 20%), or complications.\n Heparin plus low-dose aspirin provides a significantly better pregnancy outcome than low-dose aspirin alone does for antiphospholipid antibody-associated recurrent pregnancy loss.", "This study extends previous results on the effects of low-dose aspirin on blood pressure in pregnant women at differing risk of developing hypertension in pregnancy and who received aspirin at different times according to their rest-activity cycle. A double-blind, randomized, placebo-controlled trial was conducted in 240 pregnant women randomly assigned to 1 of 6 groups according to treatment (placebo or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Blood pressure and heart rate for each subject were automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery, as well as at puerperium (6 to 8 weeks after delivery). Subjects were further divided for comparative purposes according to the results of the tolerance-hyperbaric test for early identification of those with a higher risk for developing hypertensive complications in pregnancy. Results indicated that there was no effect of aspirin on blood pressure at time 1 (compared with placebo). A blood pressure reduction was, however, highly statistically significant at time 2 and, to a greater extent, at time 3 (mean reductions of 14.2 and 9.6 mm Hg in 24-hour means for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). Effects of aspirin on blood pressure were significantly larger for women with a positive test at the time of recruitment (P<0.001). Differences in blood pressure among pregnant women receiving aspirin at different times in the circadian cycle disappeared at puerperium (P>0.212). There was no effect of aspirin or placebo on heart rate. This study corroborates the statistically significant, time-dependent effect of low-dose aspirin on blood pressure in pregnant women with differing risk of developing hypertensive complications in pregnancy. Although the mechanism involved in the administration-time-dependent responsiveness of blood pressure to aspirin still remains uncertain, the use of doses of aspirin <80 mg/d that do not affect placental thromboxane, initiation of the use of aspirin after 16 weeks' gestation, and the lack of circadian timing for aspirin administration could all explain the lack of positive results in previous clinical trials.", "Forty-six nulliparous women in third trimester of pregnancy with a raised blood pressure of 30 mm Hg (systolic) or/and 15 mm Hg (diastolic) or both, over baseline values were treated with 75 mg of aspirin per day. The results are compared with another 48 age, height, weight, and gestational period matched nulliparaous women with similar condition for trial selection, who were treated as control. There is considerable more number of cases in the control group than in aspirin treated group showing subsequent rise of BP, appearance of proteinuria, and severe pre-eclamptic toxaemia. The aspirin treated group showed increased mean gestational age at termination 39.4 +/- 2.6 weeks as against 38.2 +/- 3.4, increased foetal weight 2860 +/- 552 g as against 2540 +/- 720 g. No case of neonatal haemorrhagic manifestations or congenital malformations were seen. However not much result is obtained with aspirin therapy in cases with established pregnancy induced hypertension or with proteinuria. Hence it is concluded that aspirin therapy should be given to prevent pregnancy induced hypertension. As predictability of other screening tests are not unequivocal, criterion used in this series for screening may be used.", "To evaluate the effect of adjuvant low-dose aspirin on utero-ovarian blood flow and ovarian responsiveness in poor responders undergoing IVF.\n Prospective randomized, double-blind, placebo-controlled study.\n University-affiliated teaching hospital.\n Sixty patients classified as poor responders undergoing IVF.\n Supplementation with low-dose aspirin (80 mg daily) or placebo to a long down-regulation protocol.\n Doppler measurement of intraovarian and uterine pulsatility index was performed before (baseline) and after ovarian stimulation (day of hCG administration). Duration of use and dose of gonadotropins, cycle cancellation rate, number of mature follicles recruited, and oocytes retrieved were also measured.\n High cancellation rates were found in both groups (33.3% vs. 26.7%, placebo vs. treatment). There were no significant differences in total dose of hMG used (66 vs. 57 hMG, 75 IU ampules), median number of mature follicles recruited (3.5 vs. 3.0), or median number of oocytes retrieved (4 vs. 3). No significant differences were found in either intraovarian or uterine artery pulsatility index measured at baseline or on the day of hCG administration.\n Supplementation with low-dose aspirin failed to improve either ovarian and uterine blood flow or ovarian responsiveness in poor responders undergoing IVF.", "In addition to the treatment of specific cardiovascular risk factors, intervention which interferes with the general mechanisms of atherosclerosis could further reduce the incidence of cardiovascular events. We aimed to investigate in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with one or more major cardiovascular risk factors.\n We did a randomised controlled open 2x2 factorial trial to investigate low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events, in people with one or more of the following: hypertension, hypercholesterolaemia, diabetes, obesity, family history of premature myocardial infarction, or individuals who were elderly.\n 4495 people (2583 female, mean age 64.4 years) were included in the trial. After a mean follow-up of 3.6 years the trial was prematurely stopped on ethical grounds when newly available evidence from other trials on the benefit of aspirin in primary prevention was strictly consistent with the results of the second planned interim analysis. Aspirin lowered the frequency of all the endpoints, being significant for cardiovascular death (from 1.4 to 0.8%; relative risk 0.56 [95% CI 0.31-0.99]) and total cardiovascular events (from 8.2 to 6.3%; 0.77 [0.62-0.95]). Severe bleedings were more frequent in the aspirin group than the no-aspirin group (1.1% vs 0.3%; p<0.0008). Vitamin E showed no effect on any prespecified endpoint. Analyses were by intention-to-treat.\n In women and men at risk of having a cardiovascular event because of the presence of at least one major risk factor, low-dose aspirin given in addition to treatment of specific risk factors contributes an additional preventive effect, with an acceptable safety profile. The results on vitamin E's cardiovascular primary preventive efficacy are not conclusive per se, although our results are consistent with the negative results of other large published trials on secondary prevention." ]	Antiplatelet agents, largely low-dose aspirin, have moderate benefits when used for prevention of pre-eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose. [Note: The 16 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]
CD003717	[ "17848908", "18166837", "19152024" ]	[ "A randomised controlled study of an audiovisual patient information intervention on informed consent and recruitment to cancer clinical trials.", "An educational video to increase clinical trials enrollment among lung cancer patients.", "An educational video to increase clinical trials enrollment among breast cancer patients." ]	[ "Recruitment to cancer clinical trials needs to be improved, as does patient knowledge and understanding about clinical trials, in order for patients to make an informed choice about whether or not to take part. Audiovisual patient information (AVPI) has been shown to improve knowledge and understanding in various areas of practice, but there is limited information about its effect in the cancer clinical trial setting, particularly in relation to consent rates. In this study, 173 patients were randomised to receive either the AVPI, in addition to the standard trial-specific written information, or the written information alone. There was no difference in clinical trial recruitment rates between the two groups with similar study entry rates: 72.1% in the AVPI group and 75.9% in the standard information group. The estimated odds ratio for refusal (intervention/no intervention) was 1.19 (95% CI 0.55-2.58, P=0.661). Knowledge scores increased more in the AVPI group compared to the standard group (P=0.0072). The change in anxiety score between the arms was also statistically significant (P=0.011) with anxiety improving in the intervention arm more than in the no intervention arm. Audiovisual patient information was shown to be a useful tool in improving patient knowledge and anxiety, but further work is necessary in relation to its effect on clinical trial recruitment rates.", "Only 3 to 5% of new adult cancer patients participate in clinical trials nationwide. The lack of knowledge and awareness about clinical trials is a significant barrier to clinical trials participation. A randomized trial was conducted to test the effect of an educational video on positively changing patients' knowledge and attitudes regarding clinical trials and thereby increasing enrollment rates.\n Lung cancer patients were randomized to viewing either an 18-minute video about clinical trials before first clinic appointment or to standard care. Participants completed a baseline and 2-week postintervention survey to assess their knowledge and attitudes toward trials participation. Fisher's exact test tests, t tests, and regression were used to compare patient characteristics and outcomes between arms.\n Of 145 subjects randomized, 126 (63/arm) satisfied all inclusion criteria and were included in the analysis. A linear regression showed that the video intervention was significantly associated with patients' self-assessed likelihood to enroll score measured at 2-week follow-up (p = 0.019). Although statistically insignificant, enrollment rates were found to be higher in the intervention arm for therapeutic trials alone (17.5% versus 11.1%) and for therapeutic and nontherapeutic trials combined (25.4% versus 15.9%).\n The brief educational video seems to be effective in positively changing lung cancer patients' attitudes about participation in clinical trials. Higher enrollment rates were also observed in the intervention group but the differences did not reach statistical significance. These findings suggest a potential impact of the educational video on clinical trial enrollment; however, larger studies are needed to confirm these findings.", "Only 3% of women with breast cancer participate in cancer clinical trials nationwide. The lack of awareness about clinical trials is a significant barrier towards clinical trials participation. A study was conducted at a large urban Comprehensive Cancer Center to test (1) the effectiveness of an 18-min educational video on improving attitudes toward clinical trials and trials enrollment among new breast cancer patients seen at the Karmanos Cancer Institute, and (2) to assess racial differences in attitudes regarding clinical trials. Participants were randomized to either the educational intervention prior to their first oncology clinic appointment or to standard care. A baseline and 2-week post-intervention survey to assess attitudes toward clinical trials participation was completed by participants. Of 218 subjects recruited, 196 (55% white vs. 45% African American (AA)) eligible patients were included in the analysis. A small increase in therapeutic clinical trial enrollment was observed in the intervention arm but was not statistically significant (10.4% vs. 6.1%; P = 0.277). The intervention also did not result in a clear improvement in patients' attitudes toward clinical trials at posttest. However, a lower enrollment rate for the AA women was noted after adjusting for stage (OR = 0.282, P = 0.049). Significantly more negative scores were noted in 3 out of the 5 baseline attitudinal scales for AA women. The educational video did not significantly increase enrollment in breast cancer clinical trials. The findings that AA women had significantly more negative attitudes toward clinical trials than white women may partially explain the racial disparity in enrollment. An educational video remains a simple and cost-effective way to educate patients. Future studies should focus on designing a new educational video to specifically target cultural and attitudinal barriers in the AA population to more effectively change attitudes and increase trial enrollment." ]	The value of audio-visual interventions for people considering participating in clinical trials remains unclear. Evidence is mixed as to whether audio-visual interventions enhance people's knowledge of the trial they are considering entering, and/or the health condition the trial is designed to address; one study showed improved retention of knowledge amongst intervention recipients. The intervention may also have small positive effects on the quality of information disclosed, and may increase willingness to participate in the short-term; however the evidence is weak. There were no data for several primary outcomes, including harms. In the absence of clear results, triallists should continue to explore innovative methods of providing information to potential trial participants. Further research should take the form of high-quality randomised controlled trials, with clear reporting of methods. Studies should conduct content assessment of audio-visual and other innovative interventions for people of differing levels of understanding and education; also for different age and cultural groups. Researchers should assess systematically the effects of different intervention components and delivery characteristics, and should involve consumers in intervention development. Studies should assess additional outcomes relevant to individuals' decisional capacity, using validated tools, including satisfaction; anxiety; and adherence to the subsequent trial protocol.
CD000307	[ "692838", "345313", "11760", "6120655", "394015", "406212", "7032224", "6133287", "3555385", "6996426", "354331", "6349256", "224958", "390972", "22515", "10080557", "4571196", "4871473", "227340", "7393998", "233160", "4711886", "580285", "3549879", "7172160", "6371871", "7076630", "2575796", "329327", "6437365", "2870944", "4912332", "8104468", "3415422", "4011672", "98127", "504342", "6275811", "28102", "6818587", "1487623", "8161288", "4576449", "3322467", "6114503" ]	[ "Fluphenazine decanoate and fluphenazine enanthate in the out-patient management of chronic schizophrenia.", "A comparative controlled trial of pimozide and fluphenazine decanoate in the continuation therapy of schizophrenia.", "Very high dose fluphenazine decanoate: a controlled trial in chronic schizophrenia.", "Fluphenazine enanthate and fluphenazine decanoate in the treatment of schizophrenic outpatients: extrapyramidal symptoms and therapeutic effect.", "[Double-blind comparison of 2 depot neuroleptics (perphenazine enanthate and flupentixol decanoate) in chronic schizophrenia (author's transl)].", "Clinical and social comparison of fluphenazine decanoate and flupenthixol decanoate in the community maintenance therapy of schizophrenia.", "A depot neuroleptic withdrawal study. A controlled study of the clinical effects of the withdrawal of depot fluphenazine decanoate and depot flupenthixol decanoate in chronic schizophrenic patients.", "A double-blind comparative trial of the decanoates of clopenthixol and fluphenazine in the treatment of chronic schizophrenic out-patients.", "Low- and conventional-dose maintenance therapy with fluphenazine decanoate. Two-year outcome.", "Clopenthixol decanoate and perphenazine enanthate in schizophrenic patients. A double-blind Nordic multicentre trial.", "Double-blind therapeutic evaluation of fluspirilene compared with fluphenazine decanoate in chronic schizophrenics.", "Comparative double-blind study of flupenthixol decanoate and fluphenazine decanoate in the treatment of patients relapsing in a schizophrenic symptomatology.", "The effect of fluphenazine upon social and vocational functioning in remitted schizophrenics.", "A double-blind comparison of flupenthixol decanoate and fluphenazine decanoate in the treatment of chronic schizophrenia.", "[Comparison of the effects of pipothiazine palmitate and fluphenazine decanoate. Results of a multicenter double-blind trial].", "Comparative effectiveness of fluphenazine decanoate injections every 2 weeks versus every 6 weeks.", "Outpatient maintenance of chronic schizophrenic patients with long-acting fluphenazine: double-blind placebo trial. Report to the Medical Research Council Committee on Clinical Trials in Psychiatry.", "A comparative study of two long acting phenothiazine preparations, fluphenazine-enanthate and fluphenazine-decanoate.", "Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride.", "[Drug-response differences of high and standard dosage of fluphenazine-decanoate in relation to schizophrenic symptoms (author's transl)].", "Low dose fluphenazine decanoate in maintenance treatment of schizophrenia.", "Fluphenazine decanoate trial in chronic in-patient schizophrenics failing to absorb oral chlorpromazine.", "A long term comparative trial of penfluridol and fluphenazine decanoate in schizophrenic outpatients.", "Weight gain and prolactin levels in patients on long-term antipsychotic medication: a double-blind comparative trial of haloperidol decanoate and fluphenazine decanoate.", "A double-blind comparison of fluspirilene and fluphenazine decanoate in schizophrenia.", "A double-blind, controlled clinical trial of haloperidol decanoate and fluphenazine decanoate in the maintenance treatment of schizophrenia.", "Double-blind placebo substitution: withdrawal of fluphenazine decanoate in schizophrenic patients.", "A comparative study of pipothiazine palmitate and fluphenazine decanoate in the maintenance of remission of schizophrenia.", "A one-year double-blind comparison of long-acting oral (penfluridol) versus long-acting injectable (fluphenazine decanoate) antipsychotic drugs in multiple-episode schizophrenics.", "Costs and benefits of two doses of fluphenazine.", "A comparative trial of depot pipothiazine.", "A controlled comparative study of fluphenazine and fluphenazine enanthate in acute and chronic psychotic patients.", "The decanoates of flupenthixol and clopenthixol in the treatment of chronic schizophrenic in-patients. Implications for community psychiatry.", "Dose of fluphenazine, familial expressed emotion, and outcome in schizophrenia. Results of a two-year controlled study.", "Double-blind comparison of haloperidol decanoate and fluphenazine decanoate effectiveness, side-effects, dosage and serum levels during a six months' treatment for relapse prevention.", "Long-acting oral vs injectable antipsychotic drugs in schizophrenics: a one-year double-blind comparison in multiple episode schizophrenics.", "[A comparative study of the longacting neuroleptics perphenazin-enanthate and fluspirilene (author's transl)].", "Fluphenazine vs placebo in patients with remitted, acute first-episode schizophrenia.", "Standard and long-acting depot neuroleptics in chronic schizophrenics: an 18-month open multicentric study.", "A depot neuroleptic withdrawal study. Plasma concentration of fluphenazine and flupenthixol and relapse frequency.", "Positive and negative symptoms, depression and social disability in chronic schizophrenia: a comparative trial of bromperidol and fluphenazine decanoates.", "Fluphenazine vs placebo supplementation for prodromal signs of relapse in schizophrenia.", "Fluphenazine enanthate and fluphenazine decanoate: a comparison of their duration of action and motor side effects.", "Haloperidol decanoate v. fluphenazine decanoate as maintenance therapy in chronic schizophrenic in-patients.", "Clinical blood chemistry values and long acting phenothiazines." ]	[ "39 chronic schizophrenic out-patients were given either fluphenazine decanoate or enanthate for a 1-year double-blind trial. Doses of 25 mg were given for the first 6 months and 37.5 mg for the last 6 months. For both agents the intervals between treatments lengthened significantly over the course of the trial. Fluphenazine decanoate showed a non-significant trend for a longer duration of action coupled with a significantly lower incidence of extrapyramidal side effects.", "Evidence from a controlled, comparative trial indicates that oral pimozide is clinically at least as effective as depot injections of fluphenazine decanoate in the continuation therapy of a group of schizophrenic patients discharged from hospital. The administration of pimozide was associated with fewer unwanted effects. The implications of the findings are discussed.", "In a double-blind trial of six months' duration, a very high dose (VHD) regimen of fluphenazine decanoate (250 mg weekly) was compared with a standard dose (SD) regimen (12.5 mg weekly) in 50 chronic schizophrenic patients. The rating scales used included the Brief Psychiatric Rating Scale and the Wing Ward Behavior Scale. Both treatment groups improved during the trial, but there was no significant difference between them. The VHD regimen, however, exerted better control of the psychosis in that it had fewer patient dropouts and fewer \"additional treatments\" prescribed. Some of the patients receiving standard doses were probably not receiving adequate antipsychotic drug dosage. No predictors of clinical response could be defined. Extrapyramidal side effects were not significantly higher in the VHD group.", "nan", "nan", "The clinical and social effects of flupenthixol decanoate and fluphenazine decanoate were compared in the maintenance treatment of a population of chronic schizophrenic out-patients over a period of 9 months. The results failed to show significant difference between the treatments, and in particular, reports suggesting specific advantages for flupenthixol decanoate in alleviating the negative symptoms of apathy, anergia and depression in chronic schizophrenics were not confirmed. It seems that chronic schizophrenic patients who are well established on one depot preparation are unlikely to be benefited by being changed to the alternative.", "A double-blind withdrawal trial in 41 chronic schizophrenic outpatients on neuroleptics was carried out during 6 months. Long-acting neuroleptics (fluphenazine decanoate or flupenthixol decanoate) were used in comparison with placebo to determine the value in maintenance therapy. Most patients had a rather low maintenance dose, about 12.5-25 mg fluphenazine decanoate or 20-40 mg flupenthixol decanoate every third week. Relapse was often characterized by a return of the dame symptoms as the patient had during his first schizophrenic attack. Drugs were significantly more effective than placebo in preventing relapse and readmission to hospital. 62% relapsed in the placebo groups as compared with 27% in the drug group. All patients on active substance and without relapse during the controlled study had their treatment discontinued for 24 months in an open follow-up investigation. This resulted in relapse of all patients but one, i.e. a final relapse frequency of 97%. A significant weight decrease was observed in the placebo group. The risk of withdrawal is discussed.", "Forty-five patients were entered into a 24-week double-blind trial of clopenthixol decanoate and fluphenazine decanoate. The 24-week double-blind period was preceded by a 12-week open period. Of the 45 patients entered, 6 failed to attend the second interview and 1 left the country before the final assessment. Doses administered were in the range 100 mg 4-weekly to 400 mg 2-weekly for clopenthixol decanoate and 12.5 mg 4-weekly to 37.5 mg 3-weekly for fluphenazine decanoate. Both depot neuroleptics appeared to have an equivalent duration of action, with 200 mg clopenthixol decanoate approximately equivalent to 25 mg fluphenazine decanoate. Patients' mental state was assessed on the Brief Psychiatric Rating Scale, Clinical Global Impression, Krawiecka, Goldberg and Vaughan Rating Scale, and unwanted effects were recorded on a checklist. No differences were detected between the two drugs with regard to therapeutic activity or side-effects. It is concluded that clopenthixol decanoate is as effective and as well-tolerated a depot neuroleptic as fluphenazine decanoate.", "We evaluated the effectiveness and the side effects of what we defined as low (5-mg) and conventional (25-mg) doses of fluphenazine decanoate administered every two weeks in a double-blind comparison. Subjects were 66 patients who fulfilled DSM-III criteria for schizophrenic disorder. Evaluation of the survival with each dose revealed no significant difference at one year, but significantly better survival was seen with the 25-mg dose (64%) than the 5-mg dose (31%) at two years. There was no significant difference in survival when the clinician was permitted to make a dosage adjustment up to 10 mg in the low-dose group and 50 mg in the higher-dose group when the patient demonstrated evidence of a symptomatic exacerbation. Patients assigned to the higher dose appeared to feel more uncomfortable during the early months of the study, as indicated by significantly higher scores on subscales of the Hopkins Symptom Checklist-90R and higher side effect scores for retardation and akathisia. Implications for clinical practice are discussed.", "The clinical properties of clopenthixol decanoate has been investigated versus perphenazine enanthate in a double-blind clinical multicentre trial including 14 psychiatric hospitals in Finland, Sweden, Norway, and Denmark. Test treatment was initiated in 172 chronic schizophrenic patients and the planned 6 months test period was completed by 57 patients receiving clopenthixol decanoate and 48 receiving perphenazine enanthate. The therapeutic effect was assessed by means of CGI, BPRS, and NOSIE-30 and was found significant with both test drugs. Significant differences in the effect were seen only in \"Hostile-suspiciousness\" (BPRS) and \"Social interest\" (NOSIE-30). For these items clopenthixol decanoate was found superior to perphenazine enanthate. The influence of side effects on the patients' functioning was found to be slightly, but not significantly more troublesome in the perphenazine enanthate patients.", "Fifty chronic schizophrenics were randomly assigned to a 16-week treatment either with fluspirilene or with fluphenazine decanoate. The aim of the study was to compare the antipsychotic action and the side effects of the two neuroleptics. Fluphenazine decanoate caused more side effects and the difference between the two groups was statistically significant in the items tremor, severe extrapyramidal effects and parkinsonism. More patients in the fluspirilene group (nine patients) compared with only three in the fluphenazine decanoate group remained free of side effects during the whole trial. Judged from the BPRS fluspirilene proved an equally potent neuroleptic with fluphenazine decanoate although statistically significant improvement has been obtained in more items of the scale in the fluspirilene group. The improvement in the NOSIE-30 was much more clear in the fluspirilene group. Although Clinical Global Impressions of the investigators and the nursing personnel favored fluspirilene, the differences between the two groups were not statistically significant.", "Thirty-two chronic schizophrenics who had relapsed entered a double-blind randomised study and were followed-up for 2 years with the intention of measuring any difference in therapeutic effect and side effects between flupenthixol decanoate and fluphenazine decanoate. No differences could be seen as regards the global effect or the effect on the schizophrenic symptomatology during the first 6 months. After 1 year of treatment flupenthixol decanoate showed a trend towards a better effect on schizophrenic symptomatology. A corresponding result was seen for the depressive symptoms. There were no differences in the appearance of side effects. The need for additional neuroleptics in the initial phase seemed to be identical for both drugs. A possible slow antipsychotic effect with flupenthixol decanoate is probably due to the administered dose being somewhat low (in the present study approximately 31 mg flupenthixol corresponding to 27 mg fluphenazine). This suggests that flupenthixol should have been given in a somewhat higher dose (25 mg fluphenazine decanoate corresponding to 40 mg flupenthixol decanoate).", "Thirty-six remitted schizophrenics who participated in an outpatient study of fluphenazine decanoate or oral fluphenazine vs placebo given for a year were examined for the effect of drug treatment upon social and vocational functioning. Only the period prior to any clinical relapse was evaluated. We found no difference between those on drug or placebo, and conclude that antipsychotic drugs, at least in the context of an aftercare clinic offering a rich spectrum of nonpharmacological services, and when combined with antiparkinson medication, do not interfere with social and vocational functioning.", "Sixty-four chronic stabilised schizophrenics were studied for 18 months in order to assess the possible difference in therapeutic effects and side effects between flupenthixol decanoate and fluphenazine decanoate. Although certain differences in the BPRS sub-scores in favour of flupenthixol were present at various stages in the study, there was no significant difference between the two drugs in the overall antipsychotic scores at the end of the assessment period; however, more patients on fluphenating required additional therpay for depression or anxiety during the trial period.", "Fluphenazine decanoate and pipothiazine palmitate were compared concerning their effect and side-effects. 61 schizophrenic patients were treated up to 6 months in a multicenter double-blind trial. Assessments were made on day 0 and after 5, 10, 17 and 22 weeks of treatment using the AMP system. Pipothiazine palmitate was injected every 4th week and fluphenazine decanoate every 3rd week. The most often applied dosage was 100 mg pipothiazine palmitate and 25 or 37.5 mg fluphenazine decanoate. Data analysis of the AMP system at the symptom level showed the better antipsychotic effect of pipothiazine palmitate. A comparison between the two groups by means of analysis of covariance at the syndrome level showed no statistical significant differences between the effects of fluphenazine decanoate and pipothiazine palmitate.", "Dose reduction strategies for the maintenance treatment of schizophrenia are designed to maintain the benefits of antipsychotic drug therapy while reducing risks. Previous strategies with decanoate preparations have been based on the use of lower doses per injection to achieve dose reduction; these strategies have achieved dose reduction but have resulted in some increase in symptoms. The authors tested a new dose reduction approach: increasing the interval between injections during intramuscular decanoate antipsychotic treatment.\n Fifty outpatients with schizophrenia or schizoaffective disorder were randomly assigned to receive 25 mg of fluphenazine decanoate intramuscularly either every 2 weeks or every 6 weeks for 54 weeks in a double-blind design.\n The two dose regimens did not differ significantly in relapse, symptom, or side effect measures. The every-6-weeks regimen was associated with a significant reduction in total antipsychotic exposure.\n The use of injections every 6 weeks instead of every 2 weeks may increase compliance and improve patients' comfort as well as decrease cumulative antipsychotic exposure, without increasing relapse rates or symptoms.", "A double-blind placebo trial of fluphenazine decanoate, a long-acting phenothiazine, was carried out to determine its value in maintenance therapy of chronic schizophrenic outpatients already established on the drug for a minimum period of eight weeks. In low doses it was significantly more effective than placebo in preventing relapse and admission to hospital. Relapse was accompanied by a resurgence of specifically schizophrenic symptoms and by an increase in abnormalities described by the relatives. There was no difference between the experimental and control groups in the treatment required for depression. The group on active medication required more treatment for Parkinsonism, but this difference did not reach statistical significance.In the context of a well-run special clinic for outpatient follow-up of chronic schizophrenic patients these results confirm the usefulness of long-acting fluphenazine. By inference, the benefit of this treatment highlights the need for adequate community services to deal with the residual chronic disabilities which are characteristic of these patients.", "nan", "The ability of long-acting fluphenazine decanoate and oral fluphenazine hydrochloride to forestall relapse among newly discharge schizophrenic patients is examined in the context of high and low degrees of social therapy (ST). A total of 105 patients were randomly assigned to the various treatments and maintained under controlled conditions for two years or until relapse. Relapse rates for all treatments remained traditionally high. Relpase rates for long-acting fluphenazine decanoate and oral fluphenazine hydrochloride are nearly identical in the first year, indicating that drug noncompliance does not adequately explain early schizophrenic relapse. However, patients who received long-acting fluphenazine decanoate and ST have a reduced risk of relapse over time. Relapsers who received long-acting fluphenazine decanoate appeared more affectively disturbed than other relapsers, yet both groups were diagnostically and symptomatically equivalent prior to treatment. Personal discomfort and intrafamilial stress are important predictors.", "The treatment of schizophrenic patients with high-dosed neuroleptics is discussed. The drug-response difference between a low dose and a high dose of Fluphenazine-Decanoate was investigated in 40 chronic schizophrenic patients. All patients were resistant to standard doses of neuroleptics and were therefore treated with higher doses. All patients entering the study were treated for at least three months with high doses of Fluphenazine-Decanoate, i.e. 100 mg or more within three weeks. From this pool of 40 patients two groups were created at random for the doubleblind study: In one group the high dose was continued (average dose 225 mg/in 14 days), in the other group Fluphenazine-Decanoate was reduced to a standard-dose of 25 mg in 14 days. During the 24 weeks of investigation the somatic and psychopathological state of the patient was evaluated by means of the AMP-System. Furthermore the self-rating scale EWL-K was used. After 24 weeks the patients of the high-dosed group were more often rated as unchanged, while the patients in the standard-dosed group were evaluated significantly more often as better or worse. Average condition-differences between the both groups could not be found in a covariance-analysis. A factorial covariance-analysis showed that differences in the initial hostility-syndrome and catatonic-syndrome scores are predictors for a syndrom-relevant differential dosage per group. Patients with low hostility- and low catatonic-syndrome-scores improved after reduction of the doses in the apathic, the halluzinatoric-desintegrative and the neurological syndrome, whereas patients with high initial hostility- and catatonic-syndrome-scores became psychopathologically worse after dosage reduction. Finally the possibilities of generalizing from the results obtained to the relevance of high and standard neuropletic therapy are discussed.", "To test the clinical efficacy of low dose fluphenazine decanoate (1.25 mg to 5.0 mg biweekly), we carried out two separate experiments: (1) an open trial in 57 schizophrenic outpatients, lasting 6 months; (2) a double-blind, placebo-controlled discontinuation study in a subgroup of patients who maintained good remission throughout the entire 6-month open trial. The results suggest that lower doses of fluphenazine decanoate than those usually used may be effective in preventing psychotic relapse while keeping total cumulative dosage to a minimum.", "nan", "Penfluridol, a diphenylbutylpiperidene derivative, is a new long acting neuroleptic, administered orally, once weekly. It is marketed in several European countries and has been used successfully in the treatment of various acute psychoses, for severely ill chronic schizophrenic patients, and as maintenance therapy for chronic schizophrenic patients. The present study was designed to compare, in a double-blind fashion, the efficacy of penfluridol and fluphenazine decanoate in the maintenance therapy of schizophrenic outpatients.", "A one year double-blind trial of haloperidol decanoate and fluphenazine decanoate was conducted in nineteen out-patients who had previously received at least one year's treatment with fluphenazine decanoate and were already overweight, as judged by a Body Mass Index of 25+. Although the difference was not statistically significant, patients treated with haloperidol decanoate showed a trend to less weight gain than patients who continued on fluphenazine decanoate, even though the haloperidol to fluphenazine dose ratio was 4:1. No statistically significant changes in mental state were observed and the incidence of extrapyramidal side-effects in the two treatment groups was similar.", "A double-blind comparison of fluspirilene and fluphenazine decanoate in 28 schizophrenic patients over six months showed equal improvement and the same incidence of side-effects in each group of patients. It would be expected from the literature that a better ratio of therapeutic to side-effects would appear with fluspirilene than with fluphenazine. The absence of such an effect in this study may be attributable to an initial lack of familiarity by the investigators with the use of fluspirilene, indicating an important potential variable in the comparison of a new drug with an established one.", "nan", "In a double-blind placebo substitution study, 27 chronic schizophrenic patients successfully treated for more than 2 years with fluphenazine decanoate were withdrawn from the drug. These patients showed a significantly higher relapse rate than the matched control group of 26 patients who continued to receive fluphenazine (56% versus 19%, p less than .001). This high rate of relapse is viewed as indicating the need for continued medication in most chronic schizophrenic patients.", "This paper reports a randomized, controlled, partially-blinded, flexible dose, parallel group, comparative study of the efficacy and tolerance of pipothiazine palmitate and fluphenazine decanoate in patients in remission from Schizophrenia over a 28 week period. The results show that pipothiazine palmitate is at least as efficacious and well-tolerated as fluphenazine decanoate in preventing relapses from maintained Schizophrenia.", "nan", "The relative costs and benefits of low- and conventional-dose neuroleptic maintenance therapy were evaluated in a double-blind comparison of 5 and 25 mg of fluphenazine decanoate administered every two weeks. Subjects were 50 patients fulfilling DSM-III criteria for schizophrenic disorder who had been successfully maintained with 25 mg or less of fluphenazine decanoate. A one-year survival analysis disclosed that there were no statistically significant differences between the two doses insofar as preventing relapse. Patients receiving the higher dose appeared to feel more uncomfortable, as indicated by higher scores on subscales of the Hopkins Symptom Checklist-90. In addition, patients receiving the higher dose had higher side-effect scores. These findings suggest that a substantial proportion of patients who are presently maintained with 25 mg or less of fluphenazine decanoate every two weeks will do just as well with as little as 5 mg.", "Thirty-nine chronic schizophrenic patients were selected for a 12-month double-blind evaluation of the effectiveness of pipothiazine palmitate (PPT) and flupenthixol decanoate (FPX) in the maintenance management of their illness. Allocation was at random and, in order to allow constant injection intervals, the patients typically received every 2 weeks either 40 mg of flupenthixol decanoate or alternating injections of 100 mg of pipothiazine palmitate and placebo. At monthly intervals the patients were assessed using both a battery of rating scales (which included the Brief Psychiatric Rating Scale (BPRS), the Extrapyramidal Symptoms Rating Scale (EPS] and a general side-effects evaluation. At 3-monthly intervals they were also rated on the Comprehensive Psychiatric Rating Scale (CPRS) and the Zung Depression Scale. Haematological and biochemical tests were performed every 3 months. Both drugs provided good control of psychotic symptoms and side-effects were not troublesome. No substantial difference was detected on the CPRS and the Zung scales. There was a trend in favour of PPT on the BPRS survey, detectable at 6 months and reaching statistical significance by 12 months. We conclude that the PPT regime is at least as effective as the FPX treatment and probably more so. It is possible that even longer periods of control could be obtained with PPT.", "nan", "Vagrant chronic schizophrenic subjects in a stable untreated state received in-patient treatment with either Flupenthixol decanoate or Clopenthixol decanoate. Both drugs were found to be significantly effective and well tolerated. The apparent better response to Flupenthixol decanoate was seen as dose-dependent. The findings and their implications for Community Psychiatry, particularly in developing countries are discussed.", "Issues regarding the side effects of antipsychotic medication and the possible contribution of the environment to dose requirements led to a two-year controlled dosage study of maintenance antipsychotic medication and familial environment among recently discharged schizophrenic patients. Seventy stable patients, living in high- or low-expressed emotion (EE) households, were randomized, double blind, to receive a standard dose of fluphenazine decanoate (average, 25 mg every two weeks) or a minimal dose representing 20% of the dose prescribed (average, 3.8 mg every two weeks). No differences in relapse were observed among dose, EE, or dose and EE. Patients in the minimal dose/high-EE condition experienced more minor but aborted episodes in year 2. Side effects were fewer on the minimal dose after one year, and low-EE patients were better adjusted than high-EE patients. Over time, minimal-dose recipients were significantly more improved in their instrumental and interpersonal role performance than were standard-dose recipients.", "In this present study 31 schizophrenic patients were treated for six months for relapse prevention under double-blind conditions with either haloperidol decanoate (22) or fluphenazine decanoate (9). In respect of the prophylactic action, both depot neuroleptics proved to be equal during the comparatively short period of observation. In both groups a psychotic relapse occurred that could not be managed by increasing the depot dosage. No side-effects worth mentioning appeared in either group of patients; patients under haloperidol decanoate, however, only required half the quantity of anti-parkinson medication as compared with patients treated with fluphenazine decanoate, and also displayed extrapyramidal motor symptoms (EPMS) to a lesser degree. Patients received a mean monthly injection of 80 mg of Haloperidol, reaching steady-state serum levels of about 3 ng/ml in the third injection interval. Fluphenazine serum levels known so far for seven patients amount to 0.8 ng/ml after fluphenazine injections of 21 mg every 14 days.", "Sixty patients meeting the criteria established for schizophrenia who attained a clinical plateau following hospital discharge were randomized to receive for one year either penfluridol, 20 to 160 mg orally once each week, or fluphenazine decanoate, 0.5 to 4 ml every two weeks. The relapse rate for both treatments was low and equal. The rate of recurrence of psychosis for patients receiving penfluridol was 7% and for those receiving fluphenazine decanoate 10%. A retrospective comparison of the penfluridol group was made to a similar group of patients assigned to placebo in an earlier study. Placebo-treated patients had a relapse rate of 68%. Penfluridol patients had statistically fewer psychotic relapses. Questions about the possible carcinogenicity of penfluridol in animals will have to be resolved before it can be widely used. This study demonstrates the feasibility of using an oral, long-acting antipsychotic agent. It would be a useful psychopharmacologic addition in the treatment of outpatient schizophrenics.", "The clinical profile and side-effects of perphenazin-enanthate and fluspirilene were compared in 45 female chronic schizophrenic patients. 100 mg perphenazin-enanthate fortnightly or 8 mg fluspirilene weekly were administered. During the four months' period the psychopathological and somatic symptoms were evaluated by means of the AMP-system and the self-evaluation scale PD-S (v. Zerssen). A covariance analysis was carried out covering 12 AMP syndromes and 6 PD-S factors. The antipsychotic effect of both drugs was similar concerning the paranoid, the hallucinatory-desintegrative and the catatonic syndromes. A significant difference with regard to perphenazin-enanthate was found in the AMP-syndromes of hostility, hypochondria, and autonomic symptoms. Neither drug induced any depression. In the self-rating scale, the factors anxiousness and depressivity were also significantly lower in the perphenazin-enanthate regime. The patients under perphenazin-enanthate required a smaller amount of antiparkinsonian drugs. The more pronounced sedative effect of perphenazin-enanthate can be recommended in hostile and restless schizophrenic patients, whereas fluspirilene should be given to inactive autistic patients.", "Twenty-eight patients who had recently recovered from an acute-onset, first-episode schizophrenic illness were randomly given fluphenazine hydrochloride or decanoate or placebo for a one-year period in a double-blind study. Seven of 17 patients(14%) receiving placebo experienced a psychotic relapse, whereas none of 11 drug-treated patients experienced a relapse. Eighteen (69%) of the 26 patients available for follow-up (mean interval, 3.5 years) experienced a second psychotic relapse either during the study or afterward, and 50% (14/28) of the original sample experienced a third episode.", "The overall objective of this 18-month open study was to compare standard neuroleptics and long-acting depot neuroleptics following the current psychiatric practice in order to determine the best therapy. Thirty French psychiatrists from 15 different wards participated in this experiment. One hundred eighty-one chronic schizophrenic patients were randomly assigned to receive one of the following three treatments: standard neuroleptics, pipotiazine palmitate, or fluphenazine decanoate. Criteria used for evaluation were an overall clinical evaluation by a psychiatrist, a Brief Psychiatric Rating Scale, and a Nurse's Observation Scale for Inpatient Evaluation. No significant difference (P greater than .05) was observed between the three groups in drug effectiveness or tolerance.", "A double-blind withdrawal trial in 41 chronic schizophrenic outpatients was carried out during 6 months. Depot neuroleptics (fluphenazine decanoate or flupenthixol decanoate) were compared with placebo to evaluate clinical and neurological effects during continued therapy and during withdrawal. The drugs were significantly more effective than placebo in preventing relapse and rehospitalization. In the placebo group 62% relapsed compared to 27% in the drug group. There was a weak and nonsignificant tendency to a higher relapse frequency in the flupenthixol group compared to the fluphenazine group. After withdrawal for 6 months, plasma levels for fluphenazine were detectable. Plasma levels for flupenthixol were not detectable after 9 weeks of withdrawal. The differences in the plasma levels may possibly explain the difference in relapse rate between the two depot neuroleptics. Furthermore, it was found that the patients who relapsed during fluphenazine treatment had a significantly lower plasma level of the drug than patients who did not relapse during treatment. The results from this study provide some information on the therapeutic levels of fluphenazine and flupenthixol in schizophrenic patients.", "A 1 year double-blind trial of bromperidol decanoate and fluphenazine decanoate was conducted in the maintenance treatment of 47 outpatients with schizophrenia. Six patients relapsed on bromperidol decanoate and none on fluphenazine decanoate, a difference which is statistically significant. No significant differences in positive and negative symptoms, nor depression measures were found between treatment groups when comparisons were made for change in score from entry to last visit. However, patients on fluphenazine decanoate achieved significantly better changes on social disability (Morningside scale) compared to those on bromperidol decanoate. The incidence of extrapyramidal side-effects was similar in both groups, and no statistically significant differences emerged in body weight change between treatments.", "We studied the effectiveness of treating patients with low doses of fluphenazine decanoate and supplementing them with oral fluphenazine when there was evidence of prodromal symptoms of psychotic exacerbations.\n Eighty schizophrenic patients who were receiving 5 to 10 mg of fluphenazine decanoate every 2 weeks were monitored for prodromal symptoms using an idiosyncratic prodromal rating scale. When patients met our criteria for a prodromal episode, they were randomly assigned to a double-blind comparison of oral fluphenazine hydrochloride (5 mg twice daily) or a placebo for the current and future prodromal episodes. We compared rates of psychotic exacerbations in the two treatment groups.\n Thirty-six patients (45%) met the criteria for a prodrome at some point during the trial and were randomized to drug or placebo. Using survival analysis during the entire 2 years, we did not find a significant difference between fluphenazine and placebo in the likelihood that a prodrome would continue to an exacerbation. Survival analysis beginning at the start of the second year of treatment did indicate a significant reduction in exacerbation risk for patients receiving drug supplementation (P = .032). Similarly, there was no difference between the two groups in the proportion of time at risk spent in exacerbation during the first year, but patients receiving active drug supplementation spent less time in an exacerbated state in the second year (P = .05).\n Our treatment strategy appeared to be effective for some patients, particularly those who were able to remain in the study beyond the first year. Although the occurrence of a prodrome was a fairly good marker that a patient was at high risk of ultimate exacerbation with our low-dose maintenance protocol, prodromes were not highly sensitive indicators of imminent exacerbation.", "nan", "In a double-blind study of 38 chronic schizophrenic in-patients, haloperidol decanoate was compared with fluphenazine decanoate as maintenance therapy over 60 weeks. Both drugs were given by injection at 4-week intervals. Haloperidol and fluphenazine were assumed to be equipotent; the mean starting dose of the former was 127 mg and of the latter 106 mg. The number of withdrawals over 60 weeks was similar in both groups but relapses, strictly defined, were significantly more frequent in the haloperidol group. When patients were switched to haloperidol, Parkinsonism diminished more quickly than in the fluphenazine group, but after 60 weeks there was no difference in severity in the two drug groups. The higher relapse rate and the quicker reduction in Parkinsonism in the haloperidol group might be due to a misjudgement in equivalent doses of the two drugs. Plasma haloperidol steady state levels were reached in most patients by 8-12 weeks. Plasma neuroleptic and prolactin levels, week-by-week systemic drug availability and Parkinsonism showed less variation between injections with haloperidol than with fluphenazine.", "Fifty-nine chronic schizophrenic patients received one year of treatment with either fluphenazine enanthate or pipothiazine palmitate IM. Both long acting neuroleptics significantly decreased serum albumin, total protein and creatinine values. Triglycerides were decreased only early in treatment. Pretreatment findings from therapy responders, as compared with those who failed to respond to treatment, included higher albumin values and to a lesser extent, lower lactic dehydrogenase values and greater height. These results were discussed with an eye toward the hepatocellular effects of long acting phenothiazines and the effect of liver function on the pharmacokinetics of these medications." ]	There are more data for fluphenazine decanoate than for the enanthate ester. Both are effective antipsychotic preparations. In the context of trials, there is little advantage of these depots over oral medications in terms of compliance but this is unlikely to be applicable to everyday clinical practice.
CD000060	[ "9033441", "3530643", "2879458", "8103655", "16729788", "1357551", "12890374", "17312651", "9850359", "6219156", "1357550" ]	[ "Short-term regular beta 2-adrenergic agonists treatment is safe in mild asthmatics taking low doses of inhaled steroids.", "Reduction of nocturnal asthma by an inhaled anticholinergic drug.", "Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room.", "Asthma control during and after cessation of regular beta 2-agonist treatment.", "Oral montelukast treatment of preschool-aged children with acute asthma.", "Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma.", "Inhaling beta(2)-agonist with heliox-driven in bronchial asthma.", "Management of acute asthma in children using metered dose inhaler and small volume nebulizer.", "Efficacy of chlorofluorocarbon-free beclomethasone dipropionate 400 micrograms day-1 delivered as an extrafine aerosol in adults with moderate asthma.", "Anticholinergic and sympathomimetic combination therapy of asthma.", "Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma." ]	[ "Regular treatment with beta 2-adrenergic agonists is controversial in bronchial asthma. To investigate whether beta 2-adrenergic agonists can be used safely if associated with low doses of inhaled steroids, for a short period, without a deterioration of asthma control, we have examined 24 mild asthmatics. In a parallel, double-blind, placebo-controlled study, 1 week of run-in and run-out period framed 3 weeks of treatment. All patients received inhaled beclomethasone dipropionate (BDP 250 micrograms t.i.d.); after 1 week, 12 patients inhaled 400 micrograms of broxaterol and 12 patients received placebo t.i.d. FVC, FEV1, PD20-FEV1 methacholine, morning and evening PEF, and PEF amplitude % mean were measured before, during, and after treatment. No significant changes were noted in patients receiving inhaled broxaterol. There were no differences in symptoms and the use of rescue medication (salbutamol spray). We conclude that short-term regular treatment with beta 2-adrenergic agonists is not associated with a deterioration in asthma control in mild asthmatics inhaling low doses of steroids.", "Although the mechanisms of nocturnal asthma are still uncertain, increased vagal cholinergic tone may be contributory factor. To examine this hypothesis, we have studied the effect of an anticholinergic drug, oxitropium bromide, on the early morning fall in peak expiratory flow (PEF) in patients with nocturnal asthma. Eighteen patients (aged 18 to 76 years; seven men) with documented nocturnal asthma were studied in a double-blind randomized cross-over study in which they received either oxitropium bromide (200 micrograms or 400 micrograms) or placebo in a single dose at night for two-week periods. With placebo the mean (+/- SE) fall in PEF (expressed as percentage of evening PEF) was 17.3 +/- 2.0 percent, which was significantly reduced to 10.3 +/- 3.3 percent after oxitropium (400 micrograms) (p less than 0.05; ANOVA). Closer analysis revealed that nine of the 18 patients had responded in a dose-dependent manner, with the mean percentage decreases with placebo, 200 micrograms, and 400 micrograms of oxitropium being 19.1 +/- 3.2, 11.5 +/- 4.4, and 5.0 +/- 4.5 percent, respectively (p less than 0.01 between each treatment). The remaining patients were unaffected by therapy. There were no differences between \"responders\" and \"non-responders\" in terms of age, atopic status, duration of asthma, severity of asthma, or bronchodilator response to albuterol (salbutamol). There were no differences in nocturnal symptoms between periods of treatment, and no side effects were recorded. We conclude that anticholinergic drugs may protect against nocturnal asthma in some patients, indicating the involvement of vagal cholinergic mechanisms.", "The effectiveness of nebulized anticholinergic and sympathomimetic regimens was evaluated in a double-blind study of 199 patients with acute airways obstruction. Patients were assigned to one of three treatment regimens according to a randomized schedule: 0.5 mg of ipratropium bromide, 1.25 mg of fenoterol hydrobromide, and 0.5 mg of ipratropium plus 1.25 mg of fenoterol. In 148 patients with acute exacerbations of asthma (mean one-second forced expiratory volume, 1.18 +/- 0.64 liters), all three regimens produced significant improvement in one-second forced expiratory volume (p less than 0.001). The greatest improvement followed treatment with the ipratropium-fenoterol combination (0.53 +/- 0.40 liters at 45 minutes; 0.57 +/- 0.51 liters at 90 minutes) and was significantly greater than that following either ipratropium alone (p less than 0.001) or fenoterol alone (p less than 0.05). In 51 patients with acute exacerbations of chronic obstructive pulmonary disease (mean one-second forced expiratory volume, 0.67 +/- 0.29 liter), each regimen produced significant improvement in one-second forced expiratory volume at both 45 and 90 minutes (for all, p less than 0.05), but there was no significant difference among the three treatment regimens. It is concluded that, in patients with acute asthma, combination therapy with sympathomimetic and anticholinergic agents is more efficacious than either one alone. In patients with acute exacerbations of chronic obstructive pulmonary disease, although either sympathomimetic or anticholinergic therapy provides bronchodilatation, no further benefit could be demonstrated from combination therapy.", "It has been suggested that regular treatment with high doses of beta 2-agonists might result in poorer control of asthma and increased bronchial responsiveness. We have examined change in FEV1 (delta FEV1), bronchial reactivity, peak expiratory flow (PEF), and symptoms during and after 3 wk of regular treatment with a relatively low dose of albuterol and broxaterol, a new beta 2-agonist. Eleven subjects 18 to 50 yr of age with mild asthma inhaled albuterol (200 micrograms), broxaterol (400 micrograms), or placebo three times a day for 3 wk with a 2- to 4-wk run-in/washout period between treatments. Ipratropium bromide was allowed for symptomatic relief. The PD20 (dose of histamine causing a 20% fall in FEV1) was measured before and 11, 35, and 59 h after cessation of treatment and a bronchodilator dose-response study before and 83 h after cessation of treatment. Change from baseline after albuterol and broxaterol are compared with change after placebo. Diurnal change in PEF (amplitude % mean) increased during treatment with albuterol by 6.5% (95% CI, 1.7-12.3; p < 0.02) mainly because of a fall in morning PEF. Cessation of treatment with both beta 2-agonists was associated with a fall in FEV1 and PD20 compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)", "Increased amounts of cysteinyl leukotrienes have been demonstrated in urine samples from asthmatic patients, particularly during exacerbations of asthma. Although the use of leukotriene receptor antagonists has been recommended in the treatment of chronic asthma, no guidelines are available regarding their use in the treatment of acute asthma.\n To investigate the safety and effectiveness of a 4-mg tablet of oral montelukast in addition to short-acting beta2-agonist bronchodilator as the initial treatment in mild to moderate asthma exacerbations in children between 2 and 5 years old.\n Fifty-one patients who were experiencing mild to moderate asthma exacerbation were included in a randomized, double-blind, placebo-controlled, parallel-group study. Each patient received either a 4-mg tablet of montelukast or placebo in addition to inhaled salbutamol and were followed up for 4 hours. The pulmonary index score, respiratory rate, and pulse were determined at baseline and throughout 4 hours after administration.\n Compared with placebo, the pulmonary index scores and respiratory rates were significantly lower in the montelukast group starting at 90 minutes (P = .01). This difference persisted at 120, 180, and 240 minutes of the study (P = .008, P = .02, and P = .048, respectively). At the end of the first hour of treatment, oral steroid need was 20.8% and 38.5% in patients randomized to the montelukast and placebo groups, respectively (P = .22). Hospitalization rates were not different between the 2 treatment groups.\n A single 4-mg tablet of montelukast had the potential to provide additive clinical benefit in mild to moderate acute asthma in preschool-aged children when administered concomitantly with short-acting beta2-agonist bronchodilators as the initial treatment.", "Tolerance to the direct bronchodilator effects of beta 2-agonists does not appear to occur in asthma. However, it is not known whether this is true for the nonbronchodilator effects of these agents, which protect the airways against bronchoconstrictive stimuli.\n We investigated whether tolerance develops to the protective effect of inhaled terbutaline on airway responsiveness to the bronchoconstrictors methacholine (which acts directly on airway smooth muscle) and AMP (which acts indirectly by stimulating the release of mediators from mast cells) during sustained treatment with terbutaline. In a randomized, double-blind, crossover study, 12 patients with mild asthma each inhaled a single dose of terbutaline (500 micrograms) or placebo before a challenge with a series of doubling doses of inhaled methacholine or AMP, before and after treatment for seven days with 500 micrograms of terbutaline four times daily or placebo.\n Before the seven days of treatment with terbutaline, a single dose of terbutaline reduced airway responsiveness to methacholine by 2.7 doubling doses (95 percent confidence interval, 1.9 to 3.5), but it had an even greater protective effect against AMP, reducing airway responsiveness by 3.8 doubling doses (95 percent confidence interval, 2.7 to 4.9; P less than 0.001). After seven days of treatment with terbutaline, the protective effect of terbutaline against methacholine decreased to 2.2 doubling doses (95 percent confidence interval, 1.3 to 3.0; P = 0.04), and that against AMP decreased even more, to 1.7 doubling doses (95 percent confidence interval, 1.1 to 2.4; P less than 0.001). By contrast, the bronchodilator response to terbutaline was unchanged during seven days of treatment with this agent.\n We observed tolerance to the nonbronchodilator actions of the inhaled beta 2-agonist terbutaline in patients with mild asthma, an effect that may be more pronounced in mast cells than in bronchial smooth muscle. This property of beta-agonists may constitute a drawback to their regular use in patients with asthma.", "To evaluate the effectiveness of a helium-oxygen mixture (79%He- 21%O(2)) as an aerosolizing compressed gas for beta(2)-agonist therapy in patients with an asthma exacerbation.\n Twenty-four patients in the outpatient department with a mild to moderate exacerbation of asthma were enrolled. The patients were randomly divided into an experimental group (13 cases) and a control group (11 cases). The experimental group inhaled Berotec with heliox-driven, and the control group inhaled Berotec with compressed air-driven. Eight hospitalized patients in the respiratory department with severe exacerbation of asthma were enrolled. The patients inhaled Berotec with heliox-driven or compressed air-driven in a random order.\n The results of spirometric parameters and arterial blood-gas analysis were measured. In the mild to moderate asthma patients, no statistical differences between the two groups for forced vital capacity (FVC), forced expired volume in one second (FEV(1)), and expiratory flow in 50% forced vital capacity (FEF(50)) were presented. But the severe patients showed significant differences between heliox-driven and compressed air-driven for FVC, FEV(1), FEF(50) and partial pressure of oxygen (PaO(2)).\n Compared with the traditional inhalation of beta(2)-agonist therapy using compressed air-driven, the method of inhaling beta(2)-agonist with heliox-driven has more obvious benefits for those suffering from severe asthma. This is likely due to the cooperative effects between inhaling heliox on its physical gas properties and improving delivery of beta(2)-agonist in the treatment of exacerbation of severe asthma.", "To determine whether the administration of beta2-agonist by Metered Dose inhaler (MDI) with accessory device (AD) is a as effective as the administration of beta2-agonist by small volume nebulizers (SVN) for the treatment of acute asthma.\n A cross sectional study was conducted at Emergency Room (ER) of National Institute of Child Health (NICH), Karachi, between October 2000 to March 2001. This study included 150 children, 6 months and older with a history of wheeze and presenting with an acute asthma exacerbation. Children were categorized into mild, moderate and severe asthma according to medical scoring system. Children were assigned randomly into group A and B to receive standard dose of beta2-agonist (salbutamol) by MDI/AD (group A) or SVN (group B). Baseline characteristics and asthma severity were recorded. All variables (dyspnoea, use of accessory muscles, cyanosis, respiratory rate, heart rate, blood pressure, oxygen saturation, pulsus paradoxus, and wheeze) and Peak Expiratory Flow Rate (PEFR) in children 5 years and older, were determined at pre and post inhalation therapy.\n Both groups did not differ in demographic characteristics. There were no significant differences in outcome measures. In children treated with MDI/ADs and SVNs. PEFR increased significantly in both the groups after completion of treatment, but PEFR was not statistically significant when compared in between groups.\n The data suggested that MDI/AD is an effective alternative to nebulizer for the treatment of children with acute asthma exacerbation in the ER.", "Beclomethasone dipropionate (BDP) has been reformulated in a chlorofluorocarbon-free propellant, hydrofluoroalkane-134a (HFA), resulting in an extrafine aerosol which gives improved drug delivery to the airways. The objective of this 6 week, placebo-controlled study was to evaluate the clinical efficacy of HFA-BDP 400 micrograms day-1 in 256 adult patients with moderate asthma. This is a lower daily dose than that recommended for existing BDP inhalers in current treatment guidelines for moderate asthma (NIH publication 95-3659). Another objective was to evaluate whether delivering the 400 micrograms dose as four actuations of 50 micrograms twice daily (HFA-BDP 50 micrograms) provided equivalent asthma control to delivering the dose as two actuations of 100 micrograms twice daily (HFA-BDP 100 micrograms) without the use of a spacer or holding chamber. Both active treatments produced a significant change from baseline in morning peak expiratory flow (PEF), which was significantly larger than that in the placebo group (P < or = 0.017) throughout the study. The mean changes from baseline in morning PEF at weeks 5-6 were 47.0 l min-1 in the combined HFA-BDP group and 16.5 l min-1 in the HFA-placebo group. The two dose strengths were statistically equivalent (P = 0.017 for equivalence testing). The active treatments also produced significant improvements compared with placebo in evening PEF, forced expiratory volume in the first second, forced expiratory flow over 25-75% of vital capacity, sleep disturbance scores and daily beta-agonist use. The study medication was well tolerated, with a low incidence of adverse events. The results from this study demonstrate that a daily dose of 400 micrograms HFA-BDP (given in 50 micrograms and 100 micrograms strengths) provides dose proportionality and effective control in patients with moderate asthma.", "The role of the anticholinergic drug, ipratropium bromide, in maintenance antiasthmatic therapy was evaluated in a double-blind crossover trial of three bronchodilator regimens: (1) inhaled ipratropium, placebo, and oral oxtriphylline; (2) inhaled fenoterol, placebo, and oral oxtriphylline; and (3) both inhaled ipratropium and fenoterol plus oral oxtriphylline. Twenty-two asthmatics were treated with all three regimens, each for 1 mo, allocated in random sequence. On the first and last treatment days of each month, spirometric measurements were performed before and 0.5, 1, 2, 3, 4, and 6 hr after administration of the test drugs. On the first treatment day of each month, all regimens produced significant bronchodilatation at 30 min after dose, an improvement that declined between 3 and 6 hr after dose. After continuous administration for 1 mo the two combinations employing fenoterol showed a decline in bronchodilator responsiveness from the initial treatment day, measured as the level of response (V50) or duration of response (FEV1, VC). Ipratropium plus oxtriphylline showed no such decline, suggesting the development of tolerance to long-term administration of fenoterol. Overall benefit at the end of 1 mo, measured as the area under the curves of FEV1, VC, or V50 vs time after dose, was greatest for the triple drug regimen. There were no differences in heart rate, blood pressure response, or side effects among the three treatments. It is concluded that when the anticholinergic drug ipratropium is administered concurrently with an inhaled beta 2 agonist and an oral theophylline derivative, increased bronchodilatation occurs with no detectable additional side effects.", "Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma.\n In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 micrograms, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC20) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV1).\n There was a significant increase in FEV1 one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV1, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC20 was significantly attenuated (P less than 0.001) to only a twofold increase. Two and four days after treatment ended, the PC20 was not significantly different from the value before treatment (P = 0.15).\n Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma." ]	A single dose of an anticholinergic agent is not effective for the treatment of mild and moderate exacerbations and is insufficient for the treatment of severe exacerbations. Adding multiple doses of anticholinergics to beta2 agonists appears safe, improves lung function and would avoid hospital admission in 1 of 12 such treated patients. Although multiple doses should be preferred to single doses of anticholinergics, the available evidence only supports their use in school-aged children with severe asthma exacerbation. There is no conclusive evidence for using multiple doses of anticholinergics in children with mild or moderate exacerbations.
CD007441	[ "2036277", "7665721", "17163260" ]	[ "Double-blind placebo-controlled comparison of the analgesic effects of single doses of lornoxicam and aspirin in patients with postoperative dental pain.", "A randomized, double-blind, placebo-controlled, dose-response study of the analgesic effect of lornoxicam after surgical removal of mandibular third molars.", "Analgesic efficacy and safety of lornoxicam quick-release formulation compared with diclofenac potassium: randomised, double-blind trial in acute low back pain." ]	[ "The pain experienced after third molar surgery was used as a model to evaluate the analgesic efficacy of a new non-steroidal anti-inflammatory drug, lornoxicam, in a Phase II study. One hundred and fifty fit, young adults participated in this randomised, single dose, double-blind, parallel group clinical study. Three doses of lornoxicam (2 mg, 4 mg, and 8 mg) were compared with aspirin 650 mg and placebo. Patients suffering from moderate to severe pain following surgery were monitored for up to 8 hours. All indices of efficacy showed similar results, all active treatments being associated with highly significant (P less than 0.0001) reductions in pain during the study period. Lornoxicam 8 mg demonstrated significant analgesic efficacy as compared with placebo. The two lower doses of lornoxicam and aspirin all showed apparent degrees of efficacy intermediate between that of placebo and lornoxicam 8 mg, although the trial proved to have inadequate power to show significant differences between these three treatments. Lornoxicam was very well tolerated at all three doses studied, with no adverse events definitely attributable to its administration.", "The aim of the present study was to investigate the dose-effect relationship of single doses of 4 to 32 mg of lornoxicam (LNX), a new nonsteroidal antiinflammatory drug belonging to the oxicam group, compared with placebo and 10 mg ketorolac (KET) in the treatment of pain after oral surgery. Also, it was the aim of the study to evaluate the relationship between adverse events and different doses of LNX. After the surgical removal of a mandibular third molar, test medication was taken when the patients experienced at least moderate pain. After medication, pain relief, pain intensity, and any discomfort from the medication were noted in a questionnaire. Paracetamol was used as rescue medication. A total of 278 patients completed the study according to the protocol. The primary efficacy parameter was total pain relief after 6 hours, and all active treatments showed significantly better effect than placebo, with LNX 16 and 32 mg being significantly superior to LNX 4 mg. All other efficacy parameters showed the same dose-effect relationship. A total of 37 adverse events were reported evenly distributed in the 6 treatment groups; only 3 of these were considered severe, and all disappeared without treatment. In conclusion, the study showed a dose-effect relationship of LNX without a rise in adverse events. The effect of 10 mg KET seemed to be at the level of 8 to 16 mg LNX.", "NSAIDs are widely used for patients presenting with low back pain. A quick-release formulation of lornoxicam, a potent NSAID from the chemical class of oxicams, offers a faster onset of pain relief compared with the standard tablet formulation.\n Time to onset of pain relief with lornoxicam was compared with the quick-release formulation of diclofenac potassium in acute low back pain in a randomised, double-blind, multicentre study. 220 patients received either lornoxicam 24 mg or diclofenac potassium 150 mg on day 1 followed by lornoxicam 8 mg twice daily or diclofenac potassium 50 mg twice daily for 5 days. Efficacy outcomes included time to onset of pain relief, as measured by the stopwatch method (primary outcome), pain intensity, pain relief, rescue medication, ability to perform daily activities and global evaluation of the study medication.\n The time to onset of pain relief ratios between diclofenac potassium/lornoxicam was 1.03 (95% CI 0.91, 1.26) and 1.05 (95% CI 0.93, 1.29) in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively, demonstrating the non-inferiority of lornoxicam (defined by lower limits of the 95% CIs >0.80). Time to onset of pain relief was shorter with lornoxicam (30 minutes) compared with diclofenac potassium (36 minutes). The difference was not statistically significant (ITT analysis). A higher magnitude of analgesic effect associated with better global evaluation of the study medication for lornoxicam was also demonstrated. The drugs were equally well tolerated.\n Lornoxicam administered as a quick-release formulation was shown to be non-inferior to the equivalent formulation of diclofenac potassium in terms of onset of pain relief and more effective on most of the major standard efficacy outcomes." ]	Oral lornoxicam is effective at treating moderate to severe acute postoperative pain, based on limited data. Adverse events did not differ significantly from placebo.
CD003235	[ "9487416", "8129434", "10084465", "2266671", "383024", "11868861", "7011354", "9024371", "9332112", "12645830", "8202885", "8004299" ]	[ "Treatment of hyperkalaemia by altering the transcellular gradient in patients with renal failure: effect of various therapeutic approaches.", "Treatment of hyperkalaemia using intravenous and nebulised salbutamol.", "Salbutamol metered-dose inhaler with spacer for hyperkalemia: how fast? How safe?", "Albuterol and insulin for treatment of hyperkalemia in hemodialysis patients.", "Comparison of IV salbutamol with IV aminophylline in the treatment of severe, acute asthma in childhood.", "Comparison of aminophylline and insulin-dextrose infusions in acute therapy of hyperkalemia in end-stage renal disease patients.", "Aminophylline, salbutamol and combined intravenous infusions in acute severe asthma.", "Randomised trial of intravenous salbutamol in early management of acute severe asthma in children.", "Intravenous magnesium sulfate in acute severe asthma not responding to conventional therapy.", "The salmeterol/fluticasone combination is more effective than fluticasone plus oral montelukast in asthma.", "Effect of adding aminophylline infusion to nebulised salbutamol in severe acute asthma.", "Nebulized versus intravenous albuterol in hypercapnic acute asthma. A multicenter, double-blind, randomized study." ]	[ "Ten patients with acute and 60 with chronic renal failure (both groups having hyperkalaemia), were managed at Kenyatta National Hospital in the medical wards and Renal Unit between August, 1995 and January, 1996. They were divided into seven different treatment groups, each consisting of ten patients. Treatment A glucose 25g i.v. with insulin 10 units i.v., treatment B 50 mmol of 8.4% sodium bicarbonate infusion, treatment C 0.5mg of salbutamol i.v. in 50mls 5% dextrose, treatment D was a combination of treatments A and B, treatment E was a combination of treatment B and C, treatment F was a combination of treatments A and C while treatment G was a combination of treatments A and B and C. Serum potassium was measured, 30 minutes, 1 hour, 2 hours, 4 hours and 8 hours after treatment. Plasma glucose concentration was measured before treatment was given and 1 hour after in all patients. Electrocardiography was done before treatment on all patients and repeated 30 minutes and 1 hour after treatment for the patients with hyperkalaemic changes on the initial recording. All treatment modalities had satisfactory potassium lowering effects. Of the single therapeutic approaches, treatment A and C were equieffective, but better than treatment B (P < 0.001). Amongst the two regimen combinations, treatment D and F were more efficacious than treatment E and all the single therapeutic approaches (P < 0.001). Treatment G was the most efficacious in lowering serum potassium in this study. All treatment modalities had maximum serum potassium lowering effect at 1-2 hours. A fall in plasma glucose concentration was a notable feature of treatments A and D, but significant hypoglycaemia occurred in 20% of patients receiving treatment A and in none on treatment D. The ECG changes of hyperkalaemia did not correlate with serum potassium levels. The normalisation of hyperkalaemic ECG alteration occurred within the first 30 minutes after treatment. In conclusion, combination therapies for hyperkalaemia appear to be more efficacious than single therapeutic approaches. Inclusion of salbutamol seems to protect against insulin induced hypoglycaemia. The maximum potassium lowering effect is observed 1-2 hours of administration of either agents. The potassium reducing effect remains significant compared to baseline values even after 8 hours. If dialysis cannot be instituted early enough it seems reasonable to repeat treatment every 4-6 hours to sustain the effect. Repeated administration of glucose with insulin may not be safe because of the hypoglycaemic effect. Other single and combination therapies can theoretically be repeated regularly until dialysis is initiated although this requires further clinical evaluation.", "In 11 children (aged 5-18 years) with end stage chronic renal failure, the effect on plasma potassium of two doses of salbutamol (separated by two hours) given intravenously (4 micrograms/kg) and on a separate date, of salbutamol administered by nebuliser (2.5 mg if the child weighed below 25 kg, 5 mg if above) was observed. Within 30 minutes of the first dose, the mean plasma potassium concentration fell significantly by 0.87 and 0.61 mmol/l after intravenous and nebulised administration respectively. Sixty minutes after the second dose the plasma potassium was significantly reduced by a further 0.28 and 0.53 mmol/l respectively. There was a significant difference between the two methods of administration at 300 minutes after the first dose favouring nebulisation. No major side effects were observed. Nebulised salbutamol should be the first choice emergency treatment of hyperkalaemia.", "To determine the efficacy of inhaled salbutamol (rapidly delivered, using a metered-dose inhaler with a spacer device [MDI-S]) in lowering the serum potassium levels in patients with hyperkalemia.\n A randomized, double-blind, placebo-controlled trial.\n Seventeen chronic renal failure patients referred to the Nephrology Unit between October 1, 1997 and March 31, 1998 for hemodialysis were randomized.\n Group 1 received salbutamol followed by a placebo. Group 2 received a placebo followed by salbutamol. Each patient inhaled 1,200 microg salbutamol or a placebo through an MDI-S within 2 min. Blood samples were obtained repeatedly before inhalation and after 1, 3, 5, 10, and 60 min. The pulse rate and blood pressure were repeatedly measured. Insulin levels were examined in a subset of patients (n = 10) before, and 1 and 5 min following inhalation. Salbutamol's known side effects, palpitation, tachycardia tremor, and headache, were recorded. Potassium levels rose after 1 min following the completion of treatment and then decreased steadily thereafter. A rise of > or = 0.1 mEq/L was seen in 10 of 17 patients (59%) during the treatment period and there was no change (0%) seen during the placebo period (p < 0.0001). Within 3 min after inhalation of salbutamol, potassium levels declined as a function of time. Potassium levels in those patients taking the placebo did not change as a function of time (p < 0.001). The difference between the placebo and the salbutamol-treated periods reached significance after 5 min (p < 0.05). The serum glucose levels rose following inhalation of salbutamol, with a significant rise after 3 min. The heart rate rose significantly within the first 5 min following inhalation. Serum insulin levels remained unchanged 1 min after inhalation; however, after 5 min, a significant elevation was detected.\n Salbutamol inhalation of 1,200 microg, using an MDI-S, has a relatively rapid onset of action that induces a consistent reduction in serum potassium levels, starting 3 to 5 min following delivery. Unexpectedly, a paradoxical elevation was detected in serum potassium levels in the first minutes following inhalation. This effect, although minor (0.15 mEq/L above baseline), may cast some doubt on the role of salbutamol inhalation as the first treatment for excessive hyperkalemia.", "We evaluated in maintenance hemodialysis patients the potassium lowering effects of intravenous insulin with glucose, nebulized albuterol, and a regimen combining both modalities. There was a similar decrease in plasma potassium following either insulin with glucose (0.65 +/- 0.09 mmol/liter) or albuterol (0.66 +/- 0.12 mmol/liter), and a substantially greater fall with the combined regimen (1.21 +/- 0.19 mmol/liter, P less than 0.02 vs. either drug alone). Baseline plasma glucose concentrations were similar (about 4.8 mmol/liter) prior to all three treatments. Following insulin with glucose, plasma glucose increased transiently. but then fell to 2.8 +/- 0.3 mmol/liter at one hour, with concentrations below 3 mmol/liter in 9 of 12 patients. None of the patients had symptoms of hypoglycemia. Plasma glucose increased to 6.8 +/- 0.5 mmol/liter with albuterol. After the combined drug regimen plasma glucose rose transiently and was back to baseline (4.7 +/- 0.7 mmol/liter) at one hour. Treatment with insulin or albuterol produced trivial increases in heart rate, whereas the combined drug regimen was associated with a significant rise (15.1 +/- 6.0 min-1). These observations suggest that albuterol and insulin with glucose are equally efficacious in lowering plasma potassium in uremic patients, and that the hypokalemic effects of the two drugs is additive. The hypoglycemic effect of insulin is attenuated by coadministration albuterol. Combined therapy with insulin, glucose and albuterol is efficacious and safe for the acute treatment of hyperkalemia in hemodialysis patients.", "A double-blind test to compare IV aminophylline with salbutamol in the treatment of acute, uncontrolled asthma showed that both drugs were equally effective during the first 24 hours. Salbutamol caused a relative tachycardia. Hydrocortisone was given after 2 hours, but did not appear to affect the rate of recovery.", "This study was performed to compare the efficacy of aminophylline and insulin-dextrose infusion as acute treatment modality of hyperkalemia in patients with end-stage renal disease (ESRD).\n This study was conducted on 30 ESRD patients with serum potassium > 6.0 mEq/L. These patients were divided in two groups of 15 each. Group A patients were treated with aminophylline infusion, whereas group B patients were treated with insulin-dextrose infusion. Serum potassium and other biochemical parameters such as blood sugar were measured at beginning of treatment followed by at 60 minutes, 180 minutes, and 360 minutes after treatment.\n Intervenous infusion of aminophylline lowered plasma potassium from 6.48 +/- 0.39 mEq/L to 5.92 +/- 0.40 mEq/L at 180 minutes (p < 0.001 Vs basal) and 6.05 +/- 0.53 mEq/L at 360 minutes (p < 0.01 Vs basal). Whereas, intravenous infusion of insulin-dextrose decreased plasma potassium from 6.59 +/- 0.31 mEq/L to 5.76 +/- 0.32 mEq/L (p < 0.001 Vs basal) and 5.84 +/- 0.21 mEq/L (p < 0.001 Vs basal). Thus in both groups, plasma potassium levels were significantly less than basal levels throughout the study. The decrease in plasma potassium was significantly more in group B patients (p value is < 0.001 after 60 minutes, < 0.05 after 180 minutes and < 0.05 after 360 minutes) when compared to group A patients. There was one episode of hypoglycemia (blood sugar < 60 mg%) in insulin-dextrose infusion group. No other side effects were observed throughout the study.\n Aminophylline is an effective modality for acute treatment of hyperkalemia, though it is less effective than insulin-dextrose infusion. However, more studies are required to confirm these results.", "Twenty-one patients admitted to hospital with acute severe asthma were allocated in a random, single-blind manner to receive intravenous infusions for 24 hours or either aminophylline or salbutamol or a combination of the two drugs. Infusions were administered by a slow infusion pump with an initial loading dose given over 15 minutes, followed by a continuous lower dose of the drug 24 hours as follows: 1. Aminophylline 0.285 mg/kg/min for 15 min followed by 0.014 mg/kg/min (20 mg/min. followed by 1 mg/min for a 70 kg subject). 2. Salbutamol 0.285 microgram/kg/min for 15 min followed by 0.057 microgram/kg/min (20 microgram/min followed by 4 microgram/min for a 70 kg subject). 3. Combined regimen of the above infusions. In addition each patient received intravenous hydrocortisone (4 g) and potassium chloride (4 g) in 2 litres of 5% dextrose infused over 24 hours amd 35% oxygen given via a Ventimask. Peak expiratory flow rates showed a significant improvement after 15 minutes treatment with aminophylline and the combined infusion, but this was not seen until 60 minutes with the salbutamol infusion. No synergistic bronchodilator effect was seen with the combined infusion. The results show that intravenous aminophylline is superior to intravenous salbutamol in the doses given in the initial treatment of acute asthma and that the combination when given intravenously is not better than aminophylline alone.", "The mainstay of treatment for acute asthma in children is nebulised beta 2-adrenergic agents such as salbutamol, given with corticosteroids. However, penetration of the drug to the small airways is impeded by obstruction so intravenous salbutamol may be more effective. We assessed the use of intravenous salbutamol in the management of children with acute severe asthma in a double-blind randomised study.\n Children who presented to the Emergency Department of Westmead Hospital, Sydney, Australia with asthma were assessed with a clinical assessment scale, and those with severe acute asthma were given nebulised salbutamol at a dose of 2.5 mg (age < or = 2 years) or 5.0 mg (age > 2 years), made up to 4 mL with saline. Children who did not improve were eligible to enter phase one of the study. In this phase (0 h-2 h) treatment was by a standard protocol: nebulised salbutamol at the above dose: 4 L/min or 6 L/min continuous oxygen until oxygen saturation reached 93% in room air for at least 30 min; a bolus of intravenous hydrocortisone 5 mg/kg given over 3 min; and then 15 micrograms/kg intravenous salbutamol or saline, depending on randomised allocation. In phase two (2 h-24 h) the children were given nebulised salbutamol continuously then at 30 min, 1 h, 2 h, 3 h, and 4 h, according to need. All children were transferred to the ward once they were ready to start hourly nebulisation. All patients were followed up until discharge. The primary endpoints were recovery time (no longer requiring inhaled salbutamol) and persistent moderate to severe asthma 2 h after randomisation. Analyses were by intention-to-treat although no withdrawals occurred.\n The recovery time (time to cessation of nebulised salbutamol every 30 min) was 4 h in the 14 children allocated intravenous salbutamol compared with 11.5 h for the 15 children in the control group. 2 (14%) of the intravenous salbutamol group compared with 8 (53%) of the control group needed oxygen to maintain oxygen saturation at 93% room air. The intravenous salbutamol group were ready for discharge from the emergency department 9.7 h earlier than the control group. No clinically significant side-effects were found in either group.\n Addition of a 10 min infusion of salbutamol in the early treatment of children with acute severe asthma has the potential to curtail the clinical progression of asthma, reduce demand placed on hospital resources, and improve the quality of health care provided to the acutely sick child with asthma.", "To evaluate the effectiveness of early administration of intravenous Magnesium sulfate (i.v. MgSO4) in children with acute severe asthma not responding to conventional therapy.\n Randomized double-blind, placebo-controlled trial.\n Pediatric emergency service of a large teaching hospital.\n 47 children aged between 1-12 years with acute severe asthma showing inadequate or poor response to 3 doses of nebulized salbutamol given at an interval of 20 min each.\n The MgSO4 group received 0.2 ml/kg of 50% MgSO4 as intravenous (i.v.) infusion over 35 minutes and the placebo group received normal saline infusion in the same dose and at the same rate. MgSO4 solution and normal saline were coded and dispensed in identical containers. Decoding was done at the completion of the study. All the patients received oxygen, nebulized salbutamol, i.v. aminophylline and corticosteroids.\n MgSO4 group showed early and significant improvement as compared to placebo group in PEFR and SaO2 at 30 min and 1, 2, 3 and 7 hours after stopping the infusion (p ranging from < 0.05 to < 0.01). The clinical asthma score also showed significant improvement in the MgSO4 group 1, 2, 3 and 11 hours after stopping the infusion (p < 0.01).\n Addition of MgSO4 to conventional therapy helps in achieving earlier improvement in clinical signs and symptoms of asthma and PEFR in patients not responding to conventional therapy alone.", "The aim of this study was to compare the efficacy and safety of salmeterol/fluticasone propionate combination product (SFC) with fluticasone propionate (FP) plus oral montelukast (M) over 12 weeks in symptomatic asthma patients. The study was a multinational, randomised, double-blind, double-dummy, parallel-group design in patients aged > or = 15 years. After a 4-week run-in during which all patients received FP 100 microg twice daily, patients were randomised to inhaled SFC (50/100 microg) twice daily or inhaled FP 100 microg twice daily and oral M 10 mg once daily. Patients kept daily records of their peak expiratory flow (PEF) symptom scores and use of rescue medication. Over the 12-week treatment period, the adjusted increase in mean morning PEF was significantly greater in the SFC group (36 l/min) than the FP/M group (19 l/min; P < 0.001). The improvement in FEV1 was also significantly greater in the SFC group (mean treatment difference 0.11 l; P < 0.001). SFC provided significantly better control of daytime and night-time symptoms and there were fewer exacerbations. Patients in the SFC group were also significantly more likely to have a rescue-free day. Both treatments were equally well tolerated. Combination therapy with FP plus salmeterol (SFC) produced significantly greater improvements in lung function and asthma control than the addition of montelukastto FP.", "The benefit of adding theophylline to beta 2 agonists in acute asthmatic attacks has been debated frequently.\n In an open randomised study 25 patients with severe acute asthma who presented to the emergency department were treated with either a combined nebulised salbutamol (5 mg/dose) and aminophylline infusion (0.6-0.9 mg/kg/hour), or nebulised salbutamol alone.\n The responses to treatment as measured by peak expiratory flow (PEF) and the time taken to achieve maximum PEF were similar in both groups. Side effects were observed more commonly in patients receiving the combined treatment.\n Nebulised salbutamol is equally efficacious in acute asthma when given alone or in combination with aminophylline.", "In a multicenter, randomized, double-blind study, we compared the effects of nebulized (5 mg x 2) and intravenous (0.5 mg) albuterol (salbutamol) over 1 h in 47 patients admitted to hospital with severe acute asthma defined as a peak expiratory flow (PEF) below 150 L/min and hypercapnia (Pa(CO2) > or = 40 mm Hg). Additional treatment included nasal oxygen and hydrocortisone succinate. The efficacy was assessed after 1 h. In the group treated by nebulization (NEB group, n = 22) 19 (86%) patients (95% confidence interval: 65 to 97%) had been treated successfully according to predefined criteria, versus 12 (48%) patients (95% confidence interval: 28 to 69%) in the intravenously treated group (i.v. group, n = 25), p = 0.006. The mean increase in PEF was greater in the NEB group than in the i.v. group (+107 +/- 94 L/min versus +42 +/- 66 L/min, p = 0.01) as well as the decrease in Pa(CO2) values (-10 +/- 5 mm Hg versus -2 +/- 12 mm Hg, p < 0.01). Beta agonist-induced hypokalemia was more pronounced in the i.v. group than in the NEB group. We conclude that, in hypercapnic acute asthma, the nebulized route has a greater efficacy and fewer side effects than the intravenous route." ]	Nebulised or inhaled salbutamol, or IV insulin-and-glucose are the first-line therapies for the management of emergency hyperkalaemia that are best supported by the evidence. Their combination may be more effective than either alone, and should be considered when hyperkalaemia is severe. When arrhythmias are present, a wealth of anecdotal and animal data suggests that IV calcium is effective in treating arrhythmia. Further studies of the optimal use of combination treatments and of the adverse effects of treatments are needed.
CD001269	[ "10493337", "19213766", "10411194", "9652613", "14656755", "10675165", "3123619", "3337087", "14687310", "1530193", "15195237", "18097856", "4908340", "11319482", "16303215", "9580647", "19149900", "11715169", "17596805", "11791098", "17889411", "7666874", "21658144", "1415151", "8648202", "8241913", "15612969", "7031855", "3341857", "18461182", "14506120", "11994246", "22110695", "11382801", "68383", "17142512", "925382", "2968738", "2975452", "3709244", "17006278", "12234038", "12924797", "11517426", "3524050", "8277200", "12706704", "2200894" ]	[ "Randomized, placebo-controlled double blind study on the efficacy of influenza immunization on absenteeism of health care workers.", "Relation of study quality, concordance, take home message, funding, and impact in studies of influenza vaccines: systematic review.", "Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial.", "Randomised placebo-controlled crossover trial on effect of inactivated influenza vaccine on pulmonary function in asthma.", "Influenza vaccination in children with asthma: randomized double-blind placebo-controlled trial.", "Effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial.", "Do hospital employees benefit from the influenza vaccine? A placebo-controlled clinical trial.", "Efficacy of sequential annual vaccination with inactivated influenza virus vaccine.", "Can a short period of micronutrient supplementation in older institutionalized people improve response to influenza vaccine? A randomized, controlled trial.", "Protective efficacy of combined live intranasal and inactivated influenza A virus vaccines in the elderly.", "A cohort study of the effectiveness of influenza vaccine in older people, performed using the United Kingdom general practice research database.", "Influenza vaccination in adults with asthma: safety of an inactivated trivalent influenza vaccine.", "An evaluation of influenza immunization: influence of route of administration and vaccine strain.", "Influenza vaccine in healthy preschool children.", "Safety and immunogenicity of a Proteosome -trivalent inactivated influenza vaccine, given nasally to healthy adults.", "The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children.", "Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example.", "[Effectiveness of an influenza vaccine in a working population in Colombia].", "Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia.", "Safety and tolerability of cold-adapted influenza virus vaccine in children and adolescents with asthma.", "Effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly.", "The effectiveness of vaccination against influenza in healthy, working adults.", "Pilot study of influenza vaccine effectiveness in urban Australian children attending childcare.", "Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly.", "Evaluation of live attenuated influenza vaccines in children 6-18 months of age: safety, immunogenicity, and efficacy. National Institute of Allergy and Infectious Diseases, Vaccine and Treatment Evaluation Program and the Wyeth-Ayerst ca Influenza Vaccine Investigators Group.", "Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial.", "Adverse effects associated with influenza vaccination in patients with COPD: a randomized controlled study.", "Clinical trial of a subunit influenza vaccine.", "Association of influenza immunization with reduction in mortality in an elderly population. A prospective study.", "Preliminary findings of a randomized trial of non-pharmaceutical interventions to prevent influenza transmission in households.", "Effectiveness of inactivated influenza vaccine in preventing acute otitis media in young children: a randomized controlled trial.", "Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study.", "I-MOVE multi-centre case control study 2010-11: overall and stratified estimates of influenza vaccine effectiveness in Europe.", "Efficacy of Influenza Vaccine in Elderly Persons in Welfare Nursing Homes: Reduction in Risks of Mortality and Morbidity During an Influenza A (H3N2) Epidemic.", "Longer term effects of live influenza vaccine in patients with chronic pulmonary disease.", "Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza in young children attending day care.", "Efficacy of live attenuated influenza A/Scotland/74 (H3N2) virus vaccine against challenge with influenza A/Victoria/3/75 (H3N2) virus.", "[The results of state trials of inactivated influenza vaccines for children].", "[Characteristics of the clinical and immunologic safety of inactivated influenza vaccines in children undergoing multiple immunizations].", "Lack of clinical exacerbations in adults with chronic asthma after immunization with killed influenza virus.", "Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma.", "Impact of influenza vaccination on civilian aircrew illness and absenteeism.", "Economic evaluation of influenza vaccination in Thai chronic obstructive pulmonary disease patients.", "Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans.", "Study of live recombinant cold-adapted influenza bivalent vaccine of type A for use in children: an epidemiological control trial.", "A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease.", "Efficacy trial of live, cold-adapted and inactivated influenza virus vaccines in older adults with chronic obstructive pulmonary disease: a VA cooperative study.", "Frequency of adverse reactions to influenza vaccine in the elderly. A randomized, placebo-controlled trial." ]	[ "In healthy adults influenza immunization reduces absenteeism caused by respiratory infections, but data on its efficacy among health care workers are scarce.\n To determine the effect of the conventional inactivated influenza A vaccine on reducing absenteeism related to respiratory infections among pediatric health care providers.\n A randomized, placebo-controlled, double blind study on vaccine efficacy was conducted in two pediatric hospitals during the winter season 1996 to 1997. The primary endpoint was days of work lost from the hospital because of respiratory infections. The documentation of absenteeism was based on personal sickness logs.\n Of the 547 randomized vaccinees 427 (78%) persons completed the 4-month follow-up and returned the sickness logs. Immunization failed to reduce episodes of respiratory infections (1.8 episodes/study period among vaccinees vs. 2.0 among controls). Similarly the vaccine failed to affect the total number of days the vaccinees suffered from respiratory infections (13.5 days vs. 14.6 days, respectively). However, days of work lost because of respiratory infections (1.0 days vs. 1.4 days, respectively, P = 0.02) and especially total numbers of days the study persons felt themselves unable to work when either on or off duty (2.5 days vs. 3.5 days, P 0.02) were significantly decreased.\n Influenza vaccination reduced absenteeism related to respiratory infections by 28%. We therefore believe that routine annual influenza immunizations should be recommended to health care providers working in pediatric settings.", "To explore the relation between study concordance, take home message, funding, and dissemination of comparative studies assessing the effects of influenza vaccines.\n Systematic review without meta-analysis.\n Search of the Cochrane Library, PubMed, Embase, and the web, without language restriction, for any studies comparing the effects of influenza vaccines against placebo or no intervention. Abstraction and assessment of quality of methods were carried out.\n We identified 259 primary studies (274 datasets). Higher quality studies were significantly more likely to show concordance between data presented and conclusions (odds ratio 16.35, 95% confidence interval 4.24 to 63.04) and less likely to favour effectiveness of vaccines (0.04, 0.02 to 0.09). Government funded studies were less likely to have conclusions favouring the vaccines (0.45, 0.26 to 0.90). A higher mean journal impact factor was associated with complete or partial industry funding compared with government or private funding and no funding (differences between means 5.04). Study size was not associated with concordance, content of take home message, funding, and study quality. Higher citation index factor was associated with partial or complete industry funding. This was sensitive to the exclusion from the analysis of studies with undeclared funding.\n Publication in prestigious journals is associated with partial or total industry funding, and this association is not explained by study quality or size.", "Influenza virus is a major cause of illness, disruption to daily life, and increased use of health care in all age groups.\n To assess the safety and effectiveness of intranasally administered trivalent, live, attenuated influenza virus (LAIV) vaccine for reducing illness, absenteeism, and health care use among healthy, working adults.\n Randomized, double-blind, placebo-controlled trial conducted from September 1997 through March 1998.\n Thirteen centers across the United States.\n A total of 4561 healthy, working adults aged 18 to 64 years recruited through health insurance plans, at work sites, and from the general population.\n Participants were randomized 2:1 to receive intranasally administered trivalent LAIV vaccine (n = 3041) or placebo (n = 1520) in the fall of 1997.\n Episodes of febrile illness, severe febrile illness, febrile upper respiratory tract illness, work loss, and health care use during the peak and total influenza outbreak periods, and adverse events.\n Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine vs 14.6% for placebo; P=.19). However, vaccination significantly reduced the numbers of severe febrile illnesses (18.8% reduction; 95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract illnesses (23.6% reduction; 95% CI, 12.7%-33.2%). Vaccination also led to fewer days of illness across all illness syndromes (22.9% reduction for febrile illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile upper respiratory tract illnesses), and fewer days with health care provider visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for febrile upper respiratory tract illnesses). Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes. Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination, but serious adverse events between the groups were not significantly different. The match between the type A(H3N2) vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2]) for the 1997-1998 season was poor, suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain.\n Intranasal trivalent LAIV vaccine was safe and effective in healthy, working adults in a year in which a drifted influenza A virus predominated.", "Despite current recommendations, many people with asthma do not receive annual vaccination against influenza, partly because of concern that vaccine may trigger exacerbations. Colds can trigger exacerbations, which may be mistaken for vaccine-related adverse events. We undertook a double-blind placebo-controlled multicentre crossover study to assess the safety of influenza vaccine in patients with asthma, with allowance for the occurrence of colds.\n We studied 262 patients, aged 18-75 years, who recorded daily peak expiratory flow (PEF), respiratory symptoms, medication, medical consultations, and hospital admissions for 2 weeks before the first injection and until 2 weeks after the second injection. Order of injection (vaccine and placebo) was assigned randomly. There was an interval of 2 weeks between injections. The main outcome measure was an exacerbation of asthma within 72 h of injection (defined as a fall in PEF of >20%).\n Among 255 participants with paired data, 11 recorded a fall in PEF of more than 20% after vaccine compared with three after placebo (McNemar's test p=0.06); a fall of more than 30% was recorded by eight after vaccine compared with none after placebo (binomial test p=0.008). However, when participants with colds were excluded, there was no significant difference in the numbers with falls of more than 20% between vaccine and placebo (six vs three; binomial test p=0.51), although the difference for PEF decreases of more than 30% approached significance (five vs none; binomial test, p=0.06). This association was confined to first-time vaccinees.\n Our findings indicate that pulmonary-function abnormalities may occur as a complication of influenza vaccination. However, the risk of pulmonary complications is very small and outweighed by the benefits of vaccination.", "There is little evidence that influenza vaccination reduces asthma exacerbations. We determined whether influenza vaccination is more effective than placebo in 6-18-year-old children with asthma. We performed a randomized, double-blind, placebo-controlled trial. Parenteral vaccination with inactivated influenza vaccine or placebo took place approximately November 1, and children were followed until April 1 of the next year. Airway symptoms were reported in a diary. When symptom scores reached a predefined level, a pharyngeal swab was taken. Primary outcome was the number of asthma exacerbations associated with virologically proven influenza infection. Three hundred forty-nine children were assigned placebo, and 347 were assigned vaccine. Pharyngeal swabs positive for influenza were related to 42 asthma exacerbations, 24 in the vaccine group and 18 in the placebo group, a difference of 33% favoring placebo (31% after adjustment for confounders; 95% confidence interval, -34% to 161%). Influenza-related asthma exacerbations were of similar severity in both groups; they lasted 3.1 days shorter in the vaccine group (95% confidence interval, -6.2 to 0.002 days, p = 0.06). We conclude that influenza vaccination did not result in a significant reduction of the number, severity, or duration of asthma exacerbations caused by influenza. Additional studies are warranted to justify routine influenza vaccination of children with asthma.", "Vaccination of health-care workers has been claimed to prevent nosocomial influenza infection of elderly patients in long-term care. Data are, however, limited on this strategy. We aimed to find out whether vaccination of health-care workers lowers mortality and the frequency of virologically proven influenza in such patients.\n In a parallel-group study, health-care workers in 20 long-term elderly-care hospitals (range 44-105 patients) were randomly offered or not offered influenza vaccine (cluster randomisation, stratified for policy for vaccination of patients and hospital size). All deaths among patients were recorded over 6 months in the winter of 1996-97. We selected a random sample of 50% of patients for virological surveillance for influenza, with combined nasal and throat swabs taken every 2 weeks during the epidemic period. Swabs were tested by tissue culture and PCR for influenza viruses A and B.\n Influenza vaccine uptake in health-care workers was 50.9% in hospitals in which they were routinely offered vaccine, compared with 4.9% in those in which they were not. The uncorrected rate of mortality in patients was 102 (13.6%) of 749 in vaccine hospitals compared with 154 (22.4%) of 688 in no-vaccine hospitals (odds ratio 0.58 [95% CI 0.40-0.84], p=0.014). The two groups did not differ for proportions of patients positive for influenza infection (5.4% and 6.7%, respectively); at necropsy, PCR was positive in none of 17 patients from vaccine hospitals and six (20%) of 30 from no-vaccine hospitals (p=0.055).\n Vaccination of health-care workers was associated with a substantial decrease in mortality among patients. However, virological surveillance showed no associated decrease in non-fatal influenza infection in patients.", "Although current guidelines target hospital employees who contact high-risk patients as a high priority for influenza immunization, there are few data to support or refute this recommendation. Therefore, the authors enrolled 179 hospital employees in a randomized double-blind placebo-controlled clinical trial during the 1985-1986 influenza season. Influenza immunization was performed without serious adverse reactions and there was no increase in absenteeism attributable to the vaccination. Among those who developed clinical influenza, there was a trend toward fewer days of illness in the vaccinated group compared with the placebo group (6.0 vs. 8.0, p = 0.07). There were no statistically significant differences between subjects receiving influenza vaccine and those receiving the placebo when comparing incidences of influenza-like illness, severities of illness, and sick absenteeism. Influenza immunization of hospital employees was performed at minimal cost and risk but provided little benefit, most likely because of an unexpected drift of the prevalent influenza strain away from the vaccine type.", "Inactivated influenza virus vaccine efficacy after annual revaccination has been reported to be less than that after first vaccination in boarding school children. We prospectively examined the immunogenicity and efficacy of this vaccine in healthy 30- to 60-year-old volunteers in Houston, Texas, over two epidemic seasons (1983-1985) encompassing outbreaks due to influenza A (H3N2 and H1N1) and influenza B viruses. A placebo group that had never (or not in recent years) received inactivated influenza virus vaccine, a group that received the vaccine for the first time (first vac), and a group given two or more recent vaccinations (multivac) were evaluated in a double-blind fashion each year. Vaccination induced higher frequencies of rise in serum antibody titer to vaccine components in first vac than in multivac volunteers, but mean postvaccination titers were similar. Clinical and virologic evaluations of illnesses during both epidemics and of influenza infections diagnosed serologically over the epidemic seasons revealed no overall reduction in illness from that in the placebo group for either vaccine group; modest reductions in influenza infection-related illness that were significant only for the multivac group against A/H3N2-related illness (55%; p less than 0.04); reduction in moderate-to-severe lower respiratory and/or systemic illness due to influenza for multivac (73%, p less than 0.025) but not first vac (15%, p greater than 0.10) volunteers during the A/H3N2 epidemic; reduction in influenza virus shedding in the multivac (54%, p less than 0.05) but not the first vac (16%, p greater than 0.10) group when compared with the placebo group for both years; and overall 63-81% reductions in documented infections with each influenza virus for both vaccine groups with the exception of A/H1N1 for the first vac group (24%, p greater than 0.10) and type B for the multivac group (58%, p = 0.067). Vaccine efficacy was only modest in these studies, but in contrast to the earlier report in boarding school children, efficacy appeared to be somewhat greater after repeated annual vaccination than after first administration.", "To test the hypothesis that a micronutrient supplement can improve seroconversion after influenza immunization in older institutionalized people.\n : Randomized, double-blind, placebo-controlled study.\n Nursing and residential homes in Liverpool, United Kingdom.\n One hundred sixty-four residents aged 60 and older from 31 homes were initially randomized; of these, 119 (72.6%) completed the study.\n Participants were randomized to receive a micronutrient supplement providing the reference nutrient intake for all vitamins and trace elements or identical placebo. Tablets were taken over an 8-week period during September and October 2000; influenza vaccine was administered 4 weeks after their commencement.\n The hemagglutination-inhibiting antibody response as defined by a fourfold or greater titer rise over 4 weeks and assessed separately for each of the three antigens contained in the 2000/2001 influenza vaccine (A/New Caledonia/20/99 (H1N1), A/Moscow/10/99 (H3N2), B/Beijing/184/93 (B)).\n Despite a significant increase in serum concentrations of vitamins A, C, D3, E, folate, and selenium in the supplemented group, there was no significant difference between groups (supplemented vs placebo, respectively) in the proportion of participants seroconverting to H1N1 (41% vs 49%, P=.374), H3N2 (49% vs 58%, P=.343), or B (41% vs 40%, P=.944).\n A micronutrient supplement providing the reference nutrient intake administered over 8 weeks had no beneficial effect on antibody response to influenza vaccine in older people living in long-term care.", "To evaluate the efficacy of adding intranasal live attenuated cold-adapted influenza A vaccine to inactivated influenza vaccine to prevent influenza A in elderly residents of long-term-care institutions.\n Randomized, double-blind, placebo-controlled study conducted over 3 years.\n Three large nursing homes.\n A total of 523 residents of nursing homes (mean age, 84.2 years).\n All participants received trivalent inactivated influenza vaccine parenterally and were randomly assigned to receive either live attenuated influenza A (H3N2) virus vaccine or placebo intranasally.\n Laboratory-documented influenza A was defined as a respiratory illness plus isolation of influenza A virus from nasal secretions, significant serologic response, or both. Participants were considered to have been exposed to influenza A if they resided in an institution in which cases of influenza A were documented. Outbreak-associated illnesses were defined as those occurring between the first and last isolation of influenza virus from within the institution, +/- 3 days.\n Participants who received intranasal vaccine and were subsequently exposed to influenza A had significantly lower rates of laboratory-documented influenza A (9 of 162 vaccine recipients compared with 24 of 169 placebo recipients; vaccine protective efficacy, 60.6%; 95% CI, 18% to 82%), outbreak-associated respiratory illnesses (13 of 162 vaccine recipients compared with 34 of 169 placebo recipients; vaccine protective efficacy, 56.8%; CI 23% to 76%), and outbreak-associated influenza-like illnesses (6 of 162 vaccine recipients compared with 18 of 169 placebo recipients; vaccine protective efficacy, 65.0%; CI 17% to 86%).\n Intranasal immunization with live attenuated influenza A virus vaccine provided additional protection against influenza A when added to parenteral trivalent inactivated influenza vaccine among elderly nursing home residents.", "The effectiveness of influenza vaccination against hospitalization and death can only ethically be assessed in observational studies. A concern is that individuals who are vaccinated are healthier than individuals who are not vaccinated, potentially biasing estimates of effectiveness upward.\n We conducted a historical cohort study of individuals >64 years of age, for whom there were data available in the General Practice Research Database for 1989 to 1999 in England and Wales. Rates of admissions for acute respiratory diseases and rates of death due to respiratory disease were compared over 692,819 person-years in vaccine recipients and 1,534,280 person-years in vaccine nonrecipients.\n The pooled effectiveness of vaccine against hospitalizations for acute respiratory disease was 21% (95% confidence interval [CI], 17%-26%). The rate reduction attributable to vaccination was 4.15 hospitalizations/100,000 person-weeks in the influenza season. Among vaccine recipients, no important reduction in the number of admissions to the hospital was seen outside influenza seasons. The pooled effectiveness of vaccine against deaths due to respiratory disease was 12% (95% CI, 8%-16%). A greater proportionate reduction was seen among people without medical disorders, but absolute rate reduction was higher in individuals with medical disorders, compared with individuals without such disorders (6.14 deaths due to respiratory disease/100,000 person-weeks vs. 3.12 deaths due to respiratory disease/100,000 person-weeks). Clear protection against death due to all causes was not seen.\n Influenza vaccination reduces the number of hospitalizations and deaths due to respiratory disease, after correction for confounding in individuals >64 years of age who had a high risk or a low risk for influenza. For elderly people, untargeted influenza vaccination is of confirmed benefit against serious outcomes.", "Despite recommendations in most countries for giving inactivated influenza vaccine to people with asthma, only a minority currently receive it. One reason for low vaccine coverage has been concern that vaccination may induce exacerbations of asthma. In this randomized trial, 291 patients between 18 and 65 years of age received either an inactivated influenza vaccine followed 14 days later by a saline placebo or placebo followed by the vaccine. Each patient received 1 dose of vaccine and 1 dose of placebo. The percentage of patients reporting at least one asthma exacerbation within 14 days after injection was similar following vaccine or placebo (28.3% and 25.5%, respectively). The combined exacerbation rate during the first 14-day interval was higher (31.5%) than that during the second 14-day interval (22.4%, P = 0.0135), indicating that the occurrence of exacerbations was not likely to be related to the sequence of injections. The percentages of individuals with solicited systemic symptoms were 56.6% and 44.8% after vaccine or placebo injection, respectively. We conclude that influenza vaccination did not increase the incidence of asthma exacerbations compared to placebo in this study and the vaccine was well tolerated. The results thus support annual influenza vaccination in patients with asthma.", "A field study was undertaken in Tampa, Fla., to assess the efficacy of subcutaneous and aerosol methods of administering vaccine, and to compare the protection afforded by bivalent (A2 and B) influenza virus vaccine and by A2/Hong Kong/68 virus vaccine. Further objectives of the study included a comparison of the effectiveness of single-dose and 2-dose immunization. Approximately 2100 volunteers received, in a double-blind manner, both an injection and an aerosol administration on 2 occasions 3 weeks apart. The results showed that aerosol administration gave a lower over-all protection rate, although the booster dose seemed to have a marked effect. The protection afforded by A2/Hong Kong/68 virus vaccine was considerably greater than that afforded by the bivalent vaccine, particularly when administration was subcutaneous. Results are also given on the occurrence of side-effects and on the correlation between cigarette smoking and the occurrence of influenza-like illness.", "Studies of influenza vaccination in healthy children have not definitely answered the question of their efficacy.\n We have carried out a randomized trial in a well selected population of healthy preschool children in Sardinia, Italy. During October 1995, 344 children aged 1 to 6 years, were randomly assigned to receive influenza vaccine (n=177) or no treatment (n=167). Two doses of a trivalent subvirion vaccine, containing 15mg of highly purified surface antigens from the component strains A/Johannesburg/33/94-like, A/Singapore/6/86-like and B/ Beijing/184/ 93-like were administered. Follow-up data were collected from December 1, 1995 through April 30, 1996.\n Seroconversion was documented in 17 out of 17 children. No specific systemic symptoms or severe local reactions were observed after vaccination. Influenza-like episodes, defined by the presence of fever and cough or sore throat that lasted at least 72 hours, occurred in 63 (37.7%) of unvaccinated children and in 22 (12.4%) of vaccinated ones. The corresponding reduction in disease incidence was 67% (95% CI: 0.59-0.74). Three episodes of otitis were observed among children in the control group versus zero among vaccinated children (p=0.07). Mean duration of day care center absenteism was significantly reduced by vaccination (2.3 days in unvaccinated and 0.5 day in vaccinated children, p<0.001)\n Influenza vaccine is safe and effective in healthy preschool children. However the favourable implications of vaccination on disease rate in subsequent years have to be evaluated.", "We studied the safety and immunogenicity of a nasally administered vaccine comprising three monovalent inactivated influenza antigens (A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Guangdong/120/2000) non-covalently associated with outer membrane proteins of Neisseria meningitidis (Proteosome) in normal, healthy adults. In a randomized, double-blind trial participants (n = 78) were allocated to placebo or a single nasal dose of vaccine containing 15, 30, or 45 microg of each of the three HA antigens, or two nasal doses containing 30 microg of each HA, separated by 2 weeks. The vaccine was generally well tolerated in all doses tested, and in a one or two-dose schedule. A shallow vaccine reactogenicity dose-response was seen. The most common local reaction was nasal congestion, which occurred in up to 48.3% of vaccine recipients in days 0-6 after vaccine but was mild and self-limiting; this reaction was not significantly more common among active vaccine recipients than placebo recipients. Mild to moderate headache was the most commonly reported systemic reactogenicity complaint in all treatment groups, and was the only solicited complaint to increase significantly in frequency after a second active dose. No severe systemic reactions occurred. A positive and statistically significant antibody response was observed, in serum and in nasal secretions, to increasing dose for all three antigens. Serum HAI titre responses and nasal secretory IgA immune responses were elicited against all three antigens. Further testing of this nasal influenza vaccine is warranted to determine its safety and immunogenicity in these populations and its efficacy in the prevention of clinical illness.", "Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old.\n Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions.\n The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 to 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P<0.001).\n A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children.", "Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine (TIV) against culture-confirmed influenza A and/or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic.\n 6203 subjects were randomized to receive TIV (N = 4137) or placebo (N = 2066). The sample size was based on an assumed attack rate of 4% which provided 90% power to reject the hypothesis that vaccine efficacy (VE) was > or = 45%. Cases of influenza like illness (defined as fever (oral temperature > or =37.8 degrees C) plus cough and/or sore throat) were identified both by active (biweekly phone contact) and passive (self reporting) surveillance and nasal and throat swabs were collected from subjects for viral culture.\n TIV was well tolerated and induced a good immune response. The 2005/2006 influenza season was exceptionally mild in the study area, as it was throughout Europe, and only 46 culture-confirmed cases were found in the study cohort (10 influenza A and 36 influenza B). Furthermore among the B isolates, 35 were identified as B/Hong Kong 330/2001-like (B/Victoria/2/87 lineage) which is antigenically unrelated to the vaccine B strain (B/Yamagata/16/88 lineage). The attack rate in the vaccine group (0.7%) was not statistically significantly different from the attack rate in the placebo group (0.9%).\n Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy. This experience illustrates the challenge of conducting a prospective influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance.\n Clinical trial registery: NCT00197223.", "To determine if a vaccine against influenza significantly decreases episodes of acute upper respiratory infection (AURI) and work absenteeism caused by AURI, in healthy adult employees of a banking entity in the city of Medellín, Colombia.\n This was a double-blind randomized placebo-controlled study with 493 volunteers. The volunteers were randomly assigned to two groups, an experimental group and a control group, with 247 and 246 employees, respectively. The experimental group participants received a dose of 0.5 mL of an influenza vaccine containing surface antigens of the strains recommended by the World Health Organization for the 1996-1997 period, with subtypes A/Wuhan/359/95 (H3N2), A/Texas/36/91 (H1N1), and B/Beijing/184/93. An illness was considered an episode of AURI when a participant reported having a sore throat, fever, and a cough lasting more than 24 hours. Evaluations were made every 2 weeks over a 6-month period; the severity of the episodes was assessed in terms of lost workdays due to AURI (defined according to the ninth revision of the International Classification of Diseases, or ICD-9), through monthly evaluations of incapacitating work absences certified by the Colombian Social Security system, over the period of a year.\n Side effects associated with the vaccine were erythema (relative risk (RR) = 8.0; P = 0.02) and local edema (RR = 4.5; P = 0.03). The proportion of the annual cumulative incidence of episodes of AURI was 78.5% for the vaccinated persons and 91.5% for those in the placebo group, with a reduction of 14%, with values between 7% and 20% (RR = 0.86; 95% confidence interval (CI) = 0.80-0.93). The annual cumulative incidence of incapacitating AURI was 15.8% in those vaccinated, with a reduction of 31% in comparison to the placebo group (22.8%), with values between 0% and 52% (RR = 0.69; 95% CI = 0.48-1.0). These levels of protection, both against more mildly symptomatic forms of AURI and those causing lost workdays, increased significantly (between 62% and 89%) in the months of May and October, when outbreaks caused by the influenza virus were confirmed in Colombia.\n The results demonstrated that the influenza vaccination strategy decreased the AURI episodes as well as the number of work absences due to AURI in the healthy adult employees of a banking entity in the city of Medellín, Colombia. The impact that influenza has on this population group is small, and the effect of this vaccination measure is greater then the influenza virus is in circulation.", "This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia.\n In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally > or =28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo.\n Mean age at enrollment was 23.5 +/- 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8-80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9-77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1-92.4%) and any (64.2%; 95% CI: 44.2-77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients.\n CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.", "Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children.\n To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma.\n In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination.\n The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2% vs. 0.4% for the treatment and placebo groups, respectively; P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 > or =15% from baseline, reductions in peak flows > or =15%, > or =30% or > or =2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse event occurred.\n CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.", "Annual circulation of influenza virus coincides with a peak in cardiovascular and pneumonia mortality/morbidity. This study aimed to determine the effectiveness of MF59-adjuvanted subunit influenza vaccine in preventing hospitalisation due to acute coronary syndrome (ACS), cerebrovascular accident (CVA) and pneumonia in the elderly. Three case-control studies were performed during the 2004-2005 influenza season in three health districts in Valencia, Spain (total elderly [>64 years of age] population: n=105,454). Controls were patients admitted for an acute surgical process or trauma within 10 days of case admission. In total, 159 patients were hospitalised for ACS, 148 for CVA and 242 for pneumonia. The risk of hospitalisation after the start of the influenza season was significantly lower in vaccinated patients compared with non-vaccinated patients (adjusted odds ratios: 0.13 [P=0.013] for ACS; 0.07 [P=0.007] for CVA; 0.31 [P=0.005] for pneumonia). During peak virus circulation, vaccination with MF59-adjuvanted subunit influenza vaccine was associated with an 87% relative risk reduction in hospitalisation for ACS, 93% for CVA, and 69% for pneumonia.", "Although influenza causes substantial morbidity and mortality in all age groups, current recommendations emphasize annual immunization for people at high risk for complications of influenza. We conducted a double-blind, placebo-controlled trial of vaccination against influenza in healthy, working adults.\n In the fall of 1994, we recruited working adults from 18 to 64 years of age from in and around the Minneapolis-St. Paul area and randomly assigned them to receive either influenza vaccine or placebo injections. The primary study outcomes included upper respiratory illnesses, absenteeism from work because of upper respiratory illnesses, and visits to physicians' offices for upper respiratory illnesses. The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses.\n We enrolled a total of 849 subjects. Baseline characteristics were similar in the two groups. During the follow-up period, consisting of the 1994-1995 influenza season (December 1, 1994, through March 31, 1995), those who received the vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo (105 vs. 140 episodes per 100 subjects, P < 0.001), 43 percent fewer days of sick leave from work due to upper respiratory illness (70 vs. 122 days per 100 subjects, P = 0.001), and 44 percent fewer visits to physicians' offices for upper respiratory illnesses (31 vs. 55 visits per 100 subjects, P = 0.004). The cost savings were estimated to be $46.85 per person vaccinated.\n Vaccination against influenza has substantial health-related and economic benefits for healthy, working adults.", "Influenza outbreaks in the childcare setting are a significant cause of excess winter morbidity. This study explored methods of follow up and sample collection for a proposed randomised controlled trial of influenza vaccination in children attending childcare.\n The study was conducted in four Sydney childcare centres during 2007. Healthy children aged 6-59 months eligible for vaccination were recruited in two centres, with another two acting as controls. Data on influenza-like illness (ILI: ≥37.8°C plus at least one respiratory symptom) occurrence were collected weekly. In those children with an ILI, parents were asked to collect nasal swabs and send via surface mail for viral polymerase chain reaction. Vaccine efficacy (VE) for ILI was estimated overall and for subgroups aged 6-23 and 24-59 months using the formula VE = 1 - relative risk (RR).\n Sixty-three per cent (151/238) of eligible children had parents give consent. Sixty-three children received influenza vaccine and 88 participated as controls. Of 26 specimens returned, a virus was detected in 18 (69%); none with influenza. Two symptomatic children had positive near-patient influenza tests in general practice (one a vaccine failure). The RR with 95% confidence interval in all children and those aged 6-23 months were less than one, 0.56 (0.32-1.02) and 0.46 (0.15-1.45), respectively.\n This study demonstrated the feasibility and utility of parent-collected and mailed respiratory specimens for VE research in the childcare setting. Two-thirds of parent-collected swabs proved positive for at least one virus. Finding ways to reduce reluctance of parents to submit samples could improve the representativeness of samples collected and the power of the study. No evidence was found for influenza VE, but point estimates were in the direction of protection.\n © 2011 The Authors. Journal of Paediatrics and Child Health © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).", "During the winter of 1989-1990, influenza type A(H3N2) circulated widely, causing excess morbidity and mortality nationwide. From November through April, 1989-1990, hospitalized cases of pneumonia and influenza occurring among noninstitutionalized individuals 65 or more years of age were identified by 20 acute care hospitals in southern lower Michigan. These cases were group matched on age, sex, race, and zip code to randomly sampled, community-based controls from a comprehensive listing of Medicare beneficiaries residing in the study area. Self-reported data were collected from cases and controls on influenza vaccine status for the 1989-1990 season and on a number of other factors which could have influenced vaccination status or outcome. Questionnaires were completed by 1,907 individuals, 449 of whom were cases, resulting in an overall response rate of 76%. A community-based influenza surveillance system was implemented to determine the timing and intensity of viral activity and influenza-like illness. Vaccine effectiveness in preventing overall pneumonia and influenza hospitalizations was estimated by logistic regression. During the 3-month period of surveillance-confirmed peak influenza type A(H3N2) circulation, vaccine effectiveness was 45% (95% confidence interval 14-64, p = 0.009). However, during the 3-month period of low or absent virus activity, identical methodology and model specification resulted in an effectiveness estimate of 21% that was not statistically different from zero (p = 0.36). The effectiveness determined during the peak period of virus circulation is felt to be a conservative estimate, since agents other than influenza are responsible for pneumonia and influenza hospitalizations, even during times of peak influenza activity.", "Live attenuated, cold-adapted (ca) monovalent and bivalent influenza A vaccines were evaluated in seronegative infants (ages 6-18 months) in a double-blind placebo-controlled trial to assess safety and immunogenicity. A total of 182 seronegative subjects received a single intranasal dose (10(6.2) TCID50) of ca A/Kawasaki/9/86 (H1N1) or ca A/Los Angeles/2/87 (H3N2), both as a bivalent vaccine, or placebo. Respiratory and systemic symptoms did not differ between groups after vaccination. Hemagglutination antibody seroconversions (> or = 1:8) to H3N2 exceeded 90%. In contrast, seroconversions to A/Kawasaki/9/86 (H1N1) were significantly less frequent in bivalent ca vaccine recipients (31%) than in monovalent ca H1N1 recipients (83%) (P < .002). During a subsequent H3N2 epidemic, nasal washes were cultured for viruses from any subject with respiratory illness. H3N2 infections documented by virus isolation were reduced by 65% in ca H3N2 recipients compared with placebo or ca HIM recipients (P = .01).", "To assess the frequency and type of side effects after influenza vaccination in elderly people.\n Randomised double blind placebo controlled study.\n 15 general practices in the southern Netherlands.\n 1806 patients aged 60 or older, of whom 904 received influenza vaccine and 902 placebo.\n Adverse reactions reported on postal questionnaire completed four weeks after vaccination.\n 210 (23%) patients given vaccine reported one or more adverse reactions compared with 127 (14%) given placebo. The frequency of local adverse reactions were 17.5% in the vaccine group and 7.3% in the placebo group (p < 0.001). There was no difference in systemic adverse reactions (11% v 9.4%; p = 0.34). In general, men reported fewer side effects than women.\n Only local side effects were more common in vaccinated patients and all side effects were mild.", "The aim of this study was to assess the frequency and type of adverse reactions following influenza vaccination and its effects on lung function, dyspnoeic symptoms, exercise capacity, and clinical acute respiratory illness (ARI) in patients with COPD, and the relationship of these adverse effects to the degree of airflow obstruction.\n A stratified, randomized, double-blind placebo-controlled study was conducted over an 18-month period at a single university hospital. In total, 125 patients with COPD were randomized to the vaccine group (62 patients who received purified trivalent split-virus vaccine injections) or the placebo group (63 patients). Local and systemic symptoms during the week following the injections were evaluated. Clinical ARI, lung function tests, dyspnoeic symptoms (assessed using a visual analogue scale), and a 6-min walking test were evaluated before and at 1 week and 4 weeks following vaccination.\n The frequency of local adverse reactions was 27% in the vaccine group and 6% in the placebo group (P = 0.002). There was no significant difference in systemic adverse reactions between the vaccine and placebo groups (76% vs. 81%; P= 0.5). No difference was observed in the incidence of ARI between the vaccine and placebo groups during the first week (6.4% vs. 6.3%; P= 1) and the first 4 weeks (24.2% vs. 31.7%; P= 0.5) following vaccination. There was no significant change in lung function, dyspnoeic symptoms, and exercise capacity of the patients in both groups, at 1 week and 4 weeks following vaccination, regardless of the severity of COPD.\n Influenza vaccination is associated with minimal local adverse reactions in patients with COPD. Vaccination does not cause systemic adverse reactions, induce clinical exacerbations or adversely affect lung function, dyspnoeic symptoms and exercise capacity in patients with COPD, regardless of the severity of airflow obstruction.", "A double-blind field trial was performed comparing a subunit influenza vaccine (A/Victoria/75 and B/Hongkong/73) with placebo. A good protection against influenza was induced by the vaccine. On the basis of serological determinations (enzyme immunoassay, EIA) the incidences of influenza A and B infections were reduced within a period from 3 weeks up to 5 months after the vaccination by 88 and 68%, respectively. Three weeks after the vaccination 79% of the vaccines had acquired protective serum antibody levels (greater than or equal to 32 x 10(2) by EIA) against influenza A and 62% against influenza B, while in the control subjects protective antibody levels were measured in frequencies from 4 to 13% in subsequent serum samples. With a few exceptions antibody levels were still present in 5-month samples. Side effects were recorded within the first 3 days following the vaccination. Some minor symptoms like redness and tenderness at the vaccination site and muscle ache were reported more frequently by the vaccines than by the controls, but no more harmful systemic reactions.", "We prospectively studied the efficacy of influenza vaccine during an influenza A/Arizona/80 (H3N2) outbreak at the Jewish Home and Hospital for the Aged in New York in the winter season of 1982 to 1983. All patients had been offered influenza vaccine before the outbreak; 181 chose to be vaccinated and 124 refused vaccination but agreed to participate in the study. Among those with serologic evidence of influenza infection, respiratory illness was significantly more common in the unvaccinated group (six of 14 vs one of 22). The overall mortality was 13 (7.2%) of 181 in the vaccinated group and 22 (17.7%) of 124 in the control group. The vaccinated and the control groups were examined for comparability. A logistic regression analysis, which controlled for differences in sex and level of nursing care, indicated that the difference in mortality was still significant, with a summary odds ratio of 2.7. The relative risk of death in the unvaccinated group was comparable at 2.18. Influenza vaccine reduced the mortality by 59% in the vaccinated group compared with the control group.", "There are sparse data on whether non-pharmaceutical interventions can reduce the spread of influenza. We implemented a study of the feasibility and efficacy of face masks and hand hygiene to reduce influenza transmission among Hong Kong household members.\n We conducted a cluster randomized controlled trial of households (composed of at least 3 members) where an index subject presented with influenza-like-illness of <48 hours duration. After influenza was confirmed in an index case by the QuickVue Influenza A+B rapid test, the household of the index subject was randomized to 1) control or 2) surgical face masks or 3) hand hygiene. Households were visited within 36 hours, and 3, 6 and 9 days later. Nose and throat swabs were collected from index subjects and all household contacts at each home visit and tested by viral culture. The primary outcome measure was laboratory culture confirmed influenza in a household contact; the secondary outcome was clinically diagnosed influenza (by self-reported symptoms). We randomized 198 households and completed follow up home visits in 128; the index cases in 122 of those households had laboratory-confirmed influenza. There were 21 household contacts with laboratory confirmed influenza corresponding to a secondary attack ratio of 6%. Clinical secondary attack ratios varied from 5% to 18% depending on case definitions. The laboratory-based or clinical secondary attack ratios did not significantly differ across the intervention arms. Adherence to interventions was variable.\n The secondary attack ratios were lower than anticipated, and lower than reported in other countries, perhaps due to differing patterns of susceptibility, lack of significant antigenic drift in circulating influenza virus strains recently, and/or issues related to the symptomatic recruitment design. Lessons learnt from this pilot have informed changes for the main study in 2008.\n ClinicalTrials.gov NCT00425893 HKClinicalTrials.com HKCTR-365.", "Acute otitis media (AOM) frequently complicates influenza infection. Previous studies have found influenza vaccine effective in reducing the occurrence of AOM in children mainly older than 2 years.\n To evaluate the effectiveness of inactivated influenza vaccine in preventing AOM in children aged 6 to 24 months.\n Randomized, double-blind, placebo-controlled trial of 786 children aged 6 to 24 months enrolled at Children's Hospital of Pittsburgh before the 1999-2000 (411 children) and 2000-2001 (375 children) respiratory seasons (defined as December 1 through March 31 of the respective following year). Children received influenza vaccine or placebo in a 2:1 ratio. The first cohort was observed for 1 year and the second cohort until the end of the ensuing respiratory season.\n Two doses (0.25 mL each) of inactivated trivalent subvirion influenza vaccine or placebo were administered intramuscularly approximately 4 weeks apart.\n Proportion of children who developed AOM, monthly occurrence rate of AOM, estimated proportion of time with middle ear effusion, and utilization of selected health care and related resources.\n Of the 66 children in the vaccine group from whom serum samples were collected, seroconversion against strains in the vaccine formulations developed in 88.6% to 96.8%, depending on the specific strain. The efficacy of the vaccine against culture-confirmed influenza was 66% (95% confidence interval [CI], 34%-82%) in 1999-2000 and -7% (95% CI, -247% to 67%) in 2000-2001; however, influenza attack rates differed between these 2 periods (in the placebo group, 15.9% and 3.3%, respectively). Compared with placebo, influenza vaccine did not reduce the proportion of children who had at least 1 episode of AOM during the respiratory season (in the first cohort: vaccine, 49.2% vs placebo, 52.2%; P =.56 ]; in the second cohort: vaccine, 55.8% vs placebo, 48.3%; P =.17). The vaccine also did not reduce the monthly rate of AOM; the estimated proportion of time with middle ear effusion; or the utilization of selected health care and related resources. There were also no differences between the vaccine and placebo groups regarding any of these outcomes during peak influenza periods. The vaccines administered to both cohorts of children were well tolerated.\n Administration of inactivated trivalent influenza vaccine to children aged 6 to 24 months did not reduce their burden of AOM or their utilization of selected health care and related resources.", "Recent reports have detected an increase in the number of patients with acute coronary syndromes during the flu season. In addition, the World Health Organization recommended vaccination against influenza infection for the Southern hemisphere in the winter of 2001. We evaluated the preventive impact of vaccination on subsequent ischemic events in myocardial infarction patients and in subjects undergoing planned percutaneous coronary angioplasty.\n We included 200 myocardial infarction patients admitted in the first 72 hours and 101 planned angioplasty/stent (PCI) patients without unstable coronary artery disease, prior bypass surgery, angioplasty, or tissue necrosis, in a prospective, multicenter log during the winter season. Infarct patients received a standard therapy and were then randomly allocated in a single-blind manner to either a unique intramuscular influenza vaccination or a control group. Similarly, PCI patients were allocated to either vaccination or control groups. Combined end points (death, reinfarction, and rehospitalization for ischemia) were assessed at 6 months' follow-up. The first primary outcome, cardiovascular death, occurred in 2% of the patients in the vaccine group compared with 8% in the control group (relative risk with vaccine as compared with controls, 0.25; 95% CI 0.07 to 0.86; P=0.01). The triple composite end point occurred in 11% of the patients in the vaccine group compared with 23% in controls (P=0.009).\n Influenza vaccination may reduce the risk of death and ischemic events in patients suffering from infarction and those recovering from angioplasty during flu season. This response could be related to a humoral immune response with positive consequences during flu seasons.", "In the third season of I-MOVE (Influenza Monitoring Vaccine Effectiveness in Europe), we undertook a multicentre case-control study based on sentinel practitioner surveillance networks in eight European Union (EU) member states to estimate 2010/11 influenza vaccine effectiveness (VE) against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza.\n Using systematic sampling, practitioners swabbed ILI/ARI patients within seven days of symptom onset. We compared influenza-positive to influenza laboratory-negative patients among those meeting the EU ILI case definition. A valid vaccination corresponded to > 14 days between receiving a dose of vaccine and symptom onset. We used multiple imputation with chained equations to estimate missing values. Using logistic regression with study as fixed effect we calculated influenza VE adjusting for potential confounders. We estimated influenza VE overall, by influenza type, age group and among the target group for vaccination.\n We included 2019 cases and 2391 controls in the analysis. Adjusted VE was 52% (95% CI 30-67) overall (N = 4410), 55% (95% CI 29-72) against A(H1N1) and 50% (95% CI 14-71) against influenza B. Adjusted VE against all influenza subtypes was 66% (95% CI 15-86), 41% (95% CI -3-66) and 60% (95% CI 17-81) among those aged 0-14, 15-59 and ≥60 respectively. Among target groups for vaccination (N = 1004), VE was 56% (95% CI 34-71) overall, 59% (95% CI 32-75) against A(H1N1) and 63% (95% CI 31-81) against influenza B.\n Results suggest moderate protection from 2010-11 trivalent influenza vaccines against medically-attended ILI laboratory-confirmed as influenza across Europe. Adjusted and stratified influenza VE estimates are possible with the large sample size of this multi-centre case-control. I-MOVE shows how a network can provide precise summary VE measures across Europe.", "The effect of influenza vaccination on the occurrence and severity of influenza virus infection in a population residing in nursing homes was studied through a program by the Osaka Prefectural Government, which is the first and official support for influenza vaccination of the elderly population during an influenza A (H3N2) epidemic in JAPAN:\n A cohort study located in the Osaka Prefecture, Japan, followed the outcomes of elderly nursing home residents who received influenza vaccinations (n = 10,739) in comparison with control subjects who did not receive influenza vaccinations (n = 11,723) and monitored clinically the onset of serious morbidity and mortality of influenza illness. Subjects were 22,462 persons older than 65 years who resided in 301 welfare nursing homes in the Osaka Prefecture, Japan during an influenza A (H3N2) epidemic in 1998 to 1999.\n Of 22,462 individuals living in 301 nursing homes, 10,739 received either one dose (2027 subjects) or two doses (8712 subjects) of inactivated, subunit trivalent influenza vaccine. Through the period from November 1998 to March 1999, there were 950 cases of influenza infection diagnosed clinically with cases by virus isolation and/or serology. There were statistically significantly fewer clinical cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort (256 cases, 32 hospital admissions, and one death) compared with the unvaccinated controls (694 cases, 150 hospital admissions, and five deaths). Vaccination was equally effective in those who received one dose of vaccine as in those who received two doses. No serious adverse reactions to vaccination were recorded. Thus, influenza vaccination is safe and effective in this population and should be an integral part of the routine care of persons aged 65 years and older residing in nursing homes.\n This study provides an analysis of the clinical efficacy of influenza vaccination in a large cohort of nursing home residents in JAPAN: Annual influenza vaccine administration requires the attention of all nursing home attendants, physicians, and public health organizations.", "WRL 105 strain live influenza vaccine or placebo was given to patients with chronic bronchitis in a double-blind study. The twenty-one vaccinated and twenty-three placebo-treated patients made daily self-assessments of the severity of symptoms of cough, breathlessness, tightness, wheeze, and sputum production in the following 20 weeks. Symptom scores in the first 2 weeks after vaccination or treatment with placebo were used to calculate a baseline range for each patient. Comparison of symptoms in the two groups in the baseline period showed that symptoms were more often reported by vaccinated than by placebo-treated patients but the differences were not statistically significant. One patient who responded serologically to vaccination had a moderately severe influenzal illness starting on the day after vaccination. Comparison of symptom scores during the 18-week surveillance period with baseline values showed that symptoms of breathlessness, tightness, wheeze and cough were significantly more common in vaccinated than in placebo-treated patients and that antibiotic usage was more common in the vaccinated group.", "The goal was to evaluate the safety, tolerability, and efficacy of an investigational, refrigerator-stable formulation of live attenuated influenza vaccine (cold-adapted influenza vaccine-trivalent) against culture-confirmed influenza, acute otitis media, and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons.\n Children 6 to <36 months of age who were attending day care were assigned randomly in year 1 to receive 2 doses of vaccine or placebo intranasally, 35 +/- 7 days apart. In year 2, subjects received 1 dose of the same treatment as in year 1.\n A total of 1616 subjects (vaccine: 951 subjects; placebo: 665 subjects) in year 1 and 1090 subjects (vaccine: 640 subjects; placebo: 450 subjects) in year 2 were able to be evaluated for efficacy. The mean age at first vaccination was 23.4 +/- 7.9 months. In year 1, the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4%; efficacy was 91.8% against A/H1N1 and 72.6% against B. In year 2, the overall efficacy was 88.7%; efficacy was 90.0% against H1N1, 90.3% against A/H3N2, and 81.7% against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6% in year 1 and 97.0% in year 2. Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent (82.3%) than placebo (75.4%).\n Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care.", "For evaluation of heterologous protection by live attenuated influenza virus vaccine, 42 healthy volunteers with low titers of or no antibody to A/Scotland/74 (H3N2) and A/Victoria/3/75 (H3N2) influenza viruses were given live attenuated A/Scotland/74 (H3N2) virus vaccine or placebo by the intranasal route with no resultant vaccine-related illness. Seventeen of 21 vaccine recipients and none of 21 placebo recipients developed antibody conversion. Thirty-seven days after administration of vaccine or placebo, all subjects were challenged intranasally with wild-type A/Victoria/3/75 influenza virus. Five placebo recipients and no vaccine recipients developed moderately severe illness, whereas 10 vaccine recipients and three placebo recipients developed no illness (p less than 0.025). Although 16 of 21 vaccine recipients fulfilled criteria of infection with the challenge virus, shedding of virus was significantly less frequent, less prolonged, and of significantly lower magnitude than that in the placebo recipients. Thus, live attenuated influenza virus vaccine showed a significant protective effect against illness following challenge with heterologous wild-type virus. The protective effect and the negligible side effects of this vaccine merit consideration of its use in a large-scale field trial.", "Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11-14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines. The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A (H3N2) and A (H1N1) hemagglutinins, 3.5 micrograms per 0.2 ml of the preparation each. The studies demonstrated the safety and low reactogenicity of these vaccines, as well as their high antigenic potency. In 1984 during mixed influenza B + A (H1N1) epidemic the preparations produced a pronounced prophylactic effect: the efficacy indices were 1.6-1.9 (p less than 0.001). The results obtained in these studies made it possible to recommend two inactivated influenza vaccines (chromatographic and centrifugal) for practical medicine with the aim of protecting children aged 11 years and over from influenza.", "In a strictly controlled epidemiological trial on 12,643 school children aged 11-14 years the reactogenic properties and safety of killed influenza chromatographic vaccine under the conditions of multiple immunization were studied. A single immunization dose of the vaccine (0.2 ml) contained the hemagglutinins of influenza viruses A/Philippines/82 (H3N3) and A/Kiev/59/79 (H1N1), 3.5 micrograms each. The preparation was introduced by means of a jet injector. The vaccine was shown to be clinically and immunologically safe under the conditions of the regular multiple immunization of children over the period of 4 years.", "The effects of immunization with killed influenza virus vaccine were assessed by comparison with placebo in a double-blind study of 318 adult patients with chronic asthma. The patients were randomly allocated to active vaccine and placebo. No difference was observed in peak expiratory flow rate or in clinical symptoms of bronchial obstruction between the groups receiving active vaccine and placebo during the first week after immunization. The data were analyzed separately for age, sex, duration of the disease, hypersensitivity to aspirin (acetylsalicylic acid), atopic status, patients with a history of attacks of asthma induced by viral infections, patients with a diurnal variation of baseline peak expiratory flow of 20 percent or more, and patients receiving continuous oral steroid medication, but none of these factors seemed to predict any short-term adverse effects of vaccination. Follow-up for eight months after the vaccination revealed no differences in asthmatic symptoms between the patients treated with active vaccine and those receiving placebo. The antiviral antibody response to vaccination was normal. The possible protection provided by the vaccination against exacerbation of asthma induced by influenza could not be evaluated, since the influenza epidemic expected during the season failed to occur in Finland. It is concluded that immunization with killed influenza vaccine is safe and is not associated with any significant side effects in adult patients with chronic asthma.", "Despite their potential for increased morbidity, 75% to 90% of asthmatic children do not receive influenza vaccination. Live attenuated influenza vaccine (LAIV), a cold-adapted, temperature-sensitive, trivalent influenza vaccine, is approved for prevention of influenza in healthy children 5 to 19 years of age. LAIV has been studied in only a small number of children with asthma.\n Children 6 to 17 years of age, with a clinical diagnosis of asthma, received a single dose of either intranasal CAIV-T (an investigational refrigerator-stable formulation of LAIV; n = 1114) or injectable trivalent inactivated influenza vaccine (TIV; n = 1115) in this randomized, open-label study during the 2002-2003 influenza season. Participants were followed up for culture-confirmed influenza illness, respiratory outcome, and safety.\n The incidence of community-acquired culture-confirmed influenza illness was 4.1% (CAIV-T) versus 6.2% (TIV), demonstrating a significantly greater relative efficacy of CAIV-T versus TIV of 34.7% (90% confidence interval [CI] 9.4%-53.2%; 95% CI = 3.9%-56.0%). There were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate findings, asthma symptom scores, or nighttime awakening scores. The incidence of runny nose/nasal congestion was higher for CAIV-T (66.2%) than TIV (52.5%) recipients. Approximately 70% of TIV recipients reported injection site reactions.\n CAIV-T was well tolerated in children and adolescents with asthma. There was no evidence of a significant increase in adverse pulmonary outcomes for CAIV-T compared with TIV. CAIV-T had a significantly greater relative efficacy of 35% compared with TIV in this high-risk population.", "Approximately 10% of the general population worldwide acquires influenza infection every year. Airline crews run a particularly high risk of contracting influenza and influenza-like viruses because they come in contact with hundreds of potentially infected individuals every day. Respiratory diseases are the most frequent cause of absenteeism among flight crews in airline companies. Several studies have shown the efficacy of influenza vaccination in the workplace of healthy, working adults leading to increased productivity and lower absenteeism. We conducted a double blind, randomized, placebo-controlled study on flight crews of an airline company in order to determine the safety and efficacy of a trivalent inactivated influenza vaccine in reducing illness and absences from work.\n The 813 healthy members of a Brazilian airline company were randomly assigned to receive injections of either an influenza vaccine or a placebo, with a follow-up period of 7 mo after vaccination. Primary outcomes included influenza-like illness episodes and absenteeism from work due to such episodes.\n Demographic characteristics were similar in the two groups. No significant side-effects occurred in either group. Compared to the placebo group, individuals receiving the vaccine showed 39.5% fewer episodes of flu-like illness (p < 0.001) and 26% fewer days of work lost (p = 0.03). The vaccinated group developed 33% fewer episodes of any severe flu-like illness (p < 0.01).\n The data indicates that influenza vaccination is safe in airline flight crews and may produce health-related benefits including reduced absenteeism.", "To determine the cost-effectiveness and cost-benefit of influenza vaccination in chronic obstructive pulmonary disease (COPD) patients the authors conducted a stratified randomized, double-blind, placebo-controlled trial from June 1997 to November 1998 at a university hospital in Thailand. A total of 125 COPD patients were stratified based on their FEV1 as mild COPD (FEV1 > or = 70% predicted), moderate COPD (FEV1 50-69% predicted) and severe COPD (FEV1 < 50% predicted) and in each severity stratum they were randomized to the vaccine group (received intramuscular injection with purified trivalent split-virus vaccine containing A/Texas/36/91 (H1N1), A/Nanchang 1933/95 (H3N2) and B/Harbin 107/94) or the placebo group (received intramuscular injection with vit B1). Number of episodes of acute respiratory illness (ARI) related to influenza (clinical ARI + a serum hemagglutination inhibition antibody titre of 38 or greater and a four fold titre increase in convalescent serum compared to acute serum) as well as severity of each ARI (outpatient treatment, hospitalization or required mechanical ventilation) and costs of treatment (direct medical costs comprised real drug costs from the hospital dispensary in outpatient cases and real charges in hospitalization cases) were collected and analyzed for the cost-effectiveness and cost-benefit of influenza vaccination. The incidence of influenza-related ARI in the study year was 27 per cent in the placebo group and 6.4 per cent in the vaccine group (relative risk [RR] 0.24, vaccine effectiveness 76%). The incidence was 27.3 per cent, 23.5 per cent and 29.2 per cent in mild, moderate and severe COPD respectively in the placebo group and 4.3 per cent, 12.5 per cent, and 4.3 per cent in the mild, moderate and severe COPD respectively in the vaccine group (RR 0.16, 0.53 and 0.15; vaccine effectiveness 84%, 47%, and 85% respectively). The incremental cost-effectiveness ratios demonstrated that for every 100 patients with mild COPD whom the authors decided to vaccinate, the cost would be 24,840 baht more and would prevent 18.2 outpatients, 4.8 hospitalizations and 0 patient from mechanical ventilation due to ARI related to influenza. Likewise, the authors would have prevented 5.1 outpatients, 5.9 hospitalizations, 5.9 mechanical ventilation and 20.8 outpatients, 3.9 hospitalizations, 8.3 mechanical ventilation for every 100 moderate COPD and every 100 severe COPD patients vaccinated respectively. More than 90 per cent of the costs of treatment of influenza-related ARI were costs of hospitalization and for patients with moderate and severe airflow obstruction, more than 90 per cent of these costs were attributed to the costs of treating the patients who required mechanical ventilation. Predicted cost savings for every 100 mild COPD, 100 moderate COPD and 100 severe COPD patients vaccinated were 125,629 baht, 538,184.3 baht, and 680,647.1 baht respectively. In conclusion: Influenza vaccination is highly effective in the prevention of acute respiratory illness related to influenza virus infection in COPD, regardless of severity of airflow obstruction. Vaccination is more cost-effective in preventing mechanical ventilation episodes and more cost-benefit in patients with more severe airflow obstruction. Influenza vaccination should be recommended to all patients with COPD with the higher priority provided to patients with more severe airflow obstruction.", "This study developed methods and determined the impact of influenza vaccination on elderly persons in 3 large health plans: Kaiser Permanente Northwest, HealthPartners, and Oxford Health Plans. Data for the 1996-1997 and 1997-1998 seasons were extracted from administrative databases. Subjects were health plan members > or = 65 years old. Comorbid conditions collected from the preceding year were used for risk adjustment with logistic regression. The virus-vaccine match was excellent for year 1 and fair for year 2. Both years, during peak and total periods, vaccination reduced all causes of death and hospitalization for pneumonia and influenza: hospitalizations were reduced by 19%-20% and 18%-24% for years 1 and 2, respectively, and deaths were reduced by 60%-61% and 35%-39% for the same periods. These results show that all elderly persons should be immunized annually for influenza. The methods used in this study are an efficient cost-effective way to study vaccine impact and similar questions.", "Live cold-adapted recombinant bivalent vaccine of influenza type A was studied in a controlled field trial in 1982-1983 among nearly 30,000 children 3-15 years old. The bivalent vaccine consisted of recombinants 47/25/1 (H1N1) and 47/7/2 (H3N2) of wild-type viruses A/Brazil/11/78 (H1N1) and A/Bangkok/1/79 (H3N2) with cold-adapted donor A/Leningrad/134/47/57 (H2N2). The recombinants which received mutant nonglycoprotein genes from cold-adapted donor did not suppress each other after simultaneous inoculation of children and stimulated antibody response to both strains. The bivalent vaccine was completely attenuated for children. It caused less than 1% transient febrile reactions during five days after the first vaccination, including double seronegative individuals with low antibody titres to both vaccinal strains. The cold-adapted bivalent vaccine tested proved to be safe for children according to the analysis of morbidity studies among vaccines and a control group performed during the five days and the following six months after the first immunization. There is a similar distribution of non-influenza illnesses and a statistically significant decrease in influenza-like diseases among vaccines compared to the control group. In the four months after the immunization programme was completed, epidemics of influenza A H1N1 and H3N2 occurred. The incidence of influenza-like diseases was approximately 50% less in the vaccinated than in the control groups. This is the first evidence of safety and protective efficacy of recombinant live influenza vaccine for children 3-15 years of age.", "A double-blind, randomized controlled trial over 5 years compared the safety, immunogenicity, and efficacy of cold-adapted and inactivated influenza A vaccines in 5210 normal subjects. Both vaccines were well tolerated. Inactivated vaccine significantly increased hemagglutination inhibition antibody titers. Significant titer rises were also noted after cold-adapted vaccine but of lesser magnitude than with inactivated vaccine. The efficacy of inactivated vaccine in preventing culture-positive influenza was 76% (95% confidence interval [CI], 58%-87%) for H1N1 disease and 74% (95% CI, 52%-86%) for H3N2; for cold-adapted vaccine, 85% (95% CI, 70%-92%) and 58% (95% CI, 29%-75%), respectively. The efficacy of inactivated vaccine in preventing a four-fold rise in antibody titer over the influenza season was 69% (95% CI, 61%-76%) for H1N1 and 73% (95% CI, 65%-79%) for H3N2; for cold-adapted vaccine, 54% (95% CI, 44%-62%) and 32% (95% CI, 17%-44%), respectively. Cold-adapted and inactivated influenza vaccines are safe and effective for preventing influenza A disease.", "We assessed whether trivalent live, cold-adapted influenza virus (CAIV-T) vaccine provides added protection when co-administered with trivalent inactivated influenza virus vaccine (TVV) in patients with chronic obstructive pulmonary disease (COPD). Subjects (N=2215) were randomly assigned to receive either TVV intramuscularly (IM) and CAIV-T intranasally (TC), or TVV and placebo (TP). The vaccines were well-tolerated. Efficacy of TC compared to TP was not statistically significant and was 0.16 for any influenza virus strain (95% confidence limit (CL): -0.22, 0.43), 0.26 for A (H3N2) virus (95% CL: -0.17, 0.53), and -0.05 for type B virus (95% CL: -1.13, 0.48). However, there was a possible advantage for TC over TP in reducing respiratory consequences of an influenza season measured by pulmonary function and symptoms at end of study.", "Concern about side effects constitutes a major deterrent to patient compliance with influenza vaccination, yet there is a paucity of data about the occurrence of adverse reactions in the population targeted for immunization. We conducted a randomized, double-blind, crossover trial to compare the frequency of adverse reactions following administration of 1988-1989 trivalent split-antigen influenza vaccine and saline placebo. Outpatient veterans 65 years of age or over (n = 336) were recruited by mail and were randomly assigned to receive vaccine followed 2 weeks later by placebo injection or placebo followed 2 weeks later by vaccine. There was no significant difference between influenza vaccine and placebo with respect ot the proportion of subjects reporting disability or systemic symptoms." ]	Influenza vaccines have a modest effect in reducing influenza symptoms and working days lost. There is no evidence that they affect complications, such as pneumonia, or transmission. WARNING: This review includes 15 out of 36 trials funded by industry (four had no funding declaration). An earlier systematic review of 274 influenza vaccine studies published up to 2007 found industry funded studies were published in more prestigious journals and cited more than other studies independently from methodological quality and size. Studies funded from public sources were significantly less likely to report conclusions favorable to the vaccines. The review showed that reliable evidence on influenza vaccines is thin but there is evidence of widespread manipulation of conclusions and spurious notoriety of the studies. The content and conclusions of this review should be interpreted in light of this finding.
MR000012	[ "11730399", "7823387", "15161896", "12928469", "20624806", "1483075", "11920415", "21542934", "8643884", "19901314", "10968436", "15588746", "16904951", "18227107", "1315663", "19574328" ]	[ "Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.", "Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials.", "Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles.", "Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events?", "Assessment of risk of bias among pediatric randomized controlled trials.", "Randomised controlled trial of effects of coordinating care for terminally ill cancer patients.", "Secular changes in the quality of published randomized clinical trials in rheumatology.", "Treatment success in pragmatic randomised controlled trials: a review of trials funded by the UK Health Technology Assessment programme.", "Randomized and non-randomized patients in clinical trials: experiences with comprehensive cohort studies.", "Undisclosed changes in outcomes in randomized controlled trials: an observational study.", "The uncertainty principle and industry-sponsored research.", "An analysis of the effect of funding source in randomized clinical trials of second generation antipsychotics for the treatment of schizophrenia.", "A randomised trial of the effects of an additional communication strategy on recruitment into a large-scale, multi-centre trial.", "Gynaecologic surgery from uncertainty to science: evolution of randomized control trials.", "Impact of random assignment on study outcome: an empirical examination.", "Quality of randomised trials in COPD." ]	[ "To explore whether reported methodologic quality affects estimated intervention effects in randomized trials and contributes to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.\n Meta-analyses of randomized trials that included at least one large trial (>/=1000 participants) were included, regardless of the therapeutic area. Eligible meta-analyses were identified through electronic searches and bibliographies of relevant articles.\n Full-length randomized trials.\n Methodologic quality was assessed according to reported randomization, double blinding, and follow-up as separate components and by using the Jadad composite scale.\n Fourteen meta-analyses involving 190 randomized trials from eight therapeutic areas were included. Compared with large trials, intervention effects were exaggerated in small trials with inadequate allocation sequence generation (ratio of odds ratios, 0.46 [95% CI, 0.25 to 0.83]; P = 0.011), inadequate allocation concealment (ratio of odds ratios, 0.49 [CI, 0.27 to 0.86]; P = 0.014), and no double blinding (ratio of odds ratios, 0.52 [CI, 0.28 to 0.96]; P = 0.01). Large trials did not differ significantly from small trials with adequate generation of the allocation sequence, adequate allocation concealment, or adequate double blinding. No association was seen between reported follow-up and intervention effects. The Jadad scale provided no additional information because the scale and the quality components overlapped substantially.\n Inadequate generation of the allocation sequence, allocation concealment, and double blinding lead to exaggerated estimates of intervention benefit and may contribute to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.", "To determine if inadequate approaches to randomized controlled trial design and execution are associated with evidence of bias in estimating treatment effects.\n An observational study in which we assessed the methodological quality of 250 controlled trials from 33 meta-analyses and then analyzed, using multiple logistic regression models, the associations between those assessments and estimated treatment effects.\n Meta-analyses from the Cochrane Pregnancy and Childbirth Database.\n The associations between estimates of treatment effects and inadequate allocation concealment, exclusions after randomization, and lack of double-blinding.\n Compared with trials in which authors reported adequately concealed treatment allocation, trials in which concealment was either inadequate or unclear (did not report or incompletely reported a concealment approach) yielded larger estimates of treatment effects (P < .001). Odds ratios were exaggerated by 41% for inadequately concealed trials and by 30% for unclearly concealed trials (adjusted for other aspects of quality). Trials in which participants had been excluded after randomization did not yield larger estimates of effects, but that lack of association may be due to incomplete reporting. Trials that were not double-blind also yielded larger estimates of effects (P = .01), with odds ratios being exaggerated by 17%.\n This study provides empirical evidence that inadequate methodological approaches in controlled trials, particularly those representing poor allocation concealment, are associated with bias. Readers of trial reports should be wary of these pitfalls, and investigators must improve their design, execution, and reporting of trials.", "Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected, but direct evidence of such bias is currently limited to case reports.\n To study empirically the extent and nature of outcome reporting bias in a cohort of randomized trials.\n Cohort study using protocols and published reports of randomized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg, Denmark, in 1994-1995. The number and characteristics of reported and unreported trial outcomes were recorded from protocols, journal articles, and a survey of trialists. An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta-analysis. Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias. Protocols and published articles were also compared to identify discrepancies in primary outcomes.\n Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes; consistency between primary outcomes defined in the most recent protocols and those defined in published articles.\n One hundred two trials with 122 published journal articles and 3736 outcomes were identified. Overall, 50% of efficacy and 65% of harm outcomes per trial were incompletely reported. Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy (pooled odds ratio, 2.4; 95% confidence interval [CI], 1.4-4.0) and harm (pooled odds ratio, 4.7; 95% CI, 1.8-12.0) data. In comparing published articles with protocols, 62% of trials had at least 1 primary outcome that was changed, introduced, or omitted. Eighty-six percent of survey responders (42/49) denied the existence of unreported outcomes despite clear evidence to the contrary.\n The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols. Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention. To ensure transparency, planned trials should be registered and protocols should be made publicly available prior to trial completion.", "Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions.\n To explore whether the association between funding and conclusions in randomized drug trials reflects treatment effects or adverse events.\n Observational study of 370 randomized drug trials included in meta-analyses from Cochrane reviews selected from the Cochrane Library, May 2001. From a random sample of 167 Cochrane reviews, 25 contained eligible meta-analyses (assessed a binary outcome; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment). The primary binary outcome from each meta-analysis was considered the primary outcome for all trials included in each meta-analysis. The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect, adverse events, and additional confounding factors (methodological quality, control intervention, sample size, publication year, and place of publication).\n Conclusions in trials, classified into whether the experimental drug was recommended as the treatment of choice or not.\n The experimental drug was recommended as treatment of choice in 16% of trials funded by nonprofit organizations, 30% of trials not reporting funding, 35% of trials funded by both nonprofit and for-profit organizations, and 51% of trials funded by for-profit organizations (P<.001; chi2 test). Logistic regression analyses indicated that funding, treatment effect, and double blinding were the only significant predictors of conclusions. Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice (odds ratio, 5.3; 95% confidence interval, 2.0-14.4) compared with trials funded by nonprofit organizations. This association did not appear to reflect treatment effect or adverse events.\n Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results. Readers should carefully evaluate whether conclusions in randomized trials are supported by data.", "The goal was to assess the risk of bias among pediatric, randomized, controlled trials (RCTs) reported in 8 high-impact journals.\n We searched PubMed for all pediatric RCTs reported between July 1, 2007, and June 30, 2008, in 8 journals with high impact factors. Using Cochrane Collaboration methods for risk assessment, we evaluated all reports for risk of bias according to domain (ie, randomized sequence generation, allocation concealment, masking, incomplete outcome data, selective outcome reporting, and other). We used multiple logistic regression to test for associations between the presence of a high risk of bias according to domain and funding source, intervention type, trial registration, and multicenter status.\n Industry-funded RCTs were more likely to show a high risk of bias for sequence generation, compared with government-funded RCTs (adjusted odds ratio [aOR]: 6.1 [95% confidence interval [CI]: 1.70- 21.89]), and behavioral/educational trials were more likely to show a high risk of bias for sequence generation (aOR: 2.8 [95% CI: 1.06-7.36]) and allocation concealment (aOR: 4.09 [95% CI: 1.69-9.90]), compared with drug trials. Registered trials were less likely to have a high risk of bias for sequence generation, compared with nonregistered trials (aOR: 0.33 [95% CI: 0.15-0.71]).\n Overall, we found a large proportion of pediatric RCT reports with a high risk of bias for sequence generation and allocation concealment. Factors associated with a high risk of bias included industry funding and assessment of behavioral/educational interventions, whereas trial registration was associated with a lower risk of bias.", "To measure effects on terminally ill cancer patients and their families of coordinating the services available within the NHS and from local authorities and the voluntary sector.\n Randomised controlled trial.\n Inner London health district.\n Cancer patients were routinely notified from 1987 to 1990. 554 patients expected to survive less than one year entered the trial and were randomly allocated to a coordination or a control group.\n All patients received routinely available services. Coordination group patients received the assistance of two nurse coordinators, whose role was to ensure that patients received appropriate and well coordinated services, tailored to their individual needs and circumstances.\n Patients and carers were interviewed at home on entry to the trial and at intervals until death. Interviews after bereavement were also conducted. Outcome measures included the presence and severity of physical symptoms, psychiatric morbidity, use of and satisfaction with services, and carers' problems. Results from the baseline interview, the interview closest to death, and the interview after bereavement were analysed.\n Few differences between groups were significant. Coordination group patients were less likely to suffer from vomiting, were more likely to report effective treatment for it, and less likely to be concerned about having an itchy skin. Their carers were more likely to report that in the last week of life the patient had had a cough and had had effective treatment for constipation, and they were less likely to rate the patient's difficulty swallowing as severe or to report effective treatment for anxiety. Coordination group patients were more likely to have seen a chiropodist and their carers were more likely to contact a specialist nurse in a night time emergency. These carers were less likely to feel angry about the death of the patient.\n This coordinating service made little difference to patient or family outcomes, perhaps because the service did not have a budget with which it could obtain services or because the professional skills of the nurse-coordinators may have conflicted with the requirements of the coordinating role.", "To assess the quality of published randomized clinical trials (RCTs) in rheumatology and to determine whether there has been improvement in quality between 2 time periods, 1987-1988 and 1997-1998.\n Using MEDLINE and a hand search of selected rheumatology journals, we identified RCTs of adult rheumatic diseases published in English in 1987-1988 or 1997-1998. We examined trial quality with an expanded version of the Jadad scale, which assesses the adequacy of reported random sequence generation, allocation concealment, blinding, and analysis. All trials were read by 1 reviewer, with prior standardization using a random sample read by 2 reviewers. We also evaluated \"high\"- versus \"low\"-impact journals based on citation index.\n Two hundred forty RCTs (1987-1988 119 RCTs, 1997-1998 121 RCTs) were assessed. Results showed improvement in the quality of the trials, but the rates of reported random sequence generation, allocation concealment, power, and intent-to-treat analyses were persistently low. Low rates of reports of random sequence generation, allocation concealment, and intent-to-treat analyses were present even in the high-impact journals.\n There has been improvement in the quality of reporting of RCTs in rheumatology between 1987-1988 and 1997-1998. However, methodologic problems such as lack of allocation concealment, inadequate random sequence generation, lack of reporting of power, and lack of intent-to-treat analyses remain common. Many of these problems are established sources of bias in RCTs and are easily rectifiable.", "Previous research reviewed treatment success and whether the collective uncertainty principle is met in RCTs in the US National Cancer Institute portfolio. This paper classifies clinical trials funded by the UK HTA programme by results using the method applied to the US Cancer Institute trials, and compares the two portfolios.\n Data on all completed randomised controlled trials funded by the HTA programme 1993-2008 were extracted. Each trial's primary results was classified into six categories; 1) statistically significant in favour of the new treatment, 2) statistically significant in favour of the control treatment 3) true negative, 4) truly inconclusive, 5) inconclusive in favour of new treatment or 6) inconclusive in favour of control treatment. Trials were classified by comparing the 95% confidence interval for the difference in primary outcome to the difference specified in the sample size calculation. The results were compared with Djulbegovic's analysis of NCI trials.\n Data from 51 superiority trials were included, involving over 48,000 participants and a range of diseases and interventions. 85 primary comparisons were available because some trials had more than two randomised arms or had several primary outcomes. The new treatment had superior results (whether significant or not) in 61% of the comparisons (52/85 95% CI 49.9% to 71.6%). The results were conclusive in 46% of the comparisons (19% statistically significant in favour of the new treatment, 5% statistically significant in favour of the control and 22% true negative). The results were classified as truly inconclusive (i.e. failed to answer the question asked) for 24% of comparisons (20/85). HTA trials included fewer truly inconclusive and statistically significant results and more results rated as true negative than NCI trials.\n The pattern of results in HTA trials is similar to that of the National Cancer Institute portfolio. Differences that existed were plausible given the differences in the types of trials -HTA trials are more pragmatic. The results indicate HTA trials are compatible with equipoise. This classification usefully summarises the results from clinical trials and enables comparisons of different portfolios of trials.", "In clinical research, randomized trials are widely accepted as the definitive method of evaluating the efficacy of therapies. Random assignment of patients to treatment ensures internal validity of the comparison of new treatments with controls. An assessment of external validity can best be achieved by comparing the randomized study sample to the population of patients who met the eligibility criteria but did not consent to randomization. The Comprehensive Cohort Study (CCS) is designed to recruit all patients fulfilling the clinical eligibility criteria regardless of their consent to randomization. The CCS concept was adopted in the major clinical trials of the German Breast Cancer Study Group (GBSG) conducted between 1983 and 1989. In this period 124 centres recruited 2084 patients in three clinical trials. 734 (35 per cent) of these patients accepted being randomized, while 1350 (65 per cent) chose one of the treatments under study; the randomization rates differed remarkably between trials. In this paper we examine the representativeness of the randomized patients in the three trials. Based on a median follow-up of about 5 years we present results on the external validity of the treatment effects estimated in the randomized patients by means of Cox's proportional hazards model and compare them between trials. We discuss advantages and disadvantages of the CCS design and conclude that its use is only justified under extraordinary circumstances.", "We wanted to investigate the frequency of undisclosed changes in the outcomes of randomized controlled trials (RCTs) between trial registration and publication.\n Using a retrospective, nonrandom, cross-sectional study design, we investigated RCTs published in consecutive issues of 5 major medical journals during a 6-month period and their associated trials registry entries. Articles were excluded if they did not have an available trial registry entry, did not have analyzable outcomes, or were secondary publications. The primary outcome was the proportion of publications in which the primary outcome of the trial was, without disclosure, changed between that recorded in the trial registry and that reported in the final publication. The secondary outcome was the proportion of publications in which the secondary outcome was changed without disclosure.\n We reviewed 158 reports of RCTs and included 110 in the analysis. In 34 (31%), a primary outcome had been changed, and in 77 (70%), a secondary outcome had been changed.\n There are substantial and important undisclosed changes made to the outcomes of published RCTs between trial registration and publication. This finding has important implications for the interpretation of trial results. Disclosure and discussion of changes would improve transparency in the performance and reporting of trials.", "Reporting of pharmaceutical-industry-sponsored randomised clinical trials often result in biased findings, either due to selective reporting of studies with non-equivalent arms or publication of low-quality papers, wherein unfavourable results are incompletely described. A randomised trial should be conducted only if there is substantial uncertainty about the relative value of one treatment versus another. Studies in which intervention and control are thought to be non-equivalent violates the uncertainty principle.\n We examined the quality of 136 published randomised trials that focused on one disease category (multiple myeloma) and adherence to the uncertainty principle. To evaluate whether the uncertainty principle was upheld, we compared the number of studies favouring experimental treatments over standard ones. We analysed data according to the source of funding.\n Trials funded solely or in part by 35 profit-making organisations had a trend toward higher quality scores (mean 2.94 [SD 1.3]; median 3) than randomised trials supported by 95 governmental or other non-profit organisations (2.4 [0.8]; 2; p=0.06). Overall, the uncertainty principle was upheld, with 44% of randomised trials favouring standard treatments and 56% innovative treatments (p=0.17); mean and median preference evaluation scores were 3.7 (1.0) and 4. However, when the analysis was done according to the source of funding, studies funded by non-profit organisations maintained equipoise favouring new therapies over standard ones (47% vs 53%; p=0.608) to a greater extent than randomised trials supported solely or in part by profit-making organisations (74% vs 26%; p=0.004).\n The reported bias in research sponsored by the pharmaceutical industry may be a consequence of violations of the uncertainty principle. Sponsors of clinical trials should be encouraged to report all results and to choose appropriate comparative controls.", "The effect of funding source on the outcome of randomized controlled trials has been investigated in several medical disciplines; however, psychiatry has been largely excluded from such analyses. In this article, randomized controlled trials of second generation antipsychotics in schizophrenia are reviewed and analyzed with respect to funding source (industry vs. non-industry funding).\n A literature search was conducted for randomized, double-blind trials in which at least one of the tested treatments was a second generation antipsychotic. In each study, design quality and study outcome were assessed quantitatively according to rating scales. Mean quality and outcome scores were compared in the industry-funded studies and non-industry-funded studies. An analysis of the primary author's affiliation with industry was similarly performed.\n Results of industry-funded studies significantly favored second generation over first generation antipsychotics when compared to non-industry-funded studies. Non-industry-funded studies showed a trend toward higher quality than industry-funded studies; however, the difference between the two was not significant. Also, within the industry-funded studies, outcomes of trials involving first authors employed by industry sponsors demonstrated a trend toward second generation over first generation antipsychotics to a greater degree than did trials involving first authors employed outside the industry (p=0.05).\n While the retrospective design of the study limits the strength of the findings, the data suggest that industry bias may occur in randomized controlled trials in schizophrenia. There appears to be several sources by which bias may enter clinical research, including trial design, control of data analysis and multiplicity/redundancy of trials.", "Timely participant recruitment remains a significant challenge for most clinical trials. We evaluated the effects on participant recruitment of communication between the central trial coordinators and the clinical sites in the setting of a large international multi-centre clinical trial. The effects of communication were determined in a single-blind randomised controlled trial involving 167 clinical sites in 19 countries. Clinical sites were randomised to either additional or usual communication strategies - the additional communication group received a communication package based on additional, individually-tailored feedback about recruitment, in addition to the usual correspondence from the central trial coordinators that was provided to the control group. The two study outcomes were the median time to half randomisation target and the median total number of participants randomised per clinical site. Eighty-five clinical centres were randomised to receive additional communication and 82 to receive usual communication. At the conclusion of recruitment, there was no significant difference in the median number of participants randomised per centre between the additional and usual groups (37.5 vs. 37.0, p=0.68). The median time to half randomisation target was lower in the additional communication group compared to the usual group, however this difference did not achieve conventional levels of statistical significance (4.4 months vs. 5.8 months, p=0.08). The findings suggest that the additional communication strategy may be of some incremental benefit in helping sites achieve recruitment targets sooner.", "It is now accepted that both medical and surgical practice should be based on reliable and sound clinical evidence. However, randomized control trials comparing surgical interventions have been associated with many problems. The aim of this review is to assess if there has been progress made in establishing the evidence base for surgical interventions in gynaecology.\n Relevant reviews were identified from Cochrane Database of Systematic Reviews (Issue , 2006) and data from individual randomized control trials extracted. Chi-squared test was used to compare quality pre- and post-Consolidated Standards of Reporting Trials (CONSORT) statement. Meta-regression analyses were performed to test the hypothesis that effect size decreased over time. Further multiple linear regression analyses were used to test the hypothesis that precision increased over time and finally a logistic regression model was used to estimate whether treatment effects differed between trials with and without allocation concealment.\n Twenty-three relevant reviews were identified, including 94 trials. The proportion of studies reporting allocation concealment significantly increased after the introduction of the CONSORT statement (P = 0.002). There was a trend towards improvement in precision over time. Similarly, there was a reduction in size of treatment effect over time (log of the ratio of odds ratios per year 0.96; 95% confidence interval 0.93-0.99, P = 0.04).\n Gynaecologic surgical practice appears to be benefiting from improvement in its research base in a subject where practitioners do not participate readily in randomized evaluation.", "Sixty research investigations published in the biomedical literature were analyzed to examine the effect of design attributes on outcome. All 60 studies included a controlled trial involving a pretest, a therapeutic intervention, and a posttest across at least two groups. Thirty of the trials used random assignment of participants to treatment or control conditions and 30 trials employed some nonrandom method of subject assignment. Trial results were aggregated and evaluated by comparing effect sizes for the primary statistical test of the hypothesis. Data analysis revealed that the trial results, as measured by effect size, did not vary across therapeutic trials using random assignment versus those using nonrandom allocation of subjects. The impact of design attributes in the interpretation of multiple clinical trials addressing a similar research question is examined. The argument is made that various design attributes frequently associated with methodological quality should be considered as important moderator variables and their influence on trial outcome should not be assumed a priori but rather examined empirically.", "Randomised trials can provide high-level evidence to inform treatment decisions. Since their quality in respiratory medicine is largely unknown, we assessed the quality of a large set of chronic obstructive pulmonary disease (COPD) trials. As a marker of trial quality, we assessed the procedure and concealment of random allocation, and the conduct of an intention-to-treat-analysis in 344 randomised trials published between 1957 and 2006. We used ordered logistic regression to assess the association between trial quality and type of intervention, type of journal, journal impact factor and year of publication. 257 (75%) trials assessed pharmacological and 87 (25%) assessed nonpharmacological interventions. The generation of appropriate randomisation was reported in 27.0% of the trials, concealment of random allocation in 11.6% and an intention-to-treat analysis in 21.8% of trials. Significantly higher quality was found in trials on nonpharmacological interventions (OR 2.49, 95% CI 1.56-3.99), and in trials published in general medical journals (versus specialised journals; OR 2.25, 95% CI 1.30-3.90) and after 2000 (versus 1957-2000; OR 2.28, 95% CI 1.45-3.58). The association of quality with a high impact factor was of borderline significance (p = 0.06). The quality of many COPD trials is low but tends to become better since the adoption of the CONSORT (Consolidated Standards of Reporting Trials) statement." ]	The results of randomised and non-randomised studies sometimes differed. In some instances non-randomised studies yielded larger estimates of effect and in other instances randomised trials yielded larger estimates of effect. The results of controlled trials with adequate and inadequate/unclear concealment of allocation sometimes differed. When differences occurred, most often trials with inadequate or unclear allocation concealment yielded larger estimates of effects relative to controlled trials with adequate allocation concealment. However, it is not generally possible to predict the magnitude, or even the direction, of possible selection biases and consequent distortions of treatment effects from studies with non-random allocation or controlled trials with inadequate or unclear allocation concealment.
CD007577	[ "19797133", "15136392", "14625336", "19097848", "17218551", "18852401" ]	[ "Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study.", "A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia.", "Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial.", "[Duration of antibiotic therapy for ventilator-associated pneumonia: comparison of 7 and 10 days. A pilot study].", "Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy.", "Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care." ]	[ "In patients with ventilator-associated pneumonia (VAP), guidelines recommend antibiotic therapy adjustment according to microbiology results after 72 h. Circulating procalcitonin levels may provide evidence that facilitates the reduction of antibiotic therapy. In a multicentre, randomised, controlled trial, 101 patients with VAP were assigned to an antibiotic discontinuation strategy according to guidelines (control group) or to serum procalcitonin concentrations (procalcitonin group) with an antibiotic regimen selected by the treating physician. The primary end-point was antibiotic-free days alive assessed 28 days after VAP onset and analysed on an intent-to-treat basis. Procalcitonin determination significantly increased the number of antibiotic free-days alive 28 days after VAP onset (13 (2-21) days versus 9.5 (1.5-17) days). This translated into a reduction in the overall duration of antibiotic therapy of 27% in the procalcitonin group (p = 0.038). After adjustment for age, microbiology and centre effect, the rate of antibiotic discontinuation on day 28 remained higher in the procalcitonin group compared with patients treated according to guidelines (hazard rate 1.6, 95% CI 1.02-2.71). The number of mechanical ventilation-free days alive, intensive care unit-free days alive, length of hospital stay and mortality rate on day 28 for the two groups were similar. Serum procalcitonin reduces antibiotic therapy exposure in patients with ventilator associated pneumonia.", "To evaluate an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia (VAP).\n Prospective, randomized, controlled clinical trial.\n A medical ICU from a university-affiliated urban teaching hospital.\n Between April 2002 and July 2003, 290 patients completed the clinical trial.\n Patients were assigned to have the duration of antibiotic treatment for VAP determined by an antibiotic discontinuation policy (discontinuation group) or their treating physician teams (conventional group).\n Severity of illness using APACHE (acute physiology and chronic health evaluation) II score (22.8 +/- 9.0 vs 23.2 +/- 9.4, p = 0.683) [mean +/- SD] and the clinical pulmonary infection score (7.1 +/- 0.9 vs 7.2 +/- 0.9, p = 0.222) were similar for both patient groups. The duration of antibiotic treatment for VAP was statistically shorter among patients in the discontinuation group compared to patients in the conventional antibiotic management group (6.0 +/- 4.9 days vs 8.0 +/- 5.6 days, p = 0.001). The occurrence of a secondary episode of VAP was not statistically different between these two groups (17.3% vs 19.3%, p = 0.667). Hospital mortality (32.0% vs 37.1%, p = 0.357) and ICU length of stay (6.8 +/- 6.1 days vs 7.0 +/- 7.3 days, p = 0.798) were also statistically similar.\n The application of an antibiotic discontinuation policy for clinically suspected VAP was associated with a decrease in the overall duration of antibiotic treatment. These findings suggest that shorter courses of empiric antibiotic therapy for patients treated for clinically suspected VAP can be safely achieved.", "The optimal duration of antimicrobial treatment for ventilator-associated pneumonia (VAP) is unknown. Shortening the length of treatment may help to contain the emergence of multiresistant bacteria in the intensive care unit (ICU).\n To determine whether 8 days is as effective as 15 days of antibiotic treatment of patients with microbiologically proven VAP.\n Prospective, randomized, double-blind (until day 8) clinical trial conducted in 51 French ICUs. A total of 401 patients diagnosed as having developed VAP by quantitative culture results of bronchoscopic specimens and who had received initial appropriate empirical antimicrobial therapy were enrolled between May 1999 and June 2002.\n A total of 197 patients were randomly assigned to receive 8 days and 204 to receive 15 days of therapy with an antibiotic regimen selected by the treating physician.\n Primary outcome measures-death from any cause, microbiologically documented pulmonary infection recurrence, and antibiotic-free days-were assessed 28 days after VAP onset and analyzed on an intent-to-treat basis.\n Compared with patients treated for 15 days, those treated for 8 days had neither excess mortality (18.8% vs 17.2%; difference, 1.6%; 90% confidence interval [CI], -3.7% to 6.9%) nor more recurrent infections (28.9% vs 26.0%; difference, 2.9%; 90% CI, -3.2% to 9.1%), but they had more mean (SD) antibiotic-free days (13.1 [7.4] vs 8.7 [5.2] days, P<.001). The number of mechanical ventilation-free days, the number of organ failure-free days, the length of ICU stay, and mortality rates on day 60 for the 2 groups did not differ. Although patients with VAP caused by nonfermenting gram-negative bacilli, including Pseudomonas aeruginosa, did not have more unfavorable outcomes when antimicrobial therapy lasted only 8 days, they did have a higher pulmonary infection-recurrence rate compared with those receiving 15 days of treatment (40.6% vs 25.4%; difference, 15.2%, 90% CI, 3.9%-26.6%). Among patients who developed recurrent infections, multiresistant pathogens emerged less frequently in those who had received 8 days of antibiotics (42.1% vs 62.0% of pulmonary recurrences, P =.04).\n Among patients who had received appropriate initial empirical therapy, with the possible exception of those developing nonfermenting gram-negative bacillus infections, comparable clinical effectiveness against VAP was obtained with the 8- and 15-day treatment regimens. The 8-day group had less antibiotic use.", "To compare the efficiency of a 7-day antibiotics regimen with a 10-day regimen for ventilator-associated pneumonia (VAP).\n Prospective randomized study.\n Adults patients ventilated for more than 48 hours in the intensive care unit (ICU) with a clinical diagnosis of VAP documented by positive quantitative cultures of tracheal aspiration were included in this study. All included patients were randomized in two groups. Ten-day group: 10 days antibiotic therapy, and 7-day group: 7 days antibiotic therapy. Primary judgment criteria were 14- and 28-day mortality, the number of days without antibiotics. Secondary judgments criteria were rate of recurrent pulmonary infection, the evolution of the clinical pulmonary infection scores (CPIS), the length of ICU stay and the length of mechanical ventilation.\n Thirty patients were included in this study (16 in the 10-day group and 14 in the 7-day group). The demographic and clinical characteristics of the groups assigned to receive antibiotic therapy for 7 or 10 days were generally similar. The 14-day and 28-day mortality rate following VAP onset were 31.2 and 37.5% in the 10-day group and 7.1 and 35.7% in the 7-day group. The difference was not significant. The number of day without antibiotics and without mechanical ventilation turned out: 1.75 and 2.06 days versus 4.14 and 3.43 days in the 10-day group and 7-day group respectively, the recurrent rate of pulmonary infection (12.5% versus 14.3%, p=0.6), the length of stay in the ICU (27.7 days versus 26.0 days, p=0.8) and the evolution of the CPIS were no different in the two groups.\n In patients with microbiologically confirmed VAP who received appropriate empirical antibiotic therapy, a 7-day antibiotic regimen was as efficient clinically and microbiologically as a 10-day antibiotic regimen with a reduction of antibiotic use.", "Therapy with antibiotics influences recovery only in selected cases of COPD exacerbations. We evaluated the efficacy and safety of procalcitonin guidance compared to standard therapy with antibiotic prescriptions in patients experiencing exacerbations of COPD.\n A total of 208 consecutive patients requiring hospitalization for COPD exacerbation were randomized at the index exacerbation to procalcitonin-guided or standard antibiotic therapy. Patients receiving procalcitonin-guided therapy were treated with antibiotics according to serum procalcitonin levels; standard-therapy patients received antibiotics according to the attending physician. The primary outcome was the antibiotic exposure at the index exacerbation and the subsequent antibiotic requirement for COPD exacerbation within 6 months. Secondary outcomes were clinical recovery, symptom scores, length of hospitalization, ICU stay, death, lung function, exacerbation rate, and time to next exacerbation.\n At the index exacerbation, procalcitonin guidance reduced antibiotic prescription (40% vs 72%, respectively; p < 0.0001) and antibiotic exposure (relative risk [RR], 0.56; 95% confidence interval [CI], 0.43 to 0.73; p < 0.0001) compared to standard therapy. Moreover, procalcitonin guidance at the index exacerbation allowed a significant sustained reduction in total antibiotic exposure for up to 6 months (RR, 0.76; 95% CI, 0.64 to 0.92; p = 0.004). Clinical outcome and improvement in FEV(1) at 14 days and 6 months did not differ between groups. Within 6 months, the exacerbation rate (0.62 vs 0.64, respectively), the rehospitalization rate (0.21 vs 0.24, respectively), and mean (+/- SD) time to the next exacerbation (70.0 +/- 46.1 vs 70.4 +/- 51.9 days, respectively; p = 0.523) were similar in both groups.\n Procalcitonin guidance for exacerbations of COPD offers a sustained advantage over standard therapy in reducing antibiotic use for up to 6 months with a number-needed-to-treat of 3.", "Acute respiratory tract infections are the most common reason for antibiotic therapy in primary care despite their mainly viral etiology. A laboratory test measuring procalcitonin levels in blood specimens was suggested as a tool to reduce unnecessary prescribing of antibiotics. We consider whether antibiotic therapy guided by procalcitonin reduces the use of antibiotics without increasing the restrictions experienced by patients by more than 1 day.\n Fifty-three primary care physicians recruited 458 patients, each patient with an acute respiratory tract infection and, in the physician's opinion, in need of antibiotics. Patients were centrally randomized to either a procalcitonin-guided approach to antibiotic therapy or to a standard approach. For patients randomized to procalcitonin-guided therapy, the use of antibiotics was more or less strongly discouraged (procalcitonin level, < or =0.1 or < or =0.25 microg/L, respectively) or recommended (procalcitonin level, >0.25 microg/L). Follow-up data were collected at 7 days by treating physicians and at 14 and 28 days by blinded interviewers.\n Adjusted for baseline characteristics, the mean increase at 14 days in days in which activities were restricted was 0.14 with procalcitonin-guided therapy (95% confidence interval [CI], -0.53 to 0.81 days), which met our criterion of an increase in days in which activities were restricted by no more than 1 day. With procalcitonin-guided therapy, the antibiotic prescription rate was 72% lower (95% CI, 66%-78%) than with standard therapy. Both approaches led to a similar proportion of patients reporting symptoms of ongoing or relapsing infection at 28 days (adjusted odds ratio, 1.0 [95% CI, 0.7-1.5]).\n As an adjunct to guidelines, procalcitonin-guided therapy markedly reduces antibiotic use for acute respiratory tract infections in primary care without compromising patient outcome. In practice, this could be achieved with 1 to 2 procalcitonin measurements in patients for whom the physician intends to prescribe antibiotics." ]	We conclude that for patients with VAP not due to NF-GNB, a short fixed-course (seven or eight days) antibiotic therapy may be more appropriate than a prolonged course (10 to 15 days). Use of an individualised strategy (incorporating clinical features or serum procalcitonin) appears to safely reduce duration of antibiotic therapy for VAP.
CD006443	[ "16437657", "8858747" ]	[ "Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn's disease: a double-blind, randomized, placebo-controlled study.", "Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group)." ]	[ "To assess the value of long-chain omega-3 fatty acids (FAs) supplementation in addition to amino-salicylic-acid (5-ASA) in pediatric patients with Crohn's disease (CD).\n Thirty-eight patients (20 males and 18 females, mean age 10.13 years, range 5-16 years) with CD in remission were randomized into two groups and treated for 12 mo. Group I (18 patients) received 5-ASA (50 mg/kg/d)+ omega-3 FAs as triglycerides in gastro-resistant capsules, 3 g/d (eicosapentanoic acid, EPA, 400 mg/g, docosahexaenoic acid, DHA, 200 mg/g). Group II (20 patients) received 5-ASA (50 mg/kg/d)+olive oil placebo capsules. Patients were evaluated for fatty acid incorporation in red blood cell membranes by gas chromatography at baseline 6 and 12 mo after the treatment.\n The number of patients who relapsed at 1 year was significantly lower in group I than in group II (P<0.001). Patients in group I had a significant increase in the incorporation of EPA and DHA (P<0.001) and a decrease in the presence of arachidonic acids.\n Enteric-coated omega-3 FAs in addition to treatment with 5-ASA are effective in maintaining remission of pediatric CD.", "There is no established therapy for maintaining remission in patients with Crohn's disease. Following different suggestions from the literature, two potential interventions for maintaining remission were tested against placebo, using either 5 g/day of a highly concentrated omega-3 fatty acid compound or a carbohydrate-reduced diet (84 g/day).\n A total of 204 patients were recruited after they had had an acute relapse. After remission (CDAI < or = 150) was attained with steroid therapy, patients were randomized to receive either omega-3 fatty acids (n = 70), placebo (n = 65), or diet (n = 69). Low-dose prednisolone was given to all patients for the first 8 weeks of intervention. CDAI and an acute-phase protein (CRP) were used as criteria for a relapse.\n The proportion of patients without relapse within a year were similar in the placebo and active treatment group (intention-to-treat analysis: placebo, 30%; active treatment, 30%; protocol-adhering patients, 29% versus 28%). Patients did gain benefit (53%; p = 0.023) for as long as they maintained the diet. However, intention-to-treat analysis (diet group, 40%) did not show a noticeable difference when compared with placebo.\n Omega-3 fatty acids did not show an effect on extending the remission in Crohn's disease. For the diet patients the question remains whether the noncompliant patients dropped out early because they sensed a relapse approaching or whether their condition deteriorated because they failed to comply with the diet." ]	No evidence was found that supports the use of omega 3 fatty acids for maintenance of remission in UC. Further studies using enteric coated capsules may be justified.
CD003650	[ "17593956", "12351954", "10197378", "9605804", "15661475", "15956998", "10048684", "18541571", "16310552", "7625499", "10465076", "12173139", "16479521", "16522919", "19939985", "16579803", "15640476", "15735107", "11498488", "21592508", "15699235", "14668283", "14652364", "9894821", "10102147", "17468087", "14985222", "18206226", "17522609" ]	[ "Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial.", "Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality.", "Micronutrient supplementation in the AIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial.", "Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania.", "Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: A controlled clinical trial.", "Effect of vitamin supplementation to HIV-infected pregnant women on the micronutrient status of their infants.", "A randomized trial of vitamin A supplements in relation to mortality among human immunodeficiency virus-infected and uninfected children in Tanzania.", "Randomized, double-blind, placebo-controlled trial of selenium supplements among HIV-infected pregnant women in Tanzania: effects on maternal and child outcomes.", "Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: a randomised double-blind placebo-controlled trial.", "The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women.", "Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. South African Vitamin A Study Group.", "Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi.", "Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality.", "A double-blind, randomized, clinical trial of the effect of vitamin A and zinc supplementation on diarrheal disease and respiratory tract infections in children in Mexico City, Mexico.", "A randomized trial to determine the optimal dosage of multivitamin supplements to reduce adverse pregnancy outcomes among HIV-infected women in Tanzania.", "Randomised trial of vitamin A supplementation in pregnant women in rural Malawi found to be anaemic on screening by HemoCue.", "Trial of zinc supplements in relation to pregnancy outcomes, hematologic indicators, and T cell counts among HIV-1-infected women in Tanzania.", "Efficacy of a foodlet-based multiple micronutrient supplement for preventing growth faltering, anemia, and micronutrient deficiency of infants: the four country IRIS trial pooled data analysis.", "Simultaneous zinc and vitamin A supplementation in Bangladeshi children: randomised double blind controlled trial.", "Zinc, vitamin A, and micronutrient supplementation in children with diarrhea: a randomized controlled clinical trial of combination therapy versus monotherapy.", "Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe.", "Effects of maternal micronutrient supplementation on fetal loss and infant mortality: a cluster-randomized trial in Nepal.", "Simultaneous weekly supplementation of iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infection in Bangladeshi infants.", "Impact of zinc supplementation on persistent diarrhoea in malnourished Bangladeshi children.", "Double-blind, randomized, controlled trial of zinc or vitamin A supplementation in young children with acute diarrhoea.", "Zinc-iron, but not zinc-alone supplementation, increased linear growth of stunted infants with low haemoglobin.", "Randomized controlled trial of the effect of daily supplementation with zinc or multiple micronutrients on the morbidity, growth, and micronutrient status of young Peruvian children.", "What works? Interventions for maternal and child undernutrition and survival.", "The efficacy of micronutrient supplementation in reducing the prevalence of anaemia and deficiencies of zinc and iron among adolescents in Sri Lanka." ]	[ "Prophylactic zinc supplementation has been shown to reduce diarrhea and respiratory illness in children in many developing countries, but its efficacy in children in Africa is uncertain.\n To determine if zinc, or zinc plus multiple micronutrients, reduces diarrhea and respiratory disease prevalence.\n Randomized, double-blind, controlled trial.\n Rural community in South Africa.\n THREE COHORTS: 32 HIV-infected children; 154 HIV-uninfected children born to HIV-infected mothers; and 187 HIV-uninfected children born to HIV-uninfected mothers.\n Children received either 1250 IU of vitamin A; vitamin A and 10 mg of zinc; or vitamin A, zinc, vitamins B1, B2, B6, B12, C, D, E, and K and copper, iodine, iron, and niacin starting at 6 months and continuing to 24 months of age. Homes were visited weekly.\n Primary outcome was percentage of days of diarrhea per child by study arm within each of the three cohorts. Secondary outcomes were prevalence of upper respiratory symptoms and percentage of children who ever had pneumonia by maternal report, or confirmed by the field worker.\n Among HIV-uninfected children born to HIV-infected mothers, median percentage of days with diarrhea was 2.3% for 49 children allocated to vitamin A; 2.5% in 47 children allocated to receive vitamin A and zinc; and 2.2% for 46 children allocated to multiple micronutrients (P = 0.852). Among HIV-uninfected children born to HIV-uninfected mothers, median percentage of days of diarrhea was 2.4% in 56 children in the vitamin A group; 1.8% in 57 children in the vitamin A and zinc group; and 2.7% in 52 children in the multiple micronutrient group (P = 0.857). Only 32 HIV-infected children were enrolled, and there were no differences between treatment arms in the prevalence of diarrhea. The prevalence of upper respiratory symptoms or incidence of pneumonia did not differ by treatment arms in any of the cohorts.\n When compared with vitamin A alone, supplementation with zinc, or with zinc and multiple micronutrients, did not reduce diarrhea and respiratory morbidity in rural South African children.\n ClinicalTrials.gov NCT00156832.", "HIV-1 transmission through breastfeeding is a global problem and has been associated with poor maternal micronutrient status.\n A total of 1078 HIV-infected pregnant women from Tanzania were randomly assigned to vitamin A or multivitamins excluding A from approximately 20 weeks' gestation and throughout lactation.\n Multivitamins excluding A had no effect on the total risk of HIV-1 transmission (RR 1.04, 95% CI 0.82-1.32, P= 0.76). Vitamin A increased the risk of transmission (RR 1.38, 95% CI 1.09-1.76, P = 0.009). Multivitamins were associated with non-statistically significant reductions in transmission through breastfeeding, and mortality by 24 months among those alive and not infected at 6 weeks. Multivitamins significantly reduced breastfeeding transmission in infants of mothers with low baseline lymphocyte counts (RR 0.37; 95% CI 0.16-0.85, P = 0.02) compared with infants of mothers with higher counts (RR 0.99, 95% CI 0.68-1.45, P = 0.97; -for-interaction 0.03). Multivitamins also protected against transmission among mothers with a high erythrocyte sedimentation rate (P-for-interaction 0.06), low hemoglobin (P-for-interaction 0.06), and low birthweight babies (P-for-interaction 0.04). Multivitamins reduced death and prolonged HIV-free survival significantly among children born to women with low maternal immunological or nutritional status. Vitamin A alone increased breastfeeding transmission but had no effect on mortality by 24 months.\n Vitamin A increased the risk of HIV-1 transmission. Multivitamin (B, C, and E) supplementation of breastfeeding mothers reduced child mortality and HIV-1 transmission through breastfeeding among immunologically and nutritionally compromised women. The provision of these supplements to HIV-infected lactating women should be considered.", "As HIV has spread through sub-Saharan Africa, persistent diarrhoea has emerged as a major problem in hospitals and in the community in severely affected areas. We have previously demonstrated that antiprotozoal therapy with albendazole reduces diarrhoea in AIDS patients in urban Zambia. This trial was designed to test the hypothesis that the clinical response to albendazole might be improved by oral micronutrient supplementation.\n Randomized, placebo-controlled trial.\n Home care service of Ndola Central Hospital, Zambia.\n HIV-seropositive patients with persistent diarrhoea.\n Patients were randomized to albendazole plus vitamins A, C and E, selenium and zinc orally or albendazole plus placebo, for 2 weeks.\n Time with diarrhoea following completion of treatment; mortality; adverse events.\n Serum vitamin A and E concentrations before treatment were powerful predictors of early mortality, but supplementation did not reduce time with diarrhoea or mortality during the first month, even after taking into account initial vitamin A or E concentrations, CD4 cell count or clinical markers of illness severity. Serum concentrations of vitamins A and E did not increase significantly in supplemented patients compared with those given placebo, and there were no changes in CD4 cell count or haematological parameters. No adverse events were detected except those attributable to underlying disease.\n Although micronutrient deficiency is predictive of early death in Zambian patients with the diarrhoea-wasting syndrome, short-term oral supplementation does not overcome it nor influence morbidity or mortality.", "In HIV-1-infected women, poor micronutrient status has been associated with faster progression of HIV-1 disease and adverse birth outcomes. We assessed the effects of vitamin A and multivitamins on birth outcomes in such women.\n In Tanzania, 1075 HIV-1-infected pregnant women at between 12 and 27 weeks' gestation received placebo (n=267), vitamin A (n=269), multivitamins excluding vitamin A (n=269), or multivitamins including vitamin A (n=270) in a randomised, double-blind, placebo-controlled trial with a 2x2 factorial design. We measured the effects of multivitamins and vitamin A on birth outcomes and counts of T lymphocyte subsets. We did analyses by intention to treat.\n 30 fetal deaths occurred among women assigned multivitamins compared with 49 among those not on multivitamins (relative risk 0.61 [95% CI 0.39-0.94] p=0.02). Multivitamin supplementation decreased the risk of low birthweight (<2500 g) by 44% (0.56 [0.38-0.82] p=0.003), severe preterm birth (<34 weeks of gestation) by 39% (0.61 [0.38-0.96] p=0.03), and small size for gestational age at birth by 43% (0.57 [0.39-0.82] p=0.002). Vitamin A supplementation had no significant effect on these variables. Multivitamins, but not vitamin A, resulted in a significant increase in CD4, CD8, and CD3 counts.\n Multivitamin supplementation is a low-cost way of substantially decreasing adverse pregnancy outcomes and increasing T-cell counts in HIV-1-infected women. The clinical relevance of our findings for vertical transmission and clinical progression of HIV-1 disease is yet to be ascertained.", "We investigated whether vitamin A supplementation would decrease mortality and morbidity rates in children infected with the human immunodeficiency virus (HIV).\n We conducted a randomized, double-blind, placebo-controlled clinical trial at Mulago Hospital, a large hospital that serves the urban and semiurban populations of Kampala, Uganda. One hundred eighty-one HIV-infected children were enrolled at 6 mo and randomized to receive vitamin A supplementation, 60 mg retinol equivalent, or placebo every 3 mo from ages 15 to 36 mo. Morbidity was assessed through a 7-d morbidity history every 3 mo, and vital events were measured. Children received daily trimethoprim-sulfamethoxazole prophylactic therapy.\n After age 15 mo, children were followed for a median of 17.8 mo (interquartile range = 11.1 to 21.0 mo). The trial was stopped when there was a new policy to implement a program of mass supplementation of vitamin A in the country. Mortality rates among 87 children in the vitamin A group and 94 children in the control group were 20.6% and 32.9%, respectively, yielding a relative risk of 0.54 (95% confidence interval, 0.30 to 0.98; P = 0.044) after adjusting for baseline weight-for-height Z score. Children who received vitamin A had lower modified point prevalences of persistent cough (odds ratio, 0.47; 95% confidence interval, 0.23 to 0.96; P = 0.038) and chronic diarrhea (odds ratio, 0.48; 95% confidence interval, 0.19 to 1.18; P = 0.11) and a shorter duration of ear discharge (P = 0.03). Vitamin A supplementation had no significant effect on modified point prevalences of fever, ear discharge, bloody stools, or hospitalizations.\n Vitamin A supplementation decreases mortality rate in HIV-infected children and should be considered in the care for these children in developing countries.", "We examined whether supplementation with vitamin A and/or vitamins B, C, and E to HIV-infected women during pregnancy and lactation is related to increased concentrations of vitamins A, B12, and E in their infants during the first 6 months of life.\n We carried out a randomized clinical trial among 716 mother-infant pairs in Dar-es-Salaam, Tanzania. Women were randomly allocated to receive a daily oral dose of one of four regimens: vitamin A, multivitamins (B, C, and E), multivitamins including A, or placebo. Supplementation started at first prenatal visit and continued after delivery throughout the breastfeeding period. The serum concentration of vitamins A, E and B12 was measured in infants at 6 weeks and 6 months postpartum.\n Maternal vitamin A supplementation increased serum retinol in the infants at 6 weeks (mean difference=0.09 micromol/l, P<0.0001) and 6 months (mean difference=0.06 micromol/l, P=0.0002), and decreased the prevalence of vitamin A deficiency, but had no impact on serum vitamins E or B12. Multivitamins increased serum vitamin B12 at 6 weeks and 6 months (mean differences=176 pmol/l, P<0.0001 and 127 pmol/l, P<0.0001, respectively) and vitamin E (mean differences=1.8 micromol/l, P=0.0008 and 1.1 micromol/l, P=0.004, respectively) and decreased the prevalence of vitamin B12 deficiency.\n Vitamin supplementation to HIV-1-infected women is effective in improving the vitamin status of infants during the first 6 months of age.", "To determine whether vitamin A supplements result in reduced mortality among HIV-infected and uninfected children.\n Randomized, double blind, placebo-controlled trial.\n Starting in April, 1993, we randomized 687 children age 6 months to 5 years who were admitted to the hospital with pneumonia. Children who were severely malnourished or had clinical signs of vitamin A deficiency were excluded. At baseline children received placebo or 400 000 IU (or half that for infants) of vitamin A, in addition to standard treatment for pneumonia. They received further doses of the same regimen 4 and 8 months after hospital discharge. Sera from children were tested for HIV antibodies by enzyme-linked immunosorbent assay and Western blot tests. For positive children <15 months of age, HIV infection was confirmed by amplified heat-denatured HIV-p24 antigen assays with confirmatory neutralization assays. HIV status was ascertained for 648 of 687 enrolled children. The mean duration of follow-up was 24.4 months (SD = 12.1).\n Of 648 children 58 (9%) were HIV-infected. Compared with uninfected children, all-cause mortality was higher among HIV-infected children, as was mortality caused by pneumonia or diarrhea (P < 0.001 for each). Overall vitamin A supplements resulted in a 49% reduction in mortality [relative risk (RR), 0.51; 95% confidence interval (CI), 0.29 to 0.90, P = 0.02]. Vitamin A supplements reduced all-cause mortality by 63% among HIV-infected children (RR 0.37; CI 0.14 to 0.95, P = 0.04) and by 42% among uninfected children (RR 0.58, CI 0.28 to 1.19, P = 0.14). Vitamin A supplements were also associated with a 68% reduction in AIDS-related deaths (P = 0.05) and a 92% reduction in diarrhea-related deaths (P = 0.01).\n Vitamin A deficiency, which is common among children in many developing countries, is particularly severe among HIV-infected children. Our findings indicate that vitamin A supplements, a low cost intervention, reduce mortality of HIV-infected children.", "In observational studies, adequate selenium status has been associated with better pregnancy outcomes and slowed HIV disease progression.\n We investigated the effects of daily selenium supplements on CD4 cell counts, viral load, pregnancy outcomes, and maternal and infant mortality among 913 HIV-infected pregnant women.\n In this randomized, double-blind, placebo-controlled trial, eligible women between 12 and 27 wk of gestation were given daily selenium (200 mug as selenomethionine) or placebo as supplements from recruitment until 6 mo after delivery. All women received prenatal iron, folic acid, and multivitamin supplements irrespective of experimental assignment.\n The selenium regimen had no significant effect on maternal CD4 cell counts or viral load. Selenium was marginally associated with a reduced risk of low birth weight [relative risk (RR) = 0.71; 95% CI: 0.49, 1.05; P = 0.09] and increased risk of fetal death (RR = 1.58; 95% CI = 0.95, 2.63; P = 0.08), but had no effect on risk of prematurity or small-for-gestational age birth. The regimen had no significant effect on maternal mortality (RR = 1.02; 95% CI = 0.51, 2.04; P = 0.96). There was no significant effect on neonatal or overall child mortality, but selenium reduced the risk of child mortality after 6 wk (RR = 0.43; 95% CI = 0.19, 0.99; P = 0.048).\n Among HIV-infected women from Dar es Salaam, Tanzania, selenium supplements given during and after pregnancy did not improve HIV disease progression or pregnancy outcomes, but may improve child survival. This trial was registered at clinicaltrials.gov as NCT00197561.", "Zinc deficiency is associated with impaired immune function and an increased risk of infection. Supplementation can decrease the incidence of diarrhoea and pneumonia in children in resource-poor countries. However, in children with HIV-1 infection, the safety of zinc supplementation is uncertain. We aimed to assess the role of zinc in HIV-1 replication before mass zinc supplementation is recommended in regions of high HIV-1 prevalence.\n We did a randomised double-blind placebo-controlled equivalence trial of zinc supplementation at Grey's Hospital in Pietermaritzburg, South Africa. 96 children with HIV-1 infection were randomly assigned to receive 10 mg of elemental zinc as sulphate or placebo daily for 6 months. Baseline measurements of plasma HIV-1 viral load and the percentage of CD4+ T lymphocytes were established at two study visits before randomisation, and measurements were repeated 3, 6, and 9 months after the start of supplementation. The primary outcome measure was plasma HIV-1 viral load. Analysis was per protocol.\n The mean log(10) HIV-1 viral load was 5.4 (SD 0.61) for the placebo group and 5.4 (SD 0.66) for the zinc-supplemented group 6 months after supplementation began (difference 0.0002, 95% CI -0.27 to 0.27). 3 months after supplementation ended, the corresponding values were 5.5 (SD 0.77) and 5.4 (SD 0.61), a difference of 0.05 (-0.24 to 0.35). The mean percentage of CD4+ T lymphocytes and median haemoglobin concentrations were also similar between the two groups after zinc supplementation. Two deaths occurred in the zinc supplementation group and seven in the placebo group (p=0.1). Children given zinc supplementation were less likely to get watery diarrhoea than those given placebo. Watery diarrhoea was diagnosed at 30 (7.4%) of 407 clinic visits in the zinc-supplemented group versus 65 (14.5%) of 447 visits in the placebo group (p=0.001).\n Zinc supplementation of HIV-1-infected children does not result in an increase in plasma HIV-1 viral load and could reduce morbidity caused by diarrhoea.\n Programmes to enhance zinc intake in deficient populations with a high prevalence of HIV-1 infection can be implemented without concern for adverse effects on HIV-1 replication. In view of the reductions in diarrhoea and pneumonia morbidity, zinc supplementation should be used as adjunct therapy for children with HIV-1 infection.", "The effects of vitamin A supplementation on morbidity of children born to human immunodeficiency virus (HIV)-infected women were evaluated in a population where vitamin A deficiency is not endemic.\n A randomized, placebo-controlled trial of vitamin A supplementation was carried out in 118 offspring of HIV-infected women in Durban, South Africa. Those assigned to receive a supplement were given 50,000 IU of vitamin A at 1 and 3 months of age; 100,000 IU at 6 and 9 months; and 200,000 IU at 12 and 15 months. Morbidity in the past month was then recalled at each follow-up visit. Analysis was based on 806 child-months.\n Among all children, the supplemented group had lower overall morbidity than the placebo group (OR = 0.69; 95% confidence interval [CI] = 0.48, 0.99). Among the 85 children of known HIV status (28 infected, 57 uninfected), morbidity associated with diarrhea was significantly reduced in the supplemented infected children (OR = 0.51; 95% CI = 0.27, 0.99), whereas no effect of supplementation on diarrheal morbidity was noted among the uninfected children.\n In a population not generally vitamin A deficient, vitamin A supplementation for children of HIV-infected women appeared to be beneficial, reducing morbidity. The benefit was observed particularly for diarrhea among HIV-infected children.", "Poor vitamin A status has been associated with a higher risk for mother-to-child transmission of HIV-1 and there is contradictory evidence on the impact of vitamin A on perinatal outcome. We therefore assessed the effect of vitamin A supplementation to mothers on birth outcome and mother-to-child transmission of HIV-1.\n In Durban, South Africa 728 pregnant HIV infected women received either vitamin A (368) or placebo (360) in a randomized, double-blind trial. The vitamin A treatment consisted of a daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the third trimester of pregnancy and 200000 IU retinyl palmitate at delivery. HIV infection results were available on 632 children who were included in the Kaplan-Meier transmission analysis. Results are reported on mother-to-child transmission rates up to 3 months of age.\n There was no difference in the risk of HIV infection by 3 months of age between the vitamin A [20.3%; 95% confidence interval (CI), 15.7-24.9] and placebo groups (22.3%; 95% CI, 17.5-27.1), nor were there differences in foetal or infant mortality rates between the two groups. Women receiving vitamin A supplement were, however, less likely to have a preterm delivery (11.4% in the vitamin A and 17.4% in the placebo group; P = 0.03) and among the 80 preterm deliveries, those assigned to the vitamin A group were less likely to be infected (17.9%; 95% CI, 3.5-32.2) than those assigned to the placebo group (33.8%; 95% CI, 19.8-47.8).\n Vitamin A supplementation, a low-cost intervention, does not appear to be effective in reducing overall mother-to-child transmission of HIV; however, its potential for reducing the incidence of preterm births, and the risk of mother-to-child transmission of HIV in these infants needs further investigation.", "Vitamin A is essential for immunity and growth. A controlled clinical that involved 697 human immunodeficiency virus (HIV)-infected pregnant women was conducted to determine whether vitamin A prevents anemia, low birth weight, growth failure, HIV transmission, and mortality. Women received daily doses of iron and folate, either alone or combined with vitamin A (3 mg retinol equivalent), from 18-28 weeks' gestation until delivery. In the vitamin A and control groups, respectively, the mean (+/-SE) birth weights were 2895+/-31 g and 2805+/-32 g (P=.05), the proportions of low-birth-weight infants were 14.0% and 21.1% (P=.03), the proportions of anemic infants at 6 weeks postpartum were 23.4% and 40.6% (P<.001), and the respective cumulative proportions of infants who were HIV infected at 6 weeks and 24 months of age were 26.6% and 27.8% (P=.76) and 27.7% and 32.8% (P=.21). Receipt of vitamin A improved birth weight and neonatal growth and reduced anemia, but it did not affect perinatal HIV transmission.", "Low maternal serum retinol level is a risk factor for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality. The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency; neonatal dosing is under consideration. We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT, HIV-free survival, and mortality in HIV-exposed infants.\n A total of 14,110 mother-infant pairs were enrolled < or =96 h after delivery, and both mother and infant, mother only, infant only, or neither received vitamin A supplementation in a randomized, placebo-controlled trial with a 2 x 2 factorial design. All but 4 mothers initiated breast-feeding. A total of 4495 infants born to HIV-positive women were included in the present analysis.\n Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months. However, the timing of infant HIV infection modified the effect that supplementation had on mortality. Vitamin A supplementation had no effect in infants who were polymerase chain reaction (PCR) positive [corrected] for HIV at baseline. In infants who were PCR negative at baseline and PCR positive at 6 weeks, neonatal supplementation reduced mortality by 28% (P=.01), but maternal supplementation had no effect. In infants who were PCR negative at 6 weeks, all 3 vitamin A regimens were associated with ~2-fold higher mortality (P< or =.05).\n Targeted vitamin A supplementation of HIV-positive children prolongs their survival. However, postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks. These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas.", "The efficacy of micronutrient supplementation in improving childhood health and survival in developing countries may be specific to the micronutrient used and health outcome measured.\n We evaluated the effect of vitamin A and zinc supplementation on overall rates of childhood diarrheal disease and respiratory tract infections and rates stratified by household and personal characteristics.\n A double-blind, randomized, placebo-controlled trial was carried out in which 736 children aged 6-15 mo living in a periurban area of Mexico City were assigned to receive vitamin A every 2 mo, zinc daily, vitamin A and zinc together, or placebo. Children were followed for 12 mo to determine overall counts of diarrheal episodes and respiratory tract infections.\n Vitamin A supplementation was associated with a 27% increase in diarrheal disease [risk ratio (RR): 1.27; 95% CI: 1.10, 1.45; P < 0.001] and a 23% increase in cough with fever (RR: 1.23; 95% CI: 1.02, 1.47; P = 0.02), whereas zinc had no effect on these outcomes. Vitamin A supplementation decreased diarrhea in children from households with dirt floors but increased diarrhea in children from households with nondirt floors, piped water, and indoor bathrooms. Zinc supplementation decreased diarrhea in children from households with dirt floors and whose mothers were more educated. Vitamin A supplementation increased cough with fever in children from less-crowded households that lacked indoor bathrooms and in children of less-educated mothers.\n Vitamin A increases diarrheal disease and respiratory tract infections in young children in periurban areas of Mexico City. Vitamin A and zinc have more heterogeneous effects in different subgroups of children.", "We previously reported that supplementation with multivitamins (vitamin B complex, vitamin C, and vitamin E) at multiples of the Recommended Dietary Allowance (RDA) significantly decreased the risk of adverse pregnancy outcomes among HIV-infected women. The minimum dosage of multivitamins necessary for optimal benefits is unknown.\n We investigated the efficacy of multivitamin supplements at single compared with multiple RDAs on decreasing the risk of adverse pregnancy outcomes among HIV-infected women.\n We conducted a double-blind, randomized controlled trial among 1129 HIV-infected pregnant women in Tanzania. Eligible women between 12 and 27 gestational weeks were randomly assigned to receive daily oral supplements of either single or multiple RDA multivitamins from enrollment until 6 wk after delivery.\n Multivitamins at multiple and single doses of the RDA had similar effects on the risk of low birth weight (11.6% and 10.2%, respectively; P = 0.75). We found no difference between the 2 groups in the risk of preterm birth (19.3% and 18.4%, respectively; P = 0.73) or small-for-gestational-age (14.8% and 12.0%, respectively; P = 0.18). The mean birth weights were similar in the multiple RDA (3045 + or - 549 g) and single RDA multivitamins group (3052 + or - 534 g; P = 0.83). There were no significant differences between the 2 groups in the risk of fetal death (P = 0.99) or early infant death (P = 0.19).\n Multivitamin supplements at a single dose of the RDA may be as efficacious as multiple doses of the RDA in decreasing the risk of adverse pregnancy outcomes among HIV-infected women. This trial was registered at clinicaltrials.gov as NCT00197678.", "To assess the effects of vitamin A supplementation in women with anaemia during pregnancy.\n Single-centre randomised controlled trial.\n Rural community in southern Malawi, central Africa.\n Seven hundred women with singleton pregnancies at 12-24 weeks measured by ultrasound scan and with haemoglobin <11.0 g/dl by HemoCue screening method. Analysis was by intention to treat. All received iron and folate, and sulphadoxine/pyrimethamine for antimalarial prophylaxis.\n Women were randomised to receive oral supplementation with daily 5000 or 10,000 iu vitamin A, or placebo.\n Anaemia, as assessed by Coulter counter, severe anaemia, iron status and indices of infection.\n Vitamin A deficiency was, in this rural population, less common than predicted. Vitamin A supplementation had no significant impact on anaemia, severe anaemia, iron status and indices of infection. Vitamin A stores were less likely to be depleted at the end of pregnancy in supplemented groups.\n Vitamin A supplementation programmes to reduce anaemia should not be implemented in similar antenatal populations in rural sub-Saharan Africa unless evidence emerges of positive benefit on substantive clinical outcomes. Introducing public health interventions of unknown benefit and with unclear biological mechanisms can divert scarce resources from clinical and social interventions more likely to impact maternal mortality.", "In observational studies, the zinc status of HIV-infected persons has been associated with both positive and adverse clinical outcomes. Such endpoints may affect the risk of adverse birth outcomes among HIV-infected women.\n We examined the effects of zinc supplements on birth outcomes, hematologic indicators, and counts of T lymphocyte subsets among 400 HIV-infected pregnant women.\n Eligible women between 12 and 27 wk of gestation were randomly assigned to daily oral supplementation with either 25 mg Zn or placebo between recruitment and 6 wk after delivery. All women received iron, folic acid, and multivitamin supplements irrespective of the experimental assignment.\n We observed no significant differences in birth weight, duration of gestation, or fetal and neonatal mortality between women in the zinc and placebo groups. Hemoglobin concentrations increased between baseline and 6 wk postpartum in both groups. However, the rise in hemoglobin over this period was significantly lower (P = 0.03) in the zinc group (x +/- SD: 11.5 +/- 17.9 g/L) than in the placebo group (15.2 +/- 18.6 g/L). Similarly, the changes in red blood cell count and in packed cell volume over the same period were significantly lower in the zinc group (P < 0.01 and P = 0.01, respectively). Zinc had no effect on CD4(+), CD8(+), or CD3(+) cell counts during the follow-up period.\n Because of the lack of beneficial effects of zinc on adverse pregnancy outcomes and the likelihood of negative effects on hemoglobin concentrations, no compelling evidence exists to support the addition of zinc to prenatal supplements intended for pregnant HIV-infected women.", "Diets of infants across the world are commonly deficient in multiple micronutrients during the period of growth faltering and dietary transition from milk to solid foods. A randomized placebo controlled trial was carried out in Indonesia, Peru, South Africa, and Vietnam, using a common protocol to investigate whether improving status for multiple micronutrients prevented growth faltering and anemia during infancy. The results of the pooled data analysis of the 4 countries for growth, anemia, and micronutrient status are reported. A total of 1134 infants were randomized to 4 treatment groups, with 283 receiving a daily placebo (P), 283 receiving a weekly multiple micronutrient supplement (WMM), 280 received a daily multiple micronutrient (DMM) supplement, and 288 received daily iron (DI) supplements. The DMM group had a significantly greater weight gain, growing at an average rate of 207 g/mo compared with 192 g/mo for the WMM group, and 186 g/mo for the DI and P groups. There were no differences in height gain. DMM was also the most effective treatment for controlling anemia and iron deficiency, besides improving zinc, retinol, tocopherol, and riboflavin status. DI supplementation alone increased zinc deficiency. The prevalence of multiple micronutrient deficiencies at baseline was high, with anemia affecting the majority, and was not fully controlled even after 6 mo of supplementation. These positive results indicate the need for larger effectiveness trials to examine how to deliver supplements at the program scale and to estimate cost benefits. Consideration should also be given to increasing the dosages of micronutrients being delivered in the foodlets.", "To evaluate the effect of simultaneous zinc and vitamin A supplementation on diarrhoea and acute lower respiratory infections in children.\n Randomised double blind placebo controlled trial.\n Urban slums of Dhaka, Bangladesh.\n 800 children aged 12-35 months were randomly assigned to one of four intervention groups: 20 mg zinc once daily for 14 days; 200 000 IU vitamin A, single dose on day 14; both zinc and vitamin A; placebo. The children were followed up once a week for six months, and morbidity information was collected.\n The incidence and prevalence of diarrhoea were lower in the zinc and vitamin A groups than in the placebo group. Zinc and vitamin A interaction had a rate ratio (95% confidence interval) of 0.79 (0.66 to 0.94) for the prevalence of persistent diarrhoea and 0.80 (0.67 to 0.95) for dysentery. Incidence (1.62; 1.16 to 2.25) and prevalence (2.07; 1.76 to 2.44) of acute lower respiratory infection were significantly higher in the zinc group than in the placebo group. The interaction term had rate ratios of 0.75 (0.46 to 1.20) for incidence and 0.58 (0.46 to 0.73) for prevalence of acute lower respiratory infection.\n Combined zinc and vitamin A synergistically reduced the prevalence of persistent diarrhoea and dysentery. Zinc was associated with a significant increase in acute lower respiratory infection, but this adverse effect was reduced by the interaction between zinc and vitamin A.", "To compare the clinical efficacy of supplementation of zinc, zinc plus vitamin A, and zinc plus combination of micronutrients and vitamins (iron, copper, selenium, vitamin B(12), folate, and vitamin A) on acute diarrhea in children.\n This was a double-blind, randomized, placebo-controlled trial. Children aged 6 to 24 months with diarrhea and moderate dehydration were randomized to receive zinc plus placebo vitamin A (group 1), zinc plus other micronutrients plus vitamin A (group 2), zinc plus vitamin A (group 3), or placebo (group 4) as an adjunct to oral rehydration solution. Duration, volume of diarrhea, and consumption of oral rehydration solution were compared as outcome variables within the supplemented groups and with the placebo group.\n The 167 study subjects included 41 in group 1, 39 in group 2, 44 in group 3, and 43 in group 4. All 3 supplemented groups demonstrated a significant reduction in outcome variables (P < .0001) compared with the placebo group. Group 3 had the lowest reduction of outcome variables and group 2 had a speedy recovery, but differences among the supplemented groups were not statistically significant.\n Supplementation with a combination of micronutrients and vitamins was not superior to zinc alone, confirming the clinical benefit of zinc in children with diarrhea.\n Copyright © 2011 Mosby, Inc. All rights reserved.", "Young infants are at risk of vitamin A deficiency. Supplementation of breastfeeding mothers improves the vitamin A status of their infants, but there are no data regarding its effect on infant mortality, and data on the effect of directly supplementing infants during the first few weeks of life are conflicting.\n The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single, large doses of vitamin A during the immediate postpartum period.\n A randomized, placebo-controlled, 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants; 9208 of the mothers were HIV-negative at delivery, remained such during the postpartum year, and were retained in the current analysis. The infants were randomly assigned within 96 h of delivery to 1 of 4 treatment groups: mothers and infants received vitamin A (Aa), mothers received vitamin A and infants received placebo (Ap), mothers received placebo and infants received vitamin A (Pa), and both mothers and infants received placebo (Pp). The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU. The mother-infant pairs were followed to 12 mo.\n Hazard ratios (95% CI) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 (0.87, 1.58) and 1.08 (0.80, 1.46), respectively. Hazard ratios (95% CI) for the Aa, Ap, and Pa groups compared with the Pp group were 1.28 (0.83, 1.98), 1.27 (0.82, 1.97), and 1.18 (0.76, 1.83), respectively. These data indicate no overall effect. Serum retinol concentrations among a subsample of women were similar to reference norms.\n Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status.", "We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15%.\n We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality.\n The study was a double-blind, cluster-randomized, controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal. In addition to vitamin A (1000 microg retinol equivalents), the intervention groups received either folic acid (FA; 400 microg), FA + iron (60 mg), FA + iron + zinc (30 mg), or multiple micronutrients (MNs; the foregoing plus 10 microg vitamin D, 10 mg vitamin E, 1.6 mg thiamine, 1.8 mg riboflavin, 2.2 mg vitamin B-6, 2.6 microg vitamin B-12, 100 mg vitamin C, 64 microg vitamin K, 20 mg niacin, 2 mg Cu, and 100 mg Mg). The control group received vitamin A only.\n None of the supplements reduced fetal loss. Compared with control infants, infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15-20% lower 3-mo mortality; this pattern was not observed with MNs. The effect on mortality was restricted to preterm infants, among whom the relative risks (RRs) were 0.36 (95% CI: 0.18, 0.75) for FA, 0.53 (0.30, 0.92) for FA + iron, 0.77 (0.45, 1.32) for FA + iron + zinc, and 0.70 (0.41, 1.17) for MNs. Among term infants, the RR for mortality was close to 1 for all supplements except MNs (RR: 1.74; 95% CI: 1.00, 3.04).\n Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality. Among preterm infants, FA alone or with iron reduced mortality in the first 3 mo of life. MNs may increase mortality risk among term infants, but this effect needs further evaluation.", "Given the high prevalence of micronutrient deficiencies and infectious diseases in infants in developing countries, an evaluation of the efficacy of different micronutrient formulations on infant morbidity is a priority. The efficacy of weekly supplementation of four different micronutrient formulations on diarrhea and acute lower respiratory infection (ALRI) morbidity was evaluated in Bangladeshi infants. In a double-blind, randomized, controlled community trial, 799 infants aged 6 mo were randomly assigned to one of the following 5 groups: 1) 20 mg elemental iron with 1 mg riboflavin, 2) 20 mg elemental zinc with 1 mg riboflavin, 3) 20 mg iron and 20 mg zinc with 1 mg riboflavin, 4) a micronutrient mix (MM) containing 20 mg iron, 20 mg zinc, 1 mg riboflavin along with other minerals and vitamins and 5) a control treatment, 1 mg riboflavin only. Health workers visited each infant weekly until age 12 mo to feed the supplement and to collect data on diarrhea and ALRI morbidity. Hemoglobin, serum ferritin and serum zinc levels of a sample of infants were measured at 6 and 12 mo. Compared with the control group, at 12 mo, serum ferritin levels were higher in the iron + zinc group, and serum zinc levels were higher in the zinc and iron + zinc groups. Simultaneous supplementation with iron + zinc was associated with lower risk of severe diarrhea, 19% lower in all infants and 30% lower in less well-nourished infants with weight-for-age Z-score below -1. Iron + zinc supplementation was also associated with 40% lower risk of severe ALRI in less well-nourished infants. MM supplementation was associated with a 15% higher risk of diarrhea in all infants and 22% higher risk in less well-nourished infants. Intermittent simultaneous supplementation with iron + zinc seems promising; it will be useful to determine whether higher doses would provide greater benefits.", "To evaluate the impact of zinc supplementation on the clinical recovery and body weight of children with persistent diarrhoea, a randomized, double-blind, controlled trial was conducted in 190 children with persistent diarrhoea aged between 3 and 24 months. Children were randomly allocated to receive either zinc (20 mg d(-1)) syrup with multivitamin (2 x RDA) or multivitamin alone in three divided daily doses for 2 weeks. The trial was conducted in a diarrhoeal disease hospital in Dhaka, Bangladesh. Duration until clinical recovery (d), impact on body weight and serum zinc level after 2 weeks of zinc supplementation were recorded. The duration of illness was significantly reduced (33%) with zinc supplementation among children who were underweight (< or =70% wt/age, p = 0.03). Supplemented male children also had a significant reduction (27%) in duration for recovery compared with unsupplemented children (p = 0.05). From baseline to convalescence, zinc-supplemented children maintained their serum zinc concentration (13.4 vs 13.6 micromol l(-1)), whereas unsupplemented children had a decrease in serum zinc after the 2 weeks of diarrhoea (13.6 vs 11.8 micromol l(-1),p < 0.03). The mean body weight of the children in the supplemented group was maintained (5.72 vs 5.70 kg, p = 0.62) during hospitalization, unlike that of the control group, in which there was a reduction in body weight (5.75 vs 5.67 kg, p = 0.05). Five children in the unsupplemented group and one child in the zinc-supplemented group died during the 2 weeks of supplementation (p = 0.06). Zinc supplementation in persistent diarrhoea significantly reduced the length of the recovery period in malnourished children and prevented a fall in body weight and serum zinc concentration, indicating that zinc is a beneficial therapeutic strategy in this high-risk childhood illness.", "In a double-blind, controlled trial with a factorial design, 684 patients (aged 6 months to 2 y; excludes 6 early dropouts) with acute watery diarrhoea of 3 d or less and some dehydration, who were attending a hospital, were randomly assigned to 4 groups to receive: (a) vitamin A 4500 microg retinol equivalent daily for 15 d; (b) 14.2 mg elemental zinc as acetate for the first 417 patients and 40 mg of the remaining 273 patients randomized to this group for 15 d; (c) both vitamin A 4500 microg retinol equivalent and zinc at the above doses daily for 15 d; or (d) placebo mixtures for 15 d. Patients were observed in the hospital for 24 h and followed up at home for 15 d. All received ascorbic acid 30 mg with each dose of medicine or placebo. Zinc supplementation was associated with a reduced duration of diarrhoea (13%, p = 0.03) and markedly reduced rate (43%, p = 0.017) of prolonged diarrhoea (>7 d). Vitamin A supplementation was associated with a nonsignificant trend for reduced rate of prolonged diarrhoea (p = 0.089). In conclusion, zinc supplementation as adjunct therapy had a substantial impact on the rate of prolonged diarrhoea and some impact on duration and may be beneficial in children with diarrhoea in developing countries.", "Zinc supplementation has been shown to benefit linear growth. However the effect may depend on whether zinc is the most limiting nutrient. This study aims to investigate the effect of supplementation with zinc-given alone or with iron and vitamin-A in improving infantsf micronutrient status and linear growth. The study was a double-blind-community-intervention study involving 800 infants aged 3-6 months in rural East Lombok, West Nusa Tenggara. Syrup consisting of zinc-alone, Zn (10 mg/d), zinc+iron, Zn+Fe (10 mg/d of each), zinc+iron+vitamin-A, Zn+Fe+vit.A (10 mg/d of each zinc and iron plus 1,000 IU vitamin-A), or placebo were given daily for six months. Outcomes measured were length, weight, and micronutrient status (haemoglobin, se-rum zinc, ferritin and retinol). Zn+Fe and Zn+Fe+vit.A supplementations benefit zinc and iron status of the sub-jects, while Zn-alone supplementation disadvantaged haemoglobin and iron status. The highest increment in vi-tamin A and haemoglobin status was shown in Zn+Fe+vit.A group. An effect on linear growth was observed among initially-stunted subjects in Zn+Fe and Zn+Fe+vit.A groups who grew 1.1-1.5 cm longer than placebo. On the other hand, in the Zn-alone group, mean height-for-age Z-score decreased to a greater extent than placebo. The between-group difference in HAZ among initially-stunted subjects was significant after four months sup-plementation. While the difference was not significant in follow-up after 6 months, the pattern remained the same where means height-for-age Z-score in Zn+Fe+vit.A and Zn+Fe groups were higher than placebo and Zn-alone groups. Given the low haemoglobin/iron status of the subjects, zinc supplementation would have positive effect on growth if the low haemoglobin/iron status is also addressed and corrected.", "Zinc supplements reduce childhood morbidity in populations in whom zinc deficiency is common. In such populations, deficiencies in other micronutrients may also occur.\n The objective was to determine whether the administration of other micronutrients with zinc modifies the effect of zinc supplementation on children's morbidity and physical growth.\n Two hundred forty-six children aged 6-35 mo with persistent diarrhea were randomly assigned to 1 of 3 groups to receive a daily supplement of 10 mg Zn alone (Zn; n = 81), zinc plus vitamins and other minerals at 1-2 times recommended daily intakes (Zn+VM; n = 82), or placebo (n = 83) for approximately 6 mo after the diarrhea episode ended. Morbidity information was collected on weekdays. Weight, length, and other anthropometric indicators were measured monthly, and plasma zinc and other indicators of micronutrient status were measured at baseline and 6 mo.\n Supplement consumption was high ( approximately 90%) in all groups, although slightly more vomiting was reported in the Zn+VM group (P < 0.0001, analysis of variance). The change in plasma zinc from baseline to 6 mo was greater in the 2 zinc groups (6.1, 27.3, and 16.2 micro g/dL in the placebo, Zn, and Zn+VM groups, respectively; P < 0.0001, analysis of variance). The Zn group had fewer episodes of diarrhea, dysentery, and respiratory illness and a lower prevalence of fever and cough than did the Zn+VM group and a lower prevalence of cough than did the placebo group (P = 0.05). No significant effects of supplementation on growth were observed.\n Morbidity was greater after supplementation with zinc plus multivitamins and minerals than it was after supplementation with zinc alone.", "We reviewed interventions that affect maternal and child undernutrition and nutrition-related outcomes. These interventions included promotion of breastfeeding; strategies to promote complementary feeding, with or without provision of food supplements; micronutrient interventions; general supportive strategies to improve family and community nutrition; and reduction of disease burden (promotion of handwashing and strategies to reduce the burden of malaria in pregnancy). We showed that although strategies for breastfeeding promotion have a large effect on survival, their effect on stunting is small. In populations with sufficient food, education about complementary feeding increased height-for-age Z score by 0.25 (95% CI 0.01-0.49), whereas provision of food supplements (with or without education) in populations with insufficient food increased the height-for-age Z score by 0.41 (0.05-0.76). Management of severe acute malnutrition according to WHO guidelines reduced the case-fatality rate by 55% (risk ratio 0.45, 0.32-0.62), and recent studies suggest that newer commodities, such as ready-to-use therapeutic foods, can be used to manage severe acute malnutrition in community settings. Effective micronutrient interventions for pregnant women included supplementation with iron folate (which increased haemoglobin at term by 12 g/L, 2.93-21.07) and micronutrients (which reduced the risk of low birthweight at term by 16% (relative risk 0.84, 0.74-0.95). Recommended micronutrient interventions for children included strategies for supplementation of vitamin A (in the neonatal period and late infancy), preventive zinc supplements, iron supplements for children in areas where malaria is not endemic, and universal promotion of iodised salt. We used a cohort model to assess the potential effect of these interventions on mothers and children in the 36 countries that have 90% of children with stunted linear growth. The model showed that existing interventions that were designed to improve nutrition and prevent related disease could reduce stunting at 36 months by 36%; mortality between birth and 36 months by about 25%; and disability-adjusted life-years associated with stunting, severe wasting, intrauterine growth restriction, and micronutrient deficiencies by about 25%. To eliminate stunting in the longer term, these interventions should be supplemented by improvements in the underlying determinants of undernutrition, such as poverty, poor education, disease burden, and lack of women's empowerment.", "To determine the effectiveness of combined iron and zinc over the iron or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children.\n Schoolchildren (n=821) of 12-16 years of age were randomized into four groups and supplemented with iron (50 mg/day), zinc (14 mg/day), iron+zinc or placebo capsules 5 days per week for 24 weeks. Anthropometry, and haemoglobin (Hb), serum zinc (SZn) and serum ferritin (SF) concentrations were determined before and after the intervention.\n There were no significant effects between-groups in their weight, height and Hb concentrations with the intervention when compared with the placebo group. Iron-only and combination-supplemented groups had reached mean SF concentrations of 55.1 microg/l with no difference between them (P=0.99). The zinc-only group had a mean change of 4.3 micromol//l whereas the combine-supplemented group had a mean change of 4.0 micromol/l (P=0.82). The prevalence of anaemia was found to be 70.3% in the iron group at baseline; this was reduced to 14.5% after the supplementation. In the combine-supplemented group anaemia, prevalence was reduced from 64.8 to 19.3%.\n Zinc alone or in combination with iron has not shown a significant improvement in growth in adolescence. Severe and moderate forms of anaemia were successfully treated in children who received iron supplementation. Initial high prevalence of low SZn and iron stores was significantly improved with micronutrient supplementation." ]	Multiple micronutrient supplements reduced morbidity and mortality in HIV-infected pregnant women and their offspring and also improved early child growth in one large randomised controlled trial in Africa. Additional research is needed to determine if these are generalisable findings. Vitamin A supplementation is beneficial and safe in HIV-infected children, but further evidence is needed to establish if supplementation confers similar benefits in HIV-infected adults. Zinc is safe in HIV-infected adults and children. It may have similar benefits in HIV-infected children and adults, and uninfected children with diarrhoea, as it does in HIV-uninfected children. Further trials of single supplements (vitamin D, zinc, and selenium) are required to build the evidence base. The long-term clinical benefits, adverse effects, and optimal formulation of multiple micronutrient supplements require further investigation in individuals with diverse disease status.
CD007132	[ "15992199", "11036893" ]	[ "A quality improvement intervention to increase palliative care in nursing homes.", "A palliative-care intervention and death at home: a cluster randomised trial." ]	[ "Death is common in nursing homes, but access to palliative care is limited.\n To test whether a quality improvement (QI) intervention in nursing homes increases hospice, pain management, and advance care planning.\n The QI intervention was tested in seven nursing homes using a prepoststudy design. Two additional nursing homes served as control sites.\n Nine nursing homes serving 1169 residents.\n The intervention included recruitment and training of Palliative Care Leadership Teams in each facility, followed by six technical assistance meetings for team members. Hospice providers delivered six educational sessions for all nursing home staff using a structured curriculum. Teams received feedback of performance data on hospice enrollment, pain management, and advance care planning at 0, 3, and 6 months.\n Percentage of residents receiving hospice or palliative services, pain assessment, pain treatment among residents in pain, and documented advance care planning discussions.\n Intervention facilities increased hospice enrollment from 4.0% of residents at baseline to 6.8% postintervention (p = .01) and increased pain assessments from 18% to 60% (p < .001). Among resident in pain, orders for nonpharmacologic pain treatments increased from 15% to 35% (p < .001), but pain medication use did not change. Residents with in-depth discussions about end-of-life care increased from 4% to 17% (p < .001). There were no significant changes in control sites.\n A quality improvement intervention was effective in increasing hospice enrollment, pain assessment, nonpharmacologic pain treatment, and advance care planning discussions.", "The Palliative Medicine Unit at University Hospital of Trondheim, Norway, started an intervention programme that aims to enable patients to spend more time at home and die there if they prefer. Close cooperation was needed with the community health-care professionals, who acted as the principal formal caregivers, and a multidisciplinary consultant team coordinated the care. We did a cluster randomised trial to assess the intervention's effectiveness compared with conventional care\n Community health-care districts in and around Trondheim, Norway, were defined as the clusters to be randomised. We enrolled 434 patients (235 assigned intervention and 199 conventional care [controls]) in these districts who had incurable malignant disease and an expected survival of 2-9 months. Main outcomes were place of death and time spent in institutions in the last month of life.\n 395 patients died. Of these, more intervention patients than controls died at home (54 [25%] vs 26 [15%], p<0.05). The time spent at home was not significantly increased, although intervention patients spent a smaller proportion of time in nursing homes in the last month of life than did controls (7.2 vs 14.6%, p<0.05). Hospital use was similar in the two groups.\n The palliative-care intervention enabled more patients to die at home. More resources for care in the home (palliative care training and staff) and an increased focus on use of nursing homes would be necessary, however, to increase time at home and reduce hospital admissions." ]	We found few studies, and all were in the USA. Although the results are potentially promising, high quality trials of palliative care service delivery interventions which assess outcomes for residents are needed, particularly outside the USA. These should focus on measuring standard outcomes, assessing cost-effectiveness, and reducing bias.
CD009021	[ "20357374", "21429234", "8990428", "22183208", "19747869" ]	[ "Prevention of gestational diabetes: feasibility issues for an exercise intervention in obese pregnant women.", "Feasibility of a lifestyle intervention in early pregnancy to prevent deterioration of glucose tolerance.", "Effects of a partially home-based exercise program for women with gestational diabetes.", "Regular exercise during pregnancy to prevent gestational diabetes: a randomized controlled trial.", "Supervised home-based exercise may attenuate the decline of glucose tolerance in obese pregnant women." ]	[ "To examine the feasibility of an individualized exercise program to prevent gestational diabetes mellitus (GDM) in obese pregnant women.\n The study was a pilot randomized controlled trial with obese pregnant women (intervention group, individualized exercise program [n = 25]; control group, usual care [n = 25]). Average weekly energy expenditure (MET hours per week and kilocalories per week) of exercise-specific activity was assessed during pregnancy using the Pregnancy Physical Activity Questionnaire. Fasting glucose and insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed at baseline and 20, 28, and 36 weeks' gestation.\n Of the women in the intervention group, 16 of 22 (73%) achieved more than 900 kcal/week of exercise-based activity at 28 weeks compared with 8 of 19 women in the control group (42%), P = 0.047. However, insulin resistance (HOMA-IR) did not differ between the groups.\n This intervention was feasible and prompted a modest increase in physical activity. However, we are not confident that this intervention would be sufficient to prevent GDM.", "In conjunction with the growing prevalence of obesity and the older age of pregnant women gestational diabetes (GDM) is a major health problem.The aim of the study was to evaluate if a lifestyle intervention since early pregnancy is feasible in improving the glucose tolerance of women at a high-risk for GDM in Finland.\n A 75-g oral glucose tolerance test (OGTT) was performed in early pregnancy (n = 102). Women at high risk for GDM (n = 54) were randomized at weeks 8-12 from Apr 2005 to May 2006 to a lifestyle intervention group (n = 27) or to a close follow-up group (n = 27). An OGTT was performed again at weeks 26-28 for the lifestyle intervention and close follow-up groups.\n The values of the OGTT during the second trimester did not differ between the lifestyle intervention and close follow-up groups. In the lifestyle intervention group three women had GDM in the second trimester and respectively one woman in the close follow up group. Insulin therapy was not required in both groups. The intervention resulted in somewhat lower weight gain 11.4 ± 6.0 kg vs. 13.9 ± 5.1 kg, p = 0.062, adjusted by the prepregnancy weight.\n Early intervention with an OGTT and simple lifestyle advice is feasible. A more intensive lifestyle intervention did not offer additional benefits with respect to glucose tolerance, although it tended to ameliorate the weight gain.\n ClinicalTrials.gov: NCT01130012.", "To examine the effectiveness of a partially home-based, moderate-intensity aerobic exercise program for women with gestational diabetes.\n This was a randomized experimental design. Thirty-three women with gestational diabetes were randomly assigned to the exercise or the no-exercise group. Subjects underwent hemoglobin A1C assay and submaximal cycle ergometer fitness tests at baseline and at study conclusion. Subjects kept diaries of home fasting and 2-hour postprandial blood glucose determinations. Exercise subjects were asked to exercise for 30 minutes three to four times weekly at 70% of estimated maximal heart rate for the weeks of study participation. Two exercise sessions weekly were supervised by the investigator, and two were unsupervised at home. Control-group subjects were asked to maintain their current activity level.\n Daily fasting and postprandial blood glucose levels, hemoglobin A1C, incidence of exogenous insulin therapy, and incidence of newborn hypoglycemia were not different between the groups. There was a training effect in the exercise group (P = .005) but not in the control group (P = .25). A significant decline in daily grams of carbohydrate consumed was observed in the control group (P = .03), but not in the exercise group (P = .97). No complications were found in the subjects who exercised.\n A partially home-based exercise program did not reduce blood glucose levels, but did result in a modest increase in cardiorespiratory fitness. The intervention appeared safe.", "To assess whether exercise during pregnancy can prevent gestational diabetes and improve insulin resistance.\n A total of 855 women in gestational week 18-22 were randomly assigned to receiving a 12-week standard exercise program (intervention group) or standard antenatal care (control group). The exercise program followed standard recommendations and included moderate-intensity to high-intensity activity 3 or more days per week. Primary outcomes were gestational diabetes and insulin resistance estimated by the homeostasis model assessment method. For the power calculation, we assumed a gestational diabetes prevalence of 9% in the control group and a prevalence of 4% in the exercise group (risk difference of 5%). Under these assumptions, a two-sample comparison with a 5% level of significance and power of 0.80 gave a study population of 381 patients in each group.\n At 32-36 weeks of gestation there were no differences between groups in prevalence of gestational diabetes: 25 of 375 (7%) in the intervention group compared with 18 of 327 (6%) in the control group (P=.52). There were no differences in insulin resistance between groups when adjusting for baseline values. Only 55% of women in the intervention group managed to follow the recommended exercise protocol. No serious adverse events related to physical exercise were seen, and the outcomes of pregnancy were similar in the two groups.\n There was no evidence that offering women a 12-week standard exercise program during the second half of pregnancy prevents gestational diabetes or improves insulin resistance in healthy pregnant women with normal body mass indexes.\n : ClinicalTrials.gov, www.clinicaltrials.gov, NCT00476567.", "The significant deterioration of insulin sensitivity and glucose tolerance during pregnancy can have serious health implications for both the pregnant woman and her baby. Although it is well established that regular exercise benefits insulin sensitivity in the nonpregnant population, the effect on glucose tolerance in obese pregnant women is not known. The purpose of this study was to investigate the effect of a supervised 10-week, home-based, exercise programme, beginning at week 18 of gestation, on glucose tolerance and aerobic fitness in previously sedentary obese women.\n Twelve sedentary obese women were randomized into an exercise (EX; n=6) or control (CON; n=6) group at 18 weeks of gestation. Those randomized to EX engaged in 10 weeks of supervised home-based exercise (three sessions a week of stationary cycling), while those in the CON group maintained their usual daily activity. Their glucose and insulin responses to an oral glucose tolerance test (OGTT), as well as their aerobic fitness, were assessed both pre- and postintervention.\n Reduced glucose tolerance in the CON, but not EX, group was indicated by a tendency postintervention towards higher blood glucose levels at 1h of the OGTT (P=0.072). Furthermore, at 2h of the postintervention OGTT, blood glucose tended to remain elevated from baseline in the CON (P=0.077). There was also a trend towards increased fitness in the EX (P=0.064), but not the CON group.\n Regular aerobic exercise begun during pregnancy may have favourable effects on glucose tolerance and fitness in obese women, and warrants further investigation in a larger sample population." ]	There is limited randomised controlled trial evidence available on the effect of exercise during pregnancy for preventing pregnancy glucose intolerance or GDM. Results from three randomised trials with moderate risk of bias suggested no significant difference in GDM incidence between women receiving an additional exercise intervention and routine care. Based on the limited data currently available, conclusive evidence is not available to guide practice. Larger, well-designed randomised trials, with standardised behavioural interventions are needed to assess the effects of exercise on preventing GDM and other adverse pregnancy outcomes including large-for-gestational age and perinatal mortality. Longer-term health outcomes for both women and their babies and health service costs should be included. Several such trials are in progress. We identified another seven trials which are ongoing and we will consider these for inclusion in the next update of this review.
CD000373	[ "2187377", "2672899", "9859905" ]	[ "Postoperative apnea in former preterm infants: prospective comparison of spinal and general anesthesia.", "High-dose caffeine suppresses postoperative apnea in former preterm infants.", "Efficacy of nasal intermittent positive pressure ventilation in treating apnea of prematurity." ]	[ "Thirty-six former preterm infants undergoing inguinal hernia repair were studied. All were less than or equal to 51 weeks postconceptual age at the time of operation. Patients were randomly assigned to receive general or spinal anesthesia. Group 1 patients received general inhalational anesthesia with neuromuscular blockade. Group 2 patients received spinal anesthesia using 1% tetracaine 0.4-0.6 mg/kg in conjunction with an equal volume of 10% dextrose and 0.02 ml epinephrine 1:1000. In the first part of the study, infants randomized to receive spinal anesthesia also received sedation with im ketamine 1-2 mg/kg prior to placement of the spinal anesthetic (group 2 A). The remainder of group 2 patients did not receive sedation (group 2 B). Respiratory pattern and heart rate were monitored using an impedance pneumograph for at least 12 h postoperatively. Tracings were analyzed for evidence of apnea, periodic breathing and/or bradycardia by a pulmonologist unaware of the anesthetic technique utilized. None of the patients who received spinal anesthesia without ketamine sedation developed postoperative bradycardia, prolonged apnea, or periodic breathing. Eight of nine infants (89%) who received spinal anesthesia and adjunct intraoperative sedation with ketamine developed prolonged apnea with bradycardia. Two of the eight infants had no prior history of apnea. Five of the 16 patients (31%) who received general anesthesia developed prolonged apnea with bradycardia. Two of these five infants had no prior history of apnea. When infants with no prior history of apnea were analyzed separately, there was no statistically significant increased incidence of apnea in children receiving general versus spinal anesthesia with or without ketamine sedation. Because of the small numbers of patients studied, and the multiple factors that may influence the incidence of postoperative apnea (e.g., prior history of neonatal apnea), standard postoperative respiratory monitoring of these high-risk infants is still recommended following all anesthetic techniques.", "Thirty-two former preterm infants (less than or equal to 44 weeks postconceptual age) undergoing inguinal hernia repair were prospectively studied. General inhalational anesthesia with neuromuscular blockade was used. No barbiturates or opioids were given. Infants were randomly divided into two groups. Group 1 received iv caffeine 10 mg/kg immediately after induction of anesthesia. Group 2 received iv saline. Respiratory pattern, heart rate, and SpO2 were monitored using an impedance pneumograph and a pulse oximeter, respectively, for at least 12 h postoperatively. Tracings were analyzed for evidence of apnea, periodic breathing, and/or bradycardia by a pulmonologist unaware of the drug given. None of the patients who received caffeine developed postoperative bradycardia, prolonged apnea, or periodic breathing, and none had postoperative SpO2 less than 90%. In the control group 13 (81%) developed prolonged apnea 4-6 h postoperatively. Fifty percent of the patients had SpO2 less than 90% at the time. This study shows that iv caffeine 10 mg/kg is effective in the control of apnea in otherwise healthy expremature infants between 37 and 44 weeks of postconceptual age. It is still recommended, however, that all infants at risk be monitored for at least 12 h for apnea and bradycardia following general anesthesia.", "The efficacy of nasal intermittent positive pressure ventilation (NIPPV) in treating apnea of prematurity was evaluated. Apneic preterm infants were randomly assigned to receive either NIPPV or continuous positive airway pressure (NCPAP) for 4 hr when they failed to respond to conservative therapy. The amount of reduction in apneic spells and bradycardia in the two groups after treatment was compared. Thirty-four infants (18 with NIPPV, 16 with NCPAP) were enrolled. Their birth weights ranged from 590-1,880 g (mean, 1,021 g) and gestational ages from 25-32 weeks (mean, 27.6 weeks). The baseline characteristics were comparable in the two groups. Frequency of apnea and bradycardia was reduced during both forms of treatments. However, the infants receiving NIPPV had a greater reduction of apneic spells (P = 0.02) and a tendency to greater decrease in bradycardia (P = 0.09) than those receiving NCPAP. We conclude that NIPPV is more effective than NCPAP in reducing apnea in preterm infants. NIPPV may reduce bradycardia; however, this needs to be validated by a larger number of observations." ]	Implications for practice. Prophylactic use of kinesthetic stimulation cannot be recommended to reduce apnea/bradycardia in preterm infants. Implications for research. There are currently no clear research questions regarding prophylactic use of kinesthetic stimulation to prevent apnea in preterm infants.
CD001520	[ "11083131", "9844753", "8513037", "1457626", "10484950", "2496815" ]	[ "Use of melatonin in recovery from jet-lag following an eastward flight across 10 time-zones.", "Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag.", "A double-blind trial of melatonin as a treatment for jet lag in international cabin crew.", "Melatonin and jet lag: confirmatory result using a simplified protocol.", "Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial.", "Effect of melatonin on jet lag after long haul flights." ]	[ "Subjective, physiological and physical performance variables are affected following travel across multiple time-zones (jet-lag). The objective of the study was to examine the effects of oral melatonin in alleviating jet-lag by investigating its effects on subjects who had flown from London to Eastern Australia, 10 time-zones to the east. Melatonin (5 mg day(-1)) or placebo capsules were administered to 14 experimental (13 males and 1 female) and 17 control subjects (15 males and 2 females), respectively, in a double-blind study; the time of administration was in accord with the current consensus for maximizing its hypnotic effect. Grip strength and intra-aural temperature were measured on alternate days after arrival at the destination, at four different times of day (between the times 07:00 - 08:00 h, 12:00 - 13:00 h, 16:00 - 17:00 h and 19:00 - 20:00 h local time). In addition, for the first 6 - 7 days after arrival in Australia, subjective ratings of jet-lag on a 0 - 10 visual analogue scale and responses to a Jet-lag Questionnaire (incorporating items for tiredness. sleep, meal satisfaction and ability to concentrate) were recorded at the above times and also on retiring (at about midnight). Subjects continued normally with their work schedules between the data collection times. Subjects with complete data (13 melatonin and 13 placebo subjects), in comparison with published data, showed partial adjustment of the diurnal rhythm in intra-aural temperature after 6 days. A time-of-day effect was evident in both right and left grip strength during adjustment to Australian time; there was no difference between the group taking melatonin and that using the placebo. Right and left grip strength profiles on day 6 were adjusted either by advancing or delaying the profiles, independent of whether subjects were taking melatonin or placebo tablets. Subjects reported disturbances with most measures in the Jet-lag Questionnaire but, whereas poorer concentration and some negative effects upon sleep had disappeared after 3 - 5 days, ratings of jet-lag and tiredness had not returned to 'zero' (or normal values), respectively, by the sixth day of the study. Subjects taking melatonin showed no significant differences from the placebo group in perceived irritability, concentration, meal satisfaction, ease in getting to sleep and staying asleep, frequency of bowel motion and consistency of the faeces. These results suggest that, in subjects who, after arrival, followed a busy schedule which resulted in frequent and erratic exposure to daylight, melatonin had no benefit in alleviating jet-lag or the components of jet-lag, and it did not influence the process of phase adjustment.", "To compare the impact of various dosage forms of melatonin and placebo on jet lag symptoms, 320 volunteers who had flights over 6 to 8 time zones were recruited for a double-blind, randomized, placebo-controlled study. The volunteers received either melatonin 0.5-mg fast-release (FR) formulation, melatonin 5-mg FR formulation, melatonin 2-mg controlled-release (CR) formulation, or placebo. The study medication was taken once daily at bedtime during 4 days after an eastward flight. The volunteers completed the Profile of Mood States (POMS), sleep log, and symptoms questionnaires once daily and the Karolinska Sleepiness Scale (KSS) three times daily prior to departure and during the 4 days of medication intake postflight. A total of 234 (73.1%) participants were compliant and completed the study. The FR melatonin formulations were more effective than the slow-release formulation. The 5-mg FR formulation significantly improved the self-rated sleep quality (p < .05), shortened sleep latency (p < .05), and reduced fatigue and daytime sleepiness (p < .05) after intercontinental flight. The lower physiological dose of 0.5 mg was almost as effective as the pharmacological dose of 5.0 mg. Only the hypnotic properties of melatonin, sleep quality and sleep latency, were significantly greater with the 5.0-mg dose.", "This study investigated the efficacy of oral melatonin in alleviating jet lag in flight crew after a series of international flights. The optimal time for taking melatonin in this group was also investigated. In a double-blind placebo-controlled trial, 52 international cabin crew were randomly assigned to three groups; early melatonin (5 mg started 3 days prior to arrival until 5 days after return home); late melatonin (placebo for 3 days then 5 mg melatonin for 5 days); and placebo. Daily ratings showed a trend in jet lag, mood, and sleepiness measures toward an improved recovery in the late melatonin group and a worse recovery in the early melatonin group as compared to placebo. Retrospective ratings made 6 days after arrival showed the late melatonin group reported significantly less jet lag and sleep disturbance following the flight compared to placebo. The late melatonin group also showed a significantly faster recovery of energy and alertness than the early melatonin group, which reported a worse overall recovery than placebo. These findings show melatonin may have potential benefits for international aircrew.", "This study replicates the alleviation of jet-lag with melatonin in a simplified protocol for eastward flight. At 22-n hr (n is the time-lag between the North American departure point and France), subjects took either melatonin (8 mg, n = 15), or placebo (n = 15) on the day of the return flight and for 3 consecutive days. On day 8, self-ratings significantly discriminated between melatonin and placebo for global treatment efficacy, morning fatigue, and evening sleepiness.", "The goals of this study were to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag.\n This was a randomized, double-blind trial of placebo and three alternative regimens of melatonin (5.0 mg at bedtime, 0.5 mg at bedtime, and 0.5 mg taken on a shifting schedule) for jet lag. The subjects were 257 Norwegian physicians who had visited New York for 5 days. Jet lag ratings were made on the day of travel from New York back to Oslo (6 hours eastward) and for the next 6 days in Norway. The main outcome measures were scale and item scores from a new, syndrome-specific instrument, the Columbia Jet Lag Scale, that identifies prominent daytime symptoms of jet lag distress.\n There was a marked increase in total jet lag score in all four treatment groups on the first day at home, followed by progressive improvement over the next 5 days. However, there were no significant group differences or group-by-time interactions. In addition, there was no group effect for sleep onset, time of awakening, hours slept, or hours napping. Ratings on a summary jet lag item were highly correlated with total jet lag scores (from a low of r = 0.54 on the day of travel to a high of r = 0.80 on day 3). The internal consistency of the total jet lag score was high on each day of the study.\n The use of melatonin for preventing jet lag needs further study.", "To determine whether doses of the pineal hormone melatonin alleviate jet lag.\n Double blind, placebo controlled crossover trial.\n Long haul return flights from Auckland, New Zealand, to London and back.\n Twenty volunteers with experience of transcontinental flights (eight women and 12 men aged 28 to 68).\n Melatonin (or placebo) 5 mg three days before flight, during flight, and once a day for three days after arrival.\n Symptoms of jet lag.\n Visual analogue scale for feelings of jet lag and tiredness; profile of moods states questionnaire for vigour-activity and fatigue-inertia; and retrospective ratings 10 days after arrival of sleep pattern, energy, and daytime tiredness. Feelings of jet lag were less for subjects taking melatonin (mean score 2.15 v 3.4); these subjects took fewer days than the placebo group to establish a normal sleep pattern (2.85 v 4.15), to not feel tired during the day (3.0 v 4.6), and to reach normal energy levels (3.25 v 4.7). Results for fatigue-inertia and vigour-activity were similar. For all subjects jet lag was more severe on the return (westward) than the outward (eastward) journey.\n Melatonin can alleviate jet lag and tiredness after long haul flights." ]	Melatonin is remarkably effective in preventing or reducing jet lag, and occasional short-term use appears to be safe. It should be recommended to adult travellers flying across five or more time zones, particularly in an easterly direction, and especially if they have experienced jet lag on previous journeys. Travellers crossing 2-4 time zones can also use it if need be. The pharmacology and toxicology of melatonin needs systematic study, and routine pharmaceutical quality control of melatonin products must be established. The effects of melatonin in people with epilepsy, and a possible interaction with warfarin, need investigation.
CD008358	[ "6393805", "18218147", "1443440", "2571021" ]	[ "A double-blind, placebo-controlled trial of magnesium sulfate in the ethanol withdrawal syndrome.", "Magnesium treatment in alcoholics: a randomized clinical trial.", "Oral magnesium supplementation improves metabolic variables and muscle strength in alcoholics.", "Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome." ]	[ "One hundred alcoholics treated for ethanol withdrawal were assigned randomly according to a double-blind protocol to receive four intramuscular injections of 2 g of magnesium sulfate at 6-hr intervals or an equivalent amount of normal saline. All patients were treated for signs of withdrawal according to a standardized protocol using orally-administered chlordiazepoxide for sedation. Three observers rated each patient for signs of withdrawal. There was no statistically significant difference between magnesium sulfate and placebo groups on any of the variables measured. The groups required equivalent amounts of chlordiazepoxide for control of withdrawal. The authors concluded that the routine administration of magnesium sulfate is not indicated for the management of alcohol withdrawal unless accompanied by cardiac arrhythmias.", "Magnesium (Mg) deficiency is common among alcoholics. Earlier research suggests that Mg treatment may help to normalize elevated enzyme activities and some other clinically relevant parameters among alcoholics but the evidence is weak.\n The effect of Mg was studied in a randomized, parallel group, double-blind trial. The patients were first treated for alcohol withdrawal symptoms and then received for 8 weeks either 500 mg of Mg divided into two tablets or matching placebo. Measurements were made at the beginning and in the end of the Mg treatment period. The primary outcome was serum gamma-glutamyltransferase (S-GGT) activity; secondary outcomes included aspartate-aminotransferase (S-AST) and alanine-aminotransferase (S-ALT) activity.\n The number of randomized patients (completers) was 64 (27) in the treatment and 54 (31) in the control group. In intention-to-treat-analyses and in most analyses of study completers, there were no significant differences between the Mg-treated and placebo groups in the outcome variables. When baseline serum Mg level, coffee intake, and the number of unused Mg tablets were controlled for in a multivariate regression model, after-treatment serum Mg levels were found to be higher among the Mg-treated group than in the placebo group (t-test 3.334, df = 53, p = 0.002). After controlling for age, body weight, baseline alcohol intake, subsequent change in alcohol intake and baseline S-AST, the after-treatment S-AST levels were found to be lower among the Mg-treated group than in the placebo group (t-test 2.061, df = 49, p = 0.045).\n Mg treatment may speed up the S-AST decrease in compliant patients. This might decrease the risk of death from alcoholic liver disease.\n ClinicalTrials.gov ID NCT00325299.", "Magnesium deficiency is common among chronic alcoholics, but the knowledge of oral magnesium supplementation to this group is limited. We, therefore, randomized 49 chronic alcoholics, moderate to heavy drinkers for at least 10 years to receive oral magnesium or placebo treatment for 6 weeks according to a double-blind protocol. Effects on metabolic variables and muscle strength were analyzed. Significant reduction of aspartate-aminotransferase (ASAT), alanine-aminotransferase (ALAT) and gamma-glutamyl-transpeptidase (GGT) were seen after magnesium, whereas no change was observed with placebo. Bilirubin decreased in both groups. Serum Na, Ca, and P increased significantly during magnesium therapy compared with no statistically significant change in the placebo group. Serum K and Mg increased slightly after magnesium supplementation and decreased in the placebo group, resulting in a significant difference between the two groups at the end of the study. Muscle strength increased significantly during magnesium treatment, contrasting to no change with placebo. Blood pressure, heart rate, hematological variables, serum lipids (cholesterol, HDL, TG), glucose tolerance, and creatinine were unchanged in the two groups after treatment. Alcohol consumption was similar before and during the trial and does not explain the differences between the two groups The results shows that short-term oral magnesium therapy may improve liver cell function, electrolyte status, and muscle strength in chronic alcoholics.", "The effect of gamma-hydroxybutyric acid (GHB) on ethanol withdrawal syndrome in alcoholics was investigated in a randomised double-blind study. Patients with withdrawal symptoms were treated either with GHB (orally in a syrup preparation) (11 patients) or with the syrup alone (12). GHB treatment (50 mg/kg) led to a prompt reduction in withdrawal symptoms, such as tremors, sweating, nausea, depression, anxiety, and restlessness. The only side-effect was dizziness. GHB may be useful in the management of alcohol withdrawal syndrome in man." ]	There is insufficient evidence to determine whether magnesium is beneficial or harmful for the treatment or prevention of alcohol withdrawal syndrome.
CD003557	[ "16490980", "3528240", "6344906", "12011525", "2466712", "9620490", "2669345", "19626807", "10781212", "3926169", "20693796", "3063043", "1582236", "2835836", "8497357", "6998390", "9091151" ]	[ "Quality control in chronic wound management: the role of local povidone-iodine (Betadine) therapy.", "Systemic administration of antibiotics in the management of venous ulcers. A randomized clinical trial.", "A randomized trial comparing cadexomer iodine and standard treatment in the out-patient management of chronic venous ulcers.", "The beneficial toxicity paradox of antimicrobials in leg ulcer healing impaired by a polymicrobial flora: a proof-of-concept study.", "In-patient treatment of chronic varicose venous ulcers. A randomized trial of cadexomer iodine versus standard dressings.", "The effects of cadexomer iodine paste in the treatment of venous leg ulcers compared with hydrocolloid dressing and paraffin gauze dressing. Cadexomer Iodine Study Group.", "Multicenter trial of cadexomer iodine to treat venous stasis ulcer.", "Comparison of surgical wound infection after preoperative skin preparation with 4% chlorhexidine [correction of chlohexidine] and povidone iodine: a prospective randomized trial.", "Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial.", "Controlled trial of Iodosorb in chronic venous ulcers.", "Minimizing wound contamination in a 'clean' surgery: comparison of chlorhexidine-ethanol and povidone-iodine.", "Failure of topically applied antibiotics, added to systemic prophylaxis, to reduce perineal wound infection in abdominoperineal excision of the rectum.", "Pentoxifylline in the treatment of venous leg ulcers.", "Topical antibiotics in chronic sickle cell leg ulcers.", "Preoperative skin preparation and intraoperative pelvic irrigation: impact on post-cesarean endometritis and wound infection.", "Prophylactic antibiotics in vascular surgery. Topical, systemic, or both?", "The influence of dressings on venous ulcer healing--a randomised trial." ]	[ "The treatment of venous leg ulcers is often inadequate, because of incorrect diagnosis, overuse of systemic antibiotics and inadequate use of compression therapy. Stasis dermatitis related to chronic venous insufficiency accompanied by infected superficial ulcers must be differentiated from erysipelas, cellulitis and contact eczema.\n To assess the effectiveness of (1) topical povidone-iodine with and (2) without compression bandages, (3) to compare the efficacy of systemic antibiotics and topical antimicrobial agents to prevent the progression of superficial skin ulcers.\n 63 patients presenting ulcerated stasis dermatitis due to deep venous refluxes were included in the study. The clinical stage of all patients was homogeneous determined by clinical, aetiological, anatomical and pathological classification. They were examined by taking a bacteriological swab from their ulcer area. Compression bandages were used in a total of 42 patients. Twenty-one patients with superficial infected (Staphylococcus aureus) ulcers were treated locally with povidone-iodine (Betadine), and 21 patients were treated with systemic antibiotics (amoxicillin). Twenty-one patients were treated locally with Betadine but did not use compression. The end point was the time of ulcus healing. The healing process of the ulcers was related to the impact of bacterial colonization and clinical signs of infection.\n Compression increases the ulcer healing rate compared with no compression. Using the same local povidone-iodine (Betadine) treatment with compression bandages is more effective (82%) for ulcus healing than without compression therapy (62%). The healing rate of ulcers treated with systemic antibiotics was not significantly better (85%) than that of the Betadine group. Using systemic antibiotics, the relapse rate of superficial bacterial infections (impetigo, folliculitis) was significantly higher (32%) than in patients with local disinfection (11%).\n Compression is essential in the mobilization of the interstitial lymphatic fluid from the region of stasis dermatitis. Topical disinfection and appropriate wound dressings are important to prevent wound infection. Systemic antibiotics are necessary only in systemic infections (fever, lymphangitis, lymphadenopathy, erysipelas).", "Forty-seven patients with chronic venous leg ulcers were included in a randomized clinical trial to evaluate the efficacy of systemically administered antibiotics in healing with condition. One group was treated by means of elastic support bandages only, whereas the other one received the same local treatment plus systemic antibiotics. No statistically relevant difference was noted between the two groups in healing rates of ulcers or in changes of the microbiologic flora. The results of our study do not support the routine administration of systemic antibiotics in the management of chronic venous leg ulcers.", "Ninety-three patients with treatment-resistant venous ulcers were included in a multicentre randomized trial to compare cadexomer iodine and the standard treatment used in each centre combined with compression bandages, in healing venous ulcers. The mean duration of ulcers before the trial was more than 2 years. With standard treatment the mean ulcer size increased slightly during the 6-week trial whereas with cadexomer iodine the ulcer size was significantly reduced. Cadexomer iodine was more effective than standard treatment for reduction of pain, removal of pus and debris, removal of exudate, stimulation of granulation and reduction of surrounding erythema. Bacterial infection of ulcers increased or did not change during treatment with the standard therapy whereas cadexomer iodine significantly reduced infection with Staphylococcus aureus, Pseudomonas aeruginosa and other pathogenic organisms. A correlation was seen between the time taken to reduce or eliminate infection with Staphylococcus aureus and rate of ulcer healing. Four patients complained of transient pain in the ulcer after application of the cadexomer iodine. It is concluded that cadexomer iodine increased the rate of healing of infected chronic venous ulcers.", "Some of the views contrasting the beneficial and toxic effects of antimicrobials upon wound healing remain controversial.\n To assess the clinical relevance of histological findings following antimicrobial applications on chronic leg ulcers.\n The present study was performed in three parallel groups of 17 patients suffering from at least 2 similar chronic leg ulcers. Clinical planimetric assessments were performed before and after 3 and 6 weeks of treatment using hydrocolloid dressings. In addition, 1 ulcer in each patient received applications of povidone-iodine (PVP-I), silver sulfadiazine or chlorhexidine digluconate. Histological examinations were made at inclusion and after the 6-week therapy. Time to healing was also recorded.\n At entry in the study, fibroblasts, macrophages, neutrophils and vessels were abundant in the ulcers. In addition, focal necrotizing vasculitis was related to the microbiological load. Compared to the control lesions, both the healing rate and time to healing of the leg ulcers showed a modest improvement at the sites receiving silver sulfadiazine (2-7%) or chlorhexidine digluconate (-1 to 5%). By contrast, PVP-I increased significantly the healing rate (4-18%, p < 0.01), and time to healing was reduced by 2-9 weeks (p < 0.01). The 3 antimicrobials decreased the bacterial density, and the vascular margination and migration of inflammatory cells, thus abating the vasculitic changes. PVP-I applications did not alter the microvessels and did not significantly reduce the density in dendrocytes and fibroblasts. By contrast, both silver sulfadiazine and chorhexidine digluconate appeared to alter the superficial microsvasculature including the dendrocyte population.\n Although topical antimicrobials may apparently achieve almost similar activity on the bacterial load inside chronic leg ulcers, the toxicity upon host cells was different among these agents. PVP-I appeared to be an efficient compound in these respects exhibiting a positive and relevant clinical effect.\n Copyright 2002 S. Karger AG, Basel", "A total of 67 patients with treatment resistant chronic venous ulcers were admitted to hospital for 6 weeks of bed rest and daily dressings. The patients came from a rural area in Poland with poor socioeconomic conditions. They were randomized to treatment with either standard dressings or with cadexomer iodine. After 6 weeks all but four patients had shown a clear reduction of ulcer area; the mean reduction was 54% within the former group and 71% with cadexomer iodine. The latter treatment was significantly more effective than the standard hospital dressings in debriding the ulcer, accelerating healing and reducing pain. Elevation of serum concentrations of protein-bound iodine occurred after treatment with cadexomer iodine in patients with large ulcers, but tests of thyroid function showed no changes associated with the use of cadexomer iodine. It is concluded that cadexomer iodine significantly accelerates the healing of chronic, infected, treatment-resistant, venous ulcers in hospitalized patients.", "The aim was to examine cadexomer iodine paste in a comparative clinical trial.\n A 12-week, randomized, open, controlled, multicenter, multinational trial in patients with exudating, venous leg ulcers of cadexomer iodine paste (Iodosorb/Iodoflex), hydrocolloid dressing (Duoderm E, Granuflex E), or paraffin gauze dressing (Jelonet) was carried out. All patients used short-stretch compression bandages (Comprilan) throughout the study. The primary efficacy variable was a reduction in ulcer size (%), and the secondary end-point was the time taken to stop exudation, when the patient had completed the study according to the protocol. A total of 153 patients entered the study and were treated for 12 weeks or until cessation of exudation.\n The mean reduction in ulcer size in all patients was 62% with cadexomer iodine vs. 41% and 24% for hydrocolloid and paraffin gauze (ns). Of those treated for 12 weeks (n = 51), ulcer area reduction was 66% for cadexomer iodine and 18% for hydrocolloid (p = 0.0127). For the whole material, the rate of healing (ulcer area reduction per week) was significantly higher for cadexomer iodine than for paraffin gauze (0.64 cm2/week vs. 0.19 cm2/week, p = 0.0353). The treatment costs were similar in all groups; however, when the costs were correlated with healing over a 12-week period, cadexomer iodine paste was found to be more cost effective than hydrocolloid dressing or paraffin gauze dressing.\n This study shows that cadexomer iodine paste is an efficient, cost-effective and safe alternative to hydrocolloid dressing and paraffin gauze dressing for the treatment of venous leg ulcers.", "In a crossover study designed to judge the efficacy of the topical polymeric starch iodophore, cadexomer iodine, in accelerating the healing of venous stasis ulcers, 75 patients were prospectively randomly assigned to receive either cadexomer iodine or standard treatment. The control treatment consisted of a standard saline wet-to-dry compressive dressing. The patients improved with either treatment: ulcers healed more than twice as rapidly using cadexomer iodine (n = 38) as with standard therapy (n = 37) (P = .0025). Ulcers treated with cadexomer iodine showed trends toward less pain, exudate, pus, and debris, and a more rapid development of granulation tissue. Twelve patients crossed over from control treatment to the use of cadexomer iodine because of a failure to heal, but no patients switched to control therapy from the use of cadexomer iodine (P = .01). Except for occasional mild local burning in wounds treated with cadexomer iodine, no adverse effects were noted with either regimen.", "Antiseptic scrub and paint can reduce bacterial colonization and postoperative wound infection. Two forms of antiseptics, povidone iodine and chlorhexidine, are commonly used in the operating theater.\n To study the efficacy of the reduction of bacterial colonization and surgical wound infection among these antiseptic.\n Five hundred surgical patients were randomly divided into two groups. Povidone Iodine and Chlorhexidine were used for skin preparation in group 1 and 2 respectively Bacterial colonization and postoperative wound infection were examined after skin preparation. Demographic data was analyzed by student's t test; the culture result and surgical wound infection were analyzed by Mantel-Haenszel method for relative risk and 95% CI.\n There was a significant reduction of bacterial colonization and wound infection after skin preparation in group 2 compared with group 1.\n Colonization of bacterial and postoperative surgical wound infection were significantly reduced in the chlorhexidine group. Chlorhexidine antiseptic should be the first consideration for preoperative skin preparation.", "Several small studies have indicated that the systemic administration of pentoxifylline may accelerate healing of venous leg ulcers. The goal of this study was to further evaluate these findings in a larger scale placebo controlled trial and to explore the effect of the dose of pentoxifylline on healing. The study used a prospective, randomized, double-blind, parallel group placebo controlled design in a multicenter outpatient setting. Patients with one or more venous ulcer were enrolled, with all patients receiving standardized compression bandaging for treatment for their ulcers. Patients were also randomized to receive either pentoxifylline 400 mg, pentoxifylline 800 mg (two 400 mg tablets), or placebo tablets three times a day for up to 24 weeks. The main outcome measure was time to complete healing of all leg ulcers, using life table analysis. The study was completed as planned in 131 patients. Patients receiving 800 mg three times a day of pentoxifylline healed faster than placebo (p = 0.043, Wilcoxon test). The median time to complete healing was 100, 83, and 71 days for placebo, pentoxifylline 400 mg, and pentoxifylline 800 mg three times a day, respectively. Over half of all patients were ulcer free at week 16 (placebo) and at week 12 in both pentoxifylline groups. Whereas the placebo group had only achieved complete healing in half of the cases by week 16, all of the subjects remaining in the group receiving the high dose of pentoxifylline had healed completely. Treatment with pentoxifylline was well tolerated with similar drop-out rates in all three treatment groups. Complete wound closure occurred at least 4 weeks earlier in the majority of patients treated with pentoxifylline by comparison to placebo. A higher dose of pentoxifylline (800 mg three times a day) was more effective than the lower dose. We conclude that pentoxifylline is effective in accelerating healing of leg ulcers.", "Cadexomer iodine (Iodosorb) is a hydrophilic starch powder containing iodine, which is a suitable dressing for granulating wounds such as venous ulcers. A total of 61 outpatients with chronic venous ulcers participated in a randomised optional crossover trial using cadexomer iodine or a standard dressing for their ulcers. The trial lasted for 24 weeks or until the ulcer had healed. Two patients withdrew during the course of the trial. Both treatments were highly effective, but the epithelium of ulcers dressed with cadexomer iodine grew again significantly faster (p less than 0.001). At the midpoint of the trial (12th week) 13 of 30 patients receiving standard treatment were changed to cadexomer iodine, while only three of 29 receiving cadexomer iodine changed to the standard dressing (p less than 0.02). In most cases ulcers were dressed and rebandaged daily by the patients themselves after instruction and supervision. This may be better than having dressings and bandages applied by professionals less regularly.", "There is limited work analyzing the efficacy of different antiseptics in reducing wound contamination by the skin flora during hernia repair and its influence on the incidence of wound infection, which continues to be a major problem in the developing world. This study was designed to test if chlorhexidine-ethanol has superior antimicrobial efficacy compared with povidone-iodine.\n In a prospective randomized trial, the efficacy of chlorhexidine-ethanol and povidone-iodine in the reduction of colony counts of the skin flora and the incidence of surgical site infection was compared.\n Both povidone-iodine and chlorhexidine-ethanol produced significant reduction in the skin bacterial colony counts, from 18.66 x 10(2) to 2.34 x 10(2) colony-forming units with povidone-iodine (59%) and from 12.34 x 10(2) to 0.93 x 10(2) colony-forming units (82%) with chlorhexidine-ethanol. Infection rates with the use of povidone-iodine and chlorhexidine-ethanol groups were not significantly different (9.5 vs. 7.0; p = 0.364). The reduction in colony counts in those who developed infection was only 15.6% compared with 77.1% in those who did not develop infection.\n The antibacterial efficacy of chlorhexidine-ethanol and povidone-iodine is comparable in open hernia repair.\n Copyright © 2010 S. Karger AG, Basel.", "In a prospective, randomized trial, prophylactic use of topical antibiotics in addition to systemic prophylaxis was studied in patients undergoing abdominoperineal amputation of the rectum. All patients received gentamicin 80 mg and metronidazole 500 mg intravenously at induction of anesthesia, followed by the same dose 8 hourly for 48 hours. In accordance with the randomization, half of the patients were additionally given gentamicin 160 mg + metronidazole 400 mg topically into the perineal wound at closure. Perineal wound infection appeared in 19 of the 41 patients who received both systemic and topical prophylaxis, and in 18 of the 38 with only systemic antibiotics. Cell-mediated immunity was preoperatively assessed with a skin test (Multitest) in all but three patients. Impairment of cell-mediated immunity was associated with significantly heightened rate of wound infection, and these patients did not benefit from topical antibiotics.", "A double-blind, placebo-controlled study was carried out in 12 patients suffering from chronic venous insufficiency and persistent leg ulcers to assess the efficacy of pentoxifylline treatment as an adjunct to compression bandaging in the conservative management of venous leg ulcers. Six patients were allocated at random to receive twice-daily infusions of 200 mg pentoxifylline intravenously and 400 mg pentoxifylline orally 3-times daily for 7 days then 400 mg oral doses 3-times daily for a further 60 days. The control group received matching placebo in an identical regimen. Treatment outcome was assessed by changes between the start and end of the study in venous ulcer surface area, and continuous wave Doppler ultrasound was used to monitor ankle/arm systolic pressure ratio, venous pressure at the ankle, valvular competence and possible venous reflux at intervals throughout the study period. The results showed that in the patients treated with pentoxifylline complete ulcer healing took place in 4 out of 6 and there was a significant reduction in mean ulcer surface area. In the control group, complete ulcer healing was recorded in 1 out of 6 patient only and the ulcer area was only moderately reduced in the others. There was no statistically significant differences between the two groups in the variables monitored by Doppler ultrasound but the difference between treatment outcome was significant. Treatment was well-tolerated.", "A randomized, controlled, trial of a topical antibiotic preparation (neomycin, bacitracin, and polymyxin B) was performed in 30 patients with homozygous sickle cell (SS) disease and chronic leg ulceration. Over a period of 8 weeks, the reduction in ulcer size was significantly (P less than 0.05) greater in the treatment group than in the control group. The results suggest that these topical antibiotics may contribute to the therapy of chronic leg ulceration associated with sickle cell disease.", "To determine the impact of two skin preparation methods and two techniques of pelvic irrigation on the incidence of post-cesarean endometritis and wound infection in an indigent patient population.\n A randomized study was performed in 100 cesarean patients. Subjects were assigned to one of four groups, involving either standard skin preparation (povidone-iodine [7.5%] scrub followed by povidone-iodine [10%] solution) or special skin preparation (5-minute scrub with parachlorometaxylenol followed by povidone scrub and solution), and either normal saline or antibiotic (cefazolin sodium, 1 g in 500 mL normal saline) irrigation of the pelvis and subcutaneous tissue at uterine and fascial closure. Four groups of patients were formed: standard skin preparation plus normal saline irrigation, standard preparation plus antibiotic irrigation, special preparation plus normal saline irrigation, and special preparation plus antibiotic irrigation.\n Endometritis occurred significantly more often in the combined groups that did not include antibiotic irrigation than in the combined groups involving antibiotic irrigation (P < .001). In contrast, comparison of skin preparation methods between povidone-iodine alone versus preparation including parachlorometaxylenol indicated no significant difference (P = .22).\n Skin preparation with an antibacterial scrub in addition to standard povidone-iodine scrub and solution does not appear to play as significant a role in the reduction of post-cesarean endometritis or wound infection as does intraoperative pelvic irrigation with antibiotic solution.", "A prospective, randomized, blinded study was performed to determine whether prophylactic antibiotics would reduce the incidence of infection in peripheral vascular surgery and whether the route of antibiotic administration was important. Patients undergoing a vascular procedure with a groin incision were allocated to one of four groups with respect to prophylactic antibiotics. Group I received no antibiotic. Group II had topical cephradine instilled in their incisions prior to closure. Group III received a 24-hour perioperative course of intravenous cephradine, and Group IV received both topical and intravenous cephradine. Groin and abdominal incisional infections were significantly reduced (p < 0.01) among patients who received prophylactic antibiotics by either the topical, systemic, or combined routes of administration. No significant differences were noted among the three antibiotic groups. Profundoplasty, femoral embolectomy, and femoral aneurysm repair were each associated with an increased incidence of infection (p < 0.01). Other risk factors were only important in patients not receiving antibiotics. Either intraoperative topical antibiotics or perioperative systemic antibiotics prevent infection in peripheral vascular surgery, but antibiotic administration by both routes is unnecessary.", "To assess the effect of different dressings on venous ulcer healing.\n A randomised clinical trial.\n Patients were randomised to treatment with one of three dressings: a zinc oxide impregnated bandage, a zinc oxide impregnated stockingette, or an alginate dressing. All patients were treated as outpatients and had compression bandaging with two minimal stretch bandages (Elastocrepe) and a stockingette (Tubigrip) to keep the bandages in place.\n One hundred and thirteen patients (133 ulcerated limbs) with chronic ulceration of the leg due to venous disease alone, and attending Fremantle Hospital Leg Ulcer Clinic, Western Australia were entered into the study. Healing was measured as complete healing of the ulcerated limb or failure of the limb to heal within 9 months.\n There was no significant difference between the three groups in ulcer size, duration, and other parameters compared. Healing was affected significantly by ulcer size and which leg was ulcerated. There was significantly faster healing with the paste bandage.\n The use of a paste bandage significantly improved the healing of chronic venous ulcers when used in combination with compression bandaging, and compared to an alginate dressing and a zinc oxide impregnated stockingette." ]	At present, there is no evidence to support the routine use of systemic antibiotics to promote healing in venous leg ulcers. However, the lack of reliable evidence means that it is not possible to recommend the discontinuation of any of the agents reviewed. In terms of topical preparations, there is some evidence to support the use of cadexomer iodine. Further good quality research is required before definitive conclusions can be made about the effectiveness of systemic antibiotics and topical preparations such as povidone iodine, peroxide-based preparations, ethacridine lactate, mupirocin and chlorhexidine in healing venous leg ulceration. In light of the increasing problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should only be used in cases of clinical infection and not for bacterial colonisation.
CD003483	[ "3045281", "323443", "328108", "884446", "6516811", "363995", "990784", "15210660" ]	[ "Clinical trial of naloxone in birth asphyxia.", "Use of nalotone to to reverse narcotic respiratory depression in the newborn infant.", "Effects of naloxone on pethidine-induced neonatal depression. Part I--Intravenous naloxone.", "Effects of naloxone on pethidine-induced neonatal depression. Part II--Intramuscular naloxone.", "Effects of naloxone on newborn infant behavior after maternal analgesia with pethidine during labor.", "Naloxone reversal of mild neurobehavioral depression in normal newborn infants after routine obstetric analgesia.", "Reversal of narcotic depression in the neonate by nalozone.", "A randomised controlled trial of morphine versus phenobarbitone for neonatal abstinence syndrome." ]	[ "To determine whether endogenous opiates play a role in the pathogenesis of perinatal asphyxia, a blinded clinical trial of naloxone, a competitive opiate receptor blocker, was undertaken in infants with low 1-minute Apgar scores. Of 85 infants with 1-minute Apgar score 0 to 3, 44 received an injection of naloxone (approximately 0.4 mg/kg) and 41 received saline solution. In 108 infants with 1-minute Apgar score 4 to 6, 54 received naloxone and 54 saline solution. In neither group was there a significant effect of naloxone on respiratory frequency or heart rate up to 30 minutes after injection, nor at 24 hours of age. In both groups active muscle tone of upper and lower limbs was increased by naloxone, a response that may not be beneficial in the face of inadequate oxygen delivery to vital organs. We conclude that naloxone at this dose had no readily apparent benefit in the resuscitation of the asphyxiated newborn infant.", "Twenty neonates whose mothers had received meperidine (1.0 to 1.5 mg/kg) intravenously within three hours of delivery were studied to determine the effectiveness of naloxone in reversing neonatal respiratory depression. The following measurements were carried out within 20 to 30 minutes after delivery: minute ventilation, end tidal CO2, and ventilatory response to CO2. These determinations were repeated after administration of either placebo or naloxone, 0.01 mg/kg intramuscularly. Minute ventilation and PAco were within a normal range before medication in both groups, but the slope of the CO2 response curve was decreased, indicating mild-to-moderate respiratory depression. After administration of placebo the test results did not change significantly. After administration of naloxone, VE increased significantly (P less than 0.05) and the slope of the CO2 response curve doubled (P less than 0.001). Naloxone effectively reverses narcotic depression of the respiratory center in the newborn infant.", "Infants whose mothers had had pethidine during labour were given either naloxone 40 microgram or isotonic saline administered intravenously double-blind within one minute of birth. Peak alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour, and habituation to a specific sound stimulus were measured regularly up to 48 hours after birth. Alveolar carbon dioxide tension was significantly lower and alveolar ventilation significantly higher half an hour after birth in the naloxone-treated group than in the saline-treated group, but these differences between the groups were not significant at any other time, and there were no significant differences in sucking frequency or pressure, milk consumption, or habituation to the auditory stimulus.", "Thirty full-term infants whose mothers had had pethidine during labour were given either naloxone 200 microgram or normal saline intramuscularly. The drugs were chosen blindly and administered within one minute of birth. Naloxone produced a significant reduction in mean alveolar carbon dioxide tension and an increase in carbon dioxide excretion and mean alveolar ventilation at all times up to 48 hours after birth. The mean rate of habituation to a repeated auditory stimulus, the mean sucking frequency, the sucking pressure, and the mean consumption of milk were all significantly higher in the naloxone-treated group than in the placebo-treated group up to 48 hours after birth. Intramuscular naxolone therefore seemed to reverse the undesirable effects of pethidine.", "Infants born to mothers receiving 100 mg of pethidine during labor, were randomly given either 100 micrograms of naloxone (n = 14) or 0.25 ml 0.9% NaCl (n = 13) one hour post partum. Infant behavior was assessed with the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) and the Broussard Neonatal Perception Inventory (NPI). No differences in cluster scores on the BNBAS were found between the two groups. Both groups improved scores over time in 4 out of 7 clusters. On the NPI, mothers assessed naloxone infants as having less optimal behavior than did the control mothers. The results of this study on the effects of naloxone on infant behavior and maternal perception of newborn behavior do not warrant administration of naloxone after maternal analgesia with pethidine in the absence of clinical evidence of respiratory depression in the newborn.", "To investigate the presence of subtle narcotic depression following maternal narcotic analgesia, we have evaluated the effects of naloxone versus placebo in a double-blind parallel group study in 43 normal term newborn infants whose mothers had received routine narcotic analgesia within six hours prior to delivery. Infants were given either an intramuscular injection of 20 microgram/kg naloxone or 0.20 ml/kg placebo after determination of the one-minute Apgar score, and the following measurements were compared: Apgar scores at one and five minutes, capillary blood gas values at one, 60, 120, and 240 minutes, and neurobehavioral assessments at one, 4, and 24 hours. No adverse effects from naloxone were observed. Neither Apgar scores nor capillary blood gas determinations differed significantly between the two groups. Response to sound was significantly higher in the naloxone group at 24 hours. The alertness score was significantly higher for the naloxone group at one and four hours; the general assessment score for the naloxone group was significantly higher at four and 24 hours. Average scores of naloxone and placebo groups were also different at four and 24 hours of age. These data demonstrate that maternal narcotic analgesia may produce subtle changes in alertness and general behavior not reflected by Apgar scores or respiratory status, potentially reversible by administration of naloxone shortly following delivery.", "Naloxone 40 mug was administered intravenously one minute after birth to 20 out of 44 neonates whose mother had been given pethidine in labour. These neonates were compared with 20 others whose mothers had had only lumbar epidural block. Alveolar PCO2, alveolar ventilation, and ventilatory rate were measured 10 and 30 minutes after birth. The untreated neonates of mothers who had had pethidine showed significant ventilatory depression compared with infants in the epidural and naloxone-treated groups. The naloxone-treated neonates were comparable with the epidural group, although the effects of naloxone were diminishing at 30 minutes. Naloxone is an effective narcotic antagonist which should be considered to be the drug of choice for treating narcotic depression in the neonate.", "The incidence of neonatal abstinence syndrome (NAS) has increased 10-fold over the last decade in Glasgow. In the Princess Royal Maternity Hospital, it now accounts for 17% of special care baby unit (SCBU) admissions.\n To compare opiate replacement therapy (morphine sulphate) with the present standard treatment (phenobarbitone) for management of NAS. The primary study end point was duration of pharmaceutical treatment. Secondary end points were the requirement for additional drugs and the requirement for SCBU admission.\n Double blind, randomised controlled clinical trial.\n Differential diagnoses were excluded, and two consecutive Lipsitz scores > 4 defined NAS requiring treatment. Infants were randomised to receive morphine sulphate or phenobarbitone. Treatments were identical in appearance, odour, and volume. Increments, decrements, and discontinuation of treatments were protocol driven.\n Seventy five infants participated. All mothers received opiate replacement therapy (methadone) during pregnancy and most used other drugs (n = 62, 83%). No significant difference in maternal drug use patterns was observed between treatment groups. Median treatment duration was four days shorter with opiate replacement (8 v 12 days, Mann-Whitney U test, p = 0.02). Phenobarbitone treated infants tended to require second line treatment (47% v 35%, chi(2) test, p = 0.11) and SCBU admission (62% v 30%, chi(2) test, p = 0.04) more often.\n Opiate replacement therapy appears to be superior for management of symptomatic NAS when maternal opiate use is prevalent. The shorter treatment duration and lower requirement for higher intensity nursing may have significant cost implications. Tailoring NAS treatment to local maternal drug use may result in similar benefits." ]	The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opiate. Given concerns about the safety of naloxone in this context it may be appropriate to limit its use to randomised controlled trials that aim resolve these uncertainties.
CD008514	[ "16087029" ]	[ "Dexamethasone inner ear perfusion by intratympanic injection in unilateral Ménière's disease: a two-year prospective, placebo-controlled, double-blind, randomized trial." ]	[ "To investigate the efficacy of dexamethasone inner ear perfusion by intratympanic injection in hearing loss, tinnitus, aural fullness, and vertigo in the treatment of unilateral Ménière's disease and compare it with the control group.\n A prospective, randomized, double-blind study with 2-year follow-up comparing changes secondary to dexamethasone inner ear perfusion versus placebo consisting of saline solution.\n Twenty-two patients having definite Ménière's disease as outlined by the 1995 American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium. All the patients were older than 18 years of age and were not receiving any other form of treatment with steroids for their Ménière's disease.\n Five consecutive daily intratympanic injections of dexamethasone or placebo to the involved ear.\n In the dexamethasone group at 2-year follow-up, complete control of vertigo (class A) was achieved in 9 of 11 patients (82%) and substantial control of vertigo (class B) in the remaining 2 patients (18%.) In the control group only 7 of 11 patients (64%) finished the 2-year follow-up because in the other 4 patients (36%) we had to give another treatment for the continuing vertigo and thus they were classified as failure (class F.) From the 7 patients who have finished the follow-up of 2 years in the control group, 4 patients (57%) achieved class A, 2 patients (29%) achieved class C, and 1 patient (14%) class F.\n Dexamethasone (4 mg/mL) inner ear perfusion in a group of patients with unilateral Ménière's disease (Shea's stage III) showed 82% of complete control of vertigo over placebo (57%). There was also a subjective improvement in tinnitus (48%), hearing loss (35%), and aural fullness (48%) in the dexamethasone group compared with 20%, 10%, and 20% respectively in the control group." ]	The results of a single trial provide limited evidence to support the effectiveness of intratympanic steroids in patients with Ménière's disease. This trial demonstrated a statistically and clinically significant improvement of the frequency and severity of vertigo measured 24 months after the treatment was administered. It is important to note that there were a few aspects of the study which we were unable to clarify with the study authors.
CD008132	[ "15303996", "8816034" ]	[ "Weekly iron supplements given by teachers sustain the haemoglobin concentration of schoolchildren in the Philippines.", "Does iron therapy benefit children with severe malaria-associated anaemia? A clinical trial with 12 weeks supplementation of oral iron in young children from the Turiani Division, Tanzania." ]	[ "To examine the effectiveness of weekly iron supplements given for 10 weeks by teachers to children in rural schools in the Philippines.\n Forty-nine rural primary schools took part in the study and were randomly assigned to two groups: children in 25 schools received a weekly tablet providing 108 mg iron while children in 24 schools acted as controls. All children were dewormed before the start of the iron supplementation. The haemoglobin concentration of a systematic sample of one in three children in two classes in each school was estimated before and 5-17 weeks after the end of the iron supplementation.\n A total of 1510 children aged 7-12 years were studied at both surveys. The mean haemoglobin concentration of children in the intervention group did not change significantly; in the untreated group it fell by 3.8 g/l and the prevalence of anaemia rose from 14.3% to 25.6%. The difference between study groups was significantly larger amongst the younger children (7-8 years), and was observed in both anaemic and non-anaemic children.\n Even where anaemia is only a mild public health problem, weekly iron supplements given by teachers may prevent a fall in the haemoglobin concentration, and can benefit both anaemic and non-anaemic children.", "Oral iron supplementation is often routinely given to children with malaria-associated anaemia, but its contribution to recovery is controversial. A randomized clinical trial, evaluating such routine, was carried out among 100 children, who had a haemoglobin of < or = 5 g/dl and a positive blood smear for malaria parasites. All children received malaria therapy (chloroquin + fansidar) and were randomly allocated to two groups, one receiving additional oral iron treatment, the other being the control. In the 12-week follow-up period the haemoglobin level and malaria indices were measured at 2, 4, 8, and 12 weeks. There was a 100 per cent compliance during the follow-up period. In each group 20 children (40 per cent) required a blood transfusion. In the remaining 60 children, after 2 weeks the haemoglobin had risen 3.7 g/dl in the ferrous-supplemented group compared to 3.5 g/dl in the non-ferrous group. Thereafter, the increase in haemoglobin in both groups was steady. At follow-up measurements, the groups did not differ for haemoglobin levels. The mean haemoglobin at 12 weeks was 9.2 and 9.0 g/dl, respectively. It was concluded that iron supplementation did not have any effect on the rate of parasitaemia and on parasite density during the 12 weeks. However, the iron-supplemented group had a significantly increased morbidity from other causes than malaria. It appears that iron does not have an effect on the recovery of haemoglobin level in children with malaria-associated anaemia. This study provides no evidence supporting routine iron supplementation to these children." ]	Iron supplementation (at 5 mg/kg/day of elemental iron for 16 weeks) appears to be useful in reducing the frequency and severity of breath-holding attacks. Supplementation is of particular benefit in children with iron deficiency anaemia, responses correlating with the improvements in haemoglobin values. Iron may still be of assistance in children who are not anaemic or who have low, normal haemoglobin levels. Further high-quality randomised control trials of iron supplementation to treat breath-holding attacks in children are required.
CD008603	[ "19819004", "7967990", "9014909", "10823767", "18523643", "9815355", "3392421", "19761838", "10738097", "5302329", "12075764", "17055622", "7668039", "10569747", "4603994", "5301381", "5302328", "8501336", "3540139", "798636", "15982790", "11884967", "9388905", "10674661", "5294176", "9841829", "8605522", "365388", "11895960", "8560536", "3042876", "16996172", "19720365", "7028299", "1355798", "8359923", "9207368" ]	[ "Efficacy and safety of a modified killed-whole-cell oral cholera vaccine in India: an interim analysis of a cluster-randomised, double-blind, placebo-controlled trial.", "Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits.", "Field trial of a locally produced, killed, oral cholera vaccine in Vietnam.", "Two-year study of the protective efficacy of the oral whole cell plus recombinant B subunit cholera vaccine in Peru.", "A randomized, placebo-controlled trial of the bivalent killed, whole-cell, oral cholera vaccine in adults and children in a cholera endemic area in Kolkata, India.", "Safety, Immunogenicity, and Protective Efficacy of the Whole-Cell/Recombinant B Subunit (WC/rBS) Oral Cholera Vaccine Against Travelers' Diarrhea.", "Field trial of oral cholera vaccines in Bangladesh: results of one year of follow-up.", "Immune responses following one and two doses of the reformulated, bivalent, killed, whole-cell, oral cholera vaccine among adults and children in Kolkata, India: a randomized, placebo-controlled trial.", "Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area.", "Cholera vaccine field trials in east Pakistan. 2. Effectiveness in the field.", "Introductory evaluation of an oral, killed whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Egyptian infants.", "Safety and immunogenicity of a reformulated Vietnamese bivalent killed, whole-cell, oral cholera vaccine in adults.", "Community-based assessment of safety and immunogenicity of the whole cell plus recombinant B subunit (WC/rBS) oral cholera vaccine in Peru.", "Randomized, double-blind, placebo-controlled, multicentered trial of the efficacy of a single dose of live oral cholera vaccine CVD 103-HgR in preventing cholera following challenge with Vibrio cholerae O1 El tor inaba three months after vaccination.", "A controlled field trial on the effectiveness of the intradermal and subcutaneous administration of cholera vaccine in the Philippines.", "Controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in Calcutta.", "Cholera vaccine field trials in east Pakistan. 1. Reaction and antigenicity studies.", "Safety and immunogenicity of the oral, whole cell/recombinant B subunit cholera vaccine in North American volunteers.", "B subunit-whole cell and whole cell-only oral vaccines against cholera: studies on reactogenicity and immunogenicity.", "Comparative study of reactions and serological response to cholera vaccines in a controlled field trial conducted in the USSR.", "Analysis of efficacy of CVD 103-HgR live oral cholera vaccine against all-cause travellers' diarrhoea in a randomised, double-blind, placebo-controlled study.", "Investigations into the safety and immunogenicity of a killed oral cholera vaccine developed in Viet Nam.", "[Community trial for safety and immunogenicity of oral-administered lyophilized rBS-WC cholera vaccine].", "Safety, immunogenicity, and lot stability of the whole cell/recombinant B subunit (WC/rCTB) cholera vaccine in Peruvian adults and children.", "A controlled field trial of the effectiveness of cholera and cholera El Tor vaccines in the Philippines. Preliminary report; Philippines Cholera Committee.", "Oral, inactivated, whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine: results of the initial evaluation in children. PRIDE Study Group.", "Safety and immunogenicity of oral killed whole cell recombinant B subunit cholera vaccine in Barranquilla, Colombia.", "A controlled field trial of plain and aluminium hydroxide-adsorbed cholera vaccines in Surabaya, Indonesia, during 1973--75.", "Randomized, controlled human challenge study of the safety, immunogenicity, and protective efficacy of a single dose of Peru-15, a live attenuated oral cholera vaccine.", "Immunological response to Vibrio cholerae O1 infection and an oral cholera vaccine among Peruvians.", "Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial.", "Peru-15, a live attenuated oral cholera vaccine, is safe and immunogenic in Bangladeshi toddlers and infants.", "Randomized, double-blind, placebo-controlled trial to evaluate the safety and immunogenicity of live oral cholera vaccine 638 in Cuban adults.", "A controlled field trial of an aluminum phosphate-adsorbed cholera vaccine in Calcutta.", "Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5-9-year-old Indonesian children.", "Safety, immunogenicity, and excretion pattern of single-dose live oral cholera vaccine CVD 103-HgR in Peruvian adults of high and low socioeconomic levels.", "Evaluation of Peru-15, a new live oral vaccine for cholera, in volunteers." ]	[ "Oral cholera vaccines consisting of killed whole cells have been available for many years, but they have not been used extensively in populations with endemic disease. An inexpensive, locally produced oral killed-whole-cell vaccine has been used in high-risk areas in Vietnam. To expand the use of this vaccine, it was modified to comply with WHO standards. We assessed the efficacy and safety of this modified vaccine in a population with endemic cholera.\n In this double-blind trial, 107 774 non-pregnant residents of Kolkata, India, aged 1 year or older, were cluster-randomised by dwelling to receive two doses of either modified killed-whole-cell cholera vaccine (n=52 212; 1966 clusters) or heat-killed Escherichia coli K12 placebo (n=55 562; 1967 clusters), both delivered orally. Randomisation was done by computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for the patient to seek treatment in a health-care facility. We undertook an interim, per-protocol analysis at 2 years of follow-up that included individuals who received two completely ingested doses of vaccine or placebo. We assessed first episodes of cholera that occurred between 14 days and 730 days after receipt of the second dose. This study is registered with ClinicalTrials.gov, number NCT00289224.\n 31 932 participants assigned to vaccine (1721 clusters) and 34 968 assigned to placebo (1757 clusters) received two doses of study treatment. There were 20 episodes of cholera in the vaccine group and 68 episodes in the placebo group (protective efficacy 67%; one-tailed 99% CI, lower bound 35%, p<0.0001). The vaccine protected individuals in age-groups 1.0-4.9 years, 5.0-14.9 years, and 15 years and older, and protective efficacy did not differ significantly between age-groups (p=0.28). We recorded no vaccine-related serious adverse events.\n This modified killed-whole-cell oral vaccine, compliant with WHO standards, is safe, provides protection against clinically significant cholera in an endemic setting, and can be used in children aged 1.0-4.9 years, who are at highest risk of developing cholera in endemic settings.\n Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, Governments of South Korea, Sweden, and Kuwait.", "The cholera epidemic in South America has reinforced the need for safe and effective oral vaccines. In a randomised, double-blind, placebo-controlled efficacy trial among 1563 Peruvian military recruits we have investigated the protective efficacy of an oral inactivated whole-cell/recombinant-B-subunit (WC/rBS) cholera vaccine. Participants were given two oral doses of cholera vaccine or Escherichia coli K12 placebo, with an interval of 7-14 days. 1426 (91%) subjects received the two prescribed doses and were followed up for a mean of 18 weeks (median 21 weeks). After vaccination, Vibrio cholerae O1 El Tor Ogawa was isolated from 17 subjects with diarrhoea. 16 of the cholera cases occurred 2 weeks or longer after the second dose of vaccine (14 placebo recipients, 2 vaccinees). We also detected 14 symptomless infections (11 [7 placebo recipients, 4 vaccinees]) 2 weeks or longer after the second dose. The vaccine had significant protective efficacy against cholera (86% [95% CI 37-97], p < 0.01) but not against symptomless infection (42% [-96 to 85]). All cholera cases were in people of blood group O, who made up 76% of the study population (p < 0.01). Two doses of WC/rBS vaccine, given 1 to 2 weeks apart, provide rapid, short-term protection against symptomatic cholera in adult South Americans, who are predominantly of blood group O. Long-term efficacy studies in Peruvian adults and children are under way.", "Several studies have shown that orally administered killed cholera vaccines are safe and protective in populations at risk of cholera in developing countries. However, these vaccines have not been adopted for use in developing countries because of their expense and limited efficacy in young children. We have tested an inexpensive, killed whole-cell cholera vaccine developed and produced in Vietnam.\n The efficacy of the vaccine was assessed in a large-scale, open field trial in people at least 1 year old residing in 22,653 households in the central coastal city of Hue. Alternate households were assigned vaccine (67,395 people; two doses per person) or no vaccine (67,058 people). Surveillance for cholera was conducted in all Ministry of Health facilities serving this population. Analysis was by intention to treat.\n During an outbreak of El Tor cholera 8-10 months after vaccination, 37 cases of cholera requiring inpatient care occurred among age-eligible people allocated to the vaccine group, and 92 cases among age-eligible people allocated to the no-vaccine group (protective impact 60% [95% CI 40-73]). Among the 51,975 people who received the complete two-dose vaccine regimen, the protective efficacy was 66% (46-79): in this subset, the protective efficacy was similar for children aged 1-5 years (68%) and for older people (66%).\n These findings suggest that oral killed whole-cell vaccines can confer substantial protection against El Tor cholera in young children, who are at highest risk of cholera in endemic settings. An inexpensive, locally produced, and effective oral cholera vaccine may be within reach of the limited health-care budgets of poor countries with endemic cholera, if our findings can be replicated in a randomised double-blind trial.", "The protective efficacy of an oral inactivated whole cell Vibrio cholerae plus recombinant B subunit cholera vaccine was determined against El Tor cholera among Peruvian children and adults (2-65 years old) in a randomized, double-blind manner. Study subjects received 2 doses of vaccine or placebo 2 weeks apart, followed by a booster dose 10 months later. Surveillance for cholera was performed actively, with 2 visits per week to each household, and passively, at a local hospital. Stool samples were collected during diarrhea episodes and were cultured for V. cholerae. A total of 17,799 persons received 2 doses of vaccine or placebo, and 14,997 of these persons received the booster dose. After 2 doses (first surveillance period), V. cholerae biotype O1 was isolated from 17 vaccinees and 16 placebo recipients, demonstrating vaccine efficacy (VE) of -4%. After 3 doses (second surveillance period), V. cholerae O1 was isolated from 13 vaccinees and 32 placebo recipients, demonstrating VE of 61% (95% confidence interval ¿CI, 28%-79%). In the second surveillance period, the VE for illness requiring hospitalization was 82% (95% CI, 27%-96%). VE was also higher for persons >15 years old (VE, 72%; 95% CI, 28%-89%).", "An effective vaccine against cholera has been used for public health purposes in Vietnam since the 1990s. This vaccine was reformulated to meet WHO requirements. We assessed the safety and immunogenicity of the reformulated bivalent (Vibrio cholerae 01 and 0139) killed whole cell oral vaccine in a cholera endemic area in Kolkata, India.\n Double-blind, randomized, placebo controlled trial.\n The trial was conducted in the clinical trial ward of the Infectious Diseases Hospital in Kolkata, India.\n The participants were 101 healthy adults (males and non-pregnant females) aged 18-40 years and 100 healthy children (males and non-pregnant females) aged 1-17 years.\n Participants were randomized to receive either the bivalent killed whole cell oral cholera vaccine or placebo (killed oral Escherichia coli K12).\n For safety: proportion of subjects with adverse events during the duration of study participation. For immunogenicity: Proportion of subjects who had a > or = 4-fold rise in serum vibriocidal antibody titers 14 days after the second dose of vaccine or placebo.\n Adverse reactions were observed with similar frequency among vaccine and placebo recipients in both age groups. Among adults 4% of vaccine and 8% of placebo recipients and among children 4% of vaccine and 2% of placebo recipients had at least one adverse event within 28 days of the first dose of the vaccine. Following immunization, 53% of adult and 80% of children vaccinees showed a > or = 4 fold rise in serum V. cholerae O1 vibriocidal antibody titers. A less pronounced response to V. cholerae O139 vibriocidal antibody titers post-immunization was noted among vaccinees.\n We found the vaccine to be safe and immunogenic in a cholera-endemic area in India.\n ClinicalTrials.gov NCT00119197.", "Background: A prospective, randomized, double-blind, placebo-controlled trial of WC/rBS oral cholera vaccine was conducted in 502 U.S. college students attending summer educational programs in Mexico. Methods: Two doses of vaccine (or placebo) were administered 10 days apart immediately after arrival in Mexico. Results: The vaccine was free of significant adverse side effects. Anticholera toxin seroconversion was demonstrated in 86.7% of vaccinees compared to 8.2% of controls (p <.001). Postvaccination titers varied according to disease status (travelers' diarrhea) and enteropathogen isolated when disease developed. Protective efficacy (PE) against enterotoxigenic Escherichia coli (ETEC) diarrhea was 50% (95% CI, 14-71%), beginning 7 days after the second dose of WC/rBS. However, 74% of ETEC cases occurred within 7 days of the second dose, when no efficacy was demonstrated. Conclusions: Vaccines employed to prevent travelers' diarrhea will likely need to be administered before arrival in a developing country to be predictably beneficial. An unexpected finding was that infection with LT-ETEC after primary oral cholera immunization appears to augment the antitoxin response to WC/rBS vaccine. (J Travel Med 2:22-27, 1995)", "We assessed the protective efficacy (PE) of three doses of B subunit-killed whole cell (BS-WC) and killed whole cell-only (WC) oral cholera vaccines in a randomized, double-blind trial among 62,285 children and women residing in rural Bangladesh. After one complete year of surveillance, 110 cases of cholera were detected in the placebo group, 52 in the WC group (PE, 53%; P less than .0001), and 41 in the BS-WC group (PE, 62%; P less than .0001). Protection was greater for BS-WC recipients than for WC recipients only during the initial eight months of observation. Both vaccines conferred equivalent protection against cholera associated with life-threatening dehydration and against less severe cholera. High-grade, sustained protection was observed in persons vaccinated when older than five years; in younger persons protection was transient. We conclude that BS-WC and WC vaccines confer significant protection against cholera, particularly in persons vaccinated when older than five years.", "Immune responses after one and two doses of the reformulated killed oral cholera vaccine were measured in a double-blind, randomized, placebo-controlled trial of 77 adults aged 18-40 years and 77 children aged 1-17 years residing in Kolkata, India. 65% of adults and 87% of children and 46% of adults and 82% of children exhibited a > or =4-fold rise in serum Vibrio cholerae O1 vibriocidal antibody titers from baseline following dose 1 and 2, respectively. Responses to V. cholerae O139 were less pronounced but followed a similar pattern. We demonstrate that in a cholera-endemic area, the vaccine elicited vibriocidal responses after a single-dose of the vaccine.", "A randomized, double-blind, placebo-controlled efficacy trial of one dose of CVD 103-HgR live oral cholera vaccine was performed in Indonesia from 1993 to 1997. 67,508 persons aged 2-41 years ingested vaccine or placebo and were followed for four years, detecting cholera cases using hospital-based surveillance. A nested reactogenicity study (538 vaccinees, 535 controls) revealed no vaccine-attributable side effects. A nested immunogenicity study (N=657) showed vibriocidal seroresponses in 64-70% of vaccinees vs 1-2% of controls. Cholera incidence was lower than expected. 103 cases of Vibrio cholerae O1 El Tor diarrhea were detected, 93 evaluable for vaccine efficacy (43 vaccine, 50 placebo; efficacy=14%). A suggestion of protection was observed among persons with blood group O [P=0.12]. Only seven cases occurred within six months of vaccination, precluding assessment of short-term efficacy. In Jakarta, single-dose CVD 103-HgR did not confer long-term protection. Short-term protection from a single-dose and long-term protection from two doses have yet to be studied.", "A cholera-vaccine field trial in a rural area of East Pakistan where cholera is highly endemic has indicated that a high-potency whole-cell vaccine can provide significant protection against disease due to Vibrio cholerae for at least 18 months. This vaccine gave more than 70% protection during the first cholera season after vaccination. In the second cholera season after the administration of a single dose of vaccine, protection fell in those under 5 years of age, while continuing at significantly effective levels in older persons.Purified Ogawa antigen (lipopolysaccharide) afforded significant protection to adults against disease due to the heterologous Inaba serotype, but only protected children against milder diarrhoeas.The effect of cholera vaccine on the incidence of infections among family contacts of cholera patients was variable. Vaccine had no effect on the proportion of asymptomatic infections.Diarrhoeal disease associated with V. cholerae occurred predominantly among children, while protection was most marked among adults. Adverse reactions were practically restricted to the adults, suggesting that children will not only tolerate a larger dose, but actually require a larger dose for maximum protection against infection.", "We conducted the first trial to assess the safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli plus cholera toxin B-subunit vaccine in children <2 years old.\n Three doses of vaccine or killed E. coli K-12 control were given at 2-week intervals to 64 Egyptian infants, 6 to 18 months old, in a randomized, double blind manner. Adverse events were monitored for 3 days after each dose. Blood was collected before immunization and 7 to 10 days after each dose to assess vaccine-specific serologic responses.\n There was no statistically significant intergroup difference in the percentage of subjects reporting the primary safety endpoint (diarrhea or vomiting) after the first (31%, vaccine; 30%, control) or third (14%, vaccine; 18%, control) dose, whereas there was a trend toward greater reporting in the vaccine group after Dose 2 (36%, vaccine; 18%, control; P = 0.052). The percentage of children showing IgA seroconversion after any dose was higher in the vaccine than the control group for recombinant cholera toxin B-subunit (97% vs. 46%), colonization factor antigen I (61% vs. 18%) and coli surface antigen 4 (39% vs. 4%) (P < 0.001 for each comparison). IgG seroconversion rates in the vaccine and control groups were 97 and 21% to recombinant cholera toxin B-subunit (P < 0.001), 64 and 29% for colonization factor antigen I (P < 0.01), 53 and 21% for coli surface antigen 2 (P < 0.05) and 58 and 4% for coli surface antigen 4 (P < 0.001), respectively. The third vaccine dose was followed by augmented IgG antitoxin titers.\n The oral enterotoxigenic E. coli vaccine was safe and immunogenic in this setting in Egyptian infants.", "Vietnam currently produces an orally administered, bivalent (O1 and O139) killed whole-cell vaccine and is the only country in the world with endemic cholera to use an oral cholera vaccine in public health practice. In order to allow international use, the vaccine had to be reformulated to meet World Health Organization (WHO) requirements. We performed a randomized, placebo controlled, safety and immunogenicity studies of this reformulated vaccine among Vietnamese adults. One hundred and forty-four subjects received the two-dose regimen and 143 had two blood samples obtained for analysis. We found that this reformulated oral killed whole-cell cholera vaccine was safe, well tolerated and highly immunogenic.", "Every year since its introduction in 1991, there have been epidemics of cholera in Lima, Peru. Vaccination is one approach to the control of cholera. A pilot study was conducted to assess the safety and immunogenicity of a whole cell plus recombinant B subunit (WC/rBS) cholrea vaccine in Lima, Peru. Five hundred and forty-one volunteers aged 2-65 years received two doses two weeks apart of WC/rBS vaccine or Escherichia coli K12 placebo administered in bicarbonate buffered water. Symptoms were monitored on all subjects and blood was collected from 102 persons before the first dose and two weeks after the second dose. Mild post-vaccination gastrointestinal symptoms were reported with equal frequency for both the vaccine and placebo recipients. Among 51 vaccines, 49% had a twofold or greater increase in serum vibriocidal titers (GMT = 78; range < 1:10 to 1:5120); and 92% and 82% developed a twofold or greater serum anti-cholera toxin IgG and IgA response, respectively. Persons with elevated prevaccination vibriocidal titers had a decreased response to the WC/rBS. Age and blood group did not affect the immune response. The WC/rBS vaccine was safe and immunogenic in a group of native Peruvians.", "CVD 103-HgR is a live oral cholera vaccine strain constructed by deleting 94% of the gene for the enzymatically active A subunit of cholera toxin from classical Inaba Vibrio cholerae O1 569B; the strain also contains a mercury resistance gene as an identifying marker. This vaccine was well tolerated and immunogenic in double-blind, controlled studies and was protective in open-label studies of volunteers challenged with V. cholerae O1. A randomized, double-blind, placebo-controlled, multicenter study of vaccine efficacy was designed to test longer-term protection of CVD 103-HgR against moderate and severe El Tor cholera in U.S. volunteers. A total of 85 volunteers (50 at the University of Maryland and 35 at Children's Hospital Medical Center/University of Cincinnati) were recruited for vaccination and challenge with wild-type V. cholerae El Tor Inaba. Volunteers were randomized in a double-blind manner to receive, with buffer, a single oral dose of either CVD 103-HgR (2 x 10(8) to 8 x 10(8) CFU) or placebo (killed E. coli K-12). About 3 months after immunization, 51 of these volunteers were orally challenged with 10(5) CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Ninety-one percent of the vaccinees had a >/=4-fold rise in serum vibriocidal antibodies after vaccination. After challenge, 9 (39%) of the 23 placebo recipients and 1 (4%) of the 28 vaccinees had moderate or severe diarrhea (>/=3-liter diarrheal stool) (P < 0.01; protective efficacy, 91%). A total of 21 (91%) of 23 placebo recipients and 5 (18%) of 28 vaccinees had any diarrhea (P < 0.001; protective efficacy, 80%). Peak stool V. cholerae excretion among placebo recipients was 1.1 x 10(7) CFU/g and among vaccinees was 4.9 x 10(2) CFU/g (P < 0.001). This vaccine could therefore be a safe and effective tool to prevent cholera in travelers.", "In view of the encouraging laboratory findings on the efficacy of intradermal administration of cholera vaccination in small doses, a controlled field trial was undertaken in the Philippines to evaluate the efficacy of the two routes for cholera vaccination. The trial has shown that these routes are effective, both giving a significant degree of protection against cholera. However, the vaccine afforded longer-lasting protection when administered subcutaneously (6 months) than when given intradermally (4 months), and was significantly more effective in children in the 1-5-year age group in this endemic area.", "To assess the effectiveness of cholera vaccines, 2 controlled field trials were made in Calcutta-an endemic area-during 1964 and 1965. Three Indian vaccines of which 1 was grown on casein hydrolysate and 2 on agar, a freeze-dried vaccine from the Walter Reed Army Institute of Research (WRAIR), Washington, D.C., and an El Tor vaccine from the Philippines were used, with typhoid-paratyphoid (TAB) vaccine as a control. The 210 112 volunteers were vaccinated subcutaneously with a single dose of one of the vaccines.In the 1964 trial, the number of bacteriologically confirmed cases was not enough to show statistically significant differences in incidence between the 5 vaccine groups and the control group. However, the WRAIR freeze-dried vaccine protected about 40% of the vaccinees for 6 months after vaccination, although the efficacy was higher (57%) during the first 3 months than during the subsequent 3 months (28%). Agar-grown vaccine, produced by the Central Research Institute, Kasauli, was 37% efficacious.In the 1965 trial, owing to the small number of cases in the study area, the Kasauli vaccine was the only one to show statistically significant protection (40%).", "Double-blind controlled cholera-vaccine trials were carried out in rural East Pakistan in 1963 and 1964. Pretrial studies indicated that a whole-cell cholera vaccine of high mouse protective potency, at a dose of 0.5 ml, produced an antibody response and reaction pattern consistent with use in such trials. A purified Ogawa antigen, given at a dose of 100 mug, elicited no adverse reactions and evoked both agglutinating and vibriocidal antibodies against both Inaba and Ogawa test suspensions.In the field, adverse reactions to the cholera vaccines occurred primarily among adults and were observed with both the whole-cell preparation and the purified Ogawa antigen. At the dose used in the field trials (0.4 ml), the reactions elicited by the whole-cell vaccine were acceptable to the population and no more marked than those following the locally prepared typhoid-paratyphoid vaccine. Delayed reactions to the whole-cell cholera vaccine were observed beginning 4 to 7 days after the vaccine was administered; the bulk of them (60%) did not interfere with work at any time; all resolved promptly; and none developed fluctuation or was associated with abscess formation.", "A newly formulated, oral, inactivated whole cell plus recombinant B subunit (WC/rBS) cholera vaccine was evaluated in US military personnel. In the first study, 74 subjects were given two doses 14 days apart. In the second study, 186 subjects were randomized into four groups; two groups received vaccine with either full (4 g) or half (2 g) strength bicarbonate buffer, and two groups received either full or half strength buffer without vaccine. Mild gastrointestinal symptoms were associated with full buffer (P = .02) but not with the vaccine. In the first study, 36% of all subjects and 55% with low prevaccination titers (< 1:40) had a > or = 2-fold rise in vibriocidal antibody level; > 80% of subjects developed a 4-fold rise in anti-cholera toxin (CT) titers. Post-vaccination IgA and IgG anti-CT titers were approximately 1.5-fold higher among persons receiving full strength buffer (P = .05). The WC/rBS vaccine is safe and immunogenic in North Americans, although some mild gastrointestinal symptoms occur with the high concentration of buffer necessary to protect the B subunit from gastric acid denaturation. Prior immunity to cholera conferred by parenteral vaccine decreased vibriocidal antibody response.", "We conducted a randomized trial among persons in rural Bangladesh to evaluate the side effects and immunogenicity of orally administered B subunit-killed whole cell (BS-WC) and killed whole cell-only (WC) cholera vaccines and a killed Escherichia coli strain K12 placebo proposed for field testing. Three doses of BS-WC, WC, E. coli, or a control agent were given with antacid to 1,257 women (aged greater than 15 years) and children (aged to to 15 years). The four groups exhibited no statistically significant differences in occurrence of symptoms after each dose, and rises in titers of vibriocidal (VC) antibodies to Inaba and Ogawa were twofold higher for vaccinees than for controls (P less than .001). Half of the persons with fourfold or greater VC responses to WC responded after the first dose; many additional patients, particularly young children, responded after subsequent doses. In contrast, 89% of persons who responded to BS-WC with twofold or greater rises in titer of IgG antibodies to cholera toxin did so after the first dose. After the third dose, vaccinees exhibited a fivefold higher rise in titer than did controls (P less than .001); a dose-to-dose booster effect was most evident in young children.", "This article presents the results of a comparative study of the reactogenicity and the serological response induced by a number of cholera vaccines. Conducted in the USSR on 998 adults aged 18 years and over, the study covered whole-cell heat-killed and formalin-inactivated cholera vaccines, whole-cell heat-killed El Tor vaccine, and a new partially purified toxoid preparation proposed for the immunoprophylaxis of cholera-all administered by hypodermic syringe or jet injector. The most marked reactions were found to occur with the formalin-inactivated cholera vaccine and the least marked with the partially purified toxoid. It was also established that the toxoid was no less effective than the whole-cell vaccine in inducing the intense production of antibodies to the Inaba serotype and, in somewhat lesser degree, to the Ogawa serotype of the El Tor vibrio. It was the only preparation to give rise to intense production of specific antitoxins in 95-98% of cases. The reactions to and immunogenic properties of the cholera vaccines did not show any statistically significant difference whether administered by hypodermic syringe or by jet injector.", "Enterotoxigenic Escherichia coli (ETEC), which produces heat labile toxin (LT) and/or heat stable toxin (ST), is considered to be the most common known cause of travellers' diarrhoea (TD). Owing to the antigenic similarity between cholera toxin and LT, immunization with inactivated oral B-subunit/whole-cell cholera vaccine (BS-WC) offers short term (3 months) but significant (>67%) protection against TD caused by LT-related ETEC. Since it expresses the cholera toxin B (CTB) subunit, the live attenuated oral cholera vaccine strain CVD 103-HgR, may induce similar protection. A trial was performed to determine if CVD 103-HgR live oral cholera vaccine would provide a protective efficacy of at least 50% against TD. In addition, the protective efficacy of the vaccine against TD specifically due to LT-ETEC and LT/ST-ETEC was determined. Volunteers (n=134) travelling to Indonesia, India, Thailand or West-Africa were randomised to receive either a placebo (n=65) or the vaccine (n=69). In the placebo group, 46% reported an episode of diarrhoea, compared to 52% in the vaccine group. No significant group differences were found with regard to incidence, duration or severity of all caused TD or ETEC-associated TD. However, ETEC-associated TD occurred earlier in the placebo group (median 5 days), compared to the vaccine group (median 15 days). In conclusion, CVD 103-HgR live oral cholera vaccine failed to provide a 50% protection against TD. This study does not exclude that the vaccine may offer a short-lived protection against ETEC-associated TD. However, the power of the study was limited by the unexpected low incidence of LT-ETEC-associated diarrhoea (9% of all TD) compared to ST-associated TD (24% of all TD).", "To evaluate a killed oral cholera vaccine produced in Viet Nam, and to compare the Vietnamese vaccine with one that is licensed internationally.\n Two-dose regimens of a locally produced, bivalent, anti-O1, anti-O139 killed oral whole-cell cholera vaccine (biv-WC) and of a commercially available, monovalent (anti-O1) oral recombinant B subunit-killed whole-cell cholera vaccine (rBS-WC) were compared in two trials in Viet Nam. In the first trial, 144 adults were randomized to biv-WC with or without buffer, rBS-WC with buffer, or placebo without buffer. In the second, 103 children aged 1-12 years were randomized to biv-WC without buffer, rBS-WC with buffer, or placebo without buffer.\n No regimen was associated with significant side-effects. In adults, ca 60% of recipients of either vaccine exhibited at least fourfold serum anti-O1 vibriocidal antibody responses and ca 40% of recipients of biv-WC demonstrated anti-O139 vibriocidal responses. Both anti-O1 (ca 90% in each vaccine groupand anti-O139 (68% in the biv-WC group) vibriocidal responses occurred more frequently in children. The responses to biv-WC were unaffected by the receipt of buffer.\n It was concluded that biv-WC was safe and immunogenic, that it could be administered without buffer, and that it could elicit robust immune responses even in children, for whom the risk of endemic cholera is highest.", "In order to evaluate the safety and immunogenicity of domestic produced lyophilized recombinant, B-subunit, inactivated whole cell vaccine of vibrio cholerae (rBS-WC), 369 subjects were randomly divided into three groups and observed with masking method, one with high dose of vaccine (5 mg rBS and 10\" WC), another with low dose (1 mg rBS and 10\" WC), and the control one with placebo. Three doses of vaccine were given orally at an interval of seven days and 14 days, respectively. Results showed that only one subject had mild adverse reaction in the vaccine group (1/247) and none in the control group. Serum and fecal antibody conversion rates and average levels of antibodies in the two vaccine groups were significantly higher than those in control one. There was no significant difference in serum and fecal antibody conversion rate and average antibody levels between the two vaccine groups. But, antibody response was different among subjects of various sex, age, and vaccine doses. It indicates that rBS-WC vaccine of vibrio cholerae had good immunogenicity and safety.", "To assess the safety, immunogenicity, and lot stability of the whole cell/recombinant B subunit cholera vaccine, 2 lots manufactured in June 1991 and February 1992 were tested in January 1995. Two oral doses of vaccine or placebo given 2 weeks apart were given with buffer to 216 Peruvian adults and children. Symptoms were elicited for 3 days after each dose. Serum and plasma specimens obtained from each volunteer before vaccination and 10-14 days after the second dose were tested for vibriocidal and anti-cholera toxin antibodies. The vaccine was well-tolerated. Nearly half of the 100 vaccinees had pre-vaccination vibriocidal titers > or = 1:40. Elevated titers were observed in 22% of 37 children 2-5 years of age compared with 66% of 63 vaccinees 6-65 years (P < 0.001). A > or =2-fold serum vibriocidal response was observed in 55% of 100 vaccinees and 6% of 32 placebo recipients. An elevated pre-vaccination titer (< or =1:40) did not change the proportion of vaccinees who responded with a > or =2-fold increase in vibriocidal titer (51% versus 59%, difference not significant), but did change the proportion responding with a > or =4-fold increase (41% versus 22%; P < 0.05). The vibriocidal seroconversion rate was lowest in children 2-5 years old despite low pre-vaccination titers. Two-fold or greater serum antitoxic responses in IgA and IgG were observed in >90% of the vaccinees; > or =4-fold responses were seen in 65-70% of the vaccinees with a 6-8-fold increase over baseline. Plasma specimens were as good as sera for determining anti-toxic antibodies by ELISA, but were less satisfactory for determining vibriocidal antibody titers.", "In a controlled field trial on some 584 000 people in an endemic cholera El Tor area in the Philippines, it was demonstrated that cholera vaccines gave moderate protection of short duration. Injection of a single dose of vaccine prepared from either Vibrio cholerae or Vibrio El Tor gave over 50% protection for the first two months. The immunity conferred by the V. cholerae vaccine rapidly declined after three to four months. The V. El Tor vaccine gave protection for six months, but its effectiveness declined. An oil-adjuvant vaccine prepared from V. cholerae conferred an increasing degree of protection of long duration, but, owing to severe vaccination reactions, its use could not be recommended.", "Two randomized, double-blinded trials assessed the safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli (ETEC) plus cholera toxin B subunit vaccine in Egyptian children. Two doses of vaccine or E. coli K-12 were given 2 weeks apart to 105 6- to 12-year-olds and 97 2- to 5-year-olds. Safety was monitored for 3 days after each dose. Blood was collected before immunization and 7 days after each dose to measure immune responses. Few children reported postdosing symptoms, with no differences in the frequency of symptoms between treatment groups. Most vaccinees had an IgA antibody-secreting cell response against colonization factor antigen I (100%, 6-12 years; 95%, 2-5 years), coli surface antigen 2 (92%, 6-12 years; 83%, 2-5 years), and coli surface antigen 4 (93%, 6-12 years). Vaccination evoked a >/=4-fold rise in antitoxic IgA and IgG titers in 93% and 81% of children, respectively. In conclusion, the oral ETEC vaccine was safe and immunogenic in 2- to 12-year-old children, justifying further evaluation in infants.", "In January and February 1992, an assessment was conducted of the safety and immunogenicity of two doses of a new oral cholera vaccine prepared from the recombinant B subunit of the toxin and from killed whole cells (rBS/WC) in 1,165 individuals between the ages of 12 months and 64 years in Barranquilla, Colombia. This was a randomized, double-blind placebo-controlled study. Participants received two doses of either the vaccine or a placebo (killed Escherichia coli K12) over a two-week interval. Few symptoms were detected during the three days following administration of the initial dose and even fewer following the second. Sera obtained upon administration of the first dose and two weeks after administration of the second were tested for Vibrio cholerae 01 Inaba vibriocidal antibodies and antitoxins. Geometric mean titers (GMT) of vibriocidal antibodies were found to increase two-fold in subjects receiving the vaccine. In the paired samples taken from vaccinated subjects, two-fold or greater increases were observed in 44% and four-fold or greater increases were observed in 34%, as compared to similar increases in 9.2% and 2.2% of the sera taken from those receiving the placebo (P < 0.05). The GMTs of IgG and IgA antitoxins, as determined by ELISA, increased by factors of 4 and 3.2, respectively, in those receiving the vaccine, as compared to factors of 1.1 and 1.1 in those given the placebo (P < 0.001 for IgG, P < 0.01 for IgA). Approximately 80% of the paired samples from the vaccinated group showed an increase of both IgG and IgA antitoxins > or = 1.5, as compared to only about 20% of those in the placebo group (P < 0.000001). Belonging to the O blood group did not significantly affect the immune response. Children under age four tended to show a weaker vibriocidal antibody response and a stronger antitoxin response than older subjects. The two doses of oral vaccine were found to be safe and without attributable side-effects. The vibriocidal antibody and antitoxin responses were similar to those obtained previously with the conventional oral killed whole cell B subunit cholera vaccine.", "A controlled field trial comparing the effectiveness of a plain cholera vaccine with that of a vaccine adsorbed to aluminium hydroxide was carried out in a cholera-endemic area of Indonesia during 1973-75. Tetanus toxoid adsorbed to aluminium phosphate was used as the control. In vaccinees aged 1-4 years, the adsorbed cholera vaccine provided about 88% protection for 6 months following vaccination and still provided about 50% protection between 11 and 14 months after vaccination. In the same age group, the plain vaccine provided only 53% protection during the first 6 months and no appreciable protection beyond that period. In those aged 5 years and over, both vaccines provided 50-60% protection throughout the period of observation (14 months). Neither vaccine caused any serious side effects.", "Peru-15 is a live attenuated oral vaccine derived from a Vibrio cholerae O1 El Tor Inaba strain by a series of deletions and modifications, including deletion of the entire CT genetic element. Peru-15 is also a stable, motility-defective strain and is unable to recombine with homologous DNA. We wished to determine whether a single oral dose of Peru-15 was safe and immunogenic and whether it would provide significant protection against moderate and severe diarrhea in a randomized, double-blind, placebo-controlled human volunteer cholera challenge model. A total of 59 volunteers were randomly allocated to groups to receive either 2 x 10(8) CFU of reconstituted, lyophilized Peru-15 vaccine diluted in CeraVacx buffer or placebo (CeraVacx buffer alone). Approximately 3 months after vaccination, 36 of these volunteers were challenged with approximately 10(5) CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Among vaccinees, 98% showed at least a fourfold increase in vibriocidal antibody titers. After challenge, 5 (42%) of the 12 placebo recipients and none (0%) of the 24 vaccinees had moderate or severe diarrhea (> or = 3,000 g of diarrheal stool) (P = 0.002; protective efficacy, 100%; lower one-sided 95% confidence limit, 75%). A total of 7 (58%) of the 12 placebo recipients and 1 (4%) of the 24 vaccinees had any diarrhea (P < 0.001; protective efficacy, 93%; lower one-sided 95% confidence limit, 62%). The total number of diarrheal stools, weight of diarrheal stools, incidence of fever, and peak stool V. cholerae excretion among vaccinees were all significantly lower than in placebo recipients. Peru-15 is a well-tolerated and immunogenic oral cholera vaccine that affords protective efficacy against life-threatening cholera diarrhea in a human volunteer challenge model. This vaccine may therefore be a safe and effective tool to prevent cholera in travelers and is a strong candidate for further evaluation to prevent cholera in an area where cholera is endemic.", "A 'double-blind', randomized, placebo controlled study of an oral inactivated whole cell plus recombinant B subunit (WC/rBS) cholera vaccine was conducted during February-March 1992 in Peru in 346 military recruits, 307 (89%) of whom received 2 oral doses of vaccine or Escherichia coli K12 placebo, 2 weeks apart. Paired serum samples were obtained from 155 (50%) of the recipients of 2 doses. An epidemic of cholera took place between doses. No difference in cholera attack rates was detected between vaccine and placebo recipients after one dose (8% versus 14%). Seroconversion (4-fold or higher increase in vibriocidal antibody titres) was detected in 90% and 80% of vaccine and placebo recipients, respectively, with low pre-existing vibriocidal titres (< 0.01). The anti-cholera toxin seroconversion rate among those with low pre-existing titres was higher in vaccinated subjects (97%) than in placebo recipients (68%) (P < 0.01). Administration of 2 doses of WC/rBS vaccine concomitantly with natural V. cholerae O1 infection enhanced the serum anti-cholera toxin response. The immune response to the whole cell component of the vaccine was reduced by high pre-existing vibriocidal antibody titres.", "The B subunit (BS) of cholera toxin and that of the heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli (ETEC) are antigenically similar. We therefore assessed whether a combined cholera toxin BS/whole-cell (BS-WC) oral vaccine against cholera conferred cross-protection against LT-producing ETEC (LT-ETEC) diarrhea in a randomized, double-blind field trial among rural Bangladeshi children and women. The 24,770 persons who ingested two or more doses of BS-WC vaccine were compared with 24,842 controls who took two or more doses of killed whole-cell (WC) oral cholera vaccine. Sixty-seven percent fewer episodes of LT-ETEC diarrhea were noted in the BS-WC group than in the WC group during short-term (three-month) follow-up (P less than .01), but no reduction was evident during the ensuing nine months. Short-term protection was particularly notable against LT-ETEC diarrhea causing life-threatening dehydration (protective efficacy, 86%; P less than .05).", "A live oral Vibrio cholerae O1 El Tor vaccine, Peru-15 was tested in a double-blind, randomized placebo controlled study for safety and immunogenicity in Phase I and Phase II studies in 240 Bangladeshi children aged 9 months-5 years of age. Two different doses (2x10(7) and 2x10(8)cfu) were tested. Vaccination did not elicit adverse events and the strain was genetically stable. Vibriocidal antibody responses developed in 42/50 (84%) toddlers (2-5 years) and 35/50 (70%) of younger children (9-23 months) and overall 77/100 (77%) who received the high dose. LPS-IgA-antibody responses were seen in 60% of toddlers and 34% of infants; 40% responded with IgA antibodies to cholera toxin. The responses to the reduced dose was lower. These studies demonstrate that Peru-15 at a dose of 2x10(8)cfu is safe and immunogenic in children in Bangladesh.", "A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety, reactogenicity and the immunogenicity of a 2 x 10(9)CFU dose of the 638 lyophilized live attenuated cholera vaccine for oral administration, formulated and produced at Finlay Institute, City of Havana, Cuba. Thirty-six healthy female and male adult volunteers from 18 to 40 years old were involved, clinically examined and laboratory tested after the informed consent signature. Adverse events were monitored and seroconversion rates and geometrical mean titer (GMT) of vibriocidal antibodies were tested in volunteer's sera samples. Neither serious adverse events nor other damages to the volunteers due to vaccine or placebo feeding were reported during the clinical follow-up period of this study; none of the adverse events registered within the first 72 h after inoculation were life-threatening for volunteers. Neither severe nor moderate adverse events were reported. Sixty-one percent of subjects showed mild expected adverse events in an interval lower than 24h up to the first 72 h, 75% of these in the vaccinated group and 18% in the placebo group. Fourteen days after inoculation the GMT of vibriocidal antibodies in the vaccine group significantly increased in comparison to the placebo group. All subjects in the vaccine group (24) seroconverted (100%). Results show that this vaccine is safe, well tolerated and immunogenic in healthy female and male volunteers.", "A controlled field trial to determine the efficacy of a single dose of an aluminium phosphate-adsorbed cholera vaccine was conducted in Calcutta during 1975-77. An aluminium phosphate-adsorbed tetanus toxoid was used as the placebo. Follow-up of the immunized volunteers for a period of two years showed that the adsorbed cholera vaccine provided 100% protection to children under five years of age for 6 months, 88.9% for 12 months, and 91.7% for 18 months (P<0.05). The overall protection for all age groups was 58.5% for 18 months. There were no serious side effects following the anti-cholera inoculations.", "Oral vaccines offer great promise as public-health measures to prevent disease in less-developed countries. CVD 103-HgR, a genetically engineered, attenuated, Vibrio cholerae O1 strain has proved effective in industrialised countries. We have assessed the safety, immunogenicity, and excretion of this live cholera vaccine in children in north Jakarta, Indonesia. 412 children aged 5-9 years received single doses of 5 x 10(6), 5 x 10(7), 5 x 10(8), 5 x 10(9), or 1 x 10(10) colony forming units (CFU) of CVD 103-HgR or placebo (5 x 10(8) inactivated Escherichia coli K-12) with buffer. All doses were well tolerated. The 5 x 10(8) CFU dose, which is highly immunogenic in subjects in industrialised countries (greater than 90% seroconversion), elicited seroconversions of vibriocidal antibody in only 16% of Indonesian children. By contrast, a single 5 x 10(9) CFU dose of vaccine resulted in high rates (75% and 87%) of seroconversion with two different batches of vaccine. A batch prepared with a centrifugation step gave significantly higher geometric mean titres (16-fold increase over baseline) than did a batch in which there was a filtration step between fermentation and lyophilisation (10-fold increase over baseline). At a 5 x 10(9) CFU dose, CVD 103-HgR is well tolerated and highly immunogenic in Indonesian children and should therefore be further investigated for use as a one-dose live oral cholera vaccine in developing countries.", "Groups of 122 Peruvian adults of low socioeconomic level (SEL) and 125 of high SEL received a randomly allocated 5 x 10(9)- or 5 x 10(8)-CFU dose of CVD 103-HgR live oral cholera vaccine or a placebo. The vaccine was well tolerated. Vibriocidal seroconversions occurred in 78% of high-SEL and 72% of low-SEL subjects who ingested the high dose and in 78 and 49%, respectively, of those who received the low dose.", "A new live oral cholera vaccine, Peru-15, was studied for safety, immunogenicity, and excretion in 2 groups of healthy volunteers. Twelve inpatient volunteers received freshly harvested vaccine in doses of either 10(7) or 10(9) cfu. Subsequently 50 outpatient volunteers received freeze-dried vaccine in doses of 10(8) or 10(9) cfu or placebo in a three-cell, double-masked, placebo-controlled trial. The strain was well tolerated at all dose levels, and it stimulated high levels of vibriocidal antibodies in most inpatient volunteers and in all outpatient volunteers. Although antitoxin responses were less frequent and of lower magnitude than the vibriocidal responses, antitoxin responses were seen in >60% of the outpatient volunteers. About 60% of the volunteers excreted the vaccine in their feces; however, fecal excretion did not correlate with serologic responses. It is concluded that Peru-15 is a safe and immunogenic oral vaccine for cholera." ]	The currently available oral killed whole cell vaccines can prevent 50 to 60% of cholera episodes during the first two years after the primary vaccination schedule. The impact and cost-effectiveness of adopting oral cholera vaccines into the routine vaccination schedule of endemic countries will depend on the prevalence of cholera, the frequency of epidemics, and access to basic services providing rapid rehydration therapy.
CD004210	[ "15861196", "15580195", "2730122", "2923482" ]	[ "Heat loss prevention for preterm infants in the delivery room.", "Heat Loss Prevention (HeLP) in the delivery room: A randomized controlled trial of polyethylene occlusive skin wrapping in very preterm infants.", "Rewarming preterm infants on a heated, water filled mattress.", "Providing warmth for preterm babies by a heated, water filled mattress." ]	[ "Preterm infants are prone to hypothermia immediately following birth. Among other factors, excessive evaporative heat loss and the relatively cool ambient temperature of the delivery room may be important contributors. Most infants <29 weeks gestation had temperatures <36.4 degrees C on admission to our neonatal unit (NICU). Therefore we conducted a randomized, controlled trial to evaluate the effect of placing these infants in polyurethane bags in the delivery room to prevent heat loss and reduce the occurrence of hypothermia on admission to the NICU.\n After parental consent was obtained, infants expected to be <29 weeks gestation were randomized to intervention or control groups just prior to their birth. Infants randomized to the intervention group were placed in polyurethane bags up to their necks immediately after delivery before being dried. They were then resuscitated per NRP guidelines, covered with warm blankets, and transported to the NICU, where the bags were removed and rectal temperatures were recorded. Control infants were resuscitated, covered with warm blankets, and transported without being placed in polyurethane bags. Delivery room temperatures were recorded so this potentially confounding variable could be assessed.\n Intervention patients were less likely than control patients to have temperature < 36.4 degrees C on admission , 44 vs 70% (p<0.01) and the intervention group had a higher mean admission temperature, 36.5 degrees C vs 36.0 degrees C (p<0.003). This effect remained significant (p<0.0001) when delivery room temperature was controlled in analysis. Warmer delivery room temperatures (>/=26 degrees C) were associated with higher admission temperatures in both intervention and control infants, but only the subgroup of intervention patients born in warmer delivery rooms had a mean admission temperature >36.4 degrees C.\n Placing infants <29 weeks gestation in polyurethane bags in the delivery room reduced the occurrence of hypothermia and increased their NICU admission temperatures. Maintaining warmer delivery rooms helped but was insufficient in preventing hypothermia in most of these vulnerable patients without the adjunctive use of the polyurethane bags.", "To determine if polyethylene occlusive skin wrapping of very preterm infants prevents heat loss after delivery better than conventional drying and to evaluate if any benefit is sustained after wrap removal.\n This was a randomized controlled trial of infants <28 weeks' gestation. The experimental group was wrapped from the neck down. Only the head was dried. Control infants were dried completely. Rectal temperatures were compared on admission to the neonatal intensive care unit immediately after wrap removal and 1 hour later.\n Of 55 infants randomly assigned (28 wrap, 27 control), 2 died in the delivery room and 53 completed the study. Wrapped infants had a higher mean rectal admission temperature, 36.5 degrees C (SD, 0.8 degrees C), compared with 35.6 degrees C (SD, 1.3 degrees C) in control infants ( P = .002). One hour later, mean rectal temperatures were similar in both groups (36.6 degrees C, SD, 0.7 degrees C vs 36.4 degrees C, SD, 0.9 degrees C, P = .4). Size at birth was an important determinant of heat loss: Mean rectal admission temperature increased by 0.21 degrees C (95% CI, 0.04 to 0.4) with each 100-g increase in birth weight.\n Polyethylene occlusive skin wrapping prevents rather than delays heat loss at delivery in very preterm infants.", "Sixty low birthweight infants (1000-2000 g) admitted to a neonatal care unit in Turkey were studied. Those not requiring intensive care were randomly assigned for treatment either in a cot on a heated, water filled mattress kept at 37 degrees C (n = 28) or in air heated incubators with a mean air temperature of 35 degrees C (n = 32). On admission 53 (88.3%) of the infants had body temperatures between 30 degrees and 36 degrees C. There was good correlation between axillary and rectal temperatures in the infants while they were hypothermic. Normal temperatures were achieved within the first day and remained within this range during the subsequent days after admission in all the infants treated on the heated, water filled mattress, whereas they were not achieved until three days later in the incubator group. The neonatal mortality among those treated on the heated, water filled mattress was 21%, and among those treated in the incubator 34%. The heated, water filled mattress provides a good alternative to skin to skin contact with the mother, and to the use of a complex and expensive incubator for rapidly attaining and maintaining normal temperatures in the low birthweight newborn.", "Seventeen healthy preterm babies had extra warmth provided in their cots by thermocontrolled, heated, water filled mattresses. As controls 17 babies of the same weight were nursed in air heated incubators. Both groups were studied for three weeks. No differences were found in minimal oxygen consumption (measured by indirect calorimetry), rectal and mean skin temperatures, or in daily weight gain. The babies were kept just as warm on the heated, water filled mattresses as in air heated incubators but the mattresses had the advantage of giving the mothers easy access to their babies." ]	Plastic wraps or bags, plastic caps, SSC and transwarmer mattresses all keep preterm infants warmer leading to higher temperatures on admission to neonatal units and less hypothermia. However, the small numbers of infants and studies and the absence of long-term follow-up mean that firm recommendations for clinical practice cannot be given.
CD001157	[ "16511917" ]	[ "Combination of cyclosporine and leflunomide versus single therapy in severe rheumatoid arthritis." ]	[ "This study assessed the efficacy and safety of combination (COMB) of cyclosporine (CSA) and leflunomide (LEF) versus each drug alone, in the treatment of severe rheumatoid arthritis (RA).\n One hundred six patients with active RA refractory to at least one disease modifying antirheumatic drug (methotrexate obligatorily) were entered into a 12-month open, prospective trial and were randomly allocated to receive either CSA 2.5 to 5 mg/kg/day, or LEF 20 mg/day, or the combination of both at the same initiating dose.\n The American College of Rheumatology 50% (ACR50) response rates for the 3 groups were COMB 80%, CSA 40%, and LEF 42% (p = 0.001). Combination therapy was also significantly better than CSA and LEF at the more stringent 70% response rate (69% vs 34% vs 30%, respectively; p = 0.001). Comparable Disease Activity Score 28 reduction rates were noted at trial termination for all 3 treatment arms: COMB -2.74 vs CSA -2.53 vs LEF -2.28 (p nonsignificant). Discontinuation rates were more common in LEF vs CSA arm (p = 0.046). No unexpected or serious adverse drug effects were identified in the combination group during the 12-month period.\n The combination of CSA and LEF in patients with refractory RA provided statistically significant benefit in ACR50 and ACR70. Adverse events were not substantially increased." ]	Cyclophosphamide appears to have a clinically and statistically significant benefit on the disease activity of patients with RA, similar to some disease modifying antirheumatic drugs (DMARDs) such as antimalarials or sulfasalazine, but lower than methotrexate. Toxicity however is severe, limiting its use given the low benefit-risk ratio compared to other antirheumatic agents.
CD003094	[ "508702", "11134438", "20546462", "16319260", "9508353", "12725261", "15777891", "17035697", "10651841", "3530158", "11328902", "8904521", "7665066", "14617464", "8237866", "19527380", "20615267", "2429622", "18212498" ]	[ "WHO sponsored collaborative studies on nutritional anaemia in India. The effect of parenteral iron administration in the control of anaemia of pregnancy.", "Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants.", "A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy.", "Intravenous versus oral iron for treatment of anemia in pregnancy: a randomized trial.", "A comparison between intravenous iron polymaltose complex (Ferrum Hausmann) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy.", "Comparison of oral versus intravenous iron therapy in predialysis patients of chronic renal failure receiving recombinant human erythropoietin.", "Oral versus high dose parenteral iron supplementation in pregnancy.", "A randomized controlled trial of oral versus intravenous iron in chronic kidney disease.", "Effectiveness of recombinant erythropoietin and iron sucrose vs. iron therapy only, in patients with postpartum anaemia and blunted erythropoiesis.", "The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria.", "A randomized study of oral vs intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin.", "Use of recombinant human erythropoietin in combination with parenteral iron in the treatment of postpartum anaemia.", "[Anemia in puerperium; parenteral iron substitution renders erythropoietin therapy dispensable].", "A comparative study between intramuscular iron dextran and oral ferrous sulphate in the treatment of iron deficiency anaemia in pregnancy.", "Evaluation of a gastric delivery system for iron supplementation in pregnancy.", "Comparison of effect of daily versus weekly iron supplementation during pregnancy on lipid peroxidation.", "Supplementation of iron alone and combined with vitamins improves haematological status, erythrocyte membrane fluidity and oxidative stress in anaemic pregnant women.", "Treatment with iron increases weight gain and psychomotor development.", "Intravenous iron sucrose in Chinese hemodialysis patients with renal anemia." ]	[ "1. The relative efficacy of oral and parenteral iron administration in the prophylaxis and treatment of Fe-deficiency anaemia of pregnancy has been studied. 2. Intravenous administration of Fe by total dose infusion of Fe dextran was not superior to oral Fe 120 mg/d, 6 d/week for 10-12 weeks. 3. Intramuscular Fe dextran, 100 mg twice per week for 10-12 weeks, produced a significantly greater rise in mean haemoglobin concentration than oral Fe therapy. 4. The superiority of intramuscular Fe as compared with intravenous Fe is probably related to the different handling of the Fe dextran by the reticulo-endothelial system. 5. In spite of the better response to intramuscular Fe dextran, it is not recommended for public health practice because of the risks associated with its use and the much higher cost of the preparation and its delivery.", "To test the efficacy and safety of combining intravenous iron in amounts approximating the in utero iron accretion rate and the postnatal iron loss with erythropoietin (EPO) in very low birth weight (VLBW) infants.\n A prospective, controlled, randomized, unmasked trial lasting 21 days was performed in 29 clinically stable VLBW infants <31 weeks' gestation and <1300 g birth weight not treated with red blood cell transfusions during the study period. Mean (+/- standard error of the mean) age at study entry was 23 +/- 2.9 days. After a 3-day run-in baseline period in which all participants received oral supplements of 9 mg/kg/day of iron polymaltose complex (IPC), participants were randomized to receive 18 days of treatment with: 1) oral IPC alone (oral iron group); 2) 300 U of recombinant human EPO (r-HuEPO) kg/day and daily oral IPC (EPO + oral iron group); 3) 2 mg/kg/day of intravenous iron sucrose, r-HuEPO, and oral iron (intravenous iron + EPO group). To assess efficacy of the 3 treatments, serial blood samples were analyzed for hemoglobin (Hb), hematocrit (Hct), reticulocyte count, red blood cell indices and plasma levels of transferrin, transferrin receptor (TfR), ferritin, and iron. Oxidant injury was assessed before and after treatment by plasma and urine levels of malondialdehyde (MDA) and o-tyrosine.\n At the end of treatment, Hb, Hct, reticulocyte count, and plasma TfR were markedly higher in both of the EPO-treated groups, compared with the oral iron group. At study exit a trend toward increasing Hb and Hct levels and significantly higher reticulocyte counts were observed in the intravenous iron + EPO group, compared with the EPO + oral iron group. During treatment, plasma ferritin levels increased significantly in the intravenous iron + EPO group and decreased significantly in the other 2 groups. By the end of treatment, ferritin levels were significantly higher in the intravenous iron + EPO group compared with the other 2 groups. Although plasma and urine MDA or o-tyrosine did not differ among the 3 groups, plasma MDA was significantly greater in the subgroup of intravenous iron + EPO participants sampled at the end of the 2-hour parenteral iron infusion, compared with values observed immediately before and after parenteral iron-dosing.\n In stable VLBW infants receiving EPO treatment, parenteral supplementation with 2 mg/kg/day of iron sucrose results in a small, but significant, augmentation of erythropoiesis beyond that of r-HuEPO and enteral iron alone. However, to reduce the potential adverse effects of parenteral iron/kg/day on increasing plasma ferritin levels and on causing oxidative injury, we suggest that the parenteral iron dose used should be reduced and/or the time of infusion extended to maintain a serum iron concentration below the total iron-binding capacity.", "Iron deficiency anaemia is the most common deficiency disorder in the world, affecting more than one billion people, with pregnant women at particular risk.\n We conducted a single site, prospective, nonblinded randomized-controlled trial to compare the efficacy, safety, tolerability and compliance of standard oral daily iron versus intravenous iron.\n We prospectively screened 2654 pregnant women between March 2007 and January 2009 with a full blood count and iron studies, of which 461 (18%) had moderate IDA. Two hundred women matched for haemoglobin concentration and serum ferritin level were recruited.\n Patients were randomized to daily oral ferrous sulphate 250 mg (elemental iron 80 mg) with or without a single intravenous iron polymaltose infusion.\n Prior to delivery, the intravenous plus oral iron arm was superior to the oral iron only arm as measured by the increase in haemoglobin level (mean of 19.5 g/L vs. 12 g/L; P < 0.001); the increase in mean serum ferritin level (222 microg/L vs. 18 ug/L; P < 0.001); and the percentage of mothers with ferritin levels below 30 microg/L (4.5% vs. 79%; P < 0.001). A single dose of intravenous iron polymaltose was well tolerated without significant side effects.\n Our data indicate that intravenous iron polymaltose is safe and leads to improved efficacy and iron stores compared to oral iron alone in pregnancy-related IDA.", "The aim of this study was to compare the efficacy of intravenous iron to oral iron in the treatment of anemia in pregnancy.\n In this randomized open-label study, 90 women with hemoglobin levels between 8 and 10.5 g/dL and ferritin values less than 13 microg/L received either oral iron polymaltose complex (300 mg elemental iron per day) or intravenous iron sucrose. The iron sucrose dose was calculated from the following formula: weight before pregnancy (kg) x (110 g/L - actual hemoglobin [g/L]) x 0.24 + 500 mg. Treatment efficacy was assessed by measuring hemoglobin and ferritin on the 14th and 28th days and at delivery, and the hemoglobin on the first postpartum day. Adverse drug reactions, fetal weight, hospitalization time, and blood transfusions were also recorded.\n Hemoglobin values varied significantly with time between groups (interaction effect, P < .001). The change in hemoglobin from baseline was significantly higher in the intravenous group than the oral group at each measurement; the changes with respect to subsequent hemoglobin were significantly higher on the 14th (P = .004) and 28th (P = .031) days. Ferritin values were higher in patients receiving intravenous iron throughout pregnancy. No serious adverse drug reactions were observed. Fetal weight and hospitalization time were similar in the 2 groups. Blood transfusion was required for only one patient in the oral group.\n Intravenous iron treated iron-deficiency anemia of pregnancy and restored iron stores faster and more effectively than oral iron, with no serious adverse reactions.", "Anaemia is the most common medical disorder in pregnancy with iron deficiency anaemia accounting for the majority of cases. Over 90% of the iron deficiency anaemia is due to red cell iron deficiency associated with depleted iron stores and deficient intake. The two main modalities of treating iron deficiency anaemia are oral or parenteral iron. Ferrous Hausmann (iron dextrin) is the latest iron preparation which can be used for intravenous parenteral administration as a total dose infusion. This study compares the efficacy of Ferrum Hausmann with oral ferrous fumarate therapy in the treatment of iron deficiency anaemia in pregnancy. Our study shows that treatment with intravenous Ferrum Hausmann (iron dextrin) resulted in a significantly better level and rate of increase of haemoglobin (p<0.001). Serum ferritin, which is the best indicator of iron stores, was significantly higher (p<0.001) in the intravenous group. Other indices of iron status such as serum iron, serum transferrin and zinc protoporphyrin also showed a significant improvement in the intravenous group compared to those given oral iron. The results suggest that intravenous iron as a total dose infusion is able to replenish iron stores more efficiently, completely and at a faster rate than oral iron therapy, thus providing the fuel for stimulation of full erythopoiesis compared to oral iron. There were also no reports of any adverse reactions with intravenous iron dextrin, whereas there were a considerable proportion of women on oral iron therapy who reported side effects. In conclusion, intravenous iron therapy with Ferrous Hausmann (iron dextrin) is a suitable, effective and safe alternative to oral iron therapy in the treatment of iron deficiency anaemia in pregnancy.", "To compare oral versus intravenous iron in pre-dialysis patients of chronic renal failure (CRF) receiving recombinant human erythropoietin (rHuEPO).\n The study was undertaken in 40 adult patients of chronic renal failure. The patients were randomly divided into two groups A and B of 20 patients each. Group A patients were given oral iron and group B patients were given intravenous iron. All patients in both groups were given recombinant human erythropoietin 2000 IU twice weekly subcutaneously. The study was carried for up to three months. Patients were monitored every month for renal parameters and haematological parameters which included haemoglobin, reticulocyte count and packed cell volume. Ferrokinetic studies were done at baseline and at three months.\n It was observed that haematological parameters showed significant statistical improvement in the intravenous iron group as compared to group A (oral iron group). The ferrokinetic studies revealed that serum iron, serum ferritin and transferrin saturation, decreased significantly in oral iron group, whereas significant increase was seen in group B (intravenous iron group). None of the patients developed any adverse effects because of erythropoietin or iron therapy.\n Concomitant use of intravenous iron is better than oral iron in CRF patients treated with rHuEPO. The intravenous route of iron administration may be a preferred route along with rHuEPO therapy, more so in the Indian context where prevalence of iron deficiency anaemia is fairly high.", "To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron.\n A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16-24 weeks gestation were identified and randomly divided into two groups. Group A was started on daily oral iron therapy of 100 mg of elemental iron. Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4-6 weeks. Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups. The data were analyzed using SPSS software, version 10.1.\n Definitive and comparable improvement in hemoglobin and all the blood indices (hematocrit, MCH, MCHC, MCV, Serum iron and TIBC) was observed. The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59% in oral group, 1.34+/-0.77 g% and 4.93+/-3.65% in parenteral group, respectively. Serum ferritin showed statistically significant absolute rise (10.43+/-7.92 microg/dl) after parenteral iron supplementation as compared to oral iron supplementation (9.76+/-4.78 microg/dl). Obstetric outcome was comparable in two groups.\n Two treatment regimens are biologically equivalent in terms of hematological response. Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy.", "It is unknown whether intravenous iron or oral iron repletion alone can correct anemia associated with chronic kidney disease (CKD). We conducted a randomized multicenter controlled trial in adult anemic, iron-deficient non-dialysis CKD (ND-CKD) patients (>or=stage 3) not receiving erythropoiesis-stimulating agents (ESAs).\n The participants were randomized to receive either a sodium ferric gluconate complex (intravenous iron) 250 mg i.v. weekly x 4 or ferrous sulfate (oral iron) 325 mg t.i.d. x 42 days. Hemoglobin (Hgb), ferritin and transferrin saturation (TSAT) were measured serially, and the Kidney Disease Quality of Life (KDQoL) questionnaire was administered on days 1 and 43. The primary outcome variable was change from baseline (CFB) to endpoint in Hgb values.\n Seventy-five patients were analyzed (intravenous iron n = 36, oral iron n = 39). CFB in Hgb was similar in the two groups (intravenous iron 0.4 g/dl vs. oral iron 0.2 g/dl, p = n.s.). However, the increase in Hgb was only significant with intravenous iron (p < 0.01). In comparison to oral iron, intravenous iron achieved greater improvements in ferritin (232.0 +/- 160.8 vs. 55.9 +/- 236.2 ng/ml, p < 0.001) and TSAT (8.3 +/- 7.5 vs. 2.9 +/- 8.8%, p = 0.007). Intravenous iron caused greater improvements in KDQoL scores than oral iron (p < 0.05). The most common side effect reported with intravenous iron was hypotension, while constipation was more common with oral iron.\n Oral and intravenous iron similarly increase Hgb in anemic iron-depleted ND-CKD patients not receiving ESAs. Although in comparison to oral iron, intravenous iron may result in a more rapid repletion of iron stores and greater improvement in quality of life, it exposes the patients to a greater risk of adverse effects and increases inconvenience and cost.\n Copyright (c) 2006 S. Karger AG, Basel.", "To compare efficacy between recombinant human erythropoietin (rhEPO) plus parenteral iron vs. iron alone (parenteral vs. oral) in postpartum anaemia.\n Sixty patients (haemoglobin 8.6 +/- 1.1 g dL-1) were randomized to rhEPO plus intravenous (i.v.) iron sucrose (group 1), rhEPO placebo plus i.v. iron sucrose (group 2), or oral iron alone (group 3), daily for 4 days beginning 48-72 h postpartum. Erythropoiesis and iron status were assessed before, and on 4, 7 and 14 days after, starting therapy.\n On day 7 the group 1 haematocrit increase was 7.7 +/- 3.1% vs. 5.3 +/- 1.9% (group 2, P < 0.01) and 4.4 +/- 3.2% (group 3, P < 0.01), and on day 14, 11.3 +/- 2.9% vs. 9.2 +/- 3.4% (group 2, P < 0.05) and 8 +/- 2.8% (group 3, P < 0.01). The odds of achieving a target haematocrit > 32% on day 7 and > 35% on day 14 were higher on rhEPO (1.5-2.7) than on either iron regimen alone. Group 1 reticulocyte counts were also higher on days 4 (P < 0.05 vs. oral iron) and 7 (P < 0.01 vs. oral and parenteral iron).\n All three regimens were effective in postpartum anaemia, but the haematocrit and reticulocyte responses to rhEPO plus parenteral iron were significantly greater than to iron alone. Benefit was greatest in the blunted erythropoiesis subgroup with elevated post-Caesarean section C-reactive protein levels.", "Two hundred Hausa primigravidae at Zaria were divided into five groups in a randomized double-blind trial of antenatal oral antimalarial prophylaxis, and haematinic supplements. Group 1 received no active treatment. Groups 2 to 5 were given chloroquine 600 mg base once, followed by proguanil 100 mg per day. In addition, group 3 received iron 60 mg daily, group 4 folic acid 1 mg daily, and group 5 iron plus folic acid. Forty-five percent were anaemic (haemoglobin (Hb) less than 11.0 g dl-1) at first attendance before 24 weeks of gestation, and malaria parasitaemia (predominantly Plasmodium falciparum) was seen in 27%, of whom 60% were anaemic. The mean Hb fell during pregnancy in group 1, and seven patients in this group had to be removed from the trial and treated for severe anaemia (packed cell volume (PCV) less than 0.26). Only five patients in the other groups developed severe anaemia (P = 0.006), two of whom had malaria following failure to take treatment. Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation, and patients receiving antimalarials and iron (groups 3 and 5) had the highest Hb at 28 weeks, but differences were not significant, possibly due to removal from the trial of patients with severe anaemia. Anaemia (Hb less than 12.0 g dl-1) at six weeks after delivery was observed in 61% of those not receiving active treatment (group 1), in 39% of those protected against malaria but not receiving iron supplements (groups 2 and 4) and in only 18% of patients receiving both antimalarials and iron (groups 3 and 5). Folic acid had no significant effect on mean Hb. Proguanil was confirmed to be a highly effective causal prophylaxis. Prevention of malaria, without folic acid supplements, reduced the frequency of megaloblastic erythropoiesis from 56% to 25%. Folic acid supplements abolished megaloblastosis, except in three patients who were apparently not taking the treatment prescribed. Red cell folate (RCF) concentrations were higher in subjects with malaria, probably due to intracellular synthesis by plasmodia. Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia. Maternal folate supplements raised infants' serum folate and RCF. Fourteen per cent had low birth weight (less than 2500 g), and the perinatal death rate was 11%; the greatest number were in group 1, but not significantly. A regime is proposed for the prevention of malaria, iron deficiency, folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria.", "Correction of anaemia as a result of renal failure improves cardiovascular function and also provides significant cognitive and emotional benefits. The most appropriate route for iron supplementation has not been determined for patients with chronic renal failure who are not yet on dialysis.\n Forty-five anaemic patients with progressive renal insufficiency (PRI) were prospectively randomized to receive oral (ferrous sulphate 200 mg tds) or intravenous (300 mg iron sucrose monthly) iron treatment. Erythropoietin (rHuEpo) was simultaneously commenced and the dose adjusted according to a pre-established protocol.\n There were no significant differences in baseline patient characteristics between the two groups. The average follow-up was 5.2 months. Three patients suffered possible allergic reactions to iron sucrose. Haemoglobin response and changes in red cell hypochromasia were similar in the two groups, but serum ferritin was significantly higher in the intravenous group. The starting dose of rHuEpo could be temporarily discontinued in 43% of patients on oral iron and 33% of patients receiving iron sucrose (NS). rHuEpo was increased after 3 months in 9% of patients on oral iron and 19% of patients receiving iron sucrose (NS). Final doses of rHuEpo were 33.5 (0-66) and 41.6 (0-124) U/kg/week respectively in the oral and intravenous groups (NS). Although gastro-intestinal symptoms were more commonly reported in patients taking oral iron, these were mild according to scores on visual analogue scales. Dietary protein and energy intake were not significantly different in the two groups at 0, 3 and 6 months.\n In pre-dialysis patients, the efficacy of monthly 300 mg iron sucrose given intravenously is not superior with regard to haemoglobin response and rHuEpo dose as compared with a daily oral dose of 600 mg of ferrous sulphate or equivalent. Where intravenous iron is preferred, lower doses may help to reduce the incidence of allergic or \"free iron\" reactions, especially in patients with low body mass.", "The authors compared the effect of recombinant human erythropoietin (rhEPO) in combination with iron with that of iron therapy only in the treatment of postpartum anaemia. Ninety patients (30 patients/group) received either rhEPO (300 U kg-1, i.v. or s.c., once) and iron (parenteral and oral), or iron therapy only. Erythropoiesis was assessed by haemoglobin and haematocrit increase, absolute reticulocyte counting and reticulocyte flow cytometry. Ferrokinetics was assessed by serum ferritin, transferrin and transferrin saturation measurements. There was no difference before therapy for baseline haematological values or iron status. Patients with endogenous EPO levels below 145 mU mL-1 had a significant benefit from intravenous rhEPO administration with highest haematocrit and haemoglobin levels 4 and 14 days after therapy. rhEPO-treated groups showed a higher absolute reticulocyte count 1 and 4 days after therapy and an elevated percentage of high fluorescent reticulocytes (HFRs). Parenteral iron therapy caused a significant increase of ferritin and transferrin saturation, while transferrin concentration decreased. Ferritin and transferrin levels were lowest after i.v. administration of rhEPO, 1 and 4 days after therapy. C-reactive protein concentration was highest in patients who underwent caesarean section until the end of the observation period. A single dose of rhEPO in combination with iron was more effective in treating postpartum anaemia than iron therapy only, in patients who had low EPO levels despite peripartal blood loss. Postpartum low endogenous EPO levels might be a consequence of inhibiting inflammatory cytokines that are released after spontaneous or operative deliveries.", "In a double-blind, randomised study we treated 36 women in the puerperium with haemoglobin concentration below 9 g/dl with 400 mg Fe . 20 women received 20,000 IE erythropoietin (rHuEPO) i.v. in addition, 12 women received placebos. In both groups there were no differences in the haematological and iron parameters in the first 4 weeks after delivery. The results show that the additional therapy with rHuEPO in postpartum anaemia is not justified. The limiting factor in a quick correction of the postpartum anaemia is the insufficient presence of iron at the end of pregnancy. The therapy of choice for quick and safe correction of p.p. anaemia is the effective intravenous iron supplementation.", "A comparative study was conducted to demonstrate the difference, if any, in effectiveness of treatment of iron deficiency anaemia in pregnancy with either iron dextran or ferrous sulphate. Sixty pregnant women with iron deficiency anaemia were assigned randomly to either group and treated for 6 weeks. The age and parity distributions with mean packed cell volumes (PCVs) and gestational age at onset of treatment in the two groups were comparable. Comparing the mean PCVs at week 2, week 4 and week 6 of treatment the iron dextran group recorded higher and statistically significant mean PCVs (P<0.001). Thirty-six per cent of patients in the iron dextran group compared to 3.3% in the oral iron group (P=0.004) had their anaemia corrected by the sixth week. No significant side effects accompanied the use of intramuscular iron dextran. It was concluded that iron dextran corrects iron deficiency anaemia faster than ferrous sulphate. Parenteral iron should be considered in pregnant woman with moderate and asymptomatic severe anaemia between gestation ages of 28 weeks and 34 weeks; this may reduce the frequency of blood transfusion both in the antenatal and postnatal periods in these patients.", "The present investigation was undertaken to assess the efficacy of oral iron supplementation during pregnancy by using a gastric delivery system (GDS). Three hundred seventy-six pregnant women between 16 and 35 y of age and 14 and 22 wk gestation were selected if mild anemia was present (hemoglobin concentration 80-110 g/L). The participants were randomly assigned to one of three study groups given no iron, two FeSO4 tablets (100 mg Fe) daily, or one GDS capsule (50 mg Fe) daily. Blood was obtained initially and after 6 and 12 wk for measurement of red blood cell and iron indexes, including serum transferrin receptor. There was a significant and comparable improvement in hematologic and iron-status measurements in the two groups of women given iron whereas iron deficiency evolved in women given no iron supplement. We conclude that by eliminating gastrointestinal side effects and reducing the administration frequency of an iron supplement to once daily, a GDS offers significant advantages for iron supplementation of pregnant women.", "To compare the effect of daily versus weekly iron supplementation on lipid peroxidation, hemoglobin levels and maternal and perinatal outcome in non-anemic pregnant women.\n Of 109 women randomly allocated into three groups, 90 completed the study. Group I (n = 30) received daily iron folic acid; Group II (n = 30) received weekly iron folic acid; Group III (n = 30) received daily iron (III)-hydroxide polymaltose complex. Hemoglobin levels, hematological indices, thiobarbituric acid reactive substances (TBARS) and glutathione levels were measured at baseline (14-16 weeks) and at 30-34 weeks. Statistical analysis was done using the anova test.\n Group I had a highly significant increase in TBARS level (0.61 +/- 0.26 micromol/L, P = 0.000) compared to groups II and III in which the change in TBARS was not significant (0.02 +/- 0.06 and 0.007 +/- 0.06 micromol/L, respectively). There was an insignificant fall in glutathione levels in all groups. There was no significant difference in the mean period of gestation, pregnancy complications and neonatal outcome between the three groups. Among 22.2% of women who were non-compliant, Group I had significantly higher incidence of non-compliance (P = 0.016) and side-effects (P = 0.001). Final hemoglobin was higher in Group I than II (11.9 +/- 1.2, 11.3 +/- 0.9, respectively, P = 0.041). The TBARS level was not statistically different between preterm and term deliveries. Nine out of 11 patients who developed hypertension during pregnancy had preeclampsia. The final TBARS level was significantly higher in these women (P = 0.000).\n Daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation, the latter is comparable with daily iron (III)-hydroxide polymaltose complex. Lipid peroxidation levels are significantly higher in preeclampsia.", "Pregnancy is a condition exhibiting increased susceptibility to oxidative stress, and Fe plays a central role in generating harmful oxygen species. The objective of the present study is to investigate the changes in haematological status, oxidative stress and erythrocyte membrane fluidity in anaemic pregnant women after Fe supplementation with and without combined vitamins. The study was a 2 months double-blind, randomised trial. Pregnant women (n 164) were allocated to four groups: group C was the placebo control group; group I was supplemented daily with 60 mg Fe (ferrous sulphate) daily; group IF was supplemented daily with Fe plus 400 μg folic acid; group IM was supplemented daily with Fe plus 2 mg retinol and 1 mg riboflavin, respectively. After the 2-month trial, Hb significantly increased by 15.8, 17.3 and 21.8 g/l, and ferritin by 2.8, 3.6 and 11.0 μg/l, in the I, IF and IM groups compared with placebo. Polarisation (ρ) and microviscosity (η) decreased significantly in other groups compared with placebo, indicating an increase in membrane fluidity. Significant decreases of ρ and η values compared with group C were 0.033 and 0.959 for group I, 0.037 and 1.074 for group IF and 0.064 and 1.865 for group IM, respectively. In addition, significant increases of glutathione peroxidase activities and decreases of malondialdehyde were shown in all treated groups, as well as increases of plasma retinol and urine riboflavin in group IM. The findings show that supplementation with Fe and particularly in combination with vitamins could improve the haematological status as well as oxidative stress and erythrocyte membrane fluidity.", "Previous work at this hospital and elsewhere has shown that anaemia in toddlers is common and is associated with psychomotor delay. It seemed unclear, however, whether this association was cause and effect or merely due to the same underprivileged environment. A double blind randomised intervention study was, therefore, performed. After an initial assessment 97 children with anaemia (haemoglobin 8-11 g/dl) aged 17-19 months received either iron and vitamin C or vitamin C only (control group) for two months and were then reassessed. The children who received the iron had an increased rate of weight gain and more of them achieved the expected rate of development. While iron deficiency anaemia is unlikely to be the only factor in the slower development of children living in underprivileged circumstances, it can at least be easily identified and treated. Routine child health surveillance in such areas should include a haemoglobin determination.", "Renal anemia is one of the commonest complications of chronic renal failure. Iron deficiency is the most common factor which affects the efficacy of recombinant human erythropoietin (EPO) therapy. Intravenous (i.v.) iron preparations are commonly used in Western countries, but iron sucrose is seldom used in Chinese patients on maintenance hemodialysis. The aim of the present study was to explore the safety and efficacy of i.v. iron sucrose in Chinese patients on maintenance hemodialysis and to explore the optimal administration frequency.\n One hundred and thirty-six patients on maintenance hemodialysis were involved in this randomized, controlled, parallel-group, single-center trial. Seventy patients received i.v. iron sucrose (Venofer(R), delivering 100 mg iron) twice a week for 8 weeks, then once a week for another 4 weeks. The other 66 patients received oral (p.o.) ferrous succinate 200 mg t.i.d. for 12 weeks. Levels of serum ferritin (SF), transferrin saturation (TSAT), hemoglobin (Hb) and hematocrit (Hct) were assessed at baseline and then again after 4, 8 and 12 weeks of treatment.\n There were no differences between i.v. and p.o. groups in terms of sex, age, duration of hemodialysis, dialysis frequency per week, EPO dosage per week, the level of intact parathyroid hormone, serum creatinine, blood urea nitrogen, or hematological parameters at baseline. After 8 and 12 weeks of treatment, mean Hb concentration and Hct were significantly increased in the i.v. group, and were also significantly higher than those in the p.o. group. Levels of SF and TSAT were also significantly increased in the i.v. group, and significantly higher than in the p.o. group. After 8 weeks, the response rate in the i.v. group was 88.6%, which was significantly higher than that in the p.o. group. The mean EPO dose was significantly lower in the i.v. group than the p.o. group. Hb, Hct, SF and TSAT levels were maintained between 8 and 12 weeks in the i.v. group despite the decrease in dose frequency. There were no adverse events related to i.v. iron administration. Twenty-two patients in the p.o. group had adverse gastrointestinal effects. After 12 weeks, the cost of EPO + i.v. iron was significantly higher than the cost of EPO + p.o. iron.\n Intravenous iron sucrose can effectively increase serum iron parameters and Hb levels in Chinese patients on maintenance hemodialysis and is well tolerated. Infusion of i.v. iron sucrose 100 mg per week can maintain serum iron parameters and Hb levels in Chinese patients on maintenance hemodialysis and can permit reductions in the required dose of EPO. However, the total cost of i.v. iron is relatively high.\n Copyright 2008 S. Karger AG, Basel." ]	Despite the high incidence and burden of disease associated with this condition, there is a paucity of good quality trials assessing clinical maternal and neonatal effects of iron administration in women with anaemia. Daily oral iron treatment improves haematological indices but causes frequent gastrointestinal adverse effects. Parenteral (intramuscular and intravenous) iron enhances haematological response, compared with oral iron, but there are concerns about possible important adverse effects (for intravenous treatment venous thrombosis and allergic reactions and for intramuscular treatment important pain, discolouration and allergic reactions). Large, good quality trials, assessing clinical outcomes (including adverse effects) as well as the effects of treatment by severity of anaemia are required.
CD008381	[ "21226754", "20040705", "21478777", "15466678", "21216855", "9786808", "21190455", "21196929", "20097780", "18290863", "17570858", "19729522", "19902034", "21788632" ]	[ "Treating depression in diabetes patients: does a nurse-administered minimal psychological intervention affect diabetes-specific quality of life and glycaemic control? A randomized controlled trial.", "Integrating type 2 diabetes mellitus and depression treatment among African Americans: a randomized controlled pilot trial.", "A randomized trial of telephonic counseling plus walking for depressed diabetes patients.", "The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression.", "Web-based depression treatment for type 1 and type 2 diabetic patients: a randomized, controlled trial.", "Cognitive behavior therapy for depression in type 2 diabetes mellitus. A randomized, controlled trial.", "Collaborative care for patients with depression and chronic illnesses.", "Glycemic control improvement through treatment of depression using antidepressant drugs in patients with diabetes mellitus type 1.", "Collaborative care management of major depression among low-income, predominantly Hispanic subjects with diabetes: a randomized controlled trial.", "Psychotherapy intervention to reduce depressive symptoms in patients with diabetic foot syndrome.", "Quality of life and metabolic status in mildly depressed patients with type 2 diabetes treated with paroxetine: a double-blind randomised placebo controlled 6-month trial.", "Effect of pharmacological treatment of depression on A1C and quality of life in low-income Hispanics and African Americans with diabetes: a randomized, double-blind, placebo-controlled trial.", "The impact of pharmaceutical care on the clinical outcome of diabetes mellitus among a rural patient population.", "Cluster-randomized trial of a mobile phone personalized behavioral intervention for blood glucose control." ]	[ "The aim of this study was to examine whether a nurse-administered minimal psychological intervention for depressive symptoms improves diabetes-specific quality of life and glycaemic control in older persons with diabetes.\n Depression is common among persons with diabetes and may have a negative impact on diabetes. Interventions aimed at reducing depressive symptoms may positively influence diabetes-specific quality of life as well.\n A pragmatic, randomized controlled trial was carried out comparing the intervention with usual care among 208 Dutch primary care patients of ≥60 years with type 2 diabetes and co-occurring minor to moderate depression. Data on symptom distress and emotional distress were collected during 2003-2006, and haemoglobin A1c levels were obtained from general practices. Data were analysed using mixed model, repeated measures ANCOVAS. Hba1c was collected retrospectively from general practices between December 2006-February 2007. In July 2007 we retrieved some additional HbA1c data from the medical records of the university hospital.\n Only in higher-educated persons did the intervention have statistically significant effect on both emotional distress and symptom distress (DSC-R total score at 9 months P=0.001; PAID, 9 months P=0.03). Furthermore, we found an effect on symptom distress in men (9 months P=0.01), and on emotional distress in persons with a shorter diabetes duration (<7 years) (9 months P=0.04). A significant trend over time for haemoglobin A1c was found in favour of the intervention, with a statistically significant difference between groups after 9 months (P=0.02).\n The nurse-administered intervention had limited effects on diabetes-specific quality of life. As only certain subgroups benefited, ways of increasing effectiveness in other groups should be explored. The potentially beneficial effect on glycaemic control is encouraging and needs further research because of small numbers in the analysis.\n © 2011 The Authors. Journal of Advanced Nursing © 2011 Blackwell Publishing Ltd.", "The purpose of this study was to examine whether integrating depression treatment into care for type 2 diabetes mellitus among older African Americans improved medication adherence, glycemic control, and depression outcomes.\n Older African Americans prescribed pharmacotherapy for type 2 diabetes mellitus and depression from physicians at a large primary care practice in west Philadelphia were randomly assigned to an integrated care intervention or usual care. Adherence was assessed at baseline, 2, 4, and 6 weeks using the Medication Event Monitoring System to assess adherence. Outcomes assessed at baseline and 12 weeks included standard laboratory tests to measure glycemic control and the Center for Epidemiologic Studies Depression Scale (CES-D) to assess depression.\n In all, 58 participants aged 50 to 80 years participated. The proportion of participants who had 80% or greater adherence to an oral hypoglycemic (intervention 62.1% vs usual care 24.1%) and an antidepressant (intervention 62.1% vs usual care 10.3%) was greater in the intervention group in comparison with the usual care group at 6 weeks. Participants in the integrated care intervention had lower levels of glycosylated hemoglobin (intervention 6.7% vs usual care 7.9%) and fewer depressive symptoms (CES-D mean scores: intervention 9.6 vs usual care 16.6) compared with participants in the usual care group at 12 weeks.\n A pilot randomized controlled trial integrating type 2 diabetes mellitus treatment and depression was successful in improving outcomes among older African Americans. Integrated interventions may be more feasible and effective in real-world practices with competing demands for limited resources.", "Patients with diabetes and depression often have self-management needs that require between-visit support. This study evaluated the impact of telephone-delivered cognitive behavioral therapy (CBT) targeting patients' management of depressive symptoms, physical activity levels, and diabetes-related outcomes.\n Two hundred ninety-one patients with type 2 diabetes and significant depressive symptoms (Beck Depression Inventory scores ≥ 14) were recruited from a community-based, university-based, and Veterans Affairs health care systems. A manualized telephone CBT program was delivered weekly by nurses for 12 weeks, followed by 9 monthly booster sessions. Sessions initially focused exclusively on patients' depression management and then added a pedometer-based walking program. The primary outcome was hemoglobin A1c levels measured at 12 months. Blood pressure was a secondary outcome; levels of physical activity were determined by pedometer readings; depression, coping, and health-related quality of life were measured using standardized scales.\n Baseline A1c levels were relatively good and there was no difference in A1c at follow-up. Intervention patients experienced a 4.26 mm Hg decrease in systolic blood pressure relative to controls (P=0.05). Intervention patients had significantly greater increases in step counts (mean difference, 1131 steps/d; P=0.0002) and greater reductions in depressive symptoms (58% remitted at 12 mo vs. 39%; P=0.002). Intervention patients also experienced relative improvements in coping and health-related quality of life.\n This program of telephone-delivered CBT combined with a pedometer-based walking program did not improve A1c values, but significantly decreased patients' blood pressure, increased physical activity, and decreased depressive symptoms. The intervention also improved patients' functioning and quality of life.", "There is a high prevalence of depression in patients with diabetes mellitus. Depression has been shown to be associated with poor self-management (adherence to diet, exercise, checking blood glucose levels) and high hemoglobin A1c (HbA1c) levels in patients with diabetes.\n To determine whether enhancing quality of care for depression improves both depression and diabetes outcomes in patients with depression and diabetes.\n Randomized controlled trial with recruitment from March 1, 2001, to May 31, 2002.\n Nine primary care clinics from a large health maintenance organization.\n A total of 329 patients with diabetes mellitus and comorbid major depression and/or dysthymia. Intervention Patients were randomly assigned to the Pathways case management intervention (n = 164) or usual care (n = 165). The intervention provided enhanced education and support of antidepressant medication treatment prescribed by the primary care physician or problem-solving therapy delivered in primary care.\n Independent blinded assessments at baseline and 3, 6, and 12 months of depression (Hopkins Symptom Checklist 90), global improvement, and satisfaction with care. Automated clinical data were used to evaluate adherence to antidepressant regimens, percentage receiving specialty mental health visits, and HbA1c levels.\n When compared with usual care patients, intervention patients showed greater improvement in adequacy of dosage of antidepressant medication treatment in the first 6-month period (odds ratio [OR], 4.15; 95% confidence interval [CI], 2.28-7.55) and the second 6-month period (OR, 2.90; 95% CI, 1.69-4.98), less depression severity over time (z = 2.84, P = .004), a higher rating of patient-rated global improvement at 6 months (intervention 69.4% vs usual care 39.3%; OR, 3.50; 95% CI, 2.16-5.68) and 12 months (intervention 71.9% vs usual care 42.3%; OR, 3.50; 95% CI, 2.14-5.72), and higher satisfaction with care at 6 months (OR, 2.01; 95% CI, 1.18-3.43) and 12 months (OR, 2.88; 95% CI, 1.67-4.97). Although depressive outcomes were improved, no differences in HbA1c outcomes were observed.\n The Pathways collaborative care model improved depression care and outcomes in patients with comorbid major depression and/or dysthymia and diabetes mellitus, but improved depression care alone did not result in improved glycemic control.", "Comorbid depression is common in patients with type 1 and type 2 diabetes, adversely affecting quality of life, diabetes outcomes, and mortality. Depression can be effectively treated with cognitive behavior therapy (CBT). The Internet is a new and attractive method for delivering CBT intervention on a large scale at relatively low costs. This study evaluated the effectiveness of Web-based CBT for depression treatment in adults with type 1 or type 2 diabetes, with minimal guidance.\n A randomized controlled trial was conducted in the Netherlands in 255 adult diabetic patients with elevated depressive symptoms. Primary outcomes were depressive symptoms. Secondary outcomes were diabetes-specific emotional distress and glycemic control. Assessments were at baseline, after treatment, and at the 1-month follow-up.\n The Web-based CBT was effective in reducing depressive symptoms by intention-to-treat analyses (P = 0.04, d = 0.29; clinical improvement 41% vs. 24% P < 0.001) and by per-protocol analyses (P < 0.001, d = 0.70; clinical improvement, 56% vs. 24% P < 0.001). The intervention reduced diabetes-specific emotional distress (P = 0.03) but had no beneficial effect on glycemic control (P > 0.05).\n Web-based CBT depression treatment is effective in reducing depressive symptoms in adults with type 1 and type 2 diabetes. In addition, the intervention reduces diabetes-specific emotional distress in depressed patients.", "Psychotherapy is the principal nonpharmacologic method for the management of depression, but its usefulness for depressed patients with diabetes remains unknown.\n To assess the efficacy of cognitive behavior therapy (CBT) for depression in patients with diabetes.\n Randomized, controlled trial.\n Referral-based academic medical center.\n 51 patients with type 2 diabetes and major depression.\n Patients were assigned either to a group that received 10 weeks of individual CBT or to a control group that received no specific antidepressant treatment. All patients participated in a diabetes education program to control for the effects of supportive attention and the possible influence of enhanced diabetes control on mood.\n Degree of depression was measured by using the Beck Depression Inventory; glycemic control was measured by using glycosylated hemoglobin levels. Outcomes were assessed immediately after treatment and 6 months after treatment.\n The percentage of patients achieving remission of depression (Beck Depression Inventory score < or = 9) was greater in the CBT group than in the control group: posttreatment, 85.0% of patients in the CBT group (17 of 20) compared with 27.3% of controls (6 of 22) achieved remission (difference, 57.7 percentage points [95% CI, 33 to 82 percentage points]) (P < 0.001); at follow-up, 70.0% of patients in the CBT group (14 of 20) compared with 33.3% of controls (7 of 21) achieved remission (difference, 36.7 percentage points [CI, 9 to 65 percentage points]) (P = 0.03). Post-treatment glycosylated hemoglobin levels were not different in the two groups, but follow-up mean glycosylated hemoglobin levels were significantly better in the CBT group than in the control group (9.5% compared with 10.9%; P = 0.03).\n The combination of CBT and supportive diabetes education is an effective nonpharmacologic treatment for major depression in patients with type 2 diabetes. It may also be associated with improved glycemic control.", "Patients with depression and poorly controlled diabetes, coronary heart disease, or both have an increased risk of adverse outcomes and high health care costs. We conducted a study to determine whether coordinated care management of multiple conditions improves disease control in these patients.\n We conducted a single-blind, randomized, controlled trial in 14 primary care clinics in an integrated health care system in Washington State, involving 214 participants with poorly controlled diabetes, coronary heart disease, or both and coexisting depression. Patients were randomly assigned to the usual-care group or to the intervention group, in which a medically supervised nurse, working with each patient's primary care physician, provided guideline-based, collaborative care management, with the goal of controlling risk factors associated with multiple diseases. The primary outcome was based on simultaneous modeling of glycated hemoglobin, low-density lipoprotein (LDL) cholesterol, and systolic blood-pressure levels and Symptom Checklist-20 (SCL-20) depression outcomes at 12 months; this modeling allowed estimation of a single overall treatment effect.\n As compared with controls, patients in the intervention group had greater overall 12-month improvement across glycated hemoglobin levels (difference, 0.58%), LDL cholesterol levels (difference, 6.9 mg per deciliter [0.2 mmol per liter]), systolic blood pressure (difference, 5.1 mm Hg), and SCL-20 depression scores (difference, 0.40 points) (P<0.001). Patients in the intervention group also were more likely to have one or more adjustments of insulin (P=0.006), antihypertensive medications (P<0.001), and antidepressant medications (P<0.001), and they had better quality of life (P<0.001) and greater satisfaction with care for diabetes, coronary heart disease, or both (P<0.001) and with care for depression (P<0.001).\n As compared with usual care, an intervention involving nurses who provided guideline-based, patient-centered management of depression and chronic disease significantly improved control of medical disease and depression. (Funded by the National Institute of Mental Health; ClinicalTrials.gov number, NCT00468676.).", "Depression is a common disorder among diabetic patients and affects negatively the treatment of their basic disease. The aim of the study was to assess, whether antidepressant medication could positively influence glycemic control of diabetes type 1 in depressive or anxious patients.\n A six-month, double-blinded, randomized, placebo-controlled study was performed to investigate the reaction of type 1diabetic patients (n=21) to treatment of depression and anxiety symptoms using antidepressant drug sertraline. The patients were given sertraline (100 mg/day) or placebo. The evolution of mental change was assessed using Zung Self-Rating Depression Scale (SDS), Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) along with development of somatic parameters commonly assessed in diabetic patients, especially glycosylated hemoglobin, insulin dose and body weight. The level of active substance in serum of the patients was also measured.\n Mental state improved at the level of statistical significance of p<0.001 in both patients using antidepressant and placebo. From somatic parameters, body weight and systolic blood pressure increased statistically significantly also in both groups of patients.\n The mental state of most patients who successfully completed the study improved regardless of the fact if they were using antidepressant or placebo. No statistically significant connections between the mental and somatic changes were found. This finding points out to the placebo effect of the medication, to the importance of a contact with patients, but also to the need to concentrate on their mental state.", "To determine whether evidence-based socioculturally adapted collaborative depression care improves receipt of depression care and depression and diabetes outcomes in low-income Hispanic subjects.\n This was a randomized controlled trial of 387 diabetic patients (96.5% Hispanic) with clinically significant depression recruited from two public safety-net clinics from August 2005 to July 2007 and followed over 18 months. Intervention (INT group) included problem-solving therapy and/or antidepressant medication based on a stepped-care algorithm; first-line treatment choice; telephone treatment response, adherence, and relapse prevention follow-up over 12 months; plus systems navigation assistance. Enhanced usual care (EUC group) included standard clinic care plus patient receipt of depression educational pamphlets and a community resource list.\n INT patients had significantly greater depression improvement (> or =50% reduction in Symptom Checklist-20 depression score from baseline; 57, 62, and 62% vs. the EUC group's 36, 42, and 44% at 6, 12, and 18 months, respectively; odds ratio 2.46-2.57; P < 0.001). Mixed-effects linear regression models showed a significant study group-by-time interaction over 18 months in diabetes symptoms; anxiety; Medical Outcomes Study Short-Form Health Survey (SF-12) emotional, physical, and pain-related functioning; Sheehan disability; financial situation; and number of social stressors (P = 0.04 for disability and SF-12 physical functioning, P < 0.001 for all others) but no study group-by-time interaction in A1C, diabetes complications, self-care management, or BMI.\n Socioculturally adapted collaborative depression care improved depression, functional outcomes, and receipt of depression treatment in predominantly Hispanic patients in safety-net clinics.", "Compared to the population as a whole, patients with diabetes mellitus suffer a significantly higher rate of depressive symptoms, especially when they develop complications. Psychotherapy treatments in diabetes mellitus can lead to improvements in both depressive symptoms and glycaemic control. The objective of this study was to investigate whether depressive symptoms can be reduced by psychotherapy treatment delivered as a joint interdisciplinary service to in-patients with diabetic foot syndrome and comorbid depression.\n Thirty in-patients with diabetic foot syndrome and comorbid depression were randomized to either an intervention group (n = 15) with supportive psychotherapy treatment or a control group (n = 15) that received only standard medical treatment. Patients completed a set of questionnaires at the beginning and end of treatment. These recorded sociodemographic variables, anxiety and depression (Hospital Anxiety and Depression Scale) and diabetes-related problems (Problem Areas in Diabetes Scale).\n Although the diabetic foot syndrome improved significantly in 75% of patients, the extent of depressive symptoms and anxiety reported by the control group did not decrease by the end of treatment. In contrast, in the intervention group, anxiety, depression and diabetes-related problems were all reduced. The extent of anxiety and depression was not, as had been anticipated, associated with the severity of the physical symptoms.\n These results indicate that psychotherapeutic intervention during in-patient treatment can have a positive influence on anxiety, depressive symptoms and diabetes-related problems in patients with diabetic foot syndrome.", "Depression is prevalent in people with type 2 diabetes and affects both glycaemic control and overall quality of life. The aim of this investigator-initiated trial was to evaluate the effect of the antidepressant paroxetine on quality of life, metabolic control, and mental well-being in mildly depressed diabetics aged 50-70 years.\n We randomised 49 mildly depressed primary care outpatients with non-optimally controlled diabetes to a 6-month double-blind treatment with either paroxetine 20 mg per day or matching placebo. Primary efficacy measurements were quality of life and glycaemic control. The primary global outcome of the study was defined as a 10 points improvement in the SF-36 quality of life score. The primary metabolic outcome of the study was defined as a 0.8%-units decrease in glycosylated haemoglobin A1c(GHbA1c). Psychiatric symptoms were assessed with the Hospital Anxiety and Depression Scale.\n Six patients withdrew their consent before starting medication and six dropped out later in the study. We performed analysis of covariance with the baseline value as a covariate. Quality of life and glycaemic control as well as symptoms of depression and anxiety improved in both groups over the 6-month study period. After three months of treatment we found a statistically significant difference between the two treatment groups in GHbA1c (mean difference = 0.59%-units, p = 0.018) and in SF-36 score (mean difference = 11.0 points, p = 0.039). However, at the end of the study, no statistically significant differences between the treatment groups were observed. No severe adverse events occurred.\n This pragmatic study of primary care patients did not confirm earlier preliminary findings indicating a beneficial effect of paroxetine on glycaemic control. The study indicates that in pragmatic circumstances any possible benefit from administration of paroxetine in diabetic patients with sub-threshold depression is likely to be modest and of short duration. Routine antidepressant prescription for patients with diabetes and sub-threshold depressive symptoms is not indicated.\n Current controlled trials ISRCTN55819922.", "To determine whether pharmacological treatment of depression in low-income minorities with diabetes improves A1C and quality of life (QOL).\n This was a 6-month, randomized, double-blind, placebo-controlled trial. Patients were screened for depression using Whooley's two-question tool at a county diabetes clinic. Depression was confirmed (or not) with the Computerized Diagnostic Interview Survey (CDIS) software program, and the severity of depression was assessed monthly by the Hamilton Depression Scale (HAM-D). Depressed subjects with A1C levels >or=8.0% were randomly assigned to receive either sertraline or placebo. Diabetes care was provided by nurses following detailed treatment algorithms who were unaware of therapy for depression.\n A total of 150 subjects answered positively to at least one question on Whooley's questionnaire. The positive predictive value for depression diagnosed by CDIS was 69, 67, and 84% for positive answers to question 1 only, question 2 only, or both, respectively. Of the 89 subjects who entered the study, 75 completed. An intention-to-treat analysis revealed significant differences between baseline and 6 months in HAM-D and pain scores, QOL, and A1C and systolic blood pressure levels in both groups, with no differences between groups for the first three but a significantly greater decrease with sertraline in A1C and systolic blood pressure levels. Changes in HAM-D scores and A1C levels were significantly correlated in all subjects (P = 0.45 [P < 10(-6)]).\n In this low-income minority population, pharmacological treatment of depression significantly improved A1C and systolic blood pressure levels compared with placebo.", "To evaluate the impact of pharmaceutical care on the clinical outcomes of patients enrolled in a pharmacist-coordinated diabetes management program in a rural health setup.\n Patients were registered into 'control' and 'intervention' groups by randomization at three primary health centers. The study was an open-label parallel study.\n Medical records were prospectively reviewed. Capillary blood glucose level, blood pressure and demographic data were collected at baseline and at the follow-up visits. Pharmacists gave counseling to the intervention group during every visit and their health-related quality of life (HRQoL) was assessed with the Ferrans and Powers questionnaire.\n Single factor ANOVA and the t-test were used to compare the results using SPSS version 0.9 software and MS Excel worksheets.\n The intervention group (n = 104) showed well-controlled BMI, whereas the control group (n = 50) showed significant increase in the BMI. Mean blood glucose level in the intervention group reduced to 25 units from baseline (P = 0.0001) but was significantly increased in the control group (P = 0.0001). ANOVA showed that from the second follow-up onward there was significant decrease in blood glucose levels. Overall, the HRQoL scores increased by 45% in the intervention group and decreased by 2% in the control group.\n The pharmaceutical care program was effective in improving the clinical outcome and HRQoL of diabetes patients in rural India. Such 'pharmaceutical care' models should be fine-tuned and implemented widely.", "To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with standard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes.\n A cluster-randomized clinical trial, the Mobile Diabetes Intervention Study, randomly assigned 26 primary care practices to one of three stepped treatment groups or a control group (usual care). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical (blood pressure) and laboratory (lipid) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient's glycemic control, diabetes medication management, lifestyle behaviors, and evidence-based treatment options.\n The mean declines in glycated hemoglobin were 1.9% in the maximal treatment group and 0.7% in the usual care group, a difference of 1.2% (P < 0.001) over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels (all P > 0.05).\n The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence-based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year." ]	Psychological and pharmacological interventions have a moderate and clinically significant effect on depression outcomes in diabetes patients. Glycaemic control improved moderately in pharmacological trials, while the evidence is inconclusive for psychological interventions. Adherence to diabetic treatment regimens, diabetes complications, death from any cause, health economics and QoL have not been investigated sufficiently. Overall, the evidence is sparse and inconclusive due to several low-quality trials with substantial risk of bias and the heterogeneity of examined populations and interventions.
CD004065	[ "9219072", "7853047" ]	[ "Prevalence study of the randomized controlled trials in the Journal of Intellectual Disability Research: 1957-1994.", "Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care." ]	[ "Systematic reviews of care are increasingly potent guides to clinical practice, and it is important that all relevant randomized controlled trials (RCTs) are identified by those within the speciality of learning disability who produce such works. All RCTs in the Journal of Intellectual Disability Research and its predecessor were identified by hand-searching (1957-1994), and the frequency, origin, intervention and quality of reporting of randomization were described. Electronic searches for the trials were undertaken for the years 1974-1994, and the quality of indexing was inspected and tested. These electronic searches were then compared to a 'gold standard' search. Fifty-six RCTs were identified. None contained the world 'randomized' in the title and only nine mentioned it in the abstract. Out of the 37 RCTs published between 1974 and 1994, 36 are in PsycLIT and 37 in MEDLINE. One MEDLINE record contained the wrong abstract. The methodological phrases used in the electronic records were poor, and thus, the precision of electronic searches, using both databases, was low. This international journal contains many relevant RCTs from around the world, involving several types of interventions. Unfortunately, these trials cannot be readily accessed electronically using methodological phrases designed to find RCTs. Improved quality of indexing would facilitate identification of RCTs and their dissemination.", "Cumulative meta-analysis of clinical trials (a Bayesian interpretation for accumulating evidence) will profoundly affect medical care by summarizing evidence in the assessment of technology innovations. Application of the technique to the randomized control trials (RCTs) of streptokinase treatment of acute myocardial infarction, reduction of peri-operative mortality by antibiotic prophylaxis, and prevention of death from bleeding peptic ulcers has revealed efficacy years before it was suspected by any other means. Arrangement of the trials according to event rate in the controls, effect sizes, quality of the trials or according to covariables of interest has supplied unique information. If carried out prospectively the technique supplies invaluable information regarding indications for another trial, the number of patients necessary to determine the validity of past trends, and the type of patients who might be benefitted. Careful examination in a cumulative manner of the prior trials can reduce the need for future large trials." ]	As only three relevant RCTs were identified, we have limited capacity to compare the benefits and harms of medical interventions currently used for treating EE. Further RCTs on therapies for EE are required.
CD004913	[ "15680454", "15837236", "11923490", "15353533", "16139395", "11923489", "12824212", "12925845", "16107961", "11144370" ]	[ "Safety and immunogenicity of new cell-cultured smallpox vaccine compared with calf-lymph derived vaccine: a blind, single-centre, randomised controlled trial.", "A novel, cell culture-derived smallpox vaccine in vaccinia-naive adults.", "Clinical responses to undiluted and diluted smallpox vaccine.", "Vaccination success rate and reaction profile with diluted and undiluted smallpox vaccine: a randomized controlled trial.", "Clinical and immunological responses to undiluted and diluted smallpox vaccine with vaccinia virus of Lister strain.", "Dose-related effects of smallpox vaccine.", "Response to smallpox vaccine in persons immunized in the distant past.", "Clonal vaccinia virus grown in cell culture as a new smallpox vaccine.", "Clinical responses to smallpox vaccine in vaccinia-naive and previously vaccinated populations: undiluted and diluted Lancy-Vaxina vaccine in a single-blind, randomized, prospective trial.", "Immunogenicity and safety of a new liquid hexavalent combined vaccine compared with separate administration of reference licensed vaccines in infants." ]	[ "US government organisations have identified the need for a new smallpox vaccine to replenish limited stocks of the approved, calf-lymph derived vaccine, the manufacture of which is no longer acceptable. We aimed to compare the safety and immunogenicity of the new cell-cultured smallpox vaccine (CCSV) to that of the calf-lymph derived vaccine (as a positive control) in 350 healthy, adult volunteers.\n We did a randomised controlled study at the University of Kentucky Medical Center. We randomised 150 vaccinia-naive volunteers, aged 18-30 years, and 100 vaccinia-non-naive people, aged 32-65 years, to equivalent doses of either CCSV or test vaccine (2.5x10(5) plaque-forming units) by 15 puncture scarification in double-blind fashion. Immunogenicity was assessed by pock formation (take rate), humoral immune response by plaque-reduction neutralisation titres, and cellular immune response by vaccinia-specific, interferon-gamma T-cell quantification, cytotoxicity, and T-cell proliferation response. A further 100 vaccine-naive individuals, aged 18-30 years, received one of five doses of CCSV (undiluted, diluted 1 in 5, 1 in 10, 1 in 25, and 1 in 50) in single-blind fashion. Routine laboratory assessments, physical examinations, and recording of adverse events were done to assess vaccine safety. The primary endpoints were safety and reactogenicity (take rate) of CCSV.\n 349 (99.7%) of 350 volunteers developed pock lesions; one vaccinia-naive individual who received a 1 in 25 dilution of CCSV did not. The rate of adverse events related to vaccine and the extent of humoral and cellular immune responses did not differ between the vaccine groups in vaccinia-naive or non-naive people. CCSV was immunogenic in vaccine-naive volunteers at a dose 50 times lower than that approved for Dryvax.\n CCSV seems to be a safe and immunogenic alternative to calf-lymph derived vaccine for both vaccinia-naive and non-naive people.", "Despite the eradication of smallpox as a naturally occurring disease, concern persists over its potential use as a bioterrorist agent. The development of a new-generation smallpox vaccine represents an important contribution to a cogent biodefense strategy. We conducted a phase 2 randomized, double-blind, controlled trial at four sites in the United States to determine whether a clonal smallpox vaccine manufactured in cell culture, ACAM2000, is equivalent to the standard calf-lymph vaccine, Dryvax, in terms of cutaneous response rate, antibody responses and safety. Subjects received either Dryvax or one of four dose levels of ACAM2000 administered percutaneously using a bifurcated needle. All subjects in the highest ACAM2000 dose group and the Dryvax group experienced a successful vaccination. Dilution doses of ACAM2000 were associated with success rates below the 90% threshold established for efficacy. There were no differences in the proportion of subjects who developed neutralizing antibody: 94% in the highest ACAM2000 dose group (95% CI, 84-99) and 96% in the Dryvax group (95% CI, 86-100). No significant differences were seen between the effective ACAM2000 and Dryvax groups regarding the occurrence of adverse events. One subject who received ACAM2000 developed myopericarditis. In healthy, primary vaccines ACAM2000 has a similar vaccination success rate, antibody response, and safety profile to Dryvax.", "To evaluate the potential to increase the supply of smallpox vaccine (vaccinia virus), we compared the response to vaccination with 10(8.1), 10(7.2), and 10(7.0) plaque-forming units (pfu) of vaccinia virus per milliliter.\n In this randomized, single-blind, prospective study, 680 adults who had not been previously immunized were inoculated intradermally with undiluted vaccine (mean titer, 10(8.1) pfu per milliliter), a 1:5 dilution, or a 1:10 dilution of vaccinia virus with use of a bifurcated needle, and the site was covered with a semipermeable dressing. Subjects were monitored for vesicle formation (an indicator of the success of vaccination) and adverse events for 56 days after immunization.\n Success rates did not differ significantly among the groups and ranged from 97.1 to 99.1 percent after the first vaccination. Both the undiluted and diluted vaccines were reactogenic. In addition to the formation of pustules, common adverse events included the formation of satellite lesions, regional lymphadenopathy, fever, headache, nausea, muscle aches, fatigue, and chills consistent with the presence of an acute viral illness. Generalized and localized rashes, including two cases of erythema multiforme, were also observed.\n When given by a bifurcated needle, vaccinia virus vaccine can be diluted to a titer as low as 10(7.0) pfu per milliliter (approximately 10,000 pfu per dose) and induce local viral replication and vesicle formation in more than 97 percent of persons.", "Additional smallpox vaccine doses are needed to augment current US national stockpile. Aventis Pasteur smallpox vaccine (APSV), initially manufactured in the 1950s from the New York Board of Health vaccinia strain in a frozen preparation, appears as effective as lyophilized vaccine but the effectiveness of diluted doses of APSV is unclear.\n To compare the vaccination success rate and the reaction profile of various APSV dilutions.\n A double-blind, randomized controlled trial of 340 healthy vaccinia-naive adults aged 18 to 32 years from 3 academic medical centers who were vaccinated with 1 of 3 strengths of APSV dilutions (undiluted, 1:5, and 1:10) between October 9, 2002, and February 24, 2003. Volunteers were followed up every 3 to 5 days until the vaccination site healed for bandage changes, vaccine response assessment, and adverse event evaluation, followed by 1- and 2-month clinic evaluations and 6-month telephone interview.\n Successful vaccination, defined by presence of a vesicle or pustule at the inoculation site 6 to 11 days postvaccination, and local and systemic reactions to vaccination.\n A total of 340 volunteers were vaccinated (vaccine dose: undiluted, n = 113; 1:5 dilution, n = 114; and 1:10 dilution, n = 113). Following vaccination, 99.4% (95% confidence interval [CI], 97.9%-99.9%) of all volunteers had successful vaccinations. Success rates did not differ between the dilution groups (undiluted, 100.0%; 95% CI, 96.8%-100.0%; 1:5 dilution, 98.2%; 95% CI, 93.8%-99.8%; 1:10 dilution, 100.0% 95% CI, 96.8%-100.0%; P =.33). Overall, 99.7% of volunteers reported at least 1 local symptom at the vaccination site, and 61.8% had axillary lymphadenopathy, 15.0% developed satellite lesions, and 7.6% developed a rash away from the vaccination site. Fever developed in 21.5%. No differences were noted in local or systemic reactions between the 3 dilution groups (P>.05 for each comparison). A total of 25% of volunteers missed scheduled duties due to vaccine-related symptoms.\n Even at diluted doses, APSV is an effective smallpox vaccine, allowing for expansion of the current stockpile. However, reactogenicity was not reduced with dilution of the vaccine and, as with other smallpox vaccines, may impair daily activities.", "The potential to increase the supply of vaccine by diluting the vaccinia virus of Lister strain to face possible bioterrorism with smallpox was evaluated. Vaccinia-naïve subjects (n=97) were randomized to receive either undiluted or diluted (1:5, 1:10) vaccine, and previously vaccinated subjects (n=122) were randomized to receive either undiluted or diluted (1:10, 1:30) vaccine. Except two subjects who received 1:30 diluted vaccine, the vaccination of all subjects was successful clinically. All subjects had significant vaccinia-specific T cell and antibody responses. The diluted vaccine was not associated with decreased local or systemic reactions, lower T cell responses, or higher antibody titers when compared with undiluted vaccine. Here we show the diluted vaccine of Lister strain can be used in vaccinia-naïve subjects and previously vaccinated subjects if viral titer > or =10(8) and 10(7.5) pfu/mL after dilution, respectively. The reactogenicity of vaccinia virus may not be a dose-dependent response.", "We conducted a double-blind, randomized trial of three dilutions of vaccinia virus vaccine in previously unimmunized adults in order to assess the clinical success rates, humoral responses, and virus-specific activity of cytotoxic T cells and interferon-gamma-producing T cells.\n Sixty healthy adults were inoculated intradermally by bifurcated needle with undiluted vaccine (dose, 10(7.8) plaque-forming units [pfu] per milliliter), a 1:10 dilution (dose, 10(6.5) pfu per milliliter), or a 1:100 dilution (dose, 10(5.0) pfu per milliliter); there were 20 subjects in each group. The subjects were monitored with respect to vesicle formation (an indicator of successful vaccination), the viral titer at the time of peak lesion formation, antiviral antibodies, and cellular immune responses.\n A vaccinia vesicle developed in 19 of the 20 subjects who received undiluted vaccine (95 percent), 14 of the 20 who received the 1:10 dilution (70 percent), and 3 of the 20 who received the 1:100 dilution (15 percent). One month after vaccination, 34 of 36 subjects with vesicles had antibody responses, as compared with only 1 of 24 subjects without clinical evidence of vaccinia virus replication. Vigorous cytotoxic T-cell and interferon-gamma responses occurred in 94 percent of subjects with vesicles, and a cytotoxic T-cell response occurred in only one subject without a vesicle.\n The vaccinia virus vaccine (which was produced in 1982 or earlier) still has substantial potency when administered by a bifurcated needle to previously unvaccinated adults. Diluting the vaccine reduces the rate of successful vaccination. The development of vesicular skin lesions after vaccination correlates with the induction of the antibody and T-cell responses that are considered essential for clearing vaccinia virus infections.", "There is renewed interest in use of smallpox vaccine due to the potential for a bioterrorist attack. This would involve vaccinating health care workers who were previously vaccinated.\n To evaluate the use of diluted vaccinia virus in vaccination of previously vaccinated (non-naive) participants.\n Eighty non-naive participants, aged 32 to 60 years, were randomized in a single-blinded study to receive either undiluted or diluted (1:3.2, 1:10, or 1:32) doses of smallpox vaccine. A comparison group, aged 18 to 31 years, of 10 vaccinia-naive participants received undiluted vaccine. Participants were enrolled between April 1 and May 15, 2002, at the National Institute of Allergy and Infectious Diseases Vaccine and Treatment Evaluation Unit at Saint Louis University, St Louis, Mo.\n Smallpox vaccine was administered by scarification using 15 skin punctures in the deltoid region of the arm.\n Presence of a major reaction, defined as a vesicular or pustular lesion or area of palpable induration surrounding a central lesion following vaccination, and measures of viral shedding and antibody titers.\n Initial vaccination resulted in a major reaction in 64 of 80 non-naive participants. Ninety-five percent of non-naive participants had major reactions in the undiluted group, 90% in the 1:3.2 dilution group, 81% in the 1:10 dilution group, and 52.6% in the 1:32 dilution group. All (n = 10) of the vaccinia-naive participants had major reactions. Compared with vaccinia-naive participants, non-naive participants had significantly smaller skin lesions (P =.04) and significantly less incidence of fever (P =.02). Preexisting antibody was present in 76 of 80 non-naive participants. Antibody responses were significantly higher and occurred more rapidly in the non-naive participants compared with the vaccinia-naive participants (P =.002 for day 28 and P =.003 for 6 months). Vaccinia-naive participants shed virus from the vaccination site 2 to 6 days longer and had significantly higher peak mean viral titers when compared with the non-naive participants (P =.002).\n Previously vaccinated persons can be successfully revaccinated with diluted (<or=1:10) smallpox vaccine. Fewer adverse reactions were observed in this study of non-naive participants when compared with events in vaccinia-naive participants, which may be due to immunologic memory.", "Although the smallpox virus was eradicated over 20 years ago, its potential release through bioterrorism has generated renewed interest in vaccination. To develop a modern smallpox vaccine, we have adapted vaccinia virus that was derived from the existing Dryvax vaccine for growth in a human diploid cell line. We characterized six cloned and one uncloned vaccine candidates. One clone, designated ACAM1000, was chosen for development based on its comparability to Dryvax when tested in mice, rabbits and monkeys for virulence and immunogenicity. By most measures, ACAM1000 was less virulent than Dryvax. We compared ACAM1000 and Dryvax in a randomized, double-blind human clinical study. The vaccines were equivalent in their ability to produce major cutaneous reactions ('takes') and to induce neutralizing antibody and cell-mediated immunity against vaccinia virus.", "We conducted a single-blind, randomized trial of 2 dilutions (1:1 or 1:10) of Lancy-Vaxina vaccine (Berna Biotech) in vaccinia-naive persons (n=36) and persons previously vaccinated >25 years ago (n=76). All vaccinees responded successfully to the vaccination. There were no significant differences in the size of the skin lesions, the number of adverse events, the amount of viral shedding, or the level of antibody responses between the undiluted (n=56) and diluted (n = 56) vaccine groups. Compared with vaccinia-naive persons, previously vaccinated persons exhibited significantly smaller and more rapidly evolving skin lesions and fewer adverse events. Previously vaccinated persons had significantly higher neutralizing antibody levels before the administration of the study vaccine than vaccinia-naive persons, and viral shedding from lesions in previously vaccinated persons was lower and diminished more rapidly than from lesions in vaccinia-naive persons.", "The immunogenicity and safety of a new liquid hexavalent vaccine (diphtheria-tetanus-acellular pertussis-inactivated polio vaccine-hepatitis B-polyribosyl ribitol phosphate conjugated to tetanus protein; Hexavac; Aventis Pasteur MSD, Lyon, France) are compared with those of reference vaccines [diphtheria-tetanus-acellular pertussis-inactivated polio vaccine reconstituting lyophilized purified Haemophilus influenzae polysaccharide conjugated to tetanus protein vaccine (Pentavac; Aventis Pasteur MSD) and hepatitis B vaccine (H-B-Vax II; Aventis Pasteur MSD)] injected separately at the same visit in a prospective multicenter, comparative, open label trial.\n Infants were randomized to receive Hexavac (n = 423) or Pentavac and H-B-Vax II (n = 425) as a primary immunization series at 2, 4 and 6 months of age. Seroprotection and seroconversion rates against all antigens at 1 month after the primary series were compared between the two vaccine groups with 95% confidence intervals (CI0.95) and were considered clinically equivalent (not inferior) when the upper limit of the 95% confidence interval on the difference (reference, hexavalent) was below predefined differences.\n Hexavac met and surpassed the pre-defined criteria for clinical equivalence to Pentavac and H-B-Vax II given concomitantly. It elicited similar seroprotection and seroconversion rates against all antigens. Seroprotection and seroconversion rates obtained 1 month after the third dose of Hexavac were >90% for all antigens. The postimmunization antibody geometric mean titers (GMT) for hepatitis B and purified Haemophilus influenzae polysaccharide were about 2-fold higher in infants who received the reference vaccines than in infants who had received Hexavac. GMTs for poliovirus antibodies tended to be enhanced in infants vaccinated with Hexavac. GMTs for all other antigens were very similar among both groups. Hexavac was generally well-tolerated. At least one local reaction was reported in 20.3% of Hexavac injections compared with 15.8% at the Pentavac injections site and 3.8% at the H-B-Vax II injections site. These reactions were generally mild and transient. At least one systemic adverse event was reported in 45.7% of Hexavac injections compared with 42.2% of Pentavac and H-B-Vax II injections (mild fever, irritability and drowsiness were most frequently reported). The frequency of adverse events was not significantly different between groups. No vaccine-related serious adverse event occurred during the study.\n This liquid hexavalent vaccine was generally well-tolerated and provided immune responses adequate to be protective against six infectious diseases with a single injection, given at 2, 4 and 6 months of age." ]	The evidence shows that stockpiled vaccines have maintained their immunogenicity and new cell-cultured vaccines are similar to stockpiled vaccines in terms of vaccination success rate and immunogenicity. First- and second-generation vaccines diluted to at least 1:10 are as effective as undiluted vaccine in terms of clinical success rate and immunogenicity. Dilution did not reduce the frequency of adverse events. Success rate and immunogenicity were similar in naive and previously vaccinated persons, but there were fewer adverse events in previously vaccinated persons. The rate of adverse events found in this review reveals the need for further development and improvement of smallpox vaccines.
CD003588	[ "9644707", "10432161", "3114506", "10203434", "15357156", "11310690", "10772372", "2878025", "3646182", "6708261", "8219661", "7933425" ]	[ "Changing i.v. administration sets: is 48 versus 24 hours safe for neutropenic patients with cancer?", "A randomized trial of 72- versus 24-hour intravenous tubing set changes in newborns receiving lipid therapy.", "Prospective study of replacing administration sets for intravenous therapy at 48- vs 72-hour intervals. 72 hours is safe and cost-effective.", "Changing parenteral nutrition administration sets every 24 h versus every 48 h in newborn infants.", "Routine changing of intravenous administration sets does not reduce colonization or infection in central venous catheters.", "Optimal frequency of changing intravenous administration sets: is it safe to prolong use beyond 72 hours?", "Impact of pharmacy counseling on compliance and effectiveness of combination lipid-lowering therapy in patients undergoing coronary artery revascularization: a randomized, controlled trial.", "Contamination of intravenous infusion systems--the effect of changing administration sets.", "Intravenous tubing containing burettes can be safely changed at 72 hour intervals.", "Intravenous tubing with burettes can be safely changed at 48-hour intervals.", "A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis. Rapid improvement of clinical manifestations and changes in neutrophil leukotriene profile.", "Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome." ]	[ "To examine the effects of changing i.v. administration sets at 48 versus 24 hours on the incidence of infusion-related septicemia in neutropenic patients with cancer.\n Prospective, randomized clinical trial with repeated measures.\n Large urban cancer center.\n 50 adult inpatients with a primary diagnosis of hematologic malignancy, breast cancer, or testicular cancer or who were receiving a stem cell transplant.\n Subjects were assigned randomly to have their i.v. sets changed every 48 or 24 hours. Subjects continued in the study for a maximum of five measurements, until they were no longer neutropenic, or until transferred or discharged from the hospital.\n Rates of infusate colonization, microorganisms identified, incidence of infusion-related septicemia.\n Colonized infusate was detected in 18 (5%) of 413 i.v. sets; 9 (5%) of 177 sets were changed at 48 hours, and 9 (4%) of 236 sets were changed at 24 hours (p > 0.05). A trend toward increased colonization of i.v. sets used to administer parenteral nutrition (19%) and, to a lesser extent, electrolytes (9%) was identified in the 48-hour group. Coagulase-negative staphylococci were the most frequently isolated microorganisms in the i.v. infusate. Similar organisms were isolated from blood cultures and administration sets, however, no subject had identical organisms isolated from both i.v. infusate and blood cultures. No subject with colonized infusate developed infusion-related septicemia.\n No difference existed in the incidence of colonization or infusion-related septicemia between subjects whose i.v. administration sets were changed at 48 versus 24 hours.\n Changing i.v. administration sets every 48 hours is recommended. Exceptions to this include i.v. administration sets used to administer blood products and total parenteral nutrition.", "To compare the microbial contamination rate of infusate in the intravenous tubing of newborns receiving lipid therapy, replacing the intravenous delivery system at 72-hour versus 24-hour intervals.\n Infants requiring intravenous lipid therapy were randomly assigned to have intravenous sets changed on a 72- or a 24-hour schedule, in a 3:1 ratio, in order to compare the infusate contamination rates in an equivalent number of tubing sets.\n A 35-bed, teaching, referral, neonatal intensive-care unit (NICU).\n All neonates admitted to the NICU for whom intravenous lipid was ordered.\n Patients were randomized in pharmacy, on receipt of the order for intravenous lipid therapy, to either 72- or 24-hour administration set changes, and followed until 1 week after discontinuation of lipids or discharge from the NICU. Microbial contamination of the infusate was assessed in both groups at the time of administration set changes. Contamination rates were analyzed separately for the lipid and amino acid-glucose tubing sets. Patient charts were reviewed for clinical and epidemiological data, including birth weight, gestational age, gender, age at start of lipid therapy, duration of parenteral nutrition, and type of intravenous access.\n During the study period, 1,101 and 1,112 sets were sampled in the 72- and 24-hour groups, respectively. Microbial contamination rates were higher in the 72-hour group than the 24-hour group for lipid infusions (39/1,101 [3.54%] vs 15/1,112 [1.35%]; P=.001) and for amino acid infusions (12/1,093 [1.10%] vs 4/1,103 [0.36%]; P=.076). Logistic regression analysis controlling for birth weight, gestational age, and type of venous access showed that only the tubing change interval was significantly associated with lipid set contaminations (odds ratio, 2.69; P=.0013). The rate of blood cultures ordered was higher in the 72- versus the 24-hour group (6.11 vs 4.99 per 100 patient days of total parenteral nutrition; P=.017), and a higher proportion of infants randomized to the 72-hour group died (8% vs 4%; P=.05), although the excess deaths could not clearly be attributed to bacteremia.\n Microbial contamination of infusion sets is significantly more frequent with 72- than with 24-hour set changes in neonates receiving lipid solutions. This may be associated with an increased mortality rate.", "We prospectively studied the safety of replacing intravenous delivery systems, including those used in total parenteral nutrition, at 72- compared with 48-hour intervals in 487 patients. Although the prevalence of contamination of intravenous fluid was higher in administration sets replaced at 72-hour intervals (10/664, 1.5%) than in sets replaced every 48 hours (6/710, 0.8%), the difference is not statistically significant. Contamination in both groups was almost exclusively with small numbers of coagulase-negative staphylococci (range, 1 to 27 colony-forming units/mL); no contaminated infusion was associated with clinical signs of sepsis or concordant bacteremia. Contaminants were recovered less frequently from peripheral venous infusions (0.6%) than from infusions used for central venous access or hemodynamic monitoring (1.5%) or total parenteral nutrition (3.6%); infusions in an intensive care unit were more frequently contaminated (2.5%) than infusions on medical and surgical wards (0.9%). These data indicate that extrinsic contamination of intravenous fluid is a rare cause of endemic nosocomial septicemia, and for most infusions it is unnecessary to routinely replace delivery systems more frequently than every 72 hours.", "To determine whether changing total parenteral nutrition fluid administration sets (TAS) every 48 h rather than every 24 h results in a greater infusate contamination rate.\n Prospectively, 166 infants were assigned at random to have TAS changed either every 24 h or every 48 h. Samples of the infusate were cultured to determine contamination rates of the infusate in the sets and were tested from 149 of these infants. TAS was replaced every 24 h in the control group, and 445 amino acid plus dextrose solutions (AADS) and 449 lipid emulsions samples were taken for bacterial culture. Fungal cultures were also performed on 449 samples. The study group had TAS replaced every 48 h, and 454 samples of AADS were cultured for bacteria. The numbers of lipid emulsion samples sent for bacterial culture and fungal culture were 449 and 440, respectively. Information on type of intravenous access device, administration of antibiotics and blood cultures was also collected.\n There was no difference in bacterial contamination rates for AADS or lipid emulsion from TAS changed every 24 or 48 h (c2, P>0.05). Lipid emulsion sampled from the 24 h group showed a statistically significant higher rate of fungal contamination than specimens from the 48 h group (P<0.01).\n Changing TAS every 48 h versus 24 h does not increase the contamination rate of infusate in newborns.", "To determine the effect of routine intravenous (IV) administration set changes on central venous catheter (CVC) colonization and catheter-related bacteremia.\n Prospective, randomized, controlled trial.\n Eighteen-bed intensive care unit (ICU) in a large metropolitan hospital.\n Two hundred fifty-one patients with 404 chlorhexidine gluconate and silver sulfadiazine-coated multi-lumen CVCs.\n CVCs inserted in the ICU and in situ on day 4 were randomized to have their IV administration sets changed on day 4 (n = 203) or not at all (n = 201). Use of fluid containers and blood product administration sets was limited to 24 hours. CVCs were removed when not required, infection was suspected, or in place on day 7. Catheter cultures were performed on removal by blinded laboratory staff. Catheter-related bacteremia was diagnosed by a blinded intensivist using strict definitions. Data were collected regarding catheter duration, site, Acute Physiology and Chronic Health Evaluation (APACHE) II score, patient age, diagnosis, hyperglycemia, hypoalbuminemia, immune status, number of fluid containers and IV injections, and administration of propofol, blood, total parenteral nutrition, or lipid infusion.\n There were 10 colonized CVCs in the group receiving a set change and 19 in the group not receiving one. This difference was not statistically significant on Kaplan-Meier survival analysis. There were 3 cases of catheter-related bacteremia per group. Logistic regression found that burns diagnosis and increased ICU stay significantly predicted colonization.\n IV administration sets can be used for 7 days in patients with short-term, antiseptic-coated CVCs.", "To determine the safety and cost-effectiveness of replacing the intravenous (IV) tubing sets in hospitalized patients at 4- to 7-day intervals instead of every 72 hours.\n Prospective, randomized study of infusion-related contamination associated with changing IV tubing sets within 3 days versus within 4 to 7 days of placement.\n A tertiary university cancer center.\n Cancer patients requiring IV infusion therapy were randomized to have the IV tubing sets replaced within 3 days (280 patients) or within 4 to 7 days of placement (232 patients). Demographic, microbiological, and infusion-related data were collected for all participants. The main outcome measures were infusion- or catheter-related contamination or colonization of IV tubing, determined by quantitative cultures of the infusate, and infusion- or catheter-related bloodstream infection (BSI), determined by quantitative culture of the infusate in association with blood cultures in febrile patients.\n The two groups were comparable in terms of patient and catheter characteristics and the agents given through the IV tubing. Intent-to-treat analysis demonstrated a higher level of tubing colonization in the 4- to 7-day group versus the 3-day group (median, 145 vs 50 colony-forming units; P=.02). In addition, there were three episodes of possible infusion-related BSIs, all of which occurred in the 4- to 7-day group (P=.09). However, when the 84 patients who received total parenteral nutrition, blood transfusions, or interleukin-2 through the IV tubing were excluded, the two groups had a comparable rate of colonization (0.4% vs 0.5%), with no catheter- or infusion-related BSIs in either group.\n In patients at low risk for infection from infusion- or catheter-related infection who are not receiving total parenteral nutrition, blood transfusions, or interleukin-2, delaying the replacement of IV tubing up to 7 days may be safe, as well as cost-effective", "This randomized, controlled trial evaluated the impact of personalized follow-up on compliance rates in high-risk patients receiving combination lipid-lowering therapy over 2 years. A random sample of 30 patients 7-30 days after cardiac surgery had baseline fasting low-density lipoprotein levels higher than 130 mg/dl. All patients received lovastatin 20 mg/day and colestipol 5 g twice/day. Weekly telephone contact was made with each patient for 12 weeks. Short- and long-term compliance was assessed by pill and packet counts and refill records. Compliance and lipid profile results were significantly better in the intervention group (p<0.05) up to 2 years after the start of therapy than in the control group for all parameters except high-density lipoprotein. However, this effect was not apparent during the first 12 weeks of therapy. Short-term telephone follow-up favorably affected compliance and lipid profile results up to 2 years after start of therapy.", "Intravenous administration sets were changed at varying time intervals between every 24 h and 120 h in 387 patients. The rates of intraluminal contamination of the cannulae and of local inflammation were measured in relation to the time interval between changing sets. There was no correlation between phlebitis and intraluminal contamination, but a significant association was found between phlebitis and fever, infusion of potassium at greater than 10 mmol l-1, Venflon type 140 and infusion of blood or intralipid. No correlation was found between septicaemia and intraluminal contamination of the infusion systems. Contamination of cannulae increased slightly with time, but this was not statistically significant. We conclude that there will be no clinical benefit by daily changing of administration sets, compared with changing up to every fifth day.", "No studies testing the safety of changing intravenous systems containing in-line burettes at 72 hours in an intensive care setting have been performed. Patients entering a medical or surgical intensive care unit were alternatively assigned to have any line with an in-line burette changed at either 48 hour (105 patients) or 72 hour (65 patients) intervals. Daily quantitative cultures with a 2 ml aliquot of burette fluid were obtained. Contaminated burette fluid was detected in 60 of 1181 (5.0%, 95% confidence interval, 3.7% to 6.3%) samples from the burettes changed at 48 hour intervals, and in 40 of 901 (4.4%, 95% confidence interval, 3.0% to 5.8%) samples from 72 hour interval burettes. Significant bacterial contamination of burette fluid, defined as ten or more colonies per milliliter, occurred in only seven (0.6%) cultures from patients in the 48 hour interval group compared with only three (0.3%) cultures in the 72 hour group. None of the contaminated burette fluids was associated with a primary bacteremia. Change of in-line burettes in patients in intensive care at 72-hour intervals is safe and should result in substantial cost savings to hospitals.", "No studies of safety in changing intravenous systems containing in-line burettes at 48 hours in an intensive care setting have been performed. Patients entering a surgical intensive care unit were alternatively assigned to have any line with an in-line burette changed at either 24-hour (64 patients) or 48-hour (59 patients) intervals. Daily quantitative cultures with a 2-mL aliquot of burette fluid were obtained. Contaminated burette fluid was detected in nine of 452 (2.0%; 95% confidence interval, 0.7% to 3.3%) samples from 24-hour interval burettes and in nine of 224 (4.0%; 95% confidence interval, 1.4% to 6.6%) samples from 48-hour interval burettes. Bacterial contamination of burette fluid with ten or more colonies per milliliter occurred in only five (1.1%) cultures from patients in the 24-hour interval group compared with only two cultures (0.9%) in the 48-hour group. None of the contaminated burette fluids was associated with primary bacteremia. Change of in-line burettes in intensive care at 48-hour intervals is safe and should result in substantial cost savings.", "Twenty patients hospitalized for acute psoriasis guttata with a minimum 10% of body surface area involvement (range 10-90%) completed a 10-day trial in which they were randomly allocated to receive daily infusions with either an n-3 fatty acid based lipid emulsion [100 ml/day with 2.1 g eicosapentaenoic (EPA) and 21 g docosahexaenoic acid (DHA)] or a conventional n-6 lipid emulsion (EPA + DHA < 0.1 g/100 ml). The severity of disease was evaluated by scoring daily erythema, infiltration, and desquamation and by a subjective scoring of clinical manifestations offered by the patients. Leukotriene (LT) and platelet-activating factor (PAF) generation were investigated in ionophore-stimulated neutrophils obtained on days 0, 1, 3, 5, 10, and 40. Moderate improvement in clinical manifestations was noted in the n-6 group (changes in score systems between 16-25% from baseline within 10 days). In contrast, the severity of disease markedly decreased in all patients of the n-3 group, with improvements in all score systems ranging between 45% and 76% within 10 days (P < 0.05 for each variable). The difference in response to the two regimens was evident within 4-7 days after onset of lipid infusion. A more than ten fold increase in neutrophil EPA-derived 5-lipoxygenase product formation (LTB5, its omega-oxidation products, non-enzymatic degradation products of LTA5 and 5-hydroxyeicosapentaenoic acid) was noted in the n-3 group but not in the n-6 group. Neutrophil PAF generation increased in the n-6 group but decreased in the n-3 group. In conclusion, modulation of eicosanoid metabolism by intravenous n-3 fatty acid supplementation appears to exert a rapid beneficial effect on inflammatory skin lesions in acute guttate psoriasis.", "To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome (ARDS).\n A prospective, double-blind, placebo-controlled, randomized, parallel, multicenter pilot clinical trial.\n A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome.\n Patients were randomized into four treatment groups in a 2:1:2:1 ratio, as follows: 12 hours of surfactant per day, 12 hours of 0.6% saline per day, 24 hours of surfactant per day, and 24 hours of 0.6% saline per day. Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration.\n Ventilatory data, arterial blood gases, and hemodynamic parameters were measured at baseline, every 4 or 8 hours during the 5 days of treatment, 24 hours after treatment, and 30 days after treatment, at which time mortality was also assessed. Safety was evaluated throughout the 30 days of the study.\n Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system. Although there were no differences in any physiological parameters between the treatment groups, there was a dose-dependent trend in reduction of mortality from 47% in the combined placebo group to 41% and 35% in the groups treated with 12 hours and 24 hours of surfactant per day, respectively.\n Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days; however, at the doses given, it did not result in significant improvements in patients with sepsis-induced ARDS." ]	It appears that administration sets that do not contain lipids, blood or blood products may be left in place for intervals of up to 96 hours without increasing the incidence of infection. There was no evidence to suggest that administration sets which contain lipids should not be changed every 24 hours as currently recommended.
CD009429	[ "21889410" ]	[ "Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial." ]	[ "Efficacious and safe monotherapy options are needed for adult patients with newly diagnosed epilepsy. As an adjunctive treatment for partial seizures, pregabalin compares favourably with lamotrigine and is an effective, approved treatment. We studied the efficacy and safety of pregabalin as monotherapy, using a design that complied with European regulatory requirements and International League Against Epilepsy guidelines.\n This phase 3, double-blind, randomised, non-inferiority study compared the efficacy and tolerability of pregabalin and lamotrigine monotherapy in patients with newly diagnosed partial seizures at 105 centres, mostly in Europe and Asia. Randomisation to treatment groups (1:1 ratio) was by a computer-generated pseudorandom code (random permuted blocks), with patients sequentially assigned numbers by telephone. Investigators, site staff, and patients were masked to the assigned treatment. After randomisation, patients were titrated to either 75 mg oral pregabalin or 50 mg oral lamotrigine twice daily during a 4-week dose-escalation phase, followed by a 52-week efficacy assessment phase during which the daily dose could be increased as needed to a maximum of 600 mg and 500 mg, respectively. The primary efficacy endpoint was the proportion of patients who remained seizure-free for 6 or more continuous months during the efficacy assessment phase; analysis included all patients who were randomly assigned to treatment groups and received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT00280059.\n 660 patients were randomly assigned to treatment groups (330 pregabalin, 330 lamotrigine), of whom 622 entered the efficacy assessment phase (314 pregabalin, 308 lamotrigine). Fewer patients in the pregabalin group than in the lamotrigine group became seizure-free for 6 or more continuous months (162 [52%] vs 209 [68%]; difference in proportion, -0·16, 95% CI -0·24 to -0·09). The overall incidence of adverse events was similar between the groups and consistent with that in previous studies; dizziness (55 [17%] vs 45 [14%] patients), somnolence (29 [9%] vs 14 [4%]), fatigue (27 [8%] vs 19 [6%]), and weight increase (21 [6%] vs 7 [2%]) were numerically more common in the pregabalin group than in the lamotrigine group.\n Pregabalin has similar tolerability but seems to have inferior efficacy to lamotrigine for the treatment of newly diagnosed partial seizures in adults. Inferior efficacy of pregabalin might have been attributable to limitations in the study design, as treatment doses might have not been optimised adequately or early enough.\n Pfizer Inc.\n Copyright © 2011 Elsevier Ltd. All rights reserved." ]	Pregabalin seems to have similar tolerability but inferior efficacy in comparison to lamotrigine for newly diagnosed partial seizures. However, considering the limitations in the study design (such as the short-term follow-up and the low initial target dose selection), the results should be interpreted with caution. The available data were too limited to draw any conclusions between pregabalin and gabapentin. The result indicated that the treatment effects were influenced by the study regions. The clinical disadvantage of pregabalin was more prominent in Asia when compared with lamotrigine. We should determine whether pregabalin has ethnic differences in the treatment of epilepsy in the future. This review does not inform any treatment policy for patients with generalized onset tonic-clonic seizures. Further long-term trials are needed to investigate the genuine effectiveness of pregabalin as monotherapy.
CD004241	[ "14507756", "21105974", "20565316", "3281706", "9828778", "415912", "6432887", "16547328", "3664330" ]	[ "A randomised clinical trial comparing 2% econazole and 5% natamycin for the treatment of fungal keratitis.", "Voriconazole versus natamycin as primary treatment in fungal corneal ulcers.", "Topical amphotericin B and subconjunctival injection of fluconazole (combination therapy) versus topical amphotericin B (monotherapy) in treatment of keratomycosis.", "Topical silver sulphadiazine--a new drug for ocular keratomycosis.", "Randomised trial of 0.2% chlorhexidine gluconate and 2.5% natamycin for fungal keratitis in Bangladesh.", "A controlled trial of adenine arabinoside and trifluorothymidine in herpetic keratitis.", "[Acyclovir and trifluorothymidine in herpetic kerato-uveitis. A comparative clinical study. Indications for corticoid therapy].", "Randomised controlled trial of topical ciclosporin A in steroid dependent allergic conjunctivitis.", "A randomized trial comparing ketoconazole and nystatin prophylactic therapy in neutropenic patients." ]	[ "To compare 2% econazole and 5% natamycin in the management of fungal keratitis.\n A randomised clinical trial was performed using 2% econazole or 5% natamycin as the two treatment arms on patients presenting with culture positive fungal keratitis to the cornea service at Aravind Eye Care System, Madurai, India.\n 116 patients were recruited, and 112 continued in the study. There were no significant differences between the two arms at baseline or for success (defined as a healed or healing ulcer) at final visit (p = 0.79).\n 2% Econazole appears to be as effective as 5% natamycin for the management of fungal keratitis.", "To evaluate the efficacy of topical 1% voriconazole versus 5% natamycin in treatment of fungal corneal ulcers.\n A prospective, randomized pilot study in a tertiary care hospital.\n Thirty patients of microbiologically proven fungal keratitis divided randomly in two groups of 15 patients each.\n Two groups were treated with either 5% natamycin (group A) or 1% voriconazole (group B) topically as a primary treatment for fungal keratitis. The mean size, depth of infiltrate and LogMAR visual acuity at presentation were comparable in both groups (P > 0.05). Patients were followed up for minimum of 10 weeks or till complete resolution of ulcer, whichever was later. Cultures to identify the causative organisms were performed.\n Time of resolution of the ulcer.\n Twenty-nine of the total 30 patients showed complete resolution. Average time of resolution and gain in LogMAR visual acuity was 24.3 days and 1.12 in group A and 27.2 days and 0.77 in group B. These were comparable in the two groups (P > 0.05%). Aspergillus spp. (40%) and Curvularia spp. (30.0%) were found to be most common isolates.\n Topical 1% voriconazole was found to be safe and effective drug in primary management of fungal keratitis, its efficacy matching conventional natamycin. There was no added advantage of using topical 1% voriconazole over topical natamycin as primary treatment in fungal keratitis.\n © 2011 The Authors. Clinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists.", "The aim of the study was to compare the use of combination therapy of topical amphotericin B (0.5 mg/mL) eye drops together with subconjunctival injection of fluconazole (2 mg/mL) with the use of topical amphotericin B (0.5 mg/mL) eye drops alone in dealing with cases of fungal keratitis.\n The study was performed in the Ophthalmology Department, Zagazig University and included 48 eyes of 48 patients who presented clinically with fungal keratitis. Laboratory investigations were performed, including direct microscopy of corneal smear using gram staining and culture of corneal specimens using Saboraud agar media and bacterial agar media. According to laboratory results, cases were classified into 2 groups: group 1 comprising 24 eyes treated by a combination therapy of topical amphotericin B eye drops (0.5 mg/mL) with subconjunctival injection of fluconazole (2 mg/mL) and group 2 comprising 24 eyes treated by topical amphotericin B eye drops (0.5 mg/mL) alone.\n Direct corneal smear for all 48 eyes included in the study revealed 18 eyes (38%) with positive fungal spores, 3 of them (6%) with gram-positive bacterial infection. Fungal culture of corneal specimens revealed positive result in 36 eyes (75%), including the positive corneal smear cases showing Candida in 12 eyes and filamentous fungi in 24 eyes. Treatment by a combination therapy in group 1 revealed statistically significant result (P < 0.05) of healing of corneal ulcers in 20 eyes (83%), with a mean duration of healing of 31 days (standard deviation [SD] +/-3), in comparison to group 2 with monotherapy, which revealed 16 eyes (67%), with a mean duration of healing of 37 days (SD +/-2).\n Combination therapy of topical amphotericin B eye drops with subconjunctival injection of fluconazole was more efficient (according to the percentage and the duration of healing of the ulcers) than the use of topical amphotericin B eye drops alone in dealing with cases of fungal keratitis--it may be contributed to the broad spectrum of the antifungal agents of the combination therapy than the monotherapy.", "The efficacy of silver sulphadiazine in human keratomycosis has not been evaluated so far. Encouraged by the success of an earlier experimental trial, a prospective, controlled, randomised double masked clinical study was designed to evaluate the efficacy of 1% silver sulphadiazine ophthalmic ointment in 20 eyes of mycotic keratitis. Miconazole 1% was used for comparative evaluation in another 20 eyes. Silver sulphadiazine had a higher success rate (80% vs 55%) than miconazole. It had broad antifungal activity and was found to be effective in fusarium keratitis. Absence of side effects, economy, and its efficacy in deeper and extensive lesions were additional advantages. It is concluded from this study that silver sulphadiazine is a safe and effective broad spectrum antifungal agent which can be used for the treatment of human keratomycosis.", "The management of suppurative keratitis due to filamentous fungi presents severe problems in tropical countries. The aim was to demonstrate the efficacy of chlorhexidine 0.2% drops as an inexpensive antimicrobial agent, which could be widely distributed for fungal keratitis.\n Successive patients presenting to the Chittagong Eye Institute and Training Complex with corneal ulcers were admitted to the trial when fungal hyphae had been seen on microscopy. They were randomised to drop treatment with chlorhexidine gluconate 0.2% or the standard local treatment natamycin 2.5%. The diameters, depths, and other features of the ulcers were measured and photographed at regular intervals. The outcome measures were healing at 21 days and presence or absence of toxicity. If there was not a favourable response at 5 days, \"treatment failure\" was recorded and the treatment was changed to one or more of three options, which included econazole 1% in the latter part of the trial.\n 71 patients were recruited to the trial, of which 35 were randomised to chlorhexidine and 36 to natamycin. One allocated to natamycin grew bacteria and therefore was excluded from the analysis. None of the severe ulcers was fully healed at 21 days of treatment, but three of those allocated to chlorhexidine eventually healed in times up to 60 days. Of the nonsevere ulcers, 66.7% were healed at 21 days with chlorhexidine and 36.0% with natamycin, a relative efficacy (RE) of 1.85 (CL 1.01-3.39, p = 0.04). If those ulcers were excluded where fungi were seen in the scraping but did not grow on culture, the estimated efficacy ratio does not change but becomes less precise because of smaller numbers. Equal numbers of Aspergillus (22) and Fusarium (22) were grown. The Aspergillus were the most resistant to either primary treatment.\n Chlorhexidine may have potential as an inexpensive topical agent for fungal keratitis and warrants further assessment as a first line treatment in situations where microbiological facilities and a range of antifungal agents are not available.", "The effectiveness of two anti-viral agents, adenine arabinoside and trifluorothymidine, were studied in cases of human superficial herpetic keratitis (dendritic ulceration). A highly satisfactory response to each drug was demonstrated in most cases.", "The relative efficacy of aciclovir (ACV) and trifluorothymidine (TFT) was evaluated in a randomized, open clinical trial of 37 patients with herpetic kerato-uveitis. Twenty-one patients were treated with ACV and 16 with TFT. Topical steroids were withheld as long as the degree of inflammation permitted. Although both drugs were effective in healing the herpetic corneal ulcers, TFT had a significantly shorter healing time than ACV. However, ACV was more effective in treating the iridocyclitis than TFT. In 5 cases the keratouveitis responded to ACV alone, while only one case was successfully managed with TFT alone. Both drugs seemed to prevent steroid-induced epithelial complications and no significant side-effects were observed with either drug. The treatment of herpetic keratouveitis with single agents such as ACV and TFT is dependent upon rapidly instituting therapy and minimizing the use of topical steroids. The apparently good intraocular penetration of ACV and TFT may decrease the need for adjunctive steroid therapy and thereby minimize the risks of facilitated viral replication and steroid-dependence.", "To evaluate the efficacy, safety, and therapeutic effect of topical ciclosporin A 0.05% as a steroid sparing agent in steroid dependent allergic conjunctivitis.\n Prospective, randomised, double masked, placebo controlled trial comparing signs, symptoms, and the ability to reduce or stop concurrent steroid in steroid dependent atopic keratoconjunctivitis and vernal keratoconjunctivitis using 0.05% topical ciclosporin A compared to placebo. Steroid drop usage per week (drug score), symptoms, and clinical signs scores were the main outcome measures.\n The study included an enrolment of 40 patients, 18 with atopic keratoconjunctivitis and 22 with vernal keratoconjunctivitis. There was no statistical significant difference in drug score, symptoms, or clinical signs scores between the placebo and ciclosporin group at the end of the treatment period. No adverse reactions to any of the study formulations were encountered.\n Topical ciclosporin A 0.05% was not shown to be of any benefit over placebo as a steroid sparing agent in steroid dependent allergic eye disease.", "A randomized trial was conducted comparing ketoconazole and nystatin in the prevention of oral candidiasis and appearance of invasive fungal infections in 51 neutropenic leukemic patients undergoing induction chemotherapy. Ketoconazole was administered in a 200 mg dose twice daily. Nystatin oral suspension was given in doses of 500,000 units four times daily. Surveillance cultures of the throat and urine were obtained prior to treatment and conducted weekly. Patients were enrolled in the study if the absolute granulocyte count was less than 1500/microliter, if physical examination revealed no evidence of oral candidiasis, no evidence of urinary tract infection, and there was no pulmonary infiltrate on chest x-ray. Patients were continued on study until the absolute granulocyte count reached 1500/microliter, evidence of oral candidiasis appeared, or presumed or proven invasive fungal infections appeared. Of the 46 evaluable patients, 22 received ketoconazole, 3 (14%) developed oral candidiasis, and 5 developed suspected systemic fungal infections (23%). Of 24 patients who received nystatin, 4 (17%) developed oral candidiasis and 8 (33%) developed systemic fungal infections, 4 proven and 4 suspected. Significantly more patients on the nystatin arm progressed to invasive fungal infections. Ketoconazole was not superior to nystatin in reducing the frequency of oral candidiasis but possibly reduced the frequency of invasive fungal infections." ]	Based on the trials included in this review, there is no evidence to date that any particular drug, or combination of drugs, is more effective in the management of fungal keratitis. The trials included in this review were of variable quality and were generally underpowered.
CD004500	[ "10551192" ]	[ "Evaluating the effectiveness of 2 educational interventions in family practice." ]	[ "Structured feedback of information can produce change in physician behaviour. The objective of this study was to assess the effectiveness of 2 educational interventions for improving the quality of care provided by family physicians in Ontario: the Practice Assessment Report (PAR) and the Continuing Medical Education Plan (CMEP) with a follow-up visit by a mentor.\n The study was a randomized controlled trial. Physicians in the control group received only the PAR, whereas those in the experimental group received the PAR, CMEP and mentor interventions. The participants were 56 family physicians and general practitioners (27 in the PAR group and 29 in the CMEP group) in southern Ontario who agreed to participate in the interventions and provide data. A total of 2395 patients randomly sampled from the practices returned questionnaires and consented to have their medical records abstracted. The outcome measures were global scores in 4 areas--quality of care, charting, prevention and overall use of medications--and patient ratings of satisfaction with care and preventive practices. The measures were applied at the beginning (phase 1) and end (phase 2) of the study.\n The mean global scores at the end of the study for the PAR group were 70.1% for quality of care, 84.7% for prevention, 77.7% for charting and 82.2% for overall use of medications. The corresponding scores for the CMEP group were 68.3%, 82.1%, 76.4% and 83.2%. In the patient satisfaction component, the personal care scores at phase 2 were 93.6% for the PAR group and 94.6% for the CMEP group. Examples of the scores for prevention for the PAR group were 98.3% for children's current immunization, 96.6% for blood pressure measured within the previous 5 years, 79.4% for referral of women of the appropriate age for mammography within the previous 2 years, and 58.4% for discussion about alcohol use. The corresponding scores for the CMEP group were 95.8%, 97.6%, 77.6% and 64.6%. The changes in mean scores between phase 1 and phase 2 ranged from -1.9 to 2.3 points. There were no significant differences between the 2 groups in phase 1 or phase 2 scores or in change in scores. A total of 64.3% of the physicians rated the PAR as useful, 26.5% found the CMEP to be useful, and 41.0% considered the mentor strategy to be a useful form of continuing medical education. Although changes in practice related to the PAR, CMEP or mentor were reported by some physicians, they were not related to chart audit or patient scores.\n Educational interventions based on quality-of-care assessments and directed to global improvements in quality of care did not result in improvements in the outcome measures. Educational interventions may have to be targeted to specific areas of the practice, with physicians being monitored and receiving ongoing feedback on their performance." ]	There is insufficient evidence to guide selection of appropriate PEEP levels for RDS or CMV. There is a need for well designed clinical trials evaluating the optimal application of this important and frequently applied intervention.
CD007148	[ "8619207", "9462386", "2658918", "3167527" ]	[ "Perisurgical erythropoietin application in anemic patients with colorectal cancer: A double-blind randomized study.", "Randomized multicentre trial of the influence of recombinant human erythropoietin on intraoperative and postoperative transfusion need in anaemic patients undergoing right hemicolectomy for carcinoma.", "Oral prophylaxis with neomycin and erythromycin in colorectal surgery. More proof for efficacy than failure.", "Prophylactic antibiotics in elective colorectal surgery." ]	[ "Blood transfusions are associated with higher postoperative morbidity and tumor recurrence rates in colorectal cancer surgery, To reduce the need for transfusions in patients with tumor-induced anemia who are not suitable for autologous blood donation, it was tested whether perisurgical erythropoietin application would be able to stimulate hematopoiesis adequately.\n In a double-blind randomized study 150 IU/kg body weight erythropoietin was given subcutaneously every 2 days beginning 10 days before operation and continuing until postoperative day 2. Twenty patients were randomized into the erythropoietin group with three observed dropouts and 10 patients into the placebo group.\n In the erythropoietin group two episodes of hypertension and one deep venous thrombosis were observed. Preoperative hemoglobin response in the erythropoietin group (p = 0.069) was paralleled by a highly significant reticulocyte increase (p = 0.0004). However, frequency of blood transfusion was not different between both study groups (erythropoietin, 1.82 +/- 0.80 units/ patient; placebo, 1.80 +/- 0.97 units/patient). If iron availability was analyzed, a strong correlation between ferritin blood levels and transferrin iron saturation with hemoglobin response was observed in regression analysis (p < 0.001).\n These results indicate that hematopoiesis in anemic patients with colorectal cancer can be stimulated by erythropoietin; however, clinical efficacy is to be expected only in selected patients with high iron availability, which calls for further studies combining erythropoietin and parenteral iron application.", "The possible immunosuppressive effect of blood transfusion and its influence on survival after surgery for cancer makes it worthwhile to seek methods to avoid transfusion wherever possible. Patients with right-sided colonic cancer are frequently anaemic. Such patients were entered into a study that employed erythropoietin to avoid homologous transfusion.\n In a prospectively randomized double-blind placebo-controlled multicentre trial, patients with moderate anaemia (haemoglobin concentration greater than 8.5 g/dl and less than or equal to 13.5 g/dl) presenting with right-sided colonic cancer and scheduled for hemicolectomy were treated with recombinant human erythropoietin (epoetin beta) 20,000 units/day subcutaneously or placebo for at least 10 days over the operative period.\n Perioperative treatment with epoetin beta was well tolerated and there were no significant differences in morbidity and mortality. Following hemicolectomy, median cumulative blood loss in the two groups was similar (epoetin beta 440 ml versus placebo 345 ml). Sixteen (33 per cent) of 48 patients treated with epoetin beta and 15 (28 per cent) of 54 in the placebo group received perioperative blood transfusions (P not significant). The increase in reticulocyte count between baseline and the last preoperative value was more pronounced in the epoetin beta group than in those receiving placebo (P = 0.036).\n Despite the perioperative administration of 20,000 units erythropoietin per day for at least 10 days, it was not possible to reduce the intraoperative and postoperative transfusion need. None the less, a positive change in the haematological variables of treated patients was clearly discernible. The negative result may be due to the short treatment interval and to iron deficiency, which was present in the majority of patients. The general change of attitude towards allogeneic blood transfusion is demonstrated by the overall low frequency of blood transfusion in this study.", "In an open, prospective, and randomized investigation on the prophylactic efficacy of peroral neomycin sulfate-erythromycin base vs intravenous ceftriaxone-metronidazole preparation in colorectal surgery, no significantly diverging results between regimens were recorded (1/27 [3.7%] and 2/27 [7.4%] wound infections, respectively). Commentary is made about the diverging results from earlier studies on antimicrobial prophylaxis and on the multifactorial causality of surgical infection. We believe that variables such as physical condition of the patients, virulence and local resistance patterns of bacteria, and technical skill of the surgeons are far more important in regard to the postoperative outcome concerning septic complications than is the choice of proper antibiotics. Thus, to determine the efficacy of antimicrobial prophylaxis, we call for larger investigations in the future, preferably double-blind, where it is possible to better control and diminish the influence of determinants other than the antibiotics being compared.", "A randomized prospective study was conducted on 194 patients who underwent elective colorectal surgery for carcinoma. All patients received the same mechanical bowel preparation. In addition, patients in group A received oral neomycin and erythromycin base; patients in group B received systemic metronidazole and gentamicin, while patients in group C received both oral and systemic antibiotics. Postoperative septic complications related to colorectal surgery occurred in 27.4 per cent, 11.9 per cent and 12.3 per cent respectively in groups A, B and C (chi 2 = 7; P less than 0.05). The incidence of sepsis in groups B and C was almost identical. Patients who received oral antibiotics alone (group A) had significantly higher risks of postoperative sepsis when compared with patients in either group B or group C (P less than 0.05). As there is no additional advantage of combining oral and systemic antibiotics, we recommend systemic metronidazole and gentamicin to be used with mechanical bowel preparation in elective colorectal surgery." ]	There is no sufficient evidence to date to recommend pre and peri-operative erythropoietin use in colorectal cancer surgery.
CD001526	[ "10506617", "2208013", "1281650", "6369990", "8226143", "18091051", "19836153", "18534669", "7587429", "2169587", "10344555", "11918907", "1649267", "8182811", "5345935", "16446056", "10885603", "11773176" ]	[ "Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.", "Survival of premenopausal women with metastatic breast cancer. Long-term follow-up of Eastern Cooperative Group and Cancer and Leukemia Group B studies.", "General condition of asymptomatic patients with advanced colorectal cancer receiving palliative chemotherapy. A longitudinal study.", "Long-term survival after chemotherapy for advanced epithelial ovarian carcinoma.", "Radiation therapy alone for stage I non-small cell lung cancer.", "Improved survival, quality of life, and quality-adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-brain radiation therapy for brain metastases.", "Randomized comparison of whole brain radiotherapy, 20 Gy in four daily fractions versus 40 Gy in 20 twice-daily fractions, for brain metastases.", "Surgically staged high-risk endometrial cancer: randomized study of adjuvant radiotherapy alone vs. sequential chemo-radiotherapy.", "The curative treatment by radiotherapy alone of stage I non-small cell carcinoma of the lung.", "A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer.", "[Intensive chemotherapy and autograft of hematopoietic stem cells in the treatment of metastatic cancer: results of the national protocol Pegase 04].", "Long-term effects of mammography screening: updated overview of the Swedish randomised trials.", "A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer.", "Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. The GIVIO Investigators.", "Earlier diagnosis and survival in lung cancer.", "Whole-brain radiotherapy with or without efaproxiral for the treatment of brain metastases: Determinants of response and its prognostic value for subsequent survival.", "The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer.", "Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer." ]	[ "Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease.\n Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses.\n Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01).\n MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.", "In premenopausal women with metastatic breast cancer, differences in survival curves early during follow-up can be misleading. The authors therefore analyzed long-term survival in 378 patients, entered in three randomized trials, started between 1973 and 1978. Combined data from the three trials were used to increase the power for identifying prognostic variables. Cancer and Leukemia Group B (CALGB) trial 7382 randomized patients to oophorectomy plus either cyclophosphamide or combination chemotherapy or observation. Eastern Cooperative Oncology Group (ECOG) 2174 randomized patients who had not progressed 3 months after oophorectomy to combination chemotherapy or combination chemotherapy or observation. Trial ECOG 2177 randomized estrogen receptor (ER) positive or ER-unknown patients to oophorectomy plus combination chemotherapy or immediate combination chemotherapy, and ER-negative patients were directly assigned to combination chemotherapy. Hence ER-negative patients need not have been healthy enough to be randomized to oophorectomy. With only 14% of the patients still alive, median survival on the three studies was 30, 24, and 28 months. The median survival of individual treatments changed noticeably in ECOG 2174 and ECOG 2177 with long-term follow-up. At this time there are no differences in survival between randomized regimens in any of the three trials. In a multivariate model, factors associated with significantly poorer survival were visceral-dominant disease, nodal metastases, breast metastases, age younger than 45 years, ER negativity, and not receiving chemotherapy immediately after oophorectomy. This treatment difference was thus not due to imbalances in the prognostic variables used in the model, but it may be due to imbalances of unknown prognostic factors or differences in patient selection.", "A Nordic multicenter study in asymptomatic patients with advanced colorectal cancer compared initial chemotherapy with sequential methotrexate-5-FU with leucovorin rescue (MFL) for 6 months versus primary expectancy with chemotherapy only after the appearance of symptoms. The study (183 patients randomized between January 1985 and February 1990) showed that symptom-free survival, progression-free survival and survival respectively were about 6 months longer in the group of patients randomized to initial MFL. Whether these prolongations could be achieved without an impaired 'quality of life' was studied in an associated study. Between January 1985 and March 1987, 43 patients were randomized at one of the hospitals, 36 of which were interviewed with a questionnaire at randomization. Even if all these patients were considered, by the physician, to be 'free of symptoms from their disease', 16/36 (44%) had symptoms that could be referred to the disease. In spite of this, the patients were in a good general condition, and considerably better off than patients considered to have 'symptoms from the disease' who were interviewed with the same questionnaire when randomized in a parallel study of symptomatic patients. Patients randomized to initial chemotherapy and interviewed longitudinally maintained their good condition throughout treatment. Toxicity was mild, although the patients expressed more adverse effects than the physicians recorded. Since symptom-free survival, progression-free survival and survival were statistically significantly longer in the group of patients randomized to MFL also in this associated study, it is concluded that initial chemotherapy can prolong symptom-free survival and survival without reduced 'quality of life' during the treatment period.", "Four hundred twenty-nine patients were entered into four prospective randomized clinical studies between January 1, 1973, and July 1, 1979. The records of 395 of these were analyzed to determine the proportion of patients surviving 48 months after therapy initiation. Ninety-six patients (24%) were living at 48 months, 89 of whom had second-look laparotomies. Of the 96 living patients, 53 (55%) were clinically free of disease and 43 (45%) had disease. Combination-agent chemotherapy produced a larger proportion of 48-month survivors than single-agent therapy (P = 0.001); 70% of these survivors were clinically free of disease. Patient characteristics, such as age, International Federation of Gynaecology and Obstetrics (FIGO) stage, histologic grade of tumor, and amount of residual tumor present prior to chemotherapy exerted a strong influence on length of survival. Long-term survival was not totally dependent on a complete response to chemotherapy; in fact, persistent treatment with drug regimens induced bone marrow disorders and death due to toxicity in five patients. The continued fall in survival curves after 48 months suggests that current therapy regimens are not dramatically changing long-term survival rates.", "This paper is a retrospective analysis of patients with clinical Stage I non-small cell carcinoma of the lung treated with definitive radiation therapy alone. The results of therapy, patterns of failure and the relationship of technical aspects of the delivery of radiotherapy to outcome are presented.\n From 1980 through 1990, 53 patients with Stage I non-small cell lung cancer were treated with definitive radiation therapy alone at the Radiation Oncology Center of the Mallinckrodt Institute of Radiology and its affiliated hospitals. All patients had a pathologic diagnosis of non-small cell lung cancer and were not candidates for surgical resection because of either patient refusal (10 patients), poor performance status (5 patients), or premorbid medical problems (38 patients). The median age was 73 years. Histologic cell type included squamous (32), adenocarcinoma (11), large cell (4), and unclassified non-small cell (6). Initial tumor size was < or = 3 cm in 23 patients, between 3 and 5 cm in 13 patients and > or = 5 cm in 17 patients. Diagnostic staging varied during the study period. All patients had chest X-rays and computed tomography scans of the chest. A majority had liver and bone scans, but only four underwent mediastinoscopy. The radiation therapy was of megavoltage energy in all patients, with a median primary prescription tumor dose of 63.2 Gy. Survival was measured from the date radiation therapy was initiated.\n The actuarial overall survival rate for the entire group was 19% at 3 years and 6% at 5 years, with a median survival time of 20.9 months. Of the 49 deaths, 35 died of lung cancer; 13 died of intercurrent illness, and one died of pancreatic cancer, which made the actuarial cause-specific survival 33% at 3 years and 13% at 5 years. The actuarial 3-year disease-free survival was 33%. Local primary tumor progression occurred in 22 patients, resulting in a 51% 3-year actuarial freedom from local progression. An additional four patients failed in regional lymph nodes that were included in the original treatment portals. Multivariate analysis found only T stage to be associated with overall survival (p = .02). However multivariate analysis showed age as a prognostic factor to be approaching statistical significance (p = .07). Patients under 70 years of age showed an increased survival rate compared to patients over 70 years. Radiation therapy doses > or = 65 Gy appeared to result in a decreased proportion of patients dying of lung cancer with no apparent increase in either acute or long-term complication rates.\n Results of definitive radiation therapy for inoperable Stage I non-small cell lung remain inferior to surgical therapy. Potential methods to improve local control with radiotherapy are discussed.", "To determine whether efaproxiral, an allosteric modifier of hemoglobin, improves quality of life and quality of survival in patients with primary breast cancer and brain metastases when used as an adjunct to whole-brain radiation therapy (WBRT).\n Patients with brain metastases from breast cancer were randomly assigned to receive WBRT and either efaproxiral or no efaproxiral. The primary endpoint for this analysis was quality of life and quality-adjusted survival. Quality of life was assessed prior to initiation of WBRT and periodically in follow-up using the Spitzer Quality of Life Index (SQLI).\n A subgroup of 106 eligible breast cancer patients with baseline SQLI were randomized into this study and represent the target population discussed in this report. Treatment, age, and SQLI were significant predictors of survival. The addition of efaproxiral to WBRT reduced the death rate by 46% (P = 0.0086). Quality of life was improved in the WBRT + efaproxiral arm compared with the WBRT alone arm (P = 0.019). Quality-adjusted survival was statistically significantly improved by the addition of efaproxiral to WBRT (P = 0.001).\n Survival, quality of life, and quality-adjusted survival were all improved in breast cancer patients with brain metastases receiving efaproxiral and WBRT compared with those receiving WBRT alone.", "The present study compared the intracranial control rate and quality of life for two radiation fractionation schemes for cerebral metastases.\n A total of 113 patients with a Eastern Cooperative Oncology Group performance status <3; and stable (>2 months), absent, or concurrent presentation of extracranial disease were randomized to 40 Gy in 20 twice-daily fractions (Arm A) or 20 Gy in four daily fractions (Arm B), stratified by resection status. The European Organization for Research and Treatment of Cancer Quality of Life 30-item questionnaire was administered monthly during Year 1, bimonthly during Year 2, and then every 6 months to Year 5.\n The patient age range was 28-83 years (mean 62). Of the 113 patients, 41 had undergone surgical resection, and 74 patients had extracranial disease (31 concurrent and 43 stable). The median survival time was 6.1 months in Arm A and 6.6 months in Arm B, and the overall 5-year survival rate was 3.5%. Intracranial progression occurred in 44% of Arm A and 64% of Arm B patients (p = .03). Salvage surgery or radiotherapy was used in 4% of Arm A patients and 21% of Arm B patients (p = .004). Death was attributed to central nervous system progression in 32% of patients in Arm A and 52% of patients in Arm B (p = .03). The toxicity was minimal, with a minor increase in short-term cutaneous reactions in Arm A. The patients' quality of life was not impaired by the more intense treatment in Arm A.\n Intracranial disease control was improved and the quality of life was maintained with 40 Gy in 20 twice-daily fractions. This schema should be considered for better prognosis subgroups of patients with cerebral metastases.\n (c) 2010 Elsevier Inc. All rights reserved.", "Our purpose was to establish whether platinum-based chemotherapy combined with standard surgery and radiotherapy will improve overall and disease-free survival and lower the recurrence rate in patients with high-risk endometrial cancer.\n A total of 156 patients with Stage IA-B Grade 3 (n=28), or Stage IC-IIIA Grade 1-3 (n=128) were postoperatively randomized to receive radiotherapy (56 Gy) only (Group A, n=72) or radiotherapy combined with three courses of cisplatin (50 mg/m(2)), epirubicin (60 mg/m(2)) and cyclophosphamide (500 mg/m(2)) (Group B, n=84).\n The disease-specific overall five-year survival was in Group A 84.7% vs. 82.1% in Group B (p=0.148). The median disease-free survival in A was 18 (range 9-36) months and 25 (range 12-49) months in B (p=0.134), respectively. During a five-year follow-up 32 patients relapsed. Of the recurrences 5 were local and 20 distant, while 7 were combined. As calculated from the operation, the median time to recurrence was 15 (range 6-37) months in Group A, and 20 (range 8-60) months in Group B, respectively (p=0.170). Twenty-six patients died of the disease during the five-year follow-up, 11 in A and 15 in B. The patients succumbing in A lived a median 23 (range 15-44) months as compared to 37 (range 13-50) months in B (p=0.148). Chemotherapy was associated with an acceptable rate of acute toxicity. Less than 8% of the patients complained of Grade 3/4 nausea. The rate of Grade 3/4 leucopenia was at the highest at 16.6% during the third cycle but only 6.2% of the patients had Grade 3 infection. A total of 10 patients developed intestinal complications demanding surgery, 2 in Group A (2.7%) and 8 (9.5%) in Group B, respectively.\n Adjuvant chemotherapy with cisplatin, epirubicin and cyclophosphamide failed to improve overall survival or lower the recurrence rate in patients operated on and radiated for high-risk endometrial carcinoma. Chemotherapy was associated with a low rate of acute toxicity but appeared to increase the risk of bowel complications.", "This review was initiated to assess the outcome of treatment with radical radiotherapy with curative intent for patients diagnosed as having stage I non-small cell lung cancer. The study involved a retrospective review of 347 patients with T1 and T2N0M0 tumors treated at the Queensland Radium Institute during the period 1985 to 1992. The main reasons for not proceeding to surgery included poor performance status, old age, or refusal to submit to surgery. The median age for the group was 70 years, with the range being 34 to 90 years. Patients in this group were all treated by a standard technique involving external-beam radiotherapy to 50 Gy, minimum tumor dose, in 20 fractions over 4 weeks. The overall survival rate was 27% at 5 years with a median survival of 27.9 months. The 5-year recurrence-free survival was 23% with the median being 19.5 months. There was a strong correlation of survival to tumor size with 5-year survival rates being 32% and 21% for T1 and T2 tumors, respectively. Multivariate analysis found only T stage to be associated with overall survival (p < 0.01). In addition, the analysis showed that age younger than 70 years was a prognostic factor that approached statistical significance at the p < 0.05 level of significance. We conclude from this large series of patients with stage I non-small cell lung cancer that radical radiotherapy with curative intent may be a viable alternative to surgery in those patients who either refuse surgery or are judged to be unfit for operation.", "For patients with locally or regionally advanced non-small-cell lung cancer radiation is the standard treatment, but survival remains poor. We therefore conducted a randomized trial to determine whether induction chemotherapy before irradiation improves survival.\n All the patients had documented non-small-cell cancer of the lung with Stage III disease established by clinical or surgical staging. Eligibility requirements included excellent performance status, minimal weight loss, and visible disease on radiography. Patients randomly assigned to group 1 received cisplatin (100 mg per square meter of body-surface area given intravenously on days 1 and 29) and vinblastine (5 mg per square meter given intravenously on days 1, 8, 15, 22, and 29) and then began radiation therapy on day 50 (60 Gy over a 6-week period). Patients assigned to group 2 received the same radiation therapy but began it immediately and received no chemotherapy.\n The eligible patients in group 1 (n = 78) and group 2 (n = 77) were comparable in terms of age (median, 60 years), sex, performance status, histologic features, stage of disease, and completeness of radiation therapy. The median survival was greater for those in group 1-13.8 versus 9.7 months (P = 0.0066 by log-rank test). Rates of survival in group 1 were 55 percent after one year, 26 percent after two years, and 23 percent after three years, as compared with 40, 13, and 11 percent, respectively, in group 2. Those in group 1 had a higher incidence of serious infections requiring hospitalization (7 percent, vs. 3 percent in group 2) and severe weight loss (14 percent vs. 6 percent), but there were no treatment-related deaths.\n In patients with Stage III non-small-cell lung cancer, induction chemotherapy with cisplatin and vinblastine before radiation significantly improves median survival (by about four months) and doubles the number of long-term survivors, as compared with radiation therapy alone. Since three quarters of the patients still die within three years, however, further improvements in systemic and local therapy are needed.", "We report hereby the results of the french multicentric randomized PEGASE 04 protocol established to evaluate the impact on survival of high-dose chemotherapy over conventional chemotherapy for MBC patients.\n Inclusion criteria were: age < or = 60 year, PS < 2, adenocarcinoma initially metastatic or in first relapse, chemosensitive disease. Randomization was done after 4-6 courses of conventionnal chemotherapy between high-dose (Mitoxantrone, 45 mg/m2, Cyclophosphamide: 120 mg/kg, Melphalan: 140 mg/m2), and the pursuit of the same conventionnal chemotherapy. Between 09/92 and 12/96, 61 chemosensitive patients were enrolled: 29 were referred to standard chemotherapy, 32 to intensive therapy. At randomization, 13 pts (21.3%) were in complete response and 48 in partial response.\n The median progression-free survivals were 20 and 35.3 months in the standard and intensive groups (p=0.06). The relapse rates were respectively 79.3% vs 50.8% at 3 years and 90.8% vs 90.7% at 5 years. The median overall survivals were 20 and 43.4 months, with an overall survival rate of 18.5% vs 29.8% at 5 years (p=0.12).\n The CMA regimen could prolong the progression-free survival of MBC patients, however without any significant impact on overall survival.", "There has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malmö trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods The trials (n=247010, invited group 129750, control group 117260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure.\n The median trial time-the time from randomisation until the first round was completed for the control group or if the control group was not invited, until end of follow-up-was 6.5 years (range 3.0-18.1). The median follow-up time, the time from randomisation, to the end of follow-up, was 15.8 years (5.8-20.2). There were 511 breast cancer deaths in 1864770 women-years in the invited groups and 584 breast cancer deaths in 1688440 women-years in the control groups, a significant 21% reduction in breast cancer mortality (RR=0.79, 95% CI 0.70-0.89). The reduction was greatest in the age group 60-69 years at entry (33%). Looking at 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64, and 65-69 years (RR=0.76, 0.68, and 0.69, respectively). There was a small effect in women 50-54 years at randomisation (RR=0.95). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years after randomisation and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation. The age-adjusted relative risk for the total mortality was 0.98 (0.96-1.00).\n The advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up. The recent criticism against the Swedish randomised controlled trials is misleading and scientifically unfounded.", "From April 1985 to September 1988, 128 patients with advanced non-small-cell lung cancer (NSCLC) were enrolled in a prospective randomized trial evaluating chemotherapy (arm A) versus best supportive care (arm B). Chemotherapy consisted of cyclophosphamide 500 mg/m2 intravenously (IV) day 1, epirubicin 50 mg/m2 IV day 1, and cisplatin 80 mg/m2 IV day 1 (CE'P regimen) alternating every 4 weeks with methotrexate 30 mg/m2 IV day 1, etoposide 200 mg/m2 IV day 1, and lomustine (CCNU) 70 mg/m2 orally day 1 (MEC' regimen) until progression. Of the 123 patients (62 treated and 61 controls) eligible for survival, 115 were fully evaluable for response (58 treated and 57 controls). Response rates were 21% partial response, 53% stable disease, and 26% progressive disease in arm A, and 47% stable disease and 53% progressive disease in arm B. Median survival was 34.3 weeks (range, 4.3 to 218.6+ weeks) in arm A versus 21.1 weeks (range, 4.3 to 188.6 weeks) in arm B; the difference was not significant at P = .153 (Mantel-Cox). Subgroups of patients retrospectively analyzed by age, performance status, stage M0/M1, and weight loss or not showed no significant difference in survival. Poor-risk patients (at least two of the following: poor performance status, stage M1, weight loss) of arm A survived significantly longer than poor-risk patients of arm B (23.6 weeks v 12.4 weeks, Mantel-Cox P = .008); a significant difference in survival was also observed between nonsquamous cell patients of arm A and those of arm B (median survival, 38.6 weeks v 16.7 weeks; Mantel-Cox P = .041). Toxicity on the chemotherapy arm was hematologic (World Health Organization [WHO] grade greater than 3) in 12% of CE'P and in 13% of MEC' courses and gastroenteric (WHO grade greater than 3) in 24% of CE'P courses and in 8% of MEC' courses. Our alternating treatment was not significantly superior to supportive care. It is likely that certain subgroups of the NSCLC category may have an advantage with chemotherapy.", "To assess prospectively the impact on survival and health-related quality of life of two follow-up protocols in patients with early breast cancer.\n Randomized controlled clinical trial.\n Multicenter study involving 26 general hospitals in Italy.\n A consecutive sample of 1320 women younger than 70 years with stage I, II, and III unilateral primary breast cancer.\n Patients were randomly assigned to an intensive surveillance, which included physician visits and performance of bone scan, liver echography, chest roentgenography, and laboratory tests at predefined intervals (n = 655), or to a control regimen (n = 665), in which patients were seen by their physicians at the same frequency but only clinically indicated tests were performed. Both groups received a yearly mammogram aimed at detecting contralateral breast cancer.\n Primary end points were overall survival and health-related quality of life.\n Compliance to the two follow-up protocols was more than 80%. At a median follow-up of 71 months, no difference was apparent in overall survival with 132 deaths (20%) in the intensive group and 122 deaths (18%) in the control group. No significant differences were apparent in time to detection of recurrence between the two groups. Measurements of health-related quality of life (ie, overall health and quality-of-life perception, emotional well-being, body image, social functioning, symptoms, and satisfaction with care) at 6, 12, 24, and 60 months of follow-up did not show differences by type of care received.\n Results of this trial support the view that a protocol of frequent laboratory tests and roentgenography after primary treatment for breast cancer does not improve survival or influence health-related quality of life. Routine use of these tests should be discouraged.", "In a controlled investigation the survival prospects of lung cancer in a population of men aged 40 and over who had been offered six-monthly chest radiographs over a period of three years were compared with lung cancer in a similar population without such x-ray facilities. The five-year survival rate of lung cancer in the study series was 15%, and in cases discovered by six-monthly examination 23%, compared with 6% in the control series. The average expectation of life after diagnosis was 2.5 years for the test cases and 1.2 for the control cases. Survival declined with age. Of resected lung cancer, 32% survived five years in the test series and 23% in the control series. The five-year survival rate for squamous carcinoma and adenocarcinoma in the test series was 28% and 25% respectively, compared with 15% and nil in the control series.On the basis of these results it is concluded that through earlier radiological detection a modest improvement in the prognosis of lung cancer can be achieved.", "To determine the prognostic factors for radiographic response and its prognostic value for subsequent survival in patients undergoing whole-brain radiotherapy (WBRT) for brain metastases.\n Five hundred fifteen eligible patients were randomized in a phase III trial evaluating WBRT and supplemental oxygen with or without efaproxiral, an allosteric modifier of hemoglobin that reduces hemoglobin oxygen-binding affinity and enhances tumor oxygenation, potentially increasing tumor radiosensitivity. Brain images were obtained at baseline and at scheduled follow-up visits after WBRT. Landmark analysis was used to assess the ability of response at selected time points to predict subsequent survival. Logistic regression was used to assess determinants of response at 3 months.\n Treatment arm, Karnofsky Performance Status, presence or absence of liver metastases, and primary site were all determinants of response at the 3-month follow-up visit, with patients in the efaproxiral arm experiencing a 67% greater odds of response at this visit (p = 0.02). Response at 3 and 6 months was a significant prognostic factor for longer subsequent survival.\n The 3-month scan is a valuable prognostic factor for subsequent survival in patients with brain metastases treated with WBRT. Patients in the efaproxiral arm had a higher response rate at 3 and 6 months than those in the control arm.", "204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0-1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%, 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months-8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72-151 weeks), combination arm 125 weeks (95% CI 79-170 weeks). The estimated death ratio is 0.79 (P = 0.19, 95% CI 0.56-1.12). The estimated 3-year survival is 40% (95% CI 30-50%) RT only compared with 47% (95% CI 37-57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy.", "To evaluate whether preoperative chemotherapy (PCT) could improve survival in resectable stage I (except T1N0), II, and IIIA non-small-cell lung cancer (NSCLC).\n A randomized trial compared PCT to primary surgery (PRS). PCT consisted of two cycles of mitomycin (6 mg/m(2), day 1), ifosfamide (1.5 g/m(2), days 1 to 3) and cisplatin (30 mg/m(2), days 1 to 3), and two additional postoperative cycles for responding patients. In both arms, patients with pT3 or pN2 disease received thoracic radiotherapy.\n Three hundred fifty-five eligible patients were randomized. Overall response to PCT was 64%. There were two preoperative toxic deaths. Postoperative mortality was 6.7% in the PCT arm and 4.5% in the PRS arm (P =.38). Median survival was 37 months (95% confidence interval [CI], 26.7 to 48.3) for PCT and 26.0 months (95% CI, 19.8 to 33.6) for PRS (P =.15). Survival differences between both arms increased from 3.8% (95% CI, 1.3% to 25.1%) at 1 year to 8.6% (95% CI, 2.64% to 24.4%) at 4 years. A quantitative interaction between N status and treatment was observed, with benefit confined to N0 to N1 disease (relative risk [RR], 0.68; 95% CI, 0.49 to 0.96; P =.027). After a nonsignificant excess of deaths during treatment, the effect of PCT was significantly favorable on survival (RR, 0.74; 95% CI, 0.56 to 0.99; P =.044). Disease-free survival time was significantly longer in the PCT arm (P =.033).\n Although impressive differences in median, 3-year, and 4-year survival were observed, they were not statistically significant, except for stage I and II disease." ]	MAB produces a modest overall and cancer-specific survival at five years but is associated with increased adverse events and reduced quality of life.
CD009115	[ "7844481", "15493096", "8028316" ]	[ "Early identification and remediation of phonological-processing deficits in first-grade children at risk for reading disabilities.", "Remediating the core deficits of developmental reading disability: a double-deficit perspective.", "Speech perception training can facilitate sound production learning." ]	[ "The present study assessed 486 first-quarter first graders on their reading and phonological-processing skills and intelligence. Based on this assessment, and using the classification data from Hurford et al.'s (1993) study, 99 children were identified as being at risk for reading difficulties: 53 children at risk for reading disabilities (RD) and 46 children at risk for becoming \"garden-variety\" poor readers (GV). Half of the RD and GV groups received the phonological-processing intervention. Posttraining assessment indicated that the training procedure not only was effective in increasing the phonological-processing skills of the trained participants, but also increased their reading ability. Both of the RD and GV trained groups benefited from the training. Analyses also indicated that the initial screening device was somewhat less accurate in the present study in identifying at-risk children than in our previous studies (85% vs. approximately 98%, respectively). The results of the present study indicate that it is possible to identify children at risk for reading difficulties and to significantly improve their phonological-processing and reading abilities.", "The double-deficit hypothesis (Wolf, 1997; Wolf & Bowers, 1999, this issue) contends that deficits in phonological awareness and deficits in visual naming speed represent two independent causal impediments to reading acquisition for children with developmental reading disabilities (RD). One hundred and sixty-six children with severe RD from 7 to 13 years of age were classified into three deficit subgroups according to a double-deficit framework. A total of 140 children with RD, 84% of the sample, were classified; 54% demonstrated a double deficit (DD), 22% a phonological deficit only (PHON), and 24% a visual-naming speed deficit only (VNS). Diagnostic test profiles highlighted the joint contributions of the two core deficits in depressing written language acquisition. The children in the DD group were more globally impaired than those in the other subgroups, and the VNS group children were the highest achieving and most selectively impaired readers. Following 35 hours of word identification training, sizable gains and significant generalization of training effects were achieved by all subgroups. A metacognitive phonics program resulted in greater generalized effects across the domain of real English words, and a phonological training program produced superior outcomes within the phonological processing domain. The greatest non-word reading gains were achieved by children with only phonological deficits.", "This study examined the role of speech perception training in the correction of phonological errors. Twenty-seven preschoolers with phonological impairment who misarticulated /integral of/ were randomly assigned to one of three groups: Group 1 children listened to a variety of correctly and incorrectly produced versions of the word \"shoe\"; Group 2 children listened to the words \"shoe\" and \"moo\"; Group 3 children listened to the words \"cat\" and \"Pete.\" A computer game was used to provide reinforcement for correct identification of the words. All children received the same traditional sound production training program for correction of their /integral of/ error, concurrently with speech perception training, during six weekly treatment sessions. On post-testing, Group 1 and 2 children demonstrated a superior ability to articulate the target sound in comparison to Group 3 children. The results are interpreted in relation to previous research on this topic." ]	Phonics training appears to be effective for improving some reading skills. Specifically, statistically significant effects were found for nonword reading accuracy (large effect), word reading accuracy (moderate effect), and letter-sound knowledge (small-to-moderate effect). For several other outcomes, there were small or moderate effect sizes that did not reach statistical significance but may be meaningful: word reading fluency, spelling, phonological output, and reading comprehension. The effect for nonword reading fluency, which was measured in only one study, was in a negative direction, but this was not statistically significant. Future studies of phonics training need to improve the reporting of procedures used for random sequence generation, allocation concealment, and blinding of participants, personnel, and outcome assessment.
CD003809	[ "11455374", "9239953", "9699448", "6943157", "12532056", "6948831", "288179", "17240933", "284065", "2650531", "3476237", "6593805", "16881807", "11553111" ]	[ "Effects of combined application of antimicrobial and fluoride varnishes in orthodontic patients.", "White spot reduction when using glass ionomer cement for bonding in orthodontics: a longitudinal and comparative study.", "Fluoride release and cariostatic ability of a compomer and a resin-modified glass ionomer cement used for orthodontic bonding.", "Effect of stannous fluoride treatments on the progression of initial lesions in approximal surfaces of permanent posterior teeth.", "In vivo inhibition of demineralization around orthodontic brackets.", "MFP versus stannous fluoride mouthrinses for prevention of decalcification in orthodontic patients.", "Effect of flouride varnish (Duraphat) treatment every six months compared with weekly mouthrinses with 0.2 per cent NaF solution on dental caries.", "A clinical investigation of the efficacy of three different treatment regimens for the control of plaque and gingivitis.", "The caries-preventive effect of amine fluorides and inorganic fluorides in a mouthrinse or dentifrice after 30 months of use.", "An evaluation of a fluoride-releasing, visible light-activated bonding system for orthodontic bracket placement.", "Effect of fluoride containing dentifrice, mouthrinsing, and varnish on approximal dental caries in a 3-year clinical trial.", "Three-year study of the effect of fluoride varnish (Duraphat) on proximal caries progression in teenagers.", "Clinical efficacy of flossing versus use of antimicrobial rinses.", "Relative anti-caries efficacy of 1100, 1700, 2200, and 2800 ppm fluoride ion in a sodium fluoride dentifrice over 1 year." ]	[ "A randomized prospective clinical study, with 220 patients scheduled for fixed orthodontic therapy, was conducted to test the hypothesis that application of an antimicrobial varnish in combination with a fluoride varnish (group 1) is significantly more efficient in reducing white spot lesions on the labial surfaces than application of the fluoride varnish alone (group 2). The effects of the antimicrobial varnish on the occurrence of gingivitis and plaque formation were also studied. A third aim was to investigate whether white spot lesion development could be predicted early during treatment. The antimicrobial varnish significantly reduced the number of mutans streptococci in plaque during the first 48 weeks of treatment. This effect did not result in significantly less development of white spot lesions on the labial surfaces compared with the group receiving only the fluoride varnish application. There was however a clear trend that the combination of the antimicrobial and fluoride varnishes more effectively reduced the increments of new lesions on the maxillary incisors. It was speculated that this could be due partly to an inhibiting effect of the antimicrobial varnish in an area with low oral clearance (with low pH and loss of fluoride) and partly to an inhibiting effect of the varnish on mutans streptococci. No significant differences between the groups with respect to gingivitis and plaque were found. Lesion development was difficult to predict early after bonding, despite a number of caries-relevant parameters of orthodontic importance. The best predictors for white spot lesions at debonding were visible plaque and mutans streptococci (eg, the level of oral hygiene and thus the cariogenic challenge) around the appliance shortly after bonding.", "The aim of this clinical study was to test the benefit from using glass ionomer cement (GIC) instead of a conventional diacrylate in bracket bonding for the prevention of white spot formation. Before treatment 7.2 per cent of all examined surfaces (n = 222) were classified as having white spots. No additional fluoride treatment other than fluoride toothpaste was prescribed. At debonding 8-39 months later, white spots were found in 24 per cent of the surfaces bonded with the cement, significantly lower than the 40.5 per cent bonded with the diacrylate (P < 0.01). At recall 12 months after debonding (examined surfaces n = 214) the frequency of surfaces with white spots was reduced to 22 and 24 per cent respectively. Re-examination after a further 12 months (n = 160) showed that white spot surfaces were less frequent with the cement (16 per cent compared with the diacrylate 29 per cent), but still significantly more frequent in both groups than before treatment. With longer treatment time (17 months) teeth bonded with diacrylate were more frequently affected with white spots (P < 0.05). Neither sex nor age affected the results. It is concluded that the use of a GIC for orthodontic bonding will result in a significant reduction in the number of white spot surfaces at debonding compared with the use of conventional diacrylate. Although markedly reduced in both groups, the number of affected surfaces was still higher 2 years after debonding than before treatment.", "The aims of this study were to compare the local and systemic uptake of fluoride released from a compomer material (Dyract Ortho) and a resin-modified glass ionomer cement (Vitremer) with that of a conventional resin adhesive (Right-On) and to compare the cariostatic ability of each of the test materials with that of the resin control.\n Twenty six patients were randomly allocated to have a bracket bonded to a premolar on one side of the arch with one of the test materials and on the opposite side with the control material. Premolars destined for extraction as part of an orthodontic treatment plan were selected for bonding. A non-fluoride toothpaste was used by all participants for 4 weeks prior to bracket bonding and throughout the 4 week trial period. Fluoride release was measured in saliva, plaque and urine samples taken pre-bonding and 4 weeks post-bonding. Enamel demineralisation was assessed by scoring the buccal surface of each extracted tooth using a caries index.\n Neither Vitremer nor Dyract Ortho altered salivary or urinary fluoride concentration significantly 4 weeks post-bonding but plaque fluoride concentration increased significantly around premolars bonded with Vitremer. The test materials as a combined group were associated with significantly less demineralisation than the control material but there was no significant difference in cariostatic ability detected between either Dyract Ortho or Vitremer when each group was compared separately with the control.\n Fluoride released from Dyract Ortho or Vitremer is likely to exert a local and not a systemic effect. In a 4-week clinical study, the cariostatic ability of the fluoride-releasing cements, as a combined group, was superior to that of the non-fluoride releasing control but there was no significant difference in cariostatic ability between the two test materials when each test group was compared separately with the control.", "Bite-wing radiographs were used to determine the effect of three forms of topical SnF2 therapy on the progression of initial lesions in the approximal surfaces of permanent posterior teeth. Radiographs were taken annually over a four-year period. The subjects were schoolchildren, aged 12-14 yr, living in a low fluoride area. The professional application of a 10% SnF2 solution for 30 s, semi-annually for two yr, had no discernible effect on the development of the initial lesions. However, the home use of a SnF2 dentifrice did inhibit caries progression appreciably at all but one of the four time intervals in the study. The professional application of a 10% SnF2 solution for 30 s, semi-annually for two yr, combined with the home use of a SnF2 dentifrice, was the most effective treatment in retarding lesion development. Even without topical fluoride therapy, the rate of progression of initial approximal lesions was generally quite slow. In view of these findings, it would seem sound clinical practice to treat all initial lesions in approximal surfaces with topical fluoride therapy and delay placement of restorations until there is radiographic evidence of lesions reaching dentin.", "Demineralization around orthodontic appliances is a problem. Suboptimal oral hygiene, long intervals between appointments, and potentially poor patient cooperation with using fluoride dentifrices and mouth rinses necessitate a compliance-free means of preventing tooth decay. The hypothesis of this study was that fluoride released by glass ionomer cement inhibits the formation of carious lesions around orthodontic brackets in vivo. Brackets were bonded on 2 first premolars in 21 randomized, consecutively selected patients 11 to 18 years old. Eleven test-group subjects were bonded with fluoride-releasing glass ionomer cement, and 10 control subjects were bonded with composite resin (no fluoride). The teeth were extracted after 4 weeks, sectioned, and evaluated quantitatively by cross-sectional microhardness testing. Fluoride levels in patient saliva were measured by the Taves diffusion method in samples taken at days 0 (baseline), 1, 2, 3, 7, 14, 21, and 28 to determine whether fluoride from the glass ionomer cement influenced the overall intraoral fluoride levels. The results demonstrated significantly more demineralization around the brackets of the control patients (P <.01, Wilcoxon signed rank test). For whole-mouth salivary fluoride levels, no significant overall difference between the groups (P >.05) and no noticeable trend within groups (P >.05) were found. These results indicate that using fluoride-releasing glass ionomer cement for bonding orthodontic brackets successfully inhibited caries in vivo. This cariostatic effect was localized to the area around the brackets and was statistically significant after 4 weeks.", "Twenty-two orthodontic patients in the eleven to fifteen-year age-group participated in a one-year fluoride rinsing program. A 0.1 percent SnF2 solution was compared to a MFP solution containing an equivalent amount of fluoride. A laboratory study evaluated the enamel solubility reducing capacities of the two solutions. Enamel solubility reduction by a two-minute treatment with 0.1 percent SnF2 was 77.8 percent; that for MFP solution was only 13.1 percent. Rinsing daily with SnF2 prevented decalcification completely in twelve patients; two of ten patients rinsing with MFP developed new decalcification during orthodontic treatment. Thus, SnF2 was more effective than MFP in both the laboratory and clinical phases of the study. These results support the requirement for frequent applications, if patients are at advanced risk, and suggest that the method of treatment is at least as important as the choice of specific fluoride.", "Recent studies have shown a high fluorine uptake in the enamel and a considerable caries reduction following the application of varnished containing fluoride. As the application is easy to carry out it may in certain situations serve as an alternative to other topical fluoride school programmes. The aim of the present study, therefore, was to compare the caries increment in schoolchildren exposed to a fluoride varnish (Duraphat) every six months and in children receiving the conventional weekly fluoride mouthrinsing programme with 0.2 per cent sodium fluoride over a two-year period. Two hundred 14-year-old children, divided into one test and one control group took part in the study. They were clinically and radiographically examined every year. Preexperimental data revealed no differences between the groups. During the experimental period the children in the fluoride varnish group developed a statistically significant lower number of new carious lesions compared with those in the mouthrinsing group. The difference in caries increment was about 30 per cent. Further clinical studies to compare the effects of various topical fluoride programmes are recommended.", "The objective of this examiner-blind clinical study was to investigate the efficacy of three oral hygiene regimens for the control of gingivitis and supragingival plaque.\n Following a baseline examination for gingivitis and supragingival plaque, qualifying adult male and female subjects from the San Francisco, California area were stratified into three treatment groups, which were balanced for plaque. The groups were then randomly assigned to one of three oral hygiene regimens: 1) twice-daily tooth brushing with Colgate Total Toothpaste, accompanied by once-daily flossing after brushing; 2) twice-daily tooth brushing with Colgate Total Toothpaste without flossing; and 3) twice-daily tooth brushing with a sodium fluoride toothpaste, accompanied by once-daily flossing after brushing. All subjects were given a complete oral prophylaxis, and dispensed their assigned treatment product(s), along with a soft-bristled adult toothbrush for home use. All dentifrice products were supplied in the original packaging to which overwrapping had been applied. Subjects were instructed to brush their teeth for one minute twice daily (morning and evening) using only the dentifrice provided, and to refrain from using anything other than their assigned oral hygiene products for the duration of the study. In addition, subjects were instructed to refrain from any routine dental treatment (except emergency) during the course of the study. There were no restrictions regarding diet or smoking habits over the course of the study. Examinations for gingivitis and supragingival plaque, and oral soft tissue assessments were repeated after three months, and again after six months of product use.\n One-hundred fourteen (114) subjects complied with the protocol and completed the six-month examinations. Statistical analyses showed similar results for both whole-mouth and interproximal scoring sites after six months of product use. Although not statistically significant, subjects using Colgate Total Toothpaste accompanied by the use of dental floss had numerically lower six-month scores for gingivitis and supragingival plaque formation when compared to the scores of subjects using Colgate Total Toothpaste without the use of dental floss. Relative to the sodium fluoride toothpaste accompanied by the use of dental floss, subjects using Colgate Total Toothpaste, both with and without the use of dental floss, exhibited statistically significant reductions in gingivitis and supragingival plaque formation after six months of product use.\n The results of this clinical study support the conclusion that the use of Colgate Total Toothpaste, both with and without the use of dental floss, provided statistically significant improvements over the sodium fluoride toothpaste plus flossing regimen with respect to the control of gingivitis and supragingival plaque formation. Although not statistically significant, numerically lower six-month scores for gingivitis and supragingival plaque were associated with Colgate Total Toothpaste accompanied by the use of dental floss, when compared with Colgate Total Toothpaste without the use of dental floss.", "The study groups using a dentifrice and mouthrinse both containing fluorides, a dentifrice containing stannous fluoride and a mouthrinse containing sodium fluoride, or a mouthrinse containing sodium fluoride with a placebo dentifrice had a 20.7% to 29.0% lower DMF increment than the control group after 30 months. These differences were significant. The study groups using a dentifrice containing amine fluorides and a placebo mouthrinse, a mouthrinse containing amine fluorides and a placebo dentifrice, or a dentifrice containing stannous fluoride and a placebo mouthrinse had a 13.6% to 22.4% lower DMF increment than the control group. These differences were not statistically significant. There was no significant difference in effectiveness against caries between the use of the organic or inorganic fluoride products.", "In spite of improved preventive measures, decalcification around bonded orthodontic appliances continues to be a problem for the clinician. Various fluoride-containing mediums have been proposed as aiding in the elimination of this problem; however, almost all are dependent on patient cooperation for their success. An ideal preventive system would be one that would operate independently of patient cooperation. The purpose of the present study was to compare a visible light-activated, fluoride-releasing bonding system with a visible light-activated conventional bonding system relative to bracket retention and prevalence of decalcification. Twenty-two patients were entered into the study, representing 206 experimental brackets and 206 control brackets. The average treatment period was 25 months. No significant differences in bracket retention rates were found between the two systems. Significantly, 26 teeth in the control group demonstrated decalcification (12.6%), whereas none of the teeth in the experimental group did. The results of this study suggest that a visible light-activated, fluoride-releasing bonding system is capable of adequately retaining brackets while aiding in the prevention of decalcification around bonded appliances.", "The purpose of this study was to evaluate the separate effect of fluoride dentifrice, fluoride mouthrinsing and fluoride varnish on approximal dental caries. All 252 13-14-yr-old children at an elementary school were selected at random and divided among four groups for a 3-yr longitudinal study. Group 1 received a fluoride dentifrice for home care and a fluoride mouthrinse once a week. Group 2 received a fluoride dentifrice for home care and a placebo mouthrinse once a week. Group 3 received a fluoride dentifrice for home care and a fluoride varnish once every 3 months. Group 4 received a placebo dentifrice for home care and a fluoride rinse once a week. Fluoride rinsing did not give any additional effect compared with placebo-rinsing when a fluoride dentifrice was used for home care. Fluoride varnish gave a significant caries reduction compared with fluoride rinsing.", "The effect of sodium fluoride varnish (Duraphat) applications on proximal caries progression was studied during a 3-yr period in 87 teenagers and compared to a control group (n = 107). In the fluoride varnish group the children were treated with fluoride varnish every third month during the experimental period. Caries lesions on the mesial surfaces of first premolars to the mesial surfaces of second molars were recorded annually on radiographs and an individual progression value was calculated. The study showed that topical application of fluoride varnish every third month significantly (P less than 0.05) reduced the progression of proximal caries lesions in premolars and molars. The most obvious reduction of caries progression was observed among children who developed between two and eight new proximal lesions during the test period. In the children with the highest caries activity (greater than nine new proximal lesions) Duraphat treatments did not significantly reduce proximal caries progression in premolars and molars.", "Dental floss is only used by a small part of the population on a daily basis. Therefore, an easy, applicable alternative is needed. This alternative could be a mouthrinse with antimicrobial activity for daily use. The aim of the present study was to evaluate the efficacy of two mouthrinses in reducing interdental plaque and gingivitis compared to dental floss.\n A total of 156 healthy volunteers were randomly assigned to the following groups: 1) toothbrushing and rinsing (0.06% chlorhexidine and 0.025% fluoride); 2) toothbrushing and rinsing (0.1% cetylpyridiniumchloride and 0.025% fluoride); 3) toothbrushing and flossing; and 4) toothbrushing only (N = 39 subjects in each group). At baseline, the modified proximal plaque index (MPPI) and papillary bleeding index (PBI) were recorded. Thereafter, subjects had to brush in the usual manner during 8 weeks. Additionally, test groups had to rinse once a day (groups 1 and 2: 30 seconds) or to floss (group 3). Eight weeks after baseline, indices were recorded again and improvements were calculated. Analysis of variance (ANOVA) and the Bonferroni test served for statistical analysis.\n After 8 weeks, reductions for all indices were found in all groups (P <0.05). With respect to the MPPI, mouthrinse groups performed better than the control and floss groups: 1) 0.73; 2) 0.82; 3) 0.40; and 4) 0.32 (P <0.05). The PBI showed no statistically significant difference between groups: 1) 0.46; 2); 0.50; 3); 0.42; and 4) 0.37.\n The results suggest that, in combination with toothbrushing, daily use of the tested mouthrinses may result in a higher interproximal plaque reduction than daily flossing.", "There is limited evidence from clinical trials on the dose response of sodium fluoride dentifrices at concentrations above 1100 ppm fluoride ion, with respect to caries efficacy. This randomized, double-blind study examined the anti-caries effectiveness of sodium fluoride dentifrices containing 1700 ppm, 2200 ppm and 2800 ppm fluoride ion relative to an 1100 ppm fluoride ion control. A population of 5439 elementary schoolchildren, aged 6-15 years, was recruited from an urban central Ohio area with a low fluoride content water supply (<0.3 ppm). Subjects were examined by visual-tactile and radiographic examination at baseline and after 1, 2, and 3 years of using the sodium fluoride dentifrices. Subjects were stratified according to gender, age and baseline DMFS scores derived from the visual-tactile baseline examination and randomly assigned to one of four treatment groups: 0.243% sodium fluoride (1100 ppm fluoride ion), 0.376% sodium fluoride (1700 ppm fluoride ion), 0.486% sodium fluoride (2200 ppm fluoride ion), and 0.619% sodium fluoride (2800 ppm fluoride ion). All products were formulated with the same fluoride compatible silica abrasive. Results after 1 year provided evidence of a positive sodium fluoride dose response. Compared to the 1100 ppm fluoride treatment group, the 1700 ppm fluoride treatment group had an 11.0% reduction in DMFS that was not statistically significant, while the 2200 ppm and 2800 ppm fluoride treatment groups showed statistically significant (P<0.05) reductions of 18.6% and 20.4%, respectively. The reductions in caries delivered by the higher fluoride dentifrices were present across all tooth surface types, but were most pronounced for occlusal surfaces. Results at years 2 and 3 were confounded by a concurrent fluoride rinse program, which involved portions of the study population. While the trends for the higher fluoride dentifrices observed at year 1 remained at years 2 and 3, the difference observed between treatments were substantially less and failed to reach statistical significance (P<0.05). Collectively, the data demonstrate that the 2200 ppm and the 2800 ppm fluoride treatments delivered statistically significantly greater caries efficacy than the 1100 ppm fluoride treatment. This large-scale clinical trial provides evidence of a positive statistically significant dose relationship between dental caries and sodium fluoride in a dentifrice at levels above 1100 ppm fluoride at year 1." ]	There is some evidence that the use of topical fluoride or fluoride-containing bonding materials during orthodontic treatment reduces the occurrence and severity of white spot lesions, however there is little evidence as to which method or combination of methods to deliver the fluoride is the most effective. Based on current best practice in other areas of dentistry, for which there is evidence, we recommend that patients with fixed braces rinse daily with a 0.05% sodium fluoride mouthrinse. More high quality, clinical research is required into the different modes of delivering fluoride to the orthodontic patient.

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