Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17‐butyrate cream for the treatment of atopic dermatitis A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis Generalisability of clinical trials in otitis media with effusion. Adherence to initial PDE-5 inhibitor treatment: randomized open-label study comparing tadalafil once a day, tadalafil on demand, and sildenafil on demand in patients with erectile dysfunction. Prednisolone versus dexamethasone in croup: a randomised equivalence trial Indirect comparison in evaluating relative efficacy illustrated by antimicrobial prophylaxis in colorectal surgery. Aerobic walking and strengthening exercises have similar effectiveness for knee osteoarthritis. Indirect comparisons of competing interventions. A prospective, randomized, multicenter acceptability and safety study of direct buprenorphine/naloxone induction in heroin-dependent individuals. Heuristic comparison of sertraline with nortriptyline for the treatment of depression in frail elderly patients. Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups? Some concerns about adverse event reporting in randomized clinical trials. Sleep Misperception and Chronic Insomnia in the General Population: Role of Objective Sleep Duration and Psychological Profiles Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial The challenge of evaluating surgical procedures. Double-blind randomised trial of modest salt restriction in older people ASSESS-3: A randomised, double-blind, flexible-dose clinical trial of the efficacy and safety of oral sildenafil in the treatment of men with erectile dysfunction in Taiwan Biological treatments for moderate-to-severe psoriasis: indirect comparison. A randomised, double-blind comparison of the efficacy and safety of citalopram compared to mianserin in elderly, depressed patients with or without mild to moderate dementia. Non-randomized studies as a source of complementary, sequential or replacement evidence for randomized controlled trials in systematic reviews on the effects of interventions. Vardenafil in men with stable statin therapy and dyslipidemia. Using standardised patients to measure physicians' practice: validation study using audio recordings Nurse-led paediatric pre operative assessment: an equivalence study. Validation of parent self reported home safety practices Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study. Better reporting of randomised controlled trials: the CONSORT statement The effect of sildenafil on nitric oxide–mediated vasodilation in healthy men Safety and efficiency of the Ottawa Ankle Rule in a Swiss population with ankle sprains. Effects of Ketamine in Normal and Schizophrenic Volunteers Effects of single administration of a phosphodiesterase III inhibitor during cardiopulmonary bypass: comparison of milrinone and amrinone. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial A double-blind, randomised- placebo, controlled, parallel group, multicentre, flexible-dose escalation study to assess the efficacy and safety of sildenafil administered as required to male outpatients with erectile dysfunction in Korea Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Efficacy of a small single dose of oral dexamethasone for outpatient croup: a double blind placebo controlled clinical trial Rivastigmine and donepezil treatment in moderate to moderately-severe Alzheimer's disease over a 2-year period Treatment practice in chronic epicondylitis: A survey among general practitioners and physiotherapists in Uppsala County, Sweden A Randomized Clinical Trial Comparing the Accuracy of Direct versus Indirect Bracket Placement Predicting time to nursing home care and death in individuals with Alzheimer disease. An interactive voice response system to enhance antidepressant medication compliance. Comparative Efficacy and Safety of New Oral Anticoagulants in Patients With Atrial Fibrillation Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. Who provides care for people dying of cancer? A comparison of a rural and metropolitan cohort in a South Australian bereaved population study. Paroxetine versus placebo: a double-blind comparison in depressed patients. A comparison of the relative growth velocities with budesonide and fluticasone propionate in children with asthma. Placebo found equivalent to amoxicillin for treatment of acute bronchitis in Nairobi, Kenya: a triple blind, randomised, equivalence trial Real-time estimation of daily physical activity intensity by a triaxial accelerometer and a gravity-removal classification algorithm. The Social Functioning Questionnaire: A Rapid and Robust Measure of Perceived Functioning Penile rehabilitation therapy following radical prostatectomy Balance and walking after three different models of stroke rehabilitation: early supported discharge in a day unit or at home, and traditional treatment (control) Randomised clinical trial on the effect of the Dutch obstetric peer review system. Ankles back in randomized controlled trial (ABrCt): braces versus neuromuscular exercises for the secondary prevention of ankle sprains. Design of a randomised controlled trial
Summary Background Therapeutic options to treat atopic dermatitis are limited . Leukocytes from atopic patients have an abnormally high activity of cyclic adenosine monophosphate (AMP)–phosphodiesterase ( PDE ) , which can be normalized in vitro by PDE inhibitors . Cipamfylline is a new potent and selective inhibitor of PDE‐4 Objectives The aim of this report is to demonstrate pharmacokinetic ( PK ) and pharmacodynamic ( PD ) equivalence as well as similar efficacy , safety and immunogenicity between GP2013 , a biosimilar rituximab , and innovator rituximab ( RTX ) in patients with rheumatoid arthritis ( RA ) with inadequate response or intolerance to tumour necrosis factor inhibitor ( TNFi ) treatment . Methods In this multinational , r and omised , double-blind , parallel-group study , 312 patients with active disease despite prior TNFi therapy were r and omised to receive GP2013 or either the EU ( RTX-EU ) or the US ( RTX-US ) reference product , along with methotrexate ( MTX ) and folic acid . The primary endpoint was the area under the serum concentration – time curve from study drug infusion to infinity ( AUC0-inf ) . Additional PK and PD parameters , along with efficacy , immunogenicity and safety outcomes were also assessed up to week 24 . Results The 90 % CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80 % to 125 % for all three comparisons ; GP2013 versus RTX-EU : 1.106 ( 90 % CI 1.010 to 1.210 ) ; GP2013 versus RTX-US : 1.012 ( 90 % CI 0.925 to 1.108 ) ; and RTX-EU versus RTX-US : 1.093 ( 90 % CI 0.989 to 1.208 ) . Three-way PD equivalence of B cell depletion was also demonstrated . Efficacy , safety and immunogenicity profiles were similar between GP2013 and RTX . Conclusions Three-way PK/PD equivalence of GP2013 , RTX-EU and RTX-US was demonstrated . Efficacy , safety and immunogenicity profiles were similar between GP2013 and RTX . Trial registration number NCT01274182 ; Results OBJECTIVE The impact of a r and omised controlled trial ( RCT ) upon practice depends on its external validity ( generalisability ) . This paper summarises and illustrates a framework for judging and augmenting external validity , emphasising its application to treatment trials in otitis media with effusion ( OME ) so as to permit stronger inferences in the future . METHODS The external validity of two surgical trials in the field of OME ( TARGET , UK and KNOOP-3 , the Netherl and s ) has been examined within a framework emphasising effect modification , in four specific ways : ( 1 ) comparison of the demographic characteristics of the trial population with the domain population ; ( 2 ) study ing the distributions on possible effect modifiers ( i.e. variables conditioning the benefit from intervention ) ; ( 3 ) study ing whether effect modification occurs in the analyses ; and ( 4 ) comparing outcome measures between the r and omised and the eligible but non-r and omised children . RESULTS For neither KNOOP-3 and TARGET were large discrepancies found between r and omised and non-r and omised children for any of the demographic variables . Differences in distributions along possible effect modifiers were found , but the overlaps were large enough for it still to be possible to study whether these factors indeed modified the outcome . Results for the r and omised and non-r and omised but eligible patients were similar . The results of both trials therefore appear to be generalisable to their domain population s. CONCLUSIONS A superficial contrast in the results ( KNOOP null , TARGET positive ) does not amount to a contradiction , because of differences in the clinical question appropriate to the respective age and population s defined . Attention to quality of design and external validity of r and omised controlled trials should achieve higher applicability INTRODUCTION Phosphodiesterase type 5 ( PDE-5 ) inhibitor treatment for erectile dysfunction ( ED ) is frequently discontinued ; adherence may vary depending on the initial regimen . AIM To evaluate the effects of initiating treatment with tadalafil once a day ( OaD ) , tadalafil on dem and ( pro re nata [ PRN ] ) , or sildenafil PRN on treatment adherence . METHODS In this multicenter , open-label study , men ( ≥ 18 years ) with ED , naïve to PDE-5 inhibitors , were r and omized ( 1:1:1 ) to tadalafil 5 mg OaD , tadalafil 10 mg PRN , or sildenafil 50 mg PRN . An 8-week r and omized treatment ( RT ) period ( dose adjustment possible ) was succeeded by 16 weeks of pragmatic treatment ( switches between PDE-5 inhibitors allowed ) . MAIN OUTCOME MEASURES Treatment adherence was measured as time to discontinuation of RT ( any cause ) , estimated by Kaplan-Meier product-limit method . Treatment-group differences were estimated as hazard ratio ( HR ; Cox proportional hazards ) . RESULTS Seven hundred seventy patients ( mean age 53 years ) were r and omized to tadalafil OaD ( N = 257 ) , tadalafil PRN ( N = 252 ) , and sildenafil PRN ( N = 261 ) . Kaplan-Meier estimates for patients discontinuing RT were 52.2 , 42.0 , and 66.7 % , respectively . Median time to discontinuation of RT was significantly longer for tadalafil OaD and PRN ( 130 and > 168 days ) compared with sildenafil ( 67 days ) ( HR [ 97.5 % confidence interval ] : 0.66 [ 0.51 , 0.85 ] and 0.49 [ 0.37 , 0.65 ] ; P < 0.001 ) . Reasons for discontinuation with significant differences between groups ( P < 0.05 ) included " lack of efficacy ( duration of erection ) " ( sildenafil 9.2 % vs. tadalafil OaD 4.3 % , PRN 2.8 % ) , " time constraints due to short window of action "  ( sildenafil 4.2 % vs. tadalafil OaD 0 % , PRN 0.4 % ) , and " feel medication controls my sexual life "  ( sildenafil 2.7 % vs. tadalafil OaD 0 % ) . No between-group differences were found in International Index of Erectile Function-Erectile Function domain change from baseline to end of RT ( least squares mean : 9.4 - 10.0 , P = 0.359 ) or discontinuations due to adverse events ( 1.2 - 1.6 % ) . The most common adverse event ( ≥ 4 % ) was headache . CONCLUSIONS ED patients assigned to tadalafil OaD or PRN adhered significantly longer to initial treatment than patients assigned to sildenafil PRN . Improvement of erectile function and safety profiles were similar in all three treatment groups Background : Croup remains a common respiratory problem presenting to emergency departments . A single oral treatment of oral dexamethasone results in improved outcome .  Prednisolone has similar pharmacokinetic properties and has a significant advantage in that it is commercially available in liquid preparations . Objective : To ascertain whether a single oral dose of prednisolone was equivalent to a single oral dose of dexamethasone ( matched for potency ) in children with mild to moderate croup . Design : A double blind , r and omised , controlled equivalence trial Setting : Tertiary paediatric emergency department . Patients : 133 children aged 3 to 142 months presenting with mild to moderate croup . Interventions : Children received either a single oral dose of dexamethasone 0.15 mg/kg or single oral dose of prednisolone 1 mg/kg . Outcome : The main outcome measure was unscheduled re-presentation to medical care as determined by telephone follow up at 7 to 10 days . Croup score , adrenaline ( epinephrine ) use , time spent in the emergency department , and duration of croup and viral symptoms were secondary outcome measures . Results : Children treated with prednisolone were more likely to re-present : 19 of 65 children ( 29 % ) reattended medical care compared with 5 of 68 ( 7 % ) from the dexamethasone group . The confidence intervals around this 22 % difference in outcome were 8 % to 35 % , outside the 0 % to 7.5 % range of equivalence . There were no significant differences in other outcome measures . Conclusion : A single oral dose of prednisolone is less effective than a single oral dose of dexamethasone in reducing unscheduled re-presentation to medical care in children with mild to moderate croup This paper aims to explore the potential usefulness and limitations of indirect comparisons in evaluating the relative efficacy of interventions . From a systematic review of antimicrobial prophylaxis in colorectal surgery , we identified 11 sets of r and omized trials that can be used to compare antibiotics both directly and indirectly . The discrepancy between the direct and the indirect comparison is defined as the absolute value of difference in log odds ratio . The adjusted indirect comparison has the advantages that the prognostic factors of participants in different trials can be partially taken into account and more uncertainty be incorporated into its result by providing a wider confidence interval . However , considerable discrepancies exist between the direct and the adjusted indirect comparisons . When there is no direct comparison , the adjusted indirect method may be used to obtain some evidence about the relative efficacy of competing interventions , although such indirect results should be interpreted with great caution . Further empirical and method ologic research is needed to explore the validity and generalizability of the adjusted indirect comparison for evaluating different interventions Question To compare the efficacy of aerobic walking and home based quadriceps strengthening exercises in reducing  pain and disability in knee osteoarthritis . Design Systematic review of r and omised controlled trials . Setting / population People with knee osteoarthritis . Interventions Comparison of aerobic walking or home based quadriceps strengthening exercise with a non-exercise control group . Strengthening exercise was considered to be ‘ home based ' where it was undertaken exclusively in the subject 's home environment or , where exercise was partly supervised , the regimen was intended to be continued at home unsupervised . Outcomes Pain and disability . Results 13 studies were included . One study provided a direct comparison between aerobic walking and home based strengthening exercises and control . Nine RCTs evaluated quadriceps strengthening exercises , and in three studies the exercise intervention was predominantly aerobic walking . Control interventions included education and lifestyle advice , support by telephone calls , and no intervention . When comparing aerobic walking with no exercise interventions , the pooled effect sizes for pain and disability were 0.52 ( 95 % CI 0.34 to 0.70 ) and 0.46 ( 95 % CI 0.25 to 0.67 ) respectively . Corresponding effect size for quadriceps strengthening was 0.32 ( 95 % CI 0.23 to 0.42 ) for both pain and disability . Conclusion Both aerobic walking and home based quadriceps strengthening exercises are effective at reducing pain and disability in subjects with knee osteoarthritis . No advantage of one form of exercise over the other was found on indirect comparison OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin  and  heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful AIMS To provide controlled data on direct induction with buprenorphine/naloxone ( BNX ) versus indirect buprenorphine (BPN)-to-BNX induction . DESIGN Phase 4 , prospect i ve , r and omized , active-drug controlled , parallel-group trial consisting of a 2-day , double-blind , double-dummy induction phase followed by 26 days of open-label treatment with BNX . SETTING Nineteen sites in 10 European countries from March 2008 to December 2009 . PARTICIPANTS A total of 187 opioid-dependent men and women ≥ 15 years of age . MEASUREMENTS The primary objective was assessment of patient response to direct and indirect BNX induction  [ proportion of patients receiving the scheduled 16-mg BNX dose on day 3 ( i.e. first day post-induction ) ] . Secondary assessment s included illicit drug use , treatment retention and compliance , withdrawal scale scores , and safety . FINDINGS Patient response to direct- versus indirect-BNX induction was similar [ direct 91.4 % ( 85/93 ) versus indirect 90.4 % ( 85/94 ) ; 95 % confidence interval ( CI ) : -7.3 % , 9.2 % ] . Rapid dose induction ( 16 mg of BPN equivalent on day 2 ) was acceptable and 72 % of patients completed treatment ( day 28 ) . There were no significant differences in secondary measures across groups . An average BNX maintenance dose of 15.3 mg across groups was associated with substantial reductions in illicit opioid use and no self-reported intravenous misuse . Treatment compliance and retention rates were similar ( 98.5 % and 81.3 % , respectively ) . Treatment-emergent adverse event rates were comparable : 75 % versus 74 % for direct- versus indirect-induction groups , respectively . CONCLUSIONS Direct buprenorphine/naloxone induction was a safe and effective strategy for maintenance treatment of opioid dependence . Response to high-dose direct buprenorphine/naloxone induction appears to be similar to indirect buprenorphine-to-buprenorphine/naloxone induction and was not associated with reports of intravenous buprenorphine/naloxone misuse Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents , such as tricyclic antidepressants . However , data are limited for direct comparisons with other antidepressants . The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind r and omized study of low vs. regular doses of nortriptyline . There were 97 patients enrolled in the study ( 28 treated with sertraline ) , with an average treatment duration of 55 days . There were no differences in the tolerability of sertraline vs. nortriptyline . However , in this group of frail older adults , sertraline was not as effective as  nortriptyline for the treatment of depression Background Studies suggest that expectations powerfully shape clinical outcomes . For subjective outcomes in adequately blinded trials , health improvements are substantial and largely explained by non-specific factors . The objective of this study was to investigate if unblinding in r and omized controlled trials ( RCTs ) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups . For these effects , a secondary objective was to explore potential moderating factors . Methods We included RCTs that investigated the efficacy of phosphodiesterase-5 ( PDE-5 ) inhibitors  for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo . In addition , to be included studies must have reported scores for change from baseline , or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score ( IIEF-EF )  , and be published in either English , French , Dutch , or German . We search ed for both published and unpublished relevant trials using PUBMED , EMBASE , the Cochrane Central Register of Controlled Trials , a clinical trials register ( clinical trials.gov ) and the Food and Drug Administration clinical review s through March 2012.We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool , using the domains of allocation sequence concealment , blinding of participants , healthcare providers and outcome assessors . Across these four domains , studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded . Results We included 110 studies ( 205 journal publications and 2 unpublished sources ) that involved 23,877 participants ; 93 ( 85 % ) , 51 ( 46 % ) , 93 ( 85 % ) and 93 ( 85 % ) studies were assessed with an unclear risk of bias for allocation concealment , blinding of participant , blinding of caregiver and blinding of outcome assessor , respectively . None of the studies reported testing of blinding . None of the 205 journal publications provided sufficient details to assess allocation concealment , blinding of participants , caregivers and outcome assessors . After contacting authors for additional information , we judged five studies to be adequately ( n = 1,202 ) and 16 to be inadequately ( n = 3,006 ) blinded . The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points ( 95 % CI , 0.64 to 3.20 ) versus 1.56 ( 95 % CI , 0.93 to 2.20 ) , respectively . The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 ( 95 % CI , 6.96 to 11.83 ) versus 8.33 ( 95 % CI , 7.29 to 9.37 ) , respectively . In a secondary analysis , prior experience with the drug affected the scores ; in placebo groups with participants naïve to the intervention the score was 2.89 ( 95 % CI , 2.33 to 3.45 ) versus -0.11 ( 95 % CI , -2.06 to 1.84 ) with participants having prior experience . In the intervention groups , these scores were 7.99 ( 95 % CI , 6.85 to 9.14 ) versus 8.33 ( 95 % CI , 7.51 to 9.16 ) , respectively . Unblinding lowered placebo scores ( creating a nocebo effect ) by 19 % ( 0.33 points ; 95 % CI , -0.96 to 1.62 ) . Unblinding lowered intervention scores by 11 % ( 1.0 ; 95 % CI , -1.35 to 3.47 ) . The results provided no conclusive evidence for nocebo or enhanced placebo effects .  Patients taking a PDE-5 inhibitor for the first time experience a larger placebo effect that accounts for 35 % of the total effect . Conclusions Given the overall poor reporting of blinding in clinical trial reports and the small number of trials that could be rated as adequately or inadequately blinded , we could not draw any robust conclusions about the existence or absence of nocebo and enhanced placebo effects . A large placebo effect was found for patients taking PDE-5 inhibitors for the first time . It was not clear if previous exposure to the drug impacted trial blinding . We found clear evidence that studies assessing a subjective continuous outcome fail to report on measures taken to secure double blinding . Although we observed a trend for the presence of a nocebo effect , there was insufficient evidence to quantify its impact on expectations . RCTs with patients with no prior experience with PDE-5 inhibitors reported larger placebo effects and possibly these studies were better blinded . Future research should further investigate the factors that contribute to blinding and their impact on health outcomes in r and omized trials of subjectively assessed conditions . This research is part of a PhD project and has no external funding . The authors have no competing interests to declare Reporting of adverse events ( AEs ) in r and omized clinical trials ( RCTs ) is often lacking and with limited application in the real world , as RCTs are of short duration , include small numbers of patients , and are selective for subjects lacking in comorbid conditions . It is not surprising that new and unexpected safety concerns emerge with any new drug after it has been launched and used by many more patients . Part of the problem is inherent to the way safety data are reported in RCTs . This article focuses on some of the shortcomings of AE reporting in RCTs , especially those involving tumor necrosis factor ( TNF ) inhibitors . Discussion focuses on reporting of " time-to-event " issues , use of st and ardized incidence ratios for comparison to normal population or disease controls , use of " patient-years " when reporting AEs , and the problem of adequate sample size and power calculations that are lacking in safety outcome data trials Objective : To examine the role of objective sleep duration , a novel marker in phenotyping insomnia , and psychological profiles on sleep misperception in a large , general population sample . Sleep misperception is considered by some investigators a common characteristic of chronic insomnia , whereas others propose it as a separate diagnosis . The frequency and the determinants of sleep misperception in general population sample s are unknown . Methods : A total of 142 insomniacs and 724 controls selected from a general r and om sample of 1,741 individuals ( aged ≥20 years ) underwent a polysomnographic evaluation , completed the Minnesota Multiphasic Personality Inventory-2  , and were split into two groups based on their objective sleep duration : “ normal sleep duration ” ( ≥6 hours ) and “ short sleep duration ” ( < 6 hours ) . Results : The discrepancy between subjective and objective sleep duration was determined by two independent factors . Short sleepers reported more sleep than they objective ly had , and insomniacs reported less sleep than controls with similar objective sleep duration . The additive effect of these two factors result ed in underestimation only in insomniacs with normal sleep duration . Insomniacs with normal sleep duration showed a Minnesota Multiphasic Personality Inventory-2 profile of high depression and anxiety and low ego strength , whereas insomniacs with short sleep duration showed a profile of a medical disorder . Conclusions : Underestimation of sleep duration is prevalent among insomniacs with objective normal sleep duration . Anxious-ruminative traits and poor re sources for coping with stress seem to mediate the underestimation of sleep duration . These data further support the validity and clinical utility of objective sleep measures in phenotyping insomnia . BMI = body mass index ; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ; MANCOVA = multivariate analysis of covariance ; MMPI-2 = Minnesota Multiphasic Personality Inventory-2 ; PLMS = periodic limb movements ; SDB = sleep disordered breathing Pain is a common complaint , often occurring in conjunction with inflammation . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) are the most commonly used analgesic agents in ambulatory patients . In recent studies , the cyclooxygenase-2 ( COX-2 ) inhibitor rofecoxib demonstrated analgesic effects similar to those of NSAIDs in the treatment of acute pain and primary dysmenorrhea . The present r and omized , single-dose , double-blind , double-dummy , placebo- and active-comparator-controlled , parallel-group study was undertaken to compare the analgesic efficacy of the COX-2 inhibitors rofecoxib 50 mg and celecoxib 200 mg with that of ibuprofen 400 mg and placebo in patients with postoperative dental pain . Two hundred and seventy-two patients experiencing pain after the removal of > or = 2 third molars were r and omized according to pain severity ( moderate vs severe ) to receive a single dose of placebo ( n = 45 ) , rofecoxib 50 mg ( n = 90 ) , celecoxib 200 mg ( n = 91 ) , or ibuprofen 400 mg ( n = 46 ) . Using a patient diary , patients recorded pain intensity , pain relief , and global evaluations throughout the 24-hour period after dosing . The overall analgesic effect , onset of action , peak effect , and duration of effect were evaluated , with the primary end point being total pain relief over 8 hours ( TOPAR8 ) . The safety profile was assessed on the basis of physical findings , laboratory results , and spontaneous reports of adverse experiences . The results showed that compared with celecoxib , rofecoxib had superior analgesic effects on all measures of analgesic efficacy , including overall analgesic effect ( TOPAR8 , 18.3 vs. 12.5 ; P<0.001 ) , time to onset of effect ( 30 vs. 60 minutes ; P = 0.003 ) , peak pain relief ( score , 2.8 vs 2.3 ; P<0.05 ) , and duration of effect ( > 24 vs. 5.1 hours ; P<0.001 ) . In addition , rofecoxib 's analgesic efficacy was similar to that of ibuprofen ( TOPAR8 , 18.3 vs. 17.0 ; P = 0.460 ) , but the duration was longer ( P<0.05 ) ; with ibuprofen , the time to on set was 24 minutes , peak pain relief score was 2.9 , and duration of analgesic effect was 8.9 hours . The safety profile was similar across all treatment groups . Thus rofecoxib provided analgesic efficacy superior to that of celecoxib and comparable to that of ibuprofen in the treatment of patients with acute postoperative dental pain Abstract Aims /hypothesisThere are limited data comparing dipeptidyl peptidase-4 ( DPP-4 ) inhibitors directly . We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment ( RI ) . Methods This study was a parallel-arm , r and omised , multicentre , double-blind , 24 week study conducted in 87 centres across Brazil and the USA . Patients with type 2 diabetes , either drug naive or treated with any glucose-lowering agents , who had inadequate glycaemic control ( HbA1c 6.5–10.0 % [ 48–86 mmol/mol ] ) and an estimated GFR < 30 ml min−1 [ 1.73 m]−2 were r and omised ( via interactive voice response technology ) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily . These doses are recommended in this patient population and considered maximally effective . Participants , investigators and the sponsor were blinded to group assignment . Efficacy endpoints included change in HbA1c and fasting plasma glucose ( FPG ) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events . Results In total , 148 patients were r and omised , 83 to vildagliptin and 65 to sitagliptin . All patients were analysed . After 24 weeks , the adjusted mean change in HbA1c was −0.54 % ( 5.9 mmol/mol ) from a baseline of 7.52 % ( 59 mmol/mol ) with vildagliptin and −0.56 % ( 6.1 mmol/mol ) from a baseline of 7.80 % ( 62 mmol/mol ) with sitagliptin ( p = 0.874 ) . FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin ( p = 0.185 ) . Both treatments were well tolerated with overall similar safety profiles . Conclusions /interpretationAt their recommended doses for severe RI , vildagliptin ( 50 mg once daily ) compared with sitagliptin ( 25 mg once daily ) demonstrated similar efficacy and both drugs were well tolerated . This study provides further support for the use of DPP-4 inhibitors in patients with severe RI . Trial registration : Clinical Trials.gov NCT00616811 ( completed ) Funding : This study was planned and conducted by BACKGROUND Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority . We assessed whether home-based HIV care was as effective as was facility-based care . METHODS We undertook a cluster-r and omised equivalence trial in Jinja , Ug and a. 44 geographical areas in nine strata , defined according to ratio of urban and rural participants and distance from the clinic , were r and omised  to home-based or facility-based care by drawing sealed cards from a box . The trial was integrated into normal service delivery . All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per microL who started antiretroviral therapy between Feb 15 , 2005 , and Dec 19 , 2006 , were eligible , apart from those living on isl and s. Follow-up continued until Jan 31 , 2009 . The primary endpoint was virological failure , defined as RNA more than 500 copies per mL after 6 months of treatment . The margin of equivalence was 9 % ( equivalence limits 0.69 - 1.45 ) . Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum . This trial is registered at http://is rct n.org , number IS RCT N 17184129 . FINDINGS 859 patients ( 22 clusters ) were r and omly assigned to home and 594 ( 22 clusters ) to facility care . During the first year , 93 ( 11 % ) receiving home care and 66 ( 11 % ) receiving facility care died , 29 ( 3 % ) receiving home and 36 ( 6 % ) receiving facility care withdrew , and 8 ( 1 % ) receiving home and 9 ( 2 % ) receiving facility care were lost to follow-up . 117 of 729 ( 16 % ) in home care had virological failure versus 80 of 483 ( 17 % ) in facility care : rates per 100 person-years were 8.19 ( 95 % CI 6.84 - 9.82 ) for home and 8.67 ( 6.96 - 10.79 ) for facility care ( rate ratio [ RR ] 1.04 , 0.78 - 1.40 ; equivalence shown ) . Two patients from each group were immediately lost to follow-up . Mortality rates were similar between groups ( 0.95 [ 0.71 - 1.28 ] ) . 97 of 857 ( 11 % ) patients in home and 75 of 592 ( 13 % ) in facility care were admitted at least once ( 0.91 , 0.64 - 1.28 ) . INTERPRETATION This home-based HIV-care strategy is as effective as is a clinic-based strategy , and therefore could enable improved and equitable access to HIV treatment , especially in areas with poor infrastructure and access to clinic care All new interventions and procedures must be properly assessed in comparison to the currently accepted method ( s ) . It is unethical not to do so . The optimum method is by R and omised Controlled Trial ( RCT ) . This is ideally suited to the testing of drugs because the trial can usually be double blind and placebo controlled . RCTs are less commonly used for the evaluation of new surgical techniques . There are valid and invalid reasons for this and these are discussed BACKGROUND Stroke is directly related to blood pressure and treatment trials in older hypertensive individuals show a reduction in strokes . However , the majority of strokes occur in normotensive individuals in whom no attempt is made to lower blood pressure . We compared the effects of modest salt restriction on blood pressure in older hypertensive and normotensive people . METHODS 47 untreated elderly people ( 24 men , age range 60 - 78 years ; blood-pressure range 123 - 205 mm Hg systolic and 64 - 112 mm Hg diastolic ) completed a 2-month double-blind r and omised placebo-controlled crossover study of modest salt restriction with slow sodium and placebo to give a salt intake of either 10 g ( equivalent to the normal amount for the UK population ) or 5 g. FINDINGS On the normal salt intake for the UK population , supine blood pressure was 163/90 ( SD 21/10 ) mm Hg with urinary sodium excretion of 177 ( 49 ) mmol/day . With modest sodium restriction , blood pressure fell to 156/87 ( 22/9 ) mm Hg ( p < 0.001/0.004 ) with a urinary sodium excretion of 94 ( 50 ) mmol/day . A reduction in sodium intake of 83 mmol/day was associated with a reduction of 7.2/3.2 mm Hg . There was no significant difference in the blood-pressure fall between 18 normotensive and 29 hypertensive participants ( 8.2/3.9 vs 6.6/2.7 mm Hg ) . INTERPRETATION A modest reduction in salt intake leads to a fall in blood pressure in both normotensive and hypertensive older people similar to that in outcome trials of thiazide-based treatment . Since the majority of strokes in older people occur below the current definition of hypertension , our results have important implication s for the prevention of stroke The efficacy and safety of sildenafil were evaluated in a r and omised , double-blind , placebo-controlled , flexible-dose study in Taiwanese men aged 26 to 80 y with erectile dysfunction ( ED ) of broad-spectrum aetiology and more than 6 months ' duration . A total of 236 patients were r and omised at six medical centres in Taiwan to receive either sildenafil ( 50 mg initially increased if necessary to 100 mg or decreased to 25 mg depending on efficacy and toleration ) ( n=119 ) or matching placebo ( n=117 ) taken on an ‘ as needed ’ basis 1 h prior to anticipated sexual activity for a period of 12 weeks . At the end of 12 weeks , the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse , and the secondary efficacy variables , which included : ( 1 ) the five separate domains of sexual functioning of the IIEF ( International Index of Erectile Function ) scale , ( 2 ) the percentage of successful intercourse attempts ; and ( 3 ) a global assessment of erections , were all statistically significantly improved by sildenafil in comparison with placebo ( P<0.0001 ) . Treatment-related adverse events occurred in 43.7 % of patients receiving sildenafil and 18.8 % receiving placebo . The most common adverse events with sildenafil were flushing , dizziness and headache ( 25.2 , 6.7 and 5.9 % of patients , respectively ) , and most were mild in nature . The efficacy and safety of sildenafil in the population of Taiwanese men appears similar to that reported in other studies in western population WHAT IS KNOWN AND OBJECTIVE Psoriasis is a chronic skin disease for which there is an increasing range of treatment options . Biological agents ( ustekinumab , adalimumab , infliximab and etanercept ) are indicated for moderate-to-severe plaque-type psoriasis in adults who fail to respond to , have a contraindication to , or are intolerant to other systemic therapies including cyclosporine , methotrexate and PUVA  Unfortunately , with new drugs , the pivotal trials leading to their licensing are often placebo-controlled trials rather than comparative trials vs. established therapies . Therefore , inference on comparative effectiveness of the newer agents must be derived indirectly , through estimation of effects of the new agents vs. a common comparator . The objective of this study is to compare the relative efficacy of the biological agents through a systematic review of the indirect clinical trial evidence . METHODS A systematic literature search was performed for clinical trials of biological agents in psoriasis . Pivotal , r and omized , double-blind , controlled ( placebo )  trials using intention-to-treat analysis were selected for detailed analysis . Trials must include PASI 75 as a primary end point . The indirect comparison was performed using the method of Bucher adjusted with the ITC calculator ( Indirect Treatment Comparisons of the Canadian Agency for Drugs and Technologies in Health ) , etanercept being the reference drug . We defined delta value for therapeutic equivalence as a difference in the efficacy of 25 % among the different treatment options . RESULTS AND DISCUSSION Fourteen studies ( four for ustekinumab , three for adalimumab , three for infliximab and four for etanercept ) were included . The indirect comparison results reveal that ustekinumab , adalimumab and infliximab were statistically superior to etanercept with an absolute risk difference for PASI 75 of 12 % ( 95 % CI = 5·9 - 18 % ) , 11 % ( 95 % CI = 5·3 - 16·7 % ) and 24 % ( 29·7 - 18·3 % ) respectively . However , in all situations , the 95 % confidence interval does not achieve clinical relevance as no delta exceeds the previously set value ( 25 % ) . WHAT IS NEW AND CONCLUSION Ustekinumab , adalimumab , infliximab and etanercept can be regarded as clinical equivalents for the treatment of psoriasis . Choice between these agents therefore depends on their relative safety profiles , individual contra-indications and cost effectiveness Depression is the most common psychiatric disorder among the elderly and in old age may interact with emotional and cognitive functioning . Depression in old age has been shown to be associated with degenerative changes in the brain . It is , therefore , important that in this patient population antidepressants with a favourable tolerability profile , such as the selective serotonin reuptake inhibitors ( SSRIs ) , are examined for both antidepressant efficacy and effect on cognitive function and emotional impairment . This r and omised , double-blind study compared the efficacy and tolerability of citalopram and mianserin in 336 elderly , depressed patients with or without dementia . Patients received either citalopram 20 - 40 mg/day or mianserin 30 - 60 mg/day for 12 weeks . The treatments were equivalent with respect to change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score ; patients in both treatment groups responded well . Patients with dementia showed a smaller decrease in total MADRS score than patients without dementia . Both treatments were well tolerated with a relatively low incidence of adverse events . Fatigue and somnolence were more frequent with mianserin , while insomnia was more frequent with citalopram . Overall , this study showed that the two treatments were equivalent in efficacy , and that citalopram is an effective , well-tolerated and non-sedative treatment for elderly depressed patients with or without dementia The terms applicability , generalizability , external validity and transferability are related , sometimes used interchangeably and have in common that they lack a clear and consistent definition in the classic epidemiological literature . However , all of these terms generally describe one overarching theme : whether or not available research evidence can be directly utilized to answer the healthcare questions at h and , ideally supported by a judgment about the degree of confidence for this utilization . This concept has been called directness . The objectives of this paper were to delineate how non-r and omized studies ( NRS ) inform judgments in relation to directness and the concepts that it encompasses in the context of systematic review s. We will briefly review what is known and describe the theoretical and practical issues as well as offer guidance to those tackling the challenges of judging directness and using research evidence to answer healthcare questions with evidence from NRS . In particular , we suggest a framework in which authors can use NRS as a complement , sequence or replacement for r and omized controlled trials ( RCTs ) by focusing on judgments about the population , intervention , comparison and outcomes . Authors of systematic review s will use NRS to complement judgments about the inconsistencies , the rationale and credibility of subgroup analysis , the baseline risk estimates for the determination of absolute benefits and downsides , and the directness of surrogate outcomes . This evidence includes context ual or supplementary evidence . Authors of systematic review and other summaries of the evidence use NRS as sequential evidence to provide evidence when insufficient evidence is available for an outcome from RCTs , but NRS evidence is available ( e.g. , long-term harms ) . Use of evidence from NRS may also serve to replace RCT evidence when NRS provide equivalent ( or potentially higher ) confidence in the evidence ( i.e. quality ) compared to indirect evidence from RCTs . These judgments will be made in the context of other domains that influence the overall quality of the body of evidence , including the risk of bias , publication bias ( i.e. limitations in the detailed study design and execution ) , inconsistency , imprecision and factors that increase our confidence in effects . This article will support systematic review ers in their interaction with decision makers , that is , those who use the systematic review to develop guidelines , address health policy makers , and make clinical decisions , by making these judgments transparent . Copyright © 2013 John Wiley & Sons , INTRODUCTION Phosphodiesterase type-5 ( PDE-5 ) inhibitors have previously been evaluated for their efficacy and safety in various clinical trials in men with erectile dysfunction ( ED ) with or without associated comorbidities . AIM This is the first prospect i ve , r and omized , double-blind , placebo-controlled study to evaluate the efficacy and safety of a PDE-5 inhibitor ( i.e. , vardenafil ) in an exclusive population of men with ED and dyslipidemia . MAIN OUTCOME MEASURES Three co primary efficacy measurements ( Sexual Encounter Performance [SEP]2 , SEP3 , International Index of Erectile Function-Erectile Function [ IIEF-EF ] domain scores ) were used to assess the differential effect of vardenafil vs. placebo in this patient population . Adverse events ( AEs ) safety data were obtained to compare safety outcomes . METHODS This 12-week of r and omized , double-blind , placebo-controlled study was conducted in 59 U.S. centers . Patients received either on-dem and , flexible-dose vardenafil 10 mg ( titrated to 5 mg or 20 mg based upon efficacy and safety ) or placebo . RESULTS Of the 712 patients screened and entered into the study , 395 were r and omized . Baseline demographics for the intent-to-treat population included : mean age , 54.4 years ( + /-7.5 st and ard deviation [ SD ] ) ; 76 % Caucasian ; mean body mass index ( BMI ) , 31.7 kg/m(2 ) ( + /-12.7 SD ) ; 47 % past/present smoker ; and 42 % severe ED . Aside from dyslipidemia , other comorbidities included hypertension , 61 % ; obesity ( i.e. , BMI > /= 30 ) , 51 % ; and type 1 or 2 diabetes , 40 % . During the 12-week treatment period , the least squares ( LS ) adjusted mean success rates in patients on vardenafil vs. placebo were : SEP2 , 79.09 % vs. 51.92 % ; and SEP3 , 66.69 % vs. 33.83 % ( P < 0.001 ) . The LS adjusted mean IIEF-EF domain score for week 12 using LOCF was 21.99 in patients on vardenafil therapy vs. 14.83 in those on placebo ( P < 0.001 ) . The most commonly encountered AEs were headache and nasal congestion . CONCLUSIONS Vardenafil was demonstrated to be safe and effective for managing ED in men with ED and associated dyslipidemia . The results of this study support the role of exp and ed research on outcomes related to effective ED treatment and aggressive lipid control Abstract Objective : To assess the validity of  st and ardised patients to measure the quality of physicians ' practice . Design : Validation study of st and ardised patients ' assessment s. Physicians saw unannounced st and ardised patients presenting with common outpatient conditions . The st and ardised patients covertly tape recorded their visit and completed a checklist of quality criteria immediately afterwards . Their assessment s were compared against independent assessment s of the recordings by a trained medical records abstract or . Setting : Four general internal medicine primary care clinics in California . Participants : 144 r and omly selected consenting physicians . Main outcome measures : Rates of agreement between the patients ' assessment s and independent assessment . Results : 40 visits , one per st and ardised patient , were recorded . The overall rate of agreement between the st and ardised patients ' checklists and the independent assessment of the audio transcripts was 91 % ( κ . Disaggregating the data by medical condition , site , level of physicians ' training , and domain ( stage of the consultation ) gave similar rates of agreement . Sensitivity of the st and ardised patients ' assessment s was 95 % , and specificity was 85 % . The area under the receiver operator characteristic curve was 90 % . Conclusions : St and ardised patients ' assessment s seem to be a valid measure of the quality of physicians ' care for a variety of common medical conditions in actual outpatient setting s. Properly trained st and ardised patients compare well with independent assessment of recordings of the consultations and may justify their use as a “ gold st and ard ” in comparing the quality of care across sites or evaluating data obtained from other sources , such as medical records and clinical vignettes AIM to explore whether nurses can undertake the pre operative assessment of children prior to day case surgery as safely as senior house officers . DESIGN a r and omised controlled trial involving 595 children , using an equivalence methodology ( a method which looks for similarity rather than a significant difference ) . Pre-operative assessment prior to day case surgery was r and omised to either a nurse ( experimental group ) or a junior doctor ( control group ) . Blinded expert verification of nurse/junior doctor performance was ascertained by an experienced anaesthetist ( the ' gold st and ard ' ) . RESULTS there was equivalence between nurses and senior house officers in their ability to detect clinical ly significant abnormalities within the sample population . Subgroup analysis also demonstrated equivalence in respect of history taking abilities . The smaller number of clinical ly significant physical findings within the sample meant that equivalence in respect of physical examination remains uncertain . Although the study was limited to a single setting , the results demonstrate nurses ' equivalence with junior doctors in a discrete paediatric context Objectives : To evaluate the validity of parents ’ self reported home safety practice s concerning smoke detectors , bike helmets , car seats , and water heater temperature . Setting : Parents of children 12 years old and under whose child had made at least one visit to a study clinic in the years 2000–2003 . Methods : As part of a r and omized controlled trial to improve patient provider communication and preventive practice s , parents ’ responses to telephone interview were compared with observations of safety practice s during a home visit . Home visits were completed within nine weeks of the telephone interview . Parents were not told that the visit was part of a validation study and home visit observers were unaware of the interview responses . The authors calculated sensitivities , specificities , positive and negative predictive values , and their corresponding confidence intervals . Results : Sensitivity ( 0.78 to 0.98 ) and positive predictive values ( 0.75 to 1.00 ) were high for all items . Specificities and negative predictive values were more variable and the highest estimates ( specificity 0.95 to 1.00 , negative predictive value 0.95 to 0.97 ) were for car seat types . Conclusions : The results suggest that parent self report practice of certain injury prevention behaviors ( owning a car seat , hot water temperatures ) is reliable , whereas self reports on other practice s ( working smoke detectors , properly fitting bike helmets ) may be overstated OBJECTIVE To assess the safety and efficacy of a fixed dose of recombinant activated factor VII ( rFVIIa ; NovoSeven ) in the home setting for mild to moderately severe joint , muscle ; and mucocutaneous bleeding episodes in patients with haemophilia A or B with inhibitors . DESIGN Multicentre , open-label , single arm , phase III study of one year duration . METHODS ; Patients or their caregivers administered up to three doses of rFVIIa ( 90 microg/kg i.v . ) at 3 h intervals within 8 h of the onset of a mild to moderate bleeding episode . Once the subject considered that rFVIIa had been " effective " with regard to haemostasis ( after 1 - 3 injections ) , one further ( maintenance ) dose of rFVIIa was administered . RESULTS Of 60 patients enrolled , 56 experienced at least one bleed , and 46 completed the one year study . 614 of 877 bleeds ( 70 % ) were evaluable according to protocol definitions . Haemostasis was rated as " effective " in 92 % ( 566/614 ) of evaluable bleeds after a mean of 2.2 injections . For successfully treated episodes , the time from onset of bleeding until administration of the first injection was 1.1+/-2.0 h ( mean+/-SD ) . Twenty-four hours after initial successful response , haemostasis was reported as having been maintained in 95 % of cases . Efficacy was comparable for muscle , joint and target joint , and mucocutaneous bleeding episodes . In an intent-to-treat analysis of all 877 bleeding events , efficacy outcomes were equivalent to the evaluable bleeds , with an effective response in 88 % of treated episodes . Treatment-related adverse events occurred in 32 ( 3 % of all ) bleeding episodes and consisted of re-bleeds/new bleeds in more than 50 % ( 18/32 ) of these events . A single episode of superficial thrombophlebitis was the only thrombotic complication encountered , and there were no patient withdrawals due to adverse events . Development of FVII(a ) antibodies could not be detected , and hypersensitivity reactions to rFVIIa were not reported . CONCLUSION rFVIIa is effective and well tolerated when used in the home setting to treat mild to moderate bleeding episodes in patients with haemophilia A or B with inhibitors The Ginkgo biloba special extract EGb 761 seems to produce neuroprotective effects in neurodegenerative diseases of multifactorial origin . There is still debate about the efficacy of Ginkgo biloba special extract EGb 761 compared with second-generation cholinesterase inhibitors in the treatment of mild to moderate Alzheimer 's dementia . Our aim is to assess the efficacy of the Ginkgo biloba special extract E.S. in patients with dementia of the Alzheimer type in slowing down the disease 's degenerative progression and the patients ' cognitive impairment compared with donepezil and placebo . The trial was design ed as a 24-week r and omized , placebo-controlled , double-blind study . Patients aged 50 - 80 years , suffering from mild to moderate dementia , were allocated into one of the three treatments : Ginkgo biloba ( 160 mg daily dose ) , donepezil ( 5 mg daily dose ) , or placebo group . The degree of severity of dementia was assessed by the Syndrom Kurz test and the Mini-Mental State Examination . Clinical Global Impression score was recorded to assess the change in the patients ' conditions and the therapeutic efficacy of tested medications . Our results confirm the clinical efficacy of Ginkgo biloba E.S. ( Flavogin ) in the dementia of the Alzheimer type , comparable with donepezil clinical efficacy . There are few published trials that have directly compared a cholinesterase inhibitor with Ginkgo for dementia . This study directly compares a cholinesterase inhibitor with Ginkgo biloba for dementia of the Alzheimer type and could be a valid contribution in this debate . Our study suggests that there is no evidence of relevant differences in the efficacy of EGb 761 and donepezil in the treatment of mild to moderate Alzheimer 's dementia , so the use of both substances can be justified . In addition , this study contributes to establish the efficacy and tolerability of the Ginkgo biloba special extract E.S. in the dementia of the Alzheimer type with special respect to moderately severe stages R and omised controlled trials are the best way to compare the effectiveness of different interventions . Only r and omised trials allow valid inferences of cause and effect . Only r and omised trials have the potential directly to affect patient care — occasionally as single trials but more often as the body of evidence from several trials , whether or not combined formally by meta- analysis . It is thus entirely reasonable to require higher st and ards for papers reporting r and omised trials than those describing other types of study . Like all studies , r and omised trials are open to bias if done badly.1 It is thus essential that r and omised trials are done well and reported adequately . Readers should not have to infer what was probably done , they should be told explicitly . Proper methodology should be used and be seen to have been used . Yet review s of published trials have consistently found major deficiencies in reporting,2 3 4 making the task Sildenafil , a treatment for erectile dysfunction , is a specific phosphodiesterase type 5 ( PDE 5 ) inhibitor that enhances nitric oxide (NO)–mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown . Since PDE 5 is widely expressed in the vasculature , we examined the hypothesis that sildenafil could enhance NO‐mediated vasodilation in other vascular beds and improve endothelial function OBJECTIVES We examined the accuracy of the Ottawa Ankle Rule ( OAR )  to rule out ankle and mid-foot fractures in patients presenting with acute ankle sprain and differences of accuracy between surgeons and non-surgeons . DESIGN Prospect i ve cohort study . SETTING Swiss urban secondary care centre . PARTICIPANTS Between September 2001 and October 2002 359 patients presented with a case of ankle sprain . Of these , 251 patients both met recruitment criteria and provided data for this study . A group of surgeons and non-surgeons assessed the OAR and all patients underwent blinded radiographic assessment . MAIN OUTCOME MEASURES Sensitivity , specificity of the OAR .  RESULTS Of the 251 patients with ankle sprains 33 had an ankle fracture ( 13 % ) and none had a mid-foot fracture . All cases with a fracture had a positive OAR result ( sensitivity 100 % 95 % CI ; 89 - 100 ) and of 218 patients without a fracture , the OAR was negative in 45 cases ( specificity 21 % ; 16 - 27 ) . In the subgroup of patients assessed by surgeons , sensitivity was 100 % ( 77 - 100 ) and specificity was 32 % ( 20 - 46 ) . In the non-surgical group , sensitivity was also 100 % ( 82 - 100 ) but specificity was lower ( 17 % ( 11 - 23 ) . CONCLUSIONS This validation study of the OAR in a Swiss setting produced similar results than those published previously in various other setting s. We found differences in the performance of the rule between surgical and non-surgical staff indicating that the OAR has its interpretation component which is more difficult to judge properly by well-instructed non-surgical assessors This study evaluates the effects of ketamine on healthy and schizophrenic volunteers ( SVs ) in an effort to define the detailed behavioral effects of the drug in a psychosis model . We compared the effects of ketamine on normal and SVs to establish the comparability of their responses and the extent to which normal subjects might be used experimentally as a model . Eighteen normal volunteers ( NVs ) and 17 SVs participated in ketamine interviews . Some ( n = 7 NVs ; n = 9 SVs ) had four sessions with a 0.1–0.5 mg/kg of ketamine and a placebo ; others ( n = 11 NVs ; n = 8 SVs ) had two sessions with one dose of ketamine ( 0.3 mg/kg ) and a placebo . Experienced research clinicians used the BPRS to assess any change in mental status over time and documented the specifics in a timely way . In both volunteer groups , ketamine induced a dose-related , short ( < 30 min ) increase in psychotic symptoms . The scores of NVs increased on both the Brief Psychiatric Rating Scale ( BPRS ) psychosis subscale ( p = .0001 ) and the BPRS withdrawal subscale ( p = .0001 ) , whereas SVs experienced an increase only in positive symptoms ( p = .0001 ) . Seventy percent of the patients reported an increase ( i.e. , exacerbation ) of previously experienced positive symptoms . Normal and schizophrenic groups differed only on the BPRS withdrawal score . The magnitude of  ketamine-induced changes in positive symptoms was similar , although the psychosis baseline differed , and the dose-response profiles over time were superimposable across the two population s. The similarity between ketamine-induced symptoms in SVs and their own positive symptoms suggests that ketamine provides a unique model of psychosis in human volunteers . The data suggest that the phencyclidine ( PCP ) model of schizophrenia maybe a more valid human psychosis/schizophrenia drug model than the amphetamine model , with a broader range of psychotic symptoms . This study indicates that NVs could be used for many informative experimental psychosis studies involving ketamine interviews The effects of phosphodiesterase III ( PDE III ) inhibitors administered after aortic declamping during cardiopulmonary bypass ( CPB ) for open heart surgery were investigated . Ten patients ( group M ) were administered milrinone ( 50 microg/kg ) after aortic declamping during CPB , 10 patients were administered amrinone ( 1 mg/kg ) at the same time during their surgery ( group A ) , and 10 patients served as controls with no drug administered ( group C ) . Soon after bolus infusion of the PDE III inhibitor , perfusion pressure dropped significantly in groups M and A. However , after release of CPB and at the end of surgery , there was no difference in aortic pressure between the 3 groups . There were also no differences between the groups in heart rate , pulmonary artery pressure , and pulmonary capillary wedge pressure . After weaning from CPB , the cardiac index was high and systemic vascular resistance index was low in groups M and A. There were no significant differences in the need for additional catecholamines and time for rewarming between groups . No adverse reactions were observed . A single administration of a PDE III inhibitor during CPB was useful for post-CPB management of patients undergoing open heart surgery .  Amrinone reduced perfusion pressures more than milrinone , but cardiac indices and aortic pressures after weaning from CPB showed no differences between group M and group A patients BACKGROUND High doses of intravenous methylprednisolone are recommended to treat relapses in patients with multiple sclerosis , but can be inconvenient and expensive . We aim ed to assess whether oral administration of high-dose methylprednisolone was non-inferior to intravenous administration . METHODS We did this multicentre , double-blind , r and omised , controlled , non-inferiority trial at 13 centres for multiple sclerosis in France . We enrolled patients aged 18 - 55 years with relapsing-remitting multiple sclerosis who reported a relapse within the previous 15 days that caused an increase of at least one point in one or more scores on the Kurtzke Functional System Scale .  With use of a computer-generated r and omisation list and in blocks of four , we r and omly assigned ( 1:1 ) patients to either oral or intravenous methylprednisolone , 1000 mg , once a day for 3 days . Patients , treating physicians and nurses , and data and outcome assessors were all masked to treatment allocation , which was achieved with the use of saline solution and placebo capsules . The primary endpoint was the proportion of patients who had improved by day 28 ( decrease of at least one point in most affected score on Kurtzke Functional System Scale ) , without need for retreatment with corticosteroids , in the per- protocol population . The trial was powered to assess non-inferiority of oral compared with intravenous methylprednisolone with a predetermined non-inferiority margin of 15 % . This trial is registered with Clinical Trials.gov , number NCT00984984 . FINDINGS Between Jan 29 , 2008 , and June 14 , 2013 , we screened 200 patients and enrolled 199 . We r and omly assigned 100 patients to oral methylprednisolone and 99 patients to intravenous methylprednisolone with a mean time from relapse onset to treatment of 7·0 days ( SD 3·6 ) and 7·4 days ( 3·9 ) , respectively . In the per- protocol population , 66 ( 81 % ) of 82 patients in the oral group and 72 ( 80 % ) of 90 patients in the intravenous group achieved the primary endpoint ( absolute treatment difference 0·5 % , 90 % CI -9·5 to 10·4 ) . Rates of adverse events were similar , but insomnia was more frequently reported in the oral group ( 77 [ 77 % ] ) than in the intravenous group ( 63 [ 64 % ] ) . INTERPRETATION Oral administration of high-dose methylprednisolone for 3 days was not inferior to intravenous administration for improvement of disability scores 1 month after treatment and had a similar safety profile . This finding could have implication s for access to treatment , patient comfort , and cost , but indication should always be properly considered by clinicians . FUNDING French Health Ministry , Ligue Française contre la SEP , Teva BACKGROUND Treatment of pulmonary embolism with low-molecular-weight heparin and vitamin K antagonists , such as warfarin , is not ideal . We aim ed to assess non-inferiority of idrabiotaparinux , a reversible longlasting indirect inhibitor of activated factor X , to warfarin in patients with acute symptomatic pulmonary embolism . METHODS In our r and omised , double-blind , double-dummy , non-inferiority trial , we enrolled adults with objective ly documented acute symptomatic pulmonary embolism attending 291 centres in 37 countries . We excluded patients who were pregnant , had active bleeding , kidney failure , or malignant hypertension , or were at high risk of death , bleeding , or adverse reactions to study drugs . We r and omly allocated patients to receive 5 - 10 days ' enoxaparin 1·0 mg/kg twice daily followed by subcutaneous idrabiotaparinux ( starting dose 3·0 mg ) or adjusted-dose warfarin ( target international normalised ratio 2·0 - 3·0 ) ; regimens lasted 3 months or 6 months dependent on clinical presentation . Block r and omisation was done with a central interactive computerised system , stratified by study centre and intended treatment duration . The primary efficacy outcome was recurrent venous thromboembolism at 99 days after r and omisation . We estimated the odds ratio and 95 % CI with a Mantel-Haenzsel χ(2 ) analysis ( non-inferiority margin 2·0 ) in the intention-to-treat population . The main safety outcome was clinical ly relevant bleeding ( major or non-major ) in all patients at day 99 . This study is registered with Clinical Trials.gov , number NCT00345618 . FINDINGS Between Aug 1 , 2006 , and Jan 31 , 2010 , we enrolled 3202 patients aged 18 - 96 years . 34 ( 2 % ) of 1599 patients r and omly allocated to receive enoxaparin-idrabiotaparinux and 43 ( 3 % ) of 1603 patients r and omly allocated to receive enoxaparin-warfarin  had recurrent venous thromboembolism ( odds ratio 0·79 , 95 % CI 0·50 - 1·25 ; p(non-inferiority)=0·0001 ) . 72 ( 5 % ) of 1599 patients in the enoxaparin-idrabiotaparinux group and 106 ( 7 % ) of 1603 patients in the enoxaparin-warfarin group had clinical ly relevant bleeding ( 0·67 , 0·49 - 0·91 ; p(superiority)=0·0098 ) . We noted similar differences in outcomes in those patients treated to 6 months . INTERPRETATION Idrabiotaparinux could provide an attractive alternative to warfarin for the long-term treatment of pulmonary embolism , and seems to be associated with reduced bleeding . FUNDING Sanofi-Aventis ( Paris , France ) The efficacy and safety of sildenafil was evaluated in a r and omiSed , double-blind , placebo-controlled , flexible-dose study in Korean men aged 28–78 y with erectile dysfunction ( ED ) of broad-spectrum aetiology and more than 6 months duration . A total of 133 patients were r and omised at six centres in Korea to receive either sildenafil ( 50 mg initially , increased if necessary to l00 mg or decreased to 25 mg depending on efficacy and tolerance ) ( n=66 ) or matching placebo ( n=67 ) taken on an ‘ as needed ’ basis l h prior to anticipated sexual activity for a period of 8 weeks . At the end of this time , the primary efficacy variables relating to the achievement and maintenance of erections sufficient for sexual intercourse , and the secondary efficacy variables , which included : ( 1 ) the five separate domains of sexual functioning of the International Index of Erectile Function ( IIEF ) scale , ( 2 ) the percentage of successful intercourse attempts , and ( 3 ) a global assessment of erections , were all statistically significantly improved by sildenafil in comparison with placebo ( P<0.0001 ) . Treatment-related adverse events occurred in 56.1 % of patients receiving sildenafil and 20.9 % receiving placebo . The most common adverse events with sildenafil  were vasodilatation ( flushing ) , headache and abnormalities in colour vision ( 31.8 , 22.7 and 6.1 % of patients , respectively ) , and most were mild in nature . The efficacy and safety of sildenafil in this population of Korean men appears similar to that reported in other studies in western population Sildenafil ( Viagra , UK-92,480 ) is a novel oral agent under development for the treatment of  penile erectile dysfunction .  Erection is dependent on nitric oxide and its second messenger , cyclic guanosine monophosphate ( cGMP ) . However , the relative importance of phosphodiesterase ( PDE ) isozymes is not clear . We have identified both cGMP- and cyclic adenosine monophosphate-specific phosphodiesterases ( PDEs ) in human corpora cavernosa in vitro . The main PDE activity in this tissue was due to PDE5 , with PDE2 and 3 also identified . Sildenafil is a selective inhibitor of PDE5 with a mean IC50 of 0.0039 microM. In human volunteers , we have shown sildenafil to have suitable pharmacokinetic and pharmacodynamic properties ( rapid absorption , relatively short half-life , no significant effect on heart rate and blood pressure ) for an oral agent to be taken , as required , prior to sexual activity . Moreover , in a clinical study of 12 patients with erectile dysfunction without an established organic cause , we have shown sildenafil to enhance the erectile response ( duration and rigidity of erection ) to visual sexual stimulation , thus highlighting the important role of PDE5 in human penile erection . Sildenafil holds promise as a new effective oral treatment for penile erectile dysfunction Abstract Objective : To assess the efficacy of a single dose of oral dexamethasone 0.15 mg/kg in children with mild croup not admitted to hospital . Design : Double blind , r and omised , placebo controlled clinical trial . Setting : The emergency department of a tertiary paediatric hospital . Subjects : 100 children aged 4 - 122 months presenting with mild croup . Intervention : A single oral dose of dexamethasone 0.15 mg/kg or placebo . Main outcome measure : Return to medical care with ongoing croup . Results : Baseline characteristics of the two treatment groups were similar . Eight children ( all from the placebo group ) returned to medical care with ongoing croup , one being admitted . There was no reported difference in duration of croup symptoms , duration of viral symptoms , or rate of return to medical care for other reasons . Conclusion : Oral dexamethasone in a dose of 0.15 mg/kg is effective in reducing return to medical care with ongoing croup in children with mild croup . Key messages The benefits of steroids for children admitted to hospital are now well estab- lished Most children with croup may be sent home , though up to one fifth may return with croup A small single dose of oral dexamethasone ( 0.15 mg/kg ) dramatically reduces the chance of reattending All children presenting with croup should be considered for ABSTRACT Objectives : R and omised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer 's disease have been characterised by significant method ological 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 , r and omised , controlled , multicentre trial was design ed 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 . Methods : Patients were r and omly assigned to rivastigmine 3–12 mg/day or donepezil 5–10 mg/day . Efficacy measures comprised assessment s of cognition , activities of daily living , global functioning and behavioural symptoms . Safety and tolerability assessment s included adverse events and measurement of vital signs . Results : 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 population s. In secondary sub-group 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 . Conclusions : 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 Objective . To investigate treatment practice among  general practitioners ( GPs ) and physiotherapists ( PTs ) in chronic epicondylitis of 3 months ’ duration or more . Design . Postal survey . Setting and subjects . All 129 GPs and all 77 PTs at 35 primary health care centres in Uppsala County , Sweden , received the question naire .  Main outcome measures . Proportion of responders using various treatments ( five specified alternatives + open question ) . Results . The question naire was answered by 70 % of the GPs and 61 % of the PTs .  Ergonomic counselling , stretching , and orthotic devices  were common , and used to a similar extent by GPs and PTs .  Acupuncture  was also common , but less so among GPs than PTs .  Transcutaneous electric nerve stimulation  was used by relatively few GPs and PTs . The open question revealed that dynamic exercise , particularly eccentric , was used by most PTs but only one GP . A majority of GPs prescribed sick leave and anti-inflammatory treatment  with an NSAID or cortisone injections . Conclusion . A large number of treatment methods in chronic epicondylitis were reported , none of which is properly evidence -based and some of which are even known to be ineffective . There is a need for r and omized controlled studies of potentially effective treatments in this condition Objective To determine the accuracy of  direct or indirect bracket placement . Design A prospect i ve , r and omized comparison of 2 different methods of bracket placement . Setting Queens Hospital , Burton upon Trent , UK between February and May 2001 . Material s and method Twenty-six consecutive patients requiring upper and lower MBT ™ pre-adjusted Edgewise appliances had their labial segments bonded directly or indirectly according to a split mouth system of allocation . Before and after bond-up all brackets were photographed and measured from tracings to determine positional differences from the ideal . Results Using ANOVA ( General Linear Model ) , vertical errors were found to be greater than those in the horizontal plane , which in turn were greater than angular errors ( p<0.05 ) . Errors were greater in the maxillary arch than in the m and ibular arch . There was no significant difference between the mean errors produced by the two methods of bracket placement . Conclusions Mean bracket placement errors were similar with both techniques OBJECTIVE To develop and vali date an approach that uses clinical features that can be determined in a st and ard patient visit to estimate the length of time before an individual patient with Alzheimer disease ( AD ) requires care equivalent to nursing home placement or dies . DESIGN Prospect i ve cohort study of 236 patients , followed up semiannually for up to 7 years . A second validation cohort of 105 patients was also followed . SETTING Three AD research centers . PATIENTS All patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer 's Disease and Related Disorders Association ( NINCDS-ADRDA ) criteria for probable AD and had mild dementia at the initial visit . INTERVENTION Predictive features , ascertained at the initial visit , were sex , duration of illness , age at onset , modified Mini-Mental State Examination ( mMMS ) score , and the presence or absence of extrapyramidal signs or psychotic features . MAIN OUTCOME MEASURES ( 1 ) Requiring the equivalent of nursing home placement and ( 2 ) death . RESULTS Prediction algorithms were constructed for the 2 outcomes based on Cox proportional hazard models . For each algorithm , a predictor index is calculated based on the status of each predictive feature at the initial visit . A table that specifies the number of months in which 25 % , 50 % , and 75 % of patients with any specific predictor index value are likely to reach the end point is then consulted . Survival curves for time to need for care equivalent to nursing home placement and for time to death derived from the algorithms for selected predictor indexes fell within the 95 % confidence b and s of actual survival curves for patients . When the predictor variables from the initial visit for the validation cohort patients were entered into the algorithm , the predicted survival curves for time to death fell within the 95 % confidence b and s of actual survival curves for the patients . CONCLUSIONS The prediction algorithms are a first but promising step toward providing specific prognoses to patients , families , and practitioners . This approach also has clear implication s for the design and interpretation of clinical trials in patients with AD Advances in technology can have direct and indirect benefits to clinical practice . The challenge that clinicians face is to properly match re sources and outcomes , along with patient preferences . This article explores the use of an innovative interactive voice response system  to increase  patient compliance with antidepressant medication prescribed in primary care setting s. The development of the  interactive voice response system  , its implementation , and clinical outcomes are described . The findings underscore the need to carefully match intervention strategies with the needs of specific patient population s , and the importance of human dialog in the context of healing Background — Dabigatran , an oral thrombin inhibitor , and rivaroxaban and apixaban , oral factor Xa inhibitors , have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation . We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled r and omized trials , using the method of adjusted indirect comparisons . Methods and Results — We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran  ( R and omized Evaluation of Long-Term Anticoagulation Therapy [ RELY ] ) , apixaban ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ ARISTOTLE ] ) , and rivaroxaban ( Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ ROCKET-AF ] ) , each compared with warfarin . The primary efficacy end point was stroke or systemic embolism ; the safety end point we studied was major hemorrhage . To address a lack of comparability between trial population s caused by the restriction of ROCKET-AF to high-risk patients , we conducted a subgroup analysis in patients with a CHADS2 score ≥3 . We found no statistically significant efficacy differences among the 3 drugs , although apixaban and dabigatran were numerically superior to rivaroxaban . Apixaban produced significantly fewer major hemorrhages than dabigatran and rivaroxaban . Conclusions — An indirect comparison of new anticoagulants based on existing trial data indicates that in patients with a CHADS2 score ≥3  dabigatran 150 mg , apixaban 5 mg , and rivaroxaban 20 mg result ed in statistically similar rates of stroke and systemic embolism , but apixaban had a lower risk of major hemorrhage compared with dabigatran and rivaroxaban . Until head-to-head trials or large-scale observational studies that reflect routine use of these agents are available , such adjusted indirect comparisons based on trial data are one tool to guide initial therapeutic choices A retrospective comparison was performed between 1411 hypopituitary adults without GH replacement [ mean age , 56.9 ( sd 18.6 ) yr ] and the normal population in terms of fatal and nonfatal morbidity . A similar prospect i ve comparison was then made in 289 hypopituitary patients on long-term GH replacement [ mean age , 47.6 ( sd 14.8 ) yr ; mean duration of GH treatment , 60 months ] . In the 1411 hypopituitary patients without GH replacement , overall mortality ( P < 0.001 ) , and the rates of myocardial infa rct ions ( P < 0.01 ) , cerebrovascular events ( P < 0.001 ) , and malignancies ( P < 0.001 ) were increased compared with the normal population . Colorectal cancer was the most common malignancy in this cohort ( P < 0.001 vs. the background population ) . In the 289 hypopituitary patients on GH replacement , overall mortality and the rate of malignancies were similar to the normal population . In the hypopituitary adults on GH therapy , the rate of myocardial infa rct ions was lower than that in the background population ( P < 0.05 ) , and there was a tendency toward an increased rate of cerebrovascular events . In conclusion , overall mortality and the rate of myocardial infa rct ions were increased in hypopituitary patients without GH replacement . An increased rate of malignancies was observed in the hypopituitary adults without GH therapy , with a predominance of colorectal cancer . GH replacement appeared to provide protection from myocardial infa rct ions . The rate of cerebrovascular events tended to be increased also in hypopituitary adults on GH therapy OBJECTIVE To examine and compare urban and rural palliative care service availability and patterns of care from r and omised , population -based surveys of caregivers of people at the end of life . DESIGN , SETTING & PARTICIPANTS Survey responses on the death of ' someone close ' from 23,588 interviews of South Australians conducted between 2001 and 2007 are analysed . INTERVENTIONS A r and omised population survey . MAIN OUTCOME MEASURES Explored  palliative care service availability , caregiving provided , and characteristics of the deceased and their caregivers . RESULTS There was no difference in reported rates of accessing specialist palliative care services  between rural and urban respondents ( in unadjusted and adjusted analyses ) nor did the proportion of people for whom cancer was their life-limiting illness . There was greater reliance on friends than first degree relatives in h and s-on care provided at the end of life in rural setting s. The rates of reported need for more support did not differ between urban and rural respondents for caregivers of people at the end of life . CONCLUSION Use of  palliative care services was similar for rural and urban caregivers for someone close at the end of life with similar levels of met and unmet needs BACKGROUND Paroxetine is a potent and selective serotonin reuptake inhibitor ( SSRI ) . The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed out patients . METHOD A double-blind , parallel-group study was undertaken in four st and -alone centers . Patients aged 18 - 65 years , meeting DSM-III criteria for major depression , and having a Hamilton Rating Scale for Depression ( HAM-D ) score > or = 18 on the first 17 items of the HAM-D-21 were r and omized to paroxetine or placebo for 6 weeks of treatment . Efficacy outcome variables included the HAM-D , the Montgomery-Asberg Depression Rating Scale , the Clinical Global Impressions Scale ( CGI ) , and the Covi Anxiety Scale . Tolerability was assessed by asking a non-leading question . Routine laboratory safety and vital sign data from all four centers were pooled . The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed . Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables . RESULTS Significant differences ( p < or = .05 ) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4 . Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor . Similar results were obtained when an adequate treatment group ( therapy for > or = 28 days ) was considered . A full clinical response ( CGI-severity of illness score 1 or 2 ) was seen in over 40 % of subjects . Adverse events were more common for paroxetine compared with placebo ( p < or = .01 ) . Somnolence was twice more common than nervousness . Dropout due to adverse events was similar between therapies . Paroxetine had no clinical ly significant effect on laboratory safety data or vital signs . CONCLUSION Paroxetine was an effective , well tolerated , and safe antidepressant . Side effects were typical of the SSRI class of drugs . Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects There have been no previous large , well- design ed direct comparisons of the effects of fluticasone propionate ( FP ) and budesonide ( BUD ) on growth in children .  This r and omised , double-blind study compared the effects on growth of FP and BUD in children aged 6 - 9 years with persistent asthma . Following a 6-month run-in period ( without inhaled corticosteroids ) , patients with normal growth velocity were r and omised to 12 months ' treatment with FP 100 micro g bd ( n=114 ) or BUD 200 micro g bd ( n=119 ) . Growth velocity was determined by stadiometric height measurement . Lung function , asthma symptoms and use of relief medication were also assessed . Annualised mean growth velocity during run-in was comparable in the two groups ( FP : 5.9 cm/yr ; BUD : 6.0 cm/yr ) . During the treatment period , adjusted mean growth velocity was significantly higher in the FP than the BUD group ( 5.5 cm/yr vs 4.6 cm/yr ; P<0.001 ) . Asthma control improved similarly in both treatment groups . Bone mineral density and overnight urinary cortisol : creatinine ratios were similar in the two groups . Drug-related adverse events were reported among 3 % of FP-treated children , compared with 2 % for BUD . In conclusion , this study demonstrates that FP for childhood asthma has significantly less impact on childhood growth velocity than a therapeutically equivalent dose of BUD Background : Antibiotic treatment is not recommended for acute bronchitis in immunocompetent patients in industrialised countries . Whether these recommendations are relevant to the developing world and to immunocompromised patients is unknown . Design , setting and participants : R and omised , triple blind , placebo controlled equivalence trial of amoxicillin compared with placebo in 660 adults presenting to two outpatient clinics in Nairobi , Kenya , with acute bronchitis but without evidence of chronic lung disease . Main outcome measure : The primary study end point was clinical cure , as defined by a ⩾75 % reduction in a vali date d Acute Bronchitis Severity Score by 14 days ; analysis was by intention to treat with equivalence defined as ⩽8 % difference between study arms . Results : Clinical cure rates in the amoxicillin and placebo arms were 81.7 % and 84.0 % , respectively ( difference 2.3 % , 95 % CI −8.6 % to 4.0 % ) . Of 131 HIV infected subjects ( 19.8 % ) , cure rates for those r and omised to amoxicillin ( 77.2 % ) and placebo ( 83.8 % ) differed by 6.6 % ( 95 % CI −21.7 % to 8.6 % ) . Among HIV uninfected subjects , the difference in cure rates was 1.6 % ( 95 % CI −8.5 % to 5.3 % ) . Potential drug side effects were similar in the two arms . No subjects required hospitalisation or died . Conclusion : Antibiotic treatment of acute bronchitis is unhelpful , even in population s with a high prevalence of HIV infection We have recently developed a simple algorithm for the classification of household and locomotive activities using the ratio of unfiltered to filtered synthetic acceleration ( gravity-removal physical activity classification algorithm , GRPACA ) measured by a triaxial accelerometer . The purpose of the present study was to develop a new model for the immediate estimation of daily physical activity intensities using a triaxial accelerometer .  A total of sixty-six subjects were r and omly assigned into validation ( n 44 ) and cross-validation ( n 22 ) groups . All subjects performed fourteen activities while wearing a triaxial accelerometer in a controlled laboratory setting . During each activity , energy expenditure was measured by indirect calorimetry , and physical activity intensities were expressed as metabolic equivalents ( MET ) . The validation group displayed strong relationships between measured MET and filtered synthetic accelerations for household ( r 0·907 , P < 0·001 ) and locomotive ( r 0·961 , P < 0·001 ) activities . In the cross-validation group , two GRPACA-based linear regression models provided highly accurate MET estimation for household and locomotive activities . Results were similar when equations were developed by non-linear regression or sex-specific linear or non-linear regressions . Sedentary activities were also accurately estimated by the specific linear regression classified from other activity counts . Therefore , the use of a triaxial accelerometer in combination with a GRPACA permits more accurate and immediate estimation of daily physical activity intensities , compared with previously reported cut-off classification models . This method may be useful for field investigations as well as for self-monitoring by general users Background : The Social Functioning Question naire ( SFQ ) , an eight-item selfreport scale ( score range 0–24 ) , was developed from the Social Functioning Schedule ( SFS ) , a semi-structured interview which has been used primarily with non-psychotic patients and has good test-retest and inter-rater reliability as well as construct validity . The SFQ was developed following the need for a quick assessment of perceived social function . Aims : To give further details of old and new data sets from studies involving over 4000 subjects assessed with the SFQ illustrating its epidemiological and clinical associations . Method : New data were analysed from a national epidemiological study , a comparison of key-worker and subject versions of the SFQ , and re analysis of data from three earlier clinical studies , of psychiatric emergencies , general practice psychiatric patients and those with recurrent psychotic illnesses . These data were examined further to determine their range , their relationship to other clinical measures , and change over time in clinical trials . Results : The  population mean score in 4164 subjects was 4.6 and the data from all studies suggested that a score of 10 or more indicated poor social functioning . Those presenting as psychiatric emergencies had the poorest social function ( mean 11.4 ) and psychiatric patients from general practice the best function ( mean 7.7 ) of the clinical population s. The eight item scores had a normal distribution in psychiatric population s and a skewed one in a normal population ; scores were relatively stable over the short ( weeks ) and long-term ( months ) , and were high in the presence of acute mental health disturbance and personality disorder , giving support to the validity of the scale . The results from a UK sample of a r and omly selected population specifically weighted for ethnic minorities showed similar social function across groups Purpose . To compare erectile function ( EF ) recovery of patients treated by early penile rehabilitation therapy ( PRT ) with sildenafil and with control group . Method . Forty men treated by bilateral nerve sparing radical prostatectomy ( NSRP ) and with a normal pre-operative EF were enrolled . Fourteen days after surgery , they were r and omised to a flexible-dose sildenafil group and to a control group . The International Index of Erectile Function ( IIEF ) question naire was completed before surgery and at 3 , 6 , 12 and 24 weeks after NSRP . Results . In the group treated , the mean IIEF score before surgery was 26.2 and 14.1 , 16.2 , 22.5 and 25.2 at 3 , 6 , 12 and 24 weeks after NSRP , respectively . In the control group , the respective scores were 26.5 and 12.4 , 15.8 , 15.3 and 17.4 . There was a significant difference in IIEF mean score ( 25 ± 6 vs. 17 ± 9 , p < 0.05 ) and in the potency rate ( 87 % vs. 56 % ) between the groups at 24 weeks after NSRP . The percentage of patients who were capable of having medication-unassisted intercourse was 54 % vs. 21 % ; 34 % vs. 18 % of patients had a normal EF with 72 % vs. 32 % of responders to sildenafil . Conclusions . PRT with PDE-5 inhibitors should be offered early after RP to allow the recovery of EF Objective To compare the effects on balance and walking of three models of stroke rehabilitation : early supported discharge with rehabilitation in a day unit or at home , and traditional uncoordinated treatment ( control ) . Design Group comparison study within a r and omised controlled trial . Setting Hospital stroke unit and primary healthcare . Participants Inclusion criteria : a score of 2–26 on National Institutes of Health Stroke Scale , assessed with Postural Assessment Scale for Stroke ( PASS ) , and discharge directly home from the hospital stroke unit . Interventions Two intervention groups were given early supported discharge with treatment in either a day unit or the patient 's own home . The controls were offered traditional , uncoordinated treatment . Outcome measures Primary : PASS . Secondary : Trunk Impairment Scale — modified Norwegian version ; timed Up- and -Go ; 5 m timed walk ; self-reports on problems with walking , balance , ADL , physical activity , pain and tiredness . The patients were tested before r and omisation and 3 months after inclusion . Results From a total of 306 r and omised patients , 167 were tested with PASS at baseline and discharged directly home . 105 were retested at 3 months : mean age 69 years , 63 men , 27 patients in day unit rehabilitation , 43 in home rehabilitation and 35 in a control group . There were no group differences , either at baseline for demographic and test data or for length of stroke unit stay . At 3 months , there was no group difference in change on PASS ( p>0.05 ) . Some secondary measures tended to show better outcome for the intervention groups , that is , trunk control , median ( 95 % CI ) : day unit , 2 ( 0.28 to 2.31 ) ; home rehabilitation , 4 ( 1.80 to 3.78 ) ; control , 1 ( 0.56 to 2.53 ) , p=0.044 ; and for self-report on walking , p=0.021 and ADL , p=0.016 . Conclusions There was no difference in change between the groups for postural balance , but the secondary outcomes indicated that improvement of trunk control and walking was better in the intervention groups than in the control group . Trial registration This study is part of the Early Supported Discharge after Stroke in Bergen , Clinical Trials.gov ( NCT00771771 ) The project " Obstetric Peer Review Interventions " ( Verloskundige Onderlinge Kwaliteitsspiegeling Interventies , VOKSINT ) was set-up in The Netherl and s in 1994 . It provided annual comparison data ( quality ranking , league tables ) for secondary care obstetric departments adjusted for population differences , based on the data registered in the Perinatal Data base of The Netherl and s ( L and elijke Verloskunde Registratie , LVR ) . The aim of the so-called VOKS reports was to influence obstetricians ' interventions in such a way that they led to a more homogeneous policy . To assess this influence , a trial was set-up , with departments r and omly assigned to be or not to be informed about the VOKS results . Obstetric intervention rates and the morbidity of newborns including neonatal neurological examinations ( NNEs ) were assessed . Obstetric intervention rates were similar in the report group and the control group . Practice in the report group became more homogeneous ( adjusted for population differences ) than in the control departments , but this was only statistically significant for term caesarean section Background Ankle sprains are the most common sports and physical activity related injury . There is extensive evidence that there is a twofold increased risk for injury recurrence for at least one year post injury . In up to 50 % of all cases recurrences result in disability and lead to chronic pain or instability , requiring prolonged medical care . Therefore ankle sprain recurrence prevention in athletes is essential . This RCT evaluates the effect of the combined use of braces and neuromuscular training ( e.g. proprioceptive training/sensorimotor training/balance training ) against the individual use of either braces or neuromuscular training alone on ankle sprain recurrences , when applied to individual athletes after usual care . Methods / Design This study was design ed as three way r and omized controlled trial with one year follow-up . Healthy individuals between 12 and 70 years of age , who were actively participating in sports and who had sustained a lateral ankle sprain in the two months prior to inclusion , were eligible for inclusion . After subjects had finished ankle sprain treatment by means of usual care , they were r and omised to any of the three study groups . Subjects in group 1 received an eight week neuromuscular training program , subjects in group 2 received a sports brace to be worn during all sports activities for the duration of one year , and group 3 received a combination of the neuromuscular training program and a sports brace to be worn during all sports activities for the duration of eight weeks . Outcomes were assessed at baseline and every month for 12 months therafter . The primary outcome measure was incidence of ankle sprain recurrences . Secondary outcome measures included the direct and indirect costs of recurrent injury , the severity of recurrent injury , and the residual complaints during and after the intervention . Discussion The AB rCt is the first r and omized controlled trial to directly compare the secondary preventive effect of the combined use of braces and neuromuscular training , against the use of either braces or neuromuscular training as separate secondary preventive measures . This study expects to identify the most effective and cost-efficient secondary preventive measure for ankle sprains . The study results could lead to changes in the clinical guidelines on the prevention of ankle sprains , and they will become available in 2012.Trial registration Netherl and s Trial Register ( NTR ) :
For common outcomes there was similar efficacy between PDE-5 inhibitors
Background There are no r and omised and properly blinded trials directly comparing one PDE-5 inhibitor with another in a normal home setting .
Valid indirect comparisons with a common comparator must examine equivalent doses , similar duration , similar population s , with the same outcomes reported in the same way .