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Background: Although aggregate data (AD) from randomised clinical trials (RCTs) are used in the majority of network meta-analyses (NMAs), other study designs (e.g., cohort studies and other non-randomised studies, NRS) can be informative about relative treatment effects. The individual participant data (IPD) of the study, when available, are preferred to AD for adjusting for important participant characteristics and to better handle heterogeneity and inconsistency in the network., Results: We developed the R package crossnma to perform cross-format (IPD and AD) and cross-design (RCT and NRS) NMA and network meta-regression (NMR). The models are implemented as Bayesian three-level hierarchical models using Just Another Gibbs Sampler (JAGS) software within the R environment. The R package crossnma includes functions to automatically create the JAGS model, reformat the data (based on user input), assess convergence and summarize the results. We demonstrate the workflow within crossnma by using a network of six trials comparing four treatments., Conclusions: The R package crossnma enables the user to perform NMA and NMR with different data types in a Bayesian framework and facilitates the inclusion of all types of evidence recognising differences in risk of bias., (© 2024. The Author(s).)

Importance: Placebo is the only substance systematically evaluated across common psychiatric diagnoses, but comprehensive cross-diagnostic comparisons are lacking., Objective: To compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients., Data Sources: MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched in March 2022 for the latest systematic reviews meeting predetermined high-quality criteria for 9 major psychiatric diagnoses., Study Selection: Using these reviews, the top 10 highest-quality (ie, lowest risk of bias, according to the Cochrane Risk of Bias tool) and most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs) were selected, adhering to predetermined inclusion and exclusion criteria., Data Extraction and Synthesis: Following the Cochrane Handbook, 2 authors independently carried out the study search, selection, and data extraction. Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group. This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline., Main Outcome and Measure: The primary outcome, pooled pre-post placebo effect sizes (dav) with 95% CIs per diagnosis, was determined using random-effects meta-analyses. A Q test assessed statistical significance of differences across diagnoses. Heterogeneity and small-study effects were evaluated as appropriate., Results: A total of 90 RCTs with 9985 placebo-treated participants were included. Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 0.59; 95% CI, 0.41-0.76)., Conclusion and Relevance: This systematic review and meta-analysis found that symptom improvement with placebo treatment was substantial in all conditions but varied across the 9 included diagnoses. These findings may help in assessing the necessity and ethical justification of placebo controls, in evaluating treatment effects in uncontrolled studies, and in guiding patients in treatment decisions. These findings likely encompass the true placebo effect, natural disease course, and nonspecific effects.

The LFK index has been promoted as an improved method to detect bias in meta-analysis. Putatively, its performance does not depend on the number of studies in the meta-analysis. We conducted a simulation study, comparing the LFK index test to three standard tests for funnel plot asymmetry in settings with smaller or larger group sample sizes. In general, false positive rates of the LFK index test markedly depended on the number and size of studies as well as the between-study heterogeneity with values between 0% and almost 30%. Egger's test adhered well to the pre-specified significance level of 5% under homogeneity, but was too liberal (smaller groups) or conservative (larger groups) under heterogeneity. The rank test was too conservative for most simulation scenarios. The Thompson-Sharp test was too conservative under homogeneity, but adhered well to the significance level in case of heterogeneity. The true positive rate of the LFK index test was only larger compared with classic tests if the false positive rate was inflated. The power of classic tests was similar or larger than the LFK index test if the false positive rate of the LFK index test was used as significance level for the classic tests. Under ideal conditions, the false positive rate of the LFK index test markedly and unpredictably depends on the number and sample size of studies as well as the extent of between-study heterogeneity. The LFK index test in its current implementation should not be used to assess funnel plot asymmetry in meta-analysis., (© 2024 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Background: Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms has not been quantified. An estimate of antidepressant discontinuation symptoms incidence could inform patients and clinicians in the discontinuation of treatment, and provide useful information to researchers in antidepressant treatments. We aimed to assess the incidence of antidepressant discontinuation symptoms in patients discontinuing both antidepressants and placebo in the published literature., Methods: We systematically searched Medline, EMBASE, and CENTRAL from database inception until Oct 13, 2022 for randomised controlled trials (RCTs), other controlled trials, and observational studies assessing the incidence of antidepressant discontinuation symptoms. To be included, studies must have investigated cessation or tapering of an established antidepressant drug (excluding antipsychotics, lithium, or thyroxine) or placebo in participants with any mental, behavioural, or neurodevelopmental disorder. We excluded studies in neonates, and those using antidepressants for physical conditions such as pain syndromes due to organic disease. After study selection, summary data extraction, and risk of bias evaluation, data were pooled in random-effects meta-analyses. The main outcome was the incidence of antidepressant discontinuation symptoms after discontinuation of antidepressants or placebo. We also analysed the incidence of severe discontinuation symptoms. Sensitivity and meta-regression analyses tested a selection of methodological variables., Findings: From 6095 articles screened, 79 studies (44 RCTs and 35 observational studies) covering 21 002 patients were selected (72% female, 28% male, mean age 45 years [range 19·6-64·5]). Data on ethnicity were not consistently reported. 16 532 patients discontinued from an antidepressant, and 4470 patients discontinued from placebo. Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27-0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14-0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04-0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014-0·057) compared with 0·006 (0·002-0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial., Interpretation: Considering non-specific effects, as evidenced in placebo groups, the incidence of antidepressant discontinuation symptoms is approximately 15%, affecting one in six to seven patients who discontinue their medication. Subgroup analyses and heterogeneity figures point to factors not accounted for by diagnosis, medication, or trial-related characteristics, and might indicate subjective factors on the part of investigators, patients, or both. Residual or re-emerging psychopathology needs to be considered when interpreting the results, but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm., Funding: None., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

With each update of meta-analyses from living systematic reviews, treatment effects and their confidence intervals are recalculated. This often raises the question whether or not multiplicity is an issue and whether a method to adjust for multiplicity is needed. It seems that answering these questions is not that straightforward. We approach this matter by considering the context of systematic reviews and pointing out existing methods for handling multiplicity in meta-analysis. We conclude that multiplicity is not a relevant issue in living systematic reviews when they are planned with the aim to provide up-to-date evidence, without any direct control on the decision over future research. Multiplicity might be an issue, though, in living systematic reviews designed under a protocol involving a "stopping decision", which can be the case in living guideline development or in reimbursement decisions. Several appropriate methods exist for handling multiplicity in meta-analysis. Existing methods, however, are also associated with several technical and conceptual limitations, and could be improved in future methodological projects. To better decide whether an adjustment for multiplicity is necessary at all, authors and users of living systematic reviews should be aware of the context of the work and question whether there is a dependency between the effect estimates of the living systematic review and its stopping/updating or an influence on future research., (Copyright © 2023. Published by Elsevier GmbH.)

The placebo effect is the 'effect of the simulation of treatment that occurs due to a participant's belief or expectation that a treatment is effective'. Although the effect might be of little importance for some conditions, it can have a great role in others, mostly when the evaluated symptoms are subjective. Several characteristics that include informed consent, number of arms in a study, the occurrence of adverse events and quality of blinding may influence response to placebo and possibly bias the results of randomised controlled trials. Such a bias is inherited in systematic reviews of evidence and their quantitative components, pairwise meta-analysis (when two treatments are compared) and network meta-analysis (when more than two treatments are compared). In this paper, we aim to provide red flags as to when a placebo effect is likely to bias pairwise and network meta-analysis treatment effects. The classic paradigm has been that placebo-controlled randomised trials are focused on estimating the treatment effect. However, the magnitude of placebo effect itself may also in some instances be of interest and has also lately received attention. We use component network meta-analysis to estimate placebo effects. We apply these methods to a published network meta-analysis, examining the relative effectiveness of four psychotherapies and four control treatments for depression in 123 studies., Competing Interests: Competing interests: TAF reports personal fees from Boehringer Ingelheim, DT Axis, Kyoto University Original, Shionogi and SONY, and a grant from Shionogi, outside the submitted work. In addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi Tanabe., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life., Objectives: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients., Search Methods: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data., Selection Criteria: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients., Data Collection and Analysis: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables., Main Results: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine)., Authors Conclusions: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: Back pain is common in the working population. This systematic review with network meta-analysis (NMA) aimed to compare the effects of interventions for preventing back pain among office workers., Methods: We searched eight databases and additional sources up to March 2021. We included randomized controlled trials (RCT) and cluster RCT focusing on office workers, comparing work-related interventions aimed at preventing back pain (defined as pain in any part of the spine) to a control condition and assessing back pain and/or work absence. Further outcomes considered were adverse events and participants' satisfaction. We performed both frequentist and component NMA. Risk of bias (RoB) was evaluated using RoB 2 and certainty of the evidence (CoE) was assessed using GRADE., Results: We screened 9809 records and included 24 studies with a total of 7080 participants. RoB was assessed as "some concerns" or "high" for all studies and outcomes. Included studies investigated multicomponent interventions, ergonomics, physical activity, education, behavioral interventions and no/minimal interventions. Effects were mostly not statistically significant and based on low/very low CoE. Physical activity probably reduces days of work absence slightly [mean difference (MD) -1.10, 95% confidence interval (CI) -2.07- -0.13], and combining physical activity and ergonomics may reduce back pain intensity (standardized MD -0.41, 95% CI -0.80- -0.02) when compared to no/minimal intervention. A large proportion of participants were satisfied with the interventions, adverse events were rarely assessed., Conclusions: We observed mostly minor effects of interventions on back pain and work absence among office workers. The practical relevance of these effects is questionable.

Background In the absence of randomized controlled trials, reports from nonrandomized studies comparing valve-in-valve implantation (ViV) to redo surgical aortic valve replacement (rAVR) have shown inconsistent results. Methods and Results PubMed/MEDLINE, Google Scholar, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched through December 2021. Meta-Analysis of Observational Studies in Epidemiology guidelines were followed. The protocol was registered at the International Prospective Register of Systematic Reviews. Random effects models were applied. The primary outcomes of interest were short-term and midterm mortality. Secondary outcomes included stroke, myocardial infarction, acute renal failure, and permanent pacemaker implantation, as well as prosthetic aortic valve regurgitation, mean transvalvular gradient, and severe prosthesis-patient mismatch. Of 8881 patients included in 15 studies, 4458 (50.2%) underwent ViV and 4423 (49.8%) rAVR. Short-term mortality was 2.8% in patients undergoing ViV compared with 5.0% in patients undergoing rAVR (risk ratio [RR] 0.55 [95% CI, 0.34-0.91], P =0.02). Midterm mortality did not differ in patients undergoing ViV compared with patients undergoing rAVR (hazard ratio, 1.27 [95% CI, 0.72-2.25]). The rate of acute kidney failure was lower following ViV, (RR, 0.54 [95% CI, 0.33-0.88], P =0.02), whereas prosthetic aortic valve regurgitation (RR, 4.18 [95% CI, 1.88-9.3], P =0.003) as well as severe patient-prothesis mismatch (RR, 3.12 [95% CI, 2.35-4.1], P <0.001) occurred more frequently. The mean transvalvular gradient was higher following ViV (standard mean difference, 0.44 [95% CI, 0.15-0.72], P =0.008). There were no significant differences between groups with respect to stroke ( P =0.26), myocardial infarction ( P =0.93), or pacemaker implantation ( P =0.21). Conclusions Results of this meta-analysis demonstrate better short-term mortality after ViV compared with rAVR. Midterm mortality was similar between groups. Given the likely selection bias in these individual reports, an adequately powered multicenter randomized clinical trial with sufficiently long follow-up in patients with low-to-intermediate surgical risk is warranted. Registration URL: crd.york.ac.uk/prospero/. Unique identifier: CRD42021228752.

Background: The standard treatment of occlusive processes of the femoral artery bifurcation is thrombendarterectomy (TEA). Endovascular techniques (ENDO) have recently been put forward as a potential alternative. It is unclear so far which modality yields better outcomes with respect to long-term revascularization and periprocedural complications. Method: Multiple databases were systematically searched for pertinent publications (publication date November 1965 to February 2022). From the included studies, individual patient data (IPD) were requested. Aggregate data (AD) were used when no IPD were available. Primary and secondary patency (PP and SP), perioperative morbidity/mortality, and further endpoints were determined separately for TEA and ENDO and compared with each other. AD for each modality were summarized in meta-analyses. Time-to-event analyses and comparative meta-analyses with PP as primary endpoint were carried out using IPD. Results: 42 studies (3 IPD, 39 AD; 27 TEA, 12 ENDO, 3 comparisons of TEA versus ENDO) were included. In the combined meta-analysis of IPD and AD, PP for TEA was 97% at 6 months and 92% at 12 months, while PP for ENDO was 84% at 6 months and 85% at 12 months. The differences were not statistically significant. The comparative meta-analysis regarding PP did not reveal any significant differences either (TEA versus ENDO: HR 0.30 [0.06; 1.48]). SP at 12 months was 97% (TEA) and 93% (ENDO). The periprocedural morbidity was 16% for TEA and 9% for ENDO. Conclusion: In light of a higher PP, even without formal statistical proof of superiority, TEA can still be considered the standard treatment for occlusive processes of the femoral artery bifurcation., Methods: Multiple databases were systematically searched for pertinent publications (publication date November 1965 to February 2022). From the included studies, individual patient data (IPD) were requested. Aggregate data (AD) were used when no IPD were available. Primary and secondary patency (PP and SP), perioperative morbidity/mortality, and further endpoints were determined separately for TEA and ENDO and compared with each other. AD for each modality were summarized in meta-analyses. Time-to-event analyses and comparative meta-analyses with PP as primary endpoint were carried out using IPD., Results: 42 studies (3 IPD, 39 AD; 27 TEA, 12 ENDO, 3 comparisons of TEA versus ENDO) were included. In the combined meta-analysis of IPD and AD, PP for TEA was 97% at 6 months and 92% at 12 months, while PP for ENDO was 84% at 6 months and 85% at 12 months. The differences were not statistically significant. The comparative meta-analysis regarding PP did not reveal any significant differences either (TEA versus ENDO: HR 0.30 [0.06; 1.48]). SP at 12 months was 97% (TEA) and 93% (ENDO). The periprocedural morbidity was 16% for TEA and 9% for ENDO., Conclusion: In light of a higher PP, even without formal statistical proof of superiority, TEA can still be considered the standard treatment for occlusive processes of the femoral artery bifurcation.

Introduction: The Prostate Imaging Reporting and Data System (PI-RADS) standardises reporting of prostate MRI for the detection of clinically significant prostate cancer. We provide the protocol of a planned living systematic review and meta-analysis for (1) diagnostic accuracy (sensitivity and specificity), (2) cancer detection rates of assessment categories and (3) inter-reader agreement., Methods and Analysis: Retrospective and prospective studies reporting on at least one of the outcomes of interest are included. Each step that requires literature evaluation and data extraction is performed by two independent reviewers. Since PI-RADS is intended as a living document itself, a 12-month update cycle of the systematic review and meta-analysis is planned.This protocol is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Protocols statement. The search strategies including databases, study eligibility criteria, index and reference test definitions, outcome definitions and data analysis processes are detailed. A full list of extracted data items is provided.Summary estimates of sensitivity and specificity (for PI-RADS ≥3 and PI-RADS ≥4 considered positive) are derived with bivariate binomial models. Summary estimates of cancer detection rates are calculated with random intercept logistic regression models for single proportions. Summary estimates of inter-reader agreement are derived with random effects models., Ethics and Dissemination: No original patient data are collected, ethical review board approval, therefore, is not necessary. Results are published in peer-reviewed, open-access scientific journals. We make the collected data accessible as supplemental material to guarantee transparency of results., Prospero Registration Number: CRD42022343931., Competing Interests: Competing interests: IS is a full panel member of the PI-RADS steering committee (ASR/ESR). FB has received unrestricted research grants and speaker bureau fees from Bayer Healthcare and Siemens Healthineers. CG has received grants/research support from Astellas Pharma, Bayer, GSK, MSD and Recordati and honoraria/consultation fees from Amgen, Astellas Pharma, Bayer, GSK, Ipsen, Janssen, Lilly Pharma, Recordati, Pfizer, Rottapharm, STEBA Biotech. Otherwise, we do not have a competing interest to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Only very few Cochrane nutrition reviews include cohort studies (CSs), but most evidence in nutrition research comes from CSs. We aimed to pool bodies of evidence (BoE) from randomized controlled trials (RCTs) derived from Cochrane reviews with matched BoE from CSs. The Cochrane Database of Systematic Reviews and MEDLINE were searched for systematic reviews (SRs) of RCTs and SRs of CSs. BoE from RCTs were pooled together with BoE from CSs using random-effects and common-effect models. Heterogeneity, 95% prediction intervals, contributed weight of BoE from RCTs to the pooled estimate, and whether integration of BoE from CSs modified the conclusion from BoE of RCTs were evaluated. Overall, 80 diet-disease outcome pairs based on 773 RCTs and 720 CSs were pooled. By pooling BoE from RCTs and CSs with a random-effects model, for 45 (56%) out of 80 diet-disease associations the 95% CI excluded no effect and showed mainly a reduced risk/inverse association. By pooling BoE from RCTs and CSs, median I2 = 46% and the median contributed weight of RCTs to the pooled estimates was 34%. The direction of effect between BoE from RCTs and pooled effect estimates was rarely opposite (n = 17; 21%). The integration of BoE from CSs modified the result (by examining the 95% CI) from BoE of RCTs in 35 (44%) of the 80 diet-disease associations. Our pooling scenario showed that the integration of BoE from CSs modified the conclusion from BoE of RCTs in nearly 50% of the associations, although the direction of effect was mainly concordant between BoE of RCTs and pooled estimates. Our findings provide insights for the potential impact of pooling both BoE in Cochrane nutrition reviews. CSs should be considered for inclusion in future Cochrane nutrition reviews, and we recommend analyzing RCTs and CSs in separate meta-analyses, or, if combined together, with a subgroup analysis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Importance: Combining antidepressants is frequently done in the treatment of acute depression, but studies have yielded conflicting results., Objective: To conduct a systematic review and meta-analysis assessing efficacy and tolerability of combination therapy. Combinations using presynaptic α2-autoreceptor antagonists or bupropion were investigated separately., Data Sources: MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were systematically searched from each database inception through January 2020., Study Selection: Randomized clinical trials (RCTs) comparing combinations of antidepressants with antidepressant monotherapy in adult patients with acute depression were included., Data Extraction and Synthesis: Following guidelines from Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and recommendations from the Cochrane Handbook, 2 reviewers independently performed a literature search, study selection, data extraction, and evaluation of risk of bias. Data were pooled in random-effects analyses., Main Outcomes and Measures: Primary outcome was efficacy measured as standardized mean difference (SMD); secondary outcomes were response, remission, change from baseline in rating scale scores, number of dropouts, and number of dropouts due to adverse events., Results: Thirty-nine RCTs including 6751 patients were eligible. Combination treatment was statistically significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Bupropion combinations were not superior to monotherapy (SMD = 0.10; 95% CI, -0.07 to 0.27). Numbers of dropouts and dropouts due to adverse events did not differ between treatments. Studies were heterogeneous, and there was indication of publication bias (Egger test result was positive; P = .007, df = 36), but results remained robust across prespecified secondary outcomes and sensitivity and subgroup analyses, including analyses restricted to studies with low risk of bias., Conclusions and Relevance: In this meta-analysis of RCTs comparing combinations of antidepressants with antidepressant monotherapy, combining antidepressants was associated with superior treatment outcomes but not with more patients dropping out of treatment. Combinations using an antagonist of presynaptic α2-autoreceptors may be preferable and may be applied as a first-line treatment in severe cases of depression and for patients considered nonresponders.

The meta-analysis of single proportions has become a popular application over the last two decades. Especially, systematic reviews of prevalence studies are conducted in various fields of science, including medicine, ecology, psychology, or social sciences. In this chapter, we illustrate meta-analysis methods to pool single proportions and to compare proportions from two groups. We introduce classic approaches based on the inverse variance method as well as generalized linear mixed models taking the binary structure of the data into account. The most common transformations of proportions and their back-transformations are described both for individual studies and in the meta-analysis setting., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To evaluate the relationship between mortality or relapse of bloodstream infection (BSI) due to Enterococcus faecalis and infectious diseases specialist consultation (IDC) and other factors potentially associated with outcomes., Methods: In a tertiary-care center, consecutive adult patients with E. faecalis BSI between January 1, 2016 and January 31, 2019, were prospectively followed. The management of E. faecalis BSI was evaluated in terms of adherence to evidence-based quality-of-care indicators (QCIs). IDC and other factors potentially associated with 90-day-mortality or relapse of E. faecalis BSI were analyzed by multivariate logistic regression., Results: A total of 151 patients with a median age of 68 years were studied. IDC was performed in 38% of patients with E. faecalis BSI. 30 cases of endocarditis (20%) were diagnosed. All-cause in-hospital mortality was 23%, 90-day mortality was 37%, and 90-day relapsing E. faecalis BSI was 8%. IDC was significantly associated with better adherence to 5 QCIs. Factors significantly associated with 90-day mortality or relapsing EfB in multivariate analysis were severe sepsis or septic shock at onset (HR 4.32, CI 2.36e7.88) and deep-seated focus of infection (superficial focus HR 0.33, CI 0.14e0.76)., Conclusion: Enterococcus faecalis bacteremia is associated with a high mortality. IDC contributed to improved diagnostic and therapeutic management., (© 2021. The Author(s).)

Importance: Hypothyroidism is considered a cause of or a strong risk factor for depression, but recent studies provide conflicting evidence regarding the existence and the extent of the association. It is also unclear whether the link is largely due to subsyndromal depression or holds true for clinical depression., Objective: To estimate the association of hypothyroidism and clinical depression in the general population., Data Sources: PubMed, PsycINFO, and Embase databases were searched from inception until May 2020 for studies on the association of hypothyroidism and clinical depression., Study Selection: Two reviewers independently selected epidemiologic and population-based studies that provided laboratory or International Statistical Classification of Diseases and Related Health Problems diagnoses of hypothyroidism and diagnoses of depression according to operationalized criteria (eg, Diagnostic and Statistical Manual of Mental Disorders or International Statistical Classification of Diseases and Related Health Problems) or cutoffs in established rating scales., Data Extraction and Synthesis: Two reviewers independently extracted data and evaluated studies based on the Newcastle-Ottawa Scale. Summary odds ratios (OR) were calculated in random-effects meta-analyses., Main Outcomes and Measures: Prespecified coprimary outcomes were the association of clinical depression with either hypothyroidism or autoimmunity., Results: Of 4350 articles screened, 25 studies were selected for meta-analysis, including 348 014 participants. Hypothyroidism and clinical depression were associated (OR, 1.30 [95% CI, 1.08-1.57]), while the OR for autoimmunity was inconclusive (1.24 [95% CI, 0.89-1.74]). Subgroup analyses revealed a stronger association with overt than with subclinical hypothyroidism, with ORs of 1.77 (95% CI, 1.13-2.77) and 1.13 (95% CI, 1.01-1.28), respectively. Sensitivity analyses resulted in more conservative estimates. In a post hoc analysis, the association was confirmed in female individuals (OR, 1.48 [95% CI, 1.18-1.85]) but not in male individuals (OR, 0.71 [95% CI, 0.40-1.25])., Conclusions and Relevance: In this systematic review and meta-analysis, the effect size for the association between hypothyroidism and clinical depression was considerably lower than previously assumed, and the modest association was possibly restricted to overt hypothyroidism and female individuals. Autoimmunity alone may not be the driving factor in this comorbidity.

The Peto odds ratio is a well-known effect measure in meta-analysis of binary outcomes. For pairwise comparisons, the Peto odds ratio estimator can be severely biased in the situation of unbalanced sample sizes in the two treatment groups or large treatment effects. In this publication, we evaluate Peto odds ratio estimators in the setting of multi-arm studies and in network meta-analysis using illustrative examples. We observe that Peto odds ratio estimators in a multi-arm study are inconsistent if the observed event probabilities are different or the sample sizes of treatment groups are unbalanced. The same problem emerges in network meta-analysis including only two-arm studies and translates to indirect comparisons of pairwise meta-analyses. We conclude that the Peto odds ratio should not be used as effect measure in network meta-analysis or indirect comparisons of pairwise meta-analyses., (© 2021 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Objective: To assess the methodological quality and the consideration of heterogeneity in systematic reviews (SRs)., Study Design and Setting: We conducted a methodological study (CRD42019134904) and searched three databases from January 2010 to July 2019. Interventional SRs with a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients were included. A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) 2 was used to evaluate the SRs' methodological quality. The consideration of heterogeneity was categorized in clinical or/and methodological heterogeneity and not explored., Results: From 6234 identified references, 261 SRs were included. Most SRs had a critically low quality (230, 88.1%). The majority of them (209, 80.1%) was classified as critically low because of non-registration (222, 85.1%) combined with the non-reporting of excluded full-texts and missing justifications for exclusion (218, 83.5%). Heterogeneity in trial results was not explored at all in 51 (19.5%) SRs whereas clinical heterogeneity was considered in 117 (44.8%), methodological heterogeneity in 13 (5.0%), and both clinical and methodological heterogeneity in 80 (30.7%) SRs., Conclusion: The consideration of these findings in trainings for review authors and peer reviewers could improve the awareness of quality criteria and the quality of future SRs., Trial Registration: PROSPERO-ID: CRD42019134904., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the era of the "reproducibility crisis" and the "P-value controversy" new ways of presentation and interpretation of the results of a meta-analysis are desirable. One suggestion that has been made for single studies almost six decades ago and taken up now and then is the P-value function. For a given outcome, this function assigns a P-value to each possible hypothetical value, given the data. Moreover, the P-value function simultaneously provides two-sided confidence intervals for all possible alpha levels. An application to meta-analysis, while suggested early, has not been widely established. We introduce the drapery plot that presents the P-value function for all individual studies and pooled estimates in a meta-analysis as curves and the prediction range for a single future study. We also present a scaled variant with the test statistic on the y-axis. Both plots visualize the full information of a pairwise meta-analysis. We see a drapery plot as a complementary figure to a forest plot. It may be even an alternative in meta-analyses with many studies where forest plots tend to become very large and complex., (© 2020 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Objective: Meta-analysis is of fundamental importance to obtain an unbiased assessment of the available evidence. In general, the use of meta-analysis has been increasing over the last three decades with mental health as a major research topic. It is then essential to well understand its methodology and interpret its results. In this publication, we describe how to perform a meta-analysis with the freely available statistical software environment R, using a working example taken from the field of mental health., Methods: R package meta is used to conduct standard meta-analysis. Sensitivity analyses for missing binary outcome data and potential selection bias are conducted with R package metasens. All essential R commands are provided and clearly described to conduct and report analyses., Results: The working example considers a binary outcome: we show how to conduct a fixed effect and random effects meta-analysis and subgroup analysis, produce a forest and funnel plot and to test and adjust for funnel plot asymmetry. All these steps work similar for other outcome types., Conclusions: R represents a powerful and flexible tool to conduct meta-analyses. This publication gives a brief glimpse into the topic and provides directions to more advanced meta-analysis methods available in R., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Standard generic inverse variance methods for the combination of single proportions are based on transformed proportions using the logit, arcsine, and Freeman-Tukey double arcsine transformations. Generalized linear mixed models are another more elaborate approach. Irrespective of the approach, meta-analysis results are typically back-transformed to the original scale in order to ease interpretation. Whereas the back-transformation of meta-analysis results is straightforward for most transformations, this is not the case for the Freeman-Tukey double arcsine transformation, albeit possible. In this case study with five studies, we demonstrate how seriously misleading the back-transformation of the Freeman-Tukey double arcsine transformation can be. We conclude that this transformation should only be used with special caution for the meta-analysis of single proportions due to potential problems with the back-transformation. Generalized linear mixed models seem to be a promising alternative., (© 2019 The Authors Research Synthesis Methods Published by John Wiley & Sons Ltd.)

Traditional pairwise meta-analysis (PMA) is a very useful method that pools evidence from one study design type if appropriate; its widespread use in nutrition research is an important phenomenon. Recently, a promising method for more advanced evidence-synthesis, called network meta-analysis (NMA), was introduced. NMA is an extension of PMA that enables simultaneous comparison of multiple interventions. NMA combines direct evidence (i.e., trials comparing 2 interventions directly) and indirect evidence (i.e., from a connected route via ≥1 comparators, e.g. placebo) in a network of studies. NMAs have the potential to advance knowledge in the field of nutrition as they provide insights that cannot be obtained by individual 2-arm randomized controlled trials or PMA. Thus, in this perspective paper, we aim to summarize the current (methodologic) status of published NMAs in nutrition research and emphasize advances and strengths in comparison with traditional PMA through specific examples, and highlight potential pitfalls and limitations. NMA is an emerging methodology in the field of nutrition research. A PubMed search identified only 23 nutrition research-related NMAs published since the inception of journals up to January 8, 2019 (61% of them published since 2017), compared with >5000 published PMAs. Moreover, we aim to highlight the scientific concepts and standards through the use of the following NMA example: "Which type of oils/solid fats offers the greatest impact on blood lipids?" In this regard, we discuss intervention definitions, transitivity/similarity, statistical methods, description and visualization of results, inconsistency, ranking, dissemination bias, assessing the certainty of evidence by Grading of Recommendations Assessment, Development and Evaluation, and reporting guidelines. We expect that rigorously conducted NMAs based on high-quality systematic reviews will become the new evidence synthesis benchmark in nutrition research. However, caution is warranted because abuse and misinterpretations of PMA and NMA findings could hamper the scientific field and possibly decision-making regarding public policy., (Copyright © American Society for Nutrition 2019.)

Background: Herpes simplex virus type 1 (HSV-1) epidemiology in Asia was characterized by assessing seroprevalence levels and extent to which HSV-1 is isolated from clinically diagnosed genital ulcer disease (GUD) and genital herpes., Methods: HSV-1 reports in Asia were systematically reviewed and synthesized, following PRISMA guidelines. Random-effects meta-analyses estimated pooled mean seroprevalence and proportion of HSV-1 detection in GUD and genital herpes. Random-effects meta-regressions identified predictors of seroprevalence and sources of between-study heterogeneity., Results: Forty-nine relevant publications were identified. Fifty-four overall seroprevalence measures (182 stratified measures), and 8 and 24 proportions of HSV-1 detection in GUD and in genital herpes, respectively, were extracted. The pooled mean seroprevalence was 50.0% (n = 26; 95% confidence interval [CI], 41.3%-58.7%) for children and 76.5% (n = 151; 73.3%-79.6%) for adults. By age group, the pooled mean was lowest at 55.5% (n = 37; 95% CI, 47.5%-63.4%) in individuals aged <20 years, followed by 67.9% (n = 48; 62.4%-73.3%) in those aged 20-39 and 87.5% (n = 44; 83.4%-91.1%) in those aged ≥40 years. In meta-regression, age was the major predictor of seroprevalence. The mean proportion of HSV-1 detection was 5.6% (n = 8; 95% CI, 0.8%-13.6%) in GUD and 18.8% (n = 24; 12.0%-26.7%) in genital herpes., Conclusions: HSV-1 epidemiology is transitioning in Asia. HSV-1 is probably playing a significant role as a sexually transmitted infection, explaining one-fifth of genital herpes cases. There is a need for expanded seroprevalence monitoring and GUD/genital herpes etiological surveillance., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Global migration from regions where strongyloidiasis and schistosomiasis are endemic to non-endemic countries has increased the potential individual and public health effect of these parasitic diseases. We aimed to estimate the prevalence of these infections among migrants to establish which groups are at highest risk and who could benefit from screening., Methods: We did a systematic review and meta-analysis of strongyloidiasis and schistosomiasis prevalence among migrants born in endemic countries. Original studies that included data for the prevalence of Strongyloides or Schistosoma antibodies in serum or the prevalence of larvae or eggs in stool or urine samples among migrants originating from countries endemic for these parasites and arriving or living in host countries with low endemicity-specifically the USA, Canada, Australia, New Zealand, Israel, and 23 western European countries-were eligible for inclusion. Pooled estimates of the prevalence of strongyloidiasis and schistosomiasis by stool or urine microscopy for larvae or eggs or serum antibodies were calculated with a random-effects model. Heterogeneity was explored by stratification by age, region of origin, migrant class, period of study, and type of serological antigen used., Findings: 88 studies were included. Pooled strongyloidiasis seroprevalence was 12·2% (95% CI 9·0-15·9%; I 2 96%) and stool-based prevalence was 1·8% (1·2-2·6%; 98%). Migrants from east Asia and the Pacific (17·3% [95% CI 4·1-37·0]), sub-Saharan Africa (14·6% [7·1-24·2]), and Latin America and the Caribbean (11·4% [7·8-15·7]) had the highest seroprevalence. Pooled schistosomiasis seroprevalence was 18·4% (95% CI 13·1-24·5; I 2 97%) and stool-based prevalence was 0·9% (0·2-1·9; 99%). Sub-Saharan African migrants had the highest seroprevalence (24·1·% [95% CI 16·4-32·7])., Interpretation: Strongyloidiasis affects migrants from all global regions, whereas schistosomiasis is focused in specific regions and most common among sub-Saharan African migrants. Serological prevalence estimates were several times higher than stool estimates for both parasites. These data can be used to inform screening decisions for migrants and support the use of serological screening, which is more sensitive and easier than stool testing., Funding: None., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Network meta-analysis has evolved into a core method for evidence synthesis in health care. In network meta-analysis, 3 or more treatments for a given medical condition are compared, based on a number of clinical studies, usually randomized controlled trials. Often, many different endpoints are investigated, related to different aspects of the patient's outcome, such as efficacy, safety, acceptability, or costs of a treatment. Different outcomes may lead to different rankings of the treatments. We use the existing theory of partially ordered sets and show how the relations between the treatments in a network meta-analysis can be illustrated by Hasse diagrams, that is, directed graphs showing the partial order relations, and by structured scatter plots and biplots., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objective: To systematically review methodological articles which focus on nonpublication of studies and to describe methods of detecting and/or quantifying and/or adjusting for dissemination in meta-analyses. To evaluate whether the methods have been applied to an empirical data set for which one can be reasonably confident that all studies conducted have been included., Study Design and Setting: We systematically searched Medline, the Cochrane Library, and Web of Science, for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for dissemination bias in meta-analyses., Results: The literature search retrieved 2,224 records, of which we finally included 150 full-text articles. A great variety of methods to detect, quantify, or adjust for dissemination bias were described. Methods included graphical methods mainly based on funnel plot approaches, statistical methods, such as regression tests, selection models, sensitivity analyses, and a great number of more recent statistical approaches. Only few methods have been validated in empirical evaluations using unpublished studies obtained from regulators (Food and Drug Administration, European Medicines Agency)., Conclusion: We present an overview of existing methods to detect, quantify, or adjust for dissemination bias. It remains difficult to advise which method should be used as they are all limited and their validity has rarely been assessed. Therefore, a thorough literature search remains crucial in systematic reviews, and further steps to increase the availability of all research results need to be taken., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Reporting and publication bias is a well-known problem in meta-analysis and healthcare research. In 2002 we conducted a meta-analysis on the effects of erythropoiesis-stimulating agents (ESAs) on overall survival in cancer patients, which suggested some evidence for improved survival in patients receiving ESAs compared with controls. However, a meta-analysis of individual patient data conducted several years later showed the opposite of our first meta-analysis, that is, evidence for increased on-study mortality and reduced overall survival in cancer patients receiving ESAs. We aimed to determine whether the results of our first meta-analysis could have been affected by publication and reporting biases and, if so, whether timely access to clinical study reports and individual patient data could have prevented this. We conducted a hypothetical meta-analysis for overall survival including all studies and study data that could have been available in 2002, at the time when we conducted our first meta-analysis. Compared with our original meta-analysis, which suggested an overall survival benefit for cancer patients receiving ESAs [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67‒0.99], our hypothetical meta-analysis based on the results of all studies conducted at the time of the first analysis did not show evidence for a beneficial effect of ESAs on overall survival (HR 0.97, 95% CI 0.83‒1.12). Thus we have to conclude that our first meta-analysis showed misleading overall survival benefits due to publication and reporting biases, which could have been prevented by timely access to clinical study reports and individual patient data. Unrestricted access to clinical study protocols including amendments, clinical study reports and individual patient data is needed to ensure timely detection of both beneficial and harmful effects of healthcare interventions.

Background: Pancreatic cancer is the fourth leading cause of cancer death for men and the fifth for women. The standard treatment for resectable tumours is either a classic Whipple operation or a pylorus-preserving pancreaticoduodenectomy. It is unclear which of the procedures is more favourable in terms of survival, mortality, complications and quality of life., Objectives: Several publications have highlighted advantages and disadvantages of the two techniques and the current basis of evidence remains unclear. The objective of this systematic review is to compare the effectiveness of each operation., Search Strategy: We conducted a search on 28/03/2006 to identify all RCTs, applying no language restriction.We searched the following electronic databases: CENTRAL, CDSR and DARE from The Cochrane Library (2006, issue 2), MEDLINE (1966 to 2006) and EMBASE (1980 to 2006). We handsearched abstracts from 1995 to 2006 from the American Digestive Disease Week (DDW), published in Gastroenterology, and the United European Gastroenterology Week (UEGW), published in Gut., Selection Criteria: We considered randomised controlled trials comparing the classic Whipple operation with pylorus-preserving pancreaticoduodenectomy to be eligible if they included patients with periampullary or pancreatic carcinoma., Data Collection and Analysis: Two authors independently extracted data from the included studies. We used a random-effects model for pooling data. We compared binary outcomes using odds ratios (OR), pooled continuous outcomes using weighted mean differences (WMD), and used hazard ratios (HR) for meta-analysis of survival. Two authors independently evaluated the methodological quality of included studies according to quality standards and by using a questionnaire., Main Results: We retrieved 1235 abstracts and checked these for eligibility, including seven randomised controlled trials. Our critical appraisal revealed vast heterogeneity with respect to methodological quality and outcome parameters. Our comparisons of in-hospital mortality (OR 0.49; 95% confidence interval (CI) 0.17 to 1.40; P = 0.18), overall survival (HR 0.84; 95% CI 0.61 to 1.16; P = 0.29) and morbidity showed no significant differences. However, we noted that operating time (WMD -68.26 minutes; 95% CI -105.70 to -30.83; P = 0.0004) and intra-operative blood loss (WMD -0.76 millilitres; 95% CI -0.96 to -0.56; P < 0.00001) were significantly reduced in the pylorus-preserving pancreaticoduodenectomy group., Authors' Conclusions: There is no evidence of relevant differences in mortality, morbidity and survival between the two operations. Given obvious clinical and methodological heterogeneity, future research must be undertaken to perform high-quality randomised controlled trials of complex surgical interventions on the basis of well-defined outcome parameters.

Publication bias in meta-analysis occurs if the probability of publication depends on the estimated treatment effect and the precision/size of a study. In this article we describe the funnel plot as a graphical method to evaluate the presence of publication bias. Furthermore, tests of publication bias based on funnel plots are explained, and methods are presented that estimate treatment effects adjusted for publication bias. The article closes with a critical discussion of the various statistical methods.

This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

Objective: Open angle glaucoma is one of the most common causes of blindness in industrialised nations. Treatments to lower ocular pressure are widely used in glaucoma prevention and treatment, despite conflicting evidence., Design: We performed meta-analyses to reassess the effectiveness of pressure lowering treatment to delay the development of glaucoma in ocular hypertension, as well as progression of manifest open angle glaucoma., Data Sources: Medline, Embase, and the Cochrane Library., Selection of Studies: Eligible studies were randomised controlled trials with a concurrent untreated control group and information on time to glaucomatous changes to visual field and optic disc. Trial reports were reviewed independently by two investigators in an unblinded standardised manner., Results: Meta-analysis of trials in ocular hypertension showed a significant preventive effect of reducing intraocular pressure on progression to glaucoma (hazard ratio 0.56, 95% confidence interval 0.39 to 0.81, P = 0.01; number needed to treat 12). Pooled data of studies in manifest glaucoma showed a significant delay of visual field deterioration (0.65, 0.49 to 0.87, P = 0.003; NNT = 7), with subgroup analysis showing a larger effect in patients with raised pressure and a reduced effect in normal tension glaucoma (subgroup comparison: not significant)., Conclusions: Lowering intraocular pressure in patients with ocular hypertension or manifest glaucoma is beneficial in reducing the risk of visual field loss in the long term.

Background: Anemia associated with cancer and cancer therapy is an important clinical and economic factor in the treatment of malignant diseases., Methods: We conducted a systematic literature review to assess the efficacy of erythropoietin to prevent or treat anemia in cancer patients with regard to red blood cell transfusions, hematologic response, adverse events, and overall survival. We searched the Cochrane Library, Medline, EMBASE, and other databases for relevant articles published from January 1985 to December 2001. We included all randomized controlled trials that compared the use of recombinant human erythropoietin (plus transfusion, if needed) with no erythropoietin treatment (plus transfusion, if needed). Relative risks (RRs) and 95% confidence intervals (CIs) were calculated under a fixed-effects model. Clinical and statistical heterogeneity were examined with sensitivity analyses and meta-regression. Statistical tests for effect estimates were two-sided., Results: We identified 27 trials involving 3287 adult patients. Patients treated with erythropoietin had a lower relative risk of having a blood transfusion than untreated patients (RR = 0.67, 95% CI = 0.62 to 0.73). Erythropoietin-treated patients with baseline hemoglobin levels lower than 10 g/dL were more likely to have a hematologic response than untreated patients (RR = 3.60, 95% CI = 3.07 to 4.23). The relative risk for thromboembolic complications after erythropoietin treatment was not statistically significantly increased (RR = 1.58, 95% CI = 0.94 to 2.66) compared with that of untreated patients. There is suggestive but inconclusive evidence that erythropoietin may improve overall survival (adjusted data: hazard ratio [HR] = 0.81, 95% CI = 0.67 to 0.99; unadjusted data: HR = 0.84, 95% CI = 0.69 to 1.02)., Conclusions: Erythropoietin treatment may reduce the risk for blood transfusions and improve hematologic response in cancer patients. However, our favorable survival outcome is in contrast to two large (N = 351 and 939) recently published randomized controlled trials in which erythropoietin-treated patients had statistically significantly worse survival than untreated patients. Possible reasons for the disparity with our results include differences in study population and design, higher target hemoglobin levels and higher risk of thromboembolic complications, and concerns that erythropoietin may stimulate tumor growth.

Cancer and cancer therapy-associated anemia may have an impact on tumor response and overall survival. Additionally, anemia represents an important economic factor. Therefore, therapeutic alternatives such as erythropoietin (EPO) and red blood cell transfusions have to be evaluated systematically. The effectiveness of recombinant human EPO to prevent or alleviate anemia in patients with malignant disease was determined. Randomized controlled trials comparing prophylaxis or treatment of anemia with EPO plus red blood cell transfusion (RBCT) or RBCT only in patients with malignant disease undergoing antineoplastic therapy were included. The endpoints needed for RBCT were hematological response (hemoglobin increase of 2g/dL or hematocrit increase of 6%), tumor response, and overall survival. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (1985-2001). Full-text and abstract publications were included as well as unpublished data. Data extraction and quality assessment were done in duplicate. All authors were contacted to obtain missing data. Out of 33 eligible studies, 27 trials with 3,287 randomized patients were included.

In addition to vitamin C (and other vitamins/antioxidants), clinical ecologists (functional medicine) recommend selenium supplementation as a fundamental therapeutic remedy for the treatment of environment associated health disorders. This recommendation is based on the postulation that the trace element selenium inhibits oxidative stress generated during endogenous detoxification of xenobiotics (phase 1) by increasing selenium-dependent glutathione peroxidase activity, and that it counteracts heavy metal toxicity by forming inert metal complexes. The objective of this review was to investigate whether there are any valid studies providing reliable evidence of the therapeutic benefits of selenium supplementation in potentially environment associated health disorders. A systematic review was conducted based on the rigorous and well-defined methods developed by the Cochrane Collaboration. To achieve the demanding standards for systematic review set by the Cochrane Collaboration, study selection, quality assessment and data abstraction were performed independently and in duplicate using a standardized protocol. Overall, 1290 studies were identified as being eligible for inclusion. Twelve of these met the inclusion criteria and their quality was evaluated individually. None of the studies included in the analysis provided evidence of the therapeutic benefits of selenium supplementation in environment associated health disorders.

The granulopoiesis-stimulating factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), are used to prevent neutropenia and febrile neutropenia in patients with malignant lymphoma. The question as to whether G-CSF/GM-CSF improves dose-intensity, tumour response and overall survival (OS) has not yet been answered. As the results from single studies are inconclusive, a systematic review was performed to determine the effectiveness of G-CSF/GM-CSF. Randomized controlled trials comparing prophylaxis with G-CSF/GM-CSF versus no prophylaxis in adult patients with malignant lymphoma undergoing conventional chemotherapy were included. Medical databases (Cochrane Library, Medline, Embase) and conference proceedings were searched. All authors were contacted to obtain missing data. We included 11 studies making a total of 1434 patients. Compared with no prophylaxis, G-CSF/GM-CSF significantly reduced the relative risk (RR) for neutropenia [RR 0.64 [95% confidence interval (CI) 0.55-0.75]] febrile neutropenia (RR 0.74 [95% CI 0.62-0.89]) and infection (RR 0.74 [95% CI 0.64-0.85]). G-CSF/GM-CSF did not decrease infection-related mortality (RR 2.07 [95% CI 0.81-5.34]), improve complete remission (CR) (RR 1.06 [95% CI 0.96-1.16]) or OS (HR 0.98 [95% CI 0.81-1.18]). In conclusion, G-CSF/GM-CSF given during conventional chemotherapy in malignant lymphoma patients reduced the RR of neutropenia, febrile neutropenia and infection. However, there is no evidence that G-CSF/GM-CSF improved CR and OS in this clinical setting.

The use of meta-analysis to combine results of several trials is still increasing in the medical field. The validity of a meta-analysis may be affected by various sources of bias (for example, publication bias, language bias). Therefore, an analysis of bias should be an integral part of any systematic review. Statistical tests and graphical methods have been developed for this purpose. In this paper, two statistical tests for the detection of bias in meta-analysis were investigated in a simulation study. Binary outcome data, which are very common in medical applications, were considered and relative effect measures (odds ratios, relative risk) were used for pooling. Sample sizes were generated according to findings in a survey of eight German medical journals. Simulation results indicate an inflation of type I error rates for both tests when the data are sparse. Results get worse with increasing treatment effect and number of trials combined. Valid statistical tests for the detection of bias in meta-analysis with sparse data need to be developed., (Copyright 2002 John Wiley & Sons, Ltd.)

The application of artificial neural networks (ANNs), especially feed-forward neural networks (FFNNs), has become very popular for diagnosis and prognosis in clinical medicine, often accompanied by exaggerated statements of their potential. The excitement stems mainly from the fact that ANNs were developed as attempts to model the decision process of the human brain. Traditionally, logistic regression models and proportional hazard regression models have been used in these applications. In this article, FFNNs are introduced as flexible, nonlinear regression models and necessary precautions for their use are discussed. Furthermore, the results of a literature survey of applications of ANNs in prostate cancer published between 1999 and 2001 are described; most applications suffer from methodologic deficiencies. It is concluded that there is so far no evidence that the application of ANNs provide real progress in the field of diagnosis and prognosis in prostate cancer., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

The efficacy of ceftriaxone versus other cephalosporins in the perioperative prophylaxis of surgical wound, urinary tract and respiratory tract infections was compared in a meta-analysis of randomized controlled trials published between 1986 and 1996, identified from the Medline, Embase, SIGLE, ROPU, DHSS-Data and Medikat Cologne databases. Studies were grouped by type of infection, operative specialty, wound classification, study quality and other factors, and assessed for relative risk (RR). Forty-three studies with a total of 13,482 patients met our inclusion criteria. RR for surgical wound infection (n = 13,303 patients) was 30% lower in the ceftriaxone versus control groups [98.3% confidence interval (CI): 0.55-0.89; p = 0.0002]. In urinary tract infections (n = 8,865 patients), the primary analysis of all studies showed marked superiority for ceftriaxone (RR: 0.53; 98.3% CI: 0.43-0.67) but not in studies with CDC-defined infections (RR: 0.63; 98.3% CI: 0.36-1.12). In both types of infection, ceftriaxone was superior in contaminated operations. The data showed no advantage for ceftriaxone in other operations. In respiratory tract infections (n = 9,567 patients), there was no significant difference: the RR was 0.81 (98.3% CI: 0.61-1.09; p = 0.04)., (Copyright 2002 S. Karger AG, Basel)