Systemic therapy in children and adolescents with mental disorders: a systematic review and meta-analysis.

BACKGROUND: Systemic therapy (ST) is a psychotherapeutic intervention in complex human systems (both psychological and interpersonal). Cognitive behavioural therapy (CBT) is an established treatment for children and adolescents with mental disorders. As methodologically rigorous systematic reviews on ST in this population are lacking, we conducted a systematic review and meta-analysis to compare the benefit and harm of ST (and ST as an add-on to CBT) with CBT in children and adolescents with mental disorders. METHODS: We searched MEDLINE, Embase, PsycINFO and other sources for randomised controlled trials in 14 mental disorder classes for the above comparisons in respect of effects on patient-relevant outcomes (search date: 7/2022). Where possible, meta-analyses were performed and results were graded into 3 different evidence categories: "proof", "indication", or "hint" (or none of these categories). PRISMA standards were followed. RESULTS: Fifteen studies in 5 mental disorder classes with usable data were identified. 2079 patients (mean age: 10 to 19 years) were analysed. 12/15 studies and 29/30 outcomes showed a high risk of bias. In 2 classes, statistically significant and clinically relevant effects in favour of ST were found, supporting the conclusion of a hint of greater benefit of ST for mental and behavioural disorders due to psychoactive substance use and of ST as an add-on to CBT for obsessive-compulsive disorders. In 2 other classes (eating disorders; hyperkinetic disorders), there was no evidence of greater benefit or harm of ST. For affective disorders, a statistically significant effect to the disadvantage of ST was found for 1 outcome, supporting the conclusion of a hint of lesser benefit of ST. CONCLUSIONS: Our results show a hint of greater benefit of ST (or ST as an add-on to CBT) compared with CBT for 2 mental disorder classes in children and adolescents (mental and behavioural disorders due to psychoactive substance use, obsessive compulsive disorders). Given the importance of CBT as a control intervention, ST can therefore be considered a beneficial treatment option for children and adolescents with certain mental disorders. Limitations include an overall high risk of bias of studies and outcomes and a lack of data for several disorders.

Negative pressure wound therapy in patients with wounds healing by secondary intention: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Negative pressure wound therapy (NPWT) is a widely used method of wound treatment. We performed a systematic review of randomised controlled trials (RCTs) comparing the patient-relevant benefits and harms of NPWT with standard wound therapy (SWT) in patients with wounds healing by secondary intention. METHODS: We searched for RCTs in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: July 2018) and screened reference lists of relevant systematic reviews and health technology assessments. Manufacturers and investigators were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome (e.g. wound closure). We assessed publication bias and, if feasible, performed meta-analyses, grading the results into different categories (hint, indication or proof of a greater benefit or harm). RESULTS: We identified 48 eligible studies of generally low quality with evaluable data for 4315 patients and 30 eligible studies with missing data for at least 1386 patients. Due to potential publication bias (proportion of inaccessible data, 24%), we downgraded our conclusions. A meta-analysis of all wound healing data showed a significant effect in favour of NPWT (OR 1.56, 95% CI 1.15 to 2.13, p = 0.008). As further analyses of different definitions of wound closure did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. A meta-analysis of hospital stay (in days) showed a significant difference in favour of NPWT (MD - 4.78, 95% CI - 7.79 to - 1.76, p = 0.005). As further analyses of different definitions of hospital stay/readmission did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. There was neither proof (nor indication nor hint) of greater benefit or harm of NPWT for other patient-relevant outcomes such as mortality and adverse events. CONCLUSIONS: In summary, low-quality data indicate a greater benefit of NPWT versus SWT for wound closure in patients with wounds healing by secondary intention. The length of hospital stay is also shortened. The data show no advantages or disadvantages of NPWT for other patient-relevant outcomes. Publication bias is an important problem in studies on NPWT, underlining that all clinical studies need to be fully reported.

Absolute risks rather than incidence rates should be used to estimate the number needed to treat from time-to-event data.

BACKGROUND: When estimating the number needed to treat (NNT) from randomized controlled trials (RCTs) with time-to-event outcomes, varying follow-up times have to be considered. Two methods have been proposed, namely (1) inverting risk differences estimated by survival time methods (RD approach) and (2) inverting incidence differences (ID approach). STUDY DESIGN AND SETTING: A simulation study was conducted to compare the RD and the ID approaches regarding bias and coverage probability (CP) considering various distributions, baseline risks, effect sizes, and sample sizes. Additionally, the two approaches were compared by using two real data examples. RESULTS: The RD approach showed good estimation and coverage properties with only a few exceptions in the case of small sample sizes and small effect sizes. The ID approach showed considerable bias and low CPs in most of the considered data situations. CONCLUSIONS: Absolute risks estimated by means of survival time methods rather than incidence rates should be used to estimate NNTs in RCTs with time-to-event outcomes.

Reporting of loss to follow-up information in randomised controlled trials with time-to-event outcomes: a literature survey.

BACKGROUND: To assess the reporting of loss to follow-up (LTFU) information in articles on randomised controlled trials (RCTs) with time-to-event outcomes, and to assess whether discrepancies affect the validity of study results. METHODS: Literature survey of all issues of the BMJ, Lancet, JAMA, and New England Journal of Medicine published between 2003 and 2005. Eligible articles were reports of RCTs including at least one Kaplan-Meier plot. Articles were classified as "assessable" if sufficient information was available to assess LTFU. In these articles, LTFU information was derived from Kaplan-Meier plots, extracted from the text, and compared. Articles were then classified as "consistent" or "not consistent". Sensitivity analyses were performed to assess the validity of study results. RESULTS: 319 eligible articles were identified. 187 (59%) were classified as "assessable", as they included sufficient information for evaluation; 140 of 319 (44%) presented consistent LTFU information between the Kaplan-Meier plot and text. 47 of 319 (15%) were classified as "not consistent". These 47 articles were included in sensitivity analyses. When various imputation methods were used, the results of a chi2-test applied to the corresponding 2 × 2 table changed and hence were not robust in about half of the studies. CONCLUSIONS: Less than half of the articles on RCTs using Kaplan-Meier plots provide assessable and consistent LTFU information, thus questioning the validity of the results and conclusions of many studies presenting survival analyses. Authors should improve the presentation of both Kaplan-Meier plots and LTFU information, and reviewers of study publications and journal editors should critically appraise the validity of the information provided.

Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of soft tissue sarcomas in children and adults. SEARCH STRATEGY: We searched the electronic databases CENTRAL (The Cochrane Library 2010, Issue 2), MEDLINE and EMBASE (February 2010). Online trial registers, congress abstracts and reference lists of reviews were searched and expert panels and authors were contacted. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title, abstract or keywords. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Comparative non-randomized studies were included because randomized controlled trials (RCTs) were not expected. Case series and case reports were considered for an additional descriptive analysis. DATA COLLECTION AND ANALYSIS: Study data were recorded by two review authors independently. For studies with no comparator group, we synthesised results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: We included 54 studies, from 467 full texts articles screened (11.5%), reporting on 177 participants that received HSCT and 69 participants that received standard care. Only one study reported comparative data. In the one comparative study, OS at two years after HSCT was estimated as statistically significantly higher (62.3%) compared with participants that received standard care (23.2%). In a single-arm study, the OS two years after HSCT was reported as 20%. In a pooled analysis of the individual data of 54 participants, OS at two years was estimated as 49% (95% CI 34% to 64%). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. All 54 studies had a high risk of bias. AUTHORS' CONCLUSIONS: Due to a lack of comparative studies, it is unclear whether participants with NRSTS have improved survival from autologous HSCT following HDCT. Owing to this current gap in knowledge, at present HDCT and autologous HSCT for NRSTS should only be used within controlled trials.

Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials.

OBJECTIVES: To assess the benefits and harms of reboxetine versus placebo or selective serotonin reuptake inhibitors (SSRIs) in the acute treatment of depression, and to measure the impact of potential publication bias in trials of reboxetine. DESIGN: Systematic review and meta-analysis including unpublished data. DATA SOURCES: Bibliographic databases (Medline, Embase, PsycINFO, BIOSIS, and Cochrane Library), clinical trial registries, trial results databases, and regulatory authority websites up until February 2009, as well as unpublished data from the manufacturer of reboxetine (Pfizer, Berlin). ELIGIBILITY CRITERIA: Double blind, randomised, controlled trials of acute treatment (six weeks or more) with reboxetine versus placebo or SSRIs in adults with major depression. OUTCOME MEASURES: Remission and response rates (benefit outcomes), as well as rates of patients with at least one adverse event and withdrawals owing to adverse events (harm outcomes). DATA EXTRACTION AND DATA SYNTHESIS: The procedures for data extraction and assessment of risk of bias were always conducted by one person and checked by another. If feasible, data were pooled by meta-analyses (random effects model). Publication bias was measured by comparing results of published and unpublished trials. RESULTS: We analysed 13 acute treatment trials that were placebo controlled, SSRI controlled, or both, which included 4098 patients. Data on 74% (3033/4098) of these patients were unpublished. In the reboxetine versus placebo comparison, no significant differences in remission rates were shown (odds ratio 1.17, 95% confidence interval 0.91 to 1.51; P=0.216). Substantial heterogeneity (I(2)=67.3%) was shown in the meta-analysis of the eight trials that investigated response rates for reboxetine versus placebo. A sensitivity analysis that excluded a small inpatient trial showed no significant difference in response rates between patients receiving reboxetine and those receiving placebo (OR 1.24, 95% CI 0.98 to 1.56; P=0.071; I(2)=42.1%). Reboxetine was inferior to SSRIs (fluoxetine, paroxetine, and citalopram) for remission rates (OR 0.80, 95% CI 0.67 to 0.96; P=0.015) and response rates (OR 0.80, 95% CI 0.67 to 0.95; P=0.01). Reboxetine was inferior to placebo for both harm outcomes (P<0.001 for both), and to fluoxetine for withdrawals owing to adverse events (OR 1.79, 95% CI 1.06 to 3.05; P=0.031). Published data overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm. CONCLUSIONS: Reboxetine is, overall, an ineffective and potentially harmful antidepressant. Published evidence is affected by publication bias, underlining the urgent need for mandatory publication of trial data.