Search

Background There is still no reference standard for the implantation of totally implantable venous access ports (TIVAPs). A recently published multicentre randomised controlled trial (RCT) revealed a significantly greater risk of pneumothorax after closed cannulation than after an open strategy. The aim of this meta-analysis was to provide an update of the available evidence for the safety and effectiveness of primary open versus closed cannulation strategy. Methods RCTs comparing outcomes of open cut-down of the cephalic vein and closed cannulation of the subclavian vein were sought systematically in MEDLINE, Web of Science and CENTRAL. The primary outcome was the occurrence of pneumothorax. A beta-binominal model was applied to combine the respective outcomes, and results are presented as odds ratios (OR) with 95% confidence interval (CI). Results Six RCTs with a total of 1831 patients were included in final analysis. Meta-analysis showed statistically significant superiority of the open cut-down technique regarding pneumothorax (OR 0.308, 95% CI 0.122 to 0.776), but a statistically significant higher failure of the primary technique for the open cut-down technique than for closed cannulation (OR 2.364, 95% CI 1.051 to 5.315). There were no significant differences between the two procedures regarding other morbidity endpoints. Conclusion This meta-analysis shows a general superiority of open cut-down of the cephalic vein over closed cannulation of the subclavian vein regarding the occurrence of pneumothorax. Open cut-down should be the first-line approach for TIVAP implantation. Closed cannulation should be performed with ultrasound as second-line procedure if the open technique fails. Systematic review registration PROSPERO CRD42013005180

OBJECTIVE Generation of pilot data for planning of prospective BET-studies for treatment of dilatory Eustachian tube (ET) dysfunction in children. STUDY DESIGN Retrospective multicenter analysis. SETTING Nine ENT departments at tertiary care teaching hospitals. PATIENTS 4-12-year-old children with chronic otitis media with effusion (COME) for more than 3 months or more than 3 episodes of acute otitis media during the last year, having failed standard surgical therapy at least once. INTERVENTION BET with or without paracentesis, ventilation tube insertion, or tympanoplasty. MAIN OUTCOME MEASURES Tympanic membrane appearance, tympanometry, and hearing threshold. RESULTS Two hundred ninety-nine ETs of 167 children were treated. Mean age was 9.1 years (95% confidence interval [95% CI]: 8.7-9.4 yr). In 249 ears (83.3%), COME and/or retraction of the tympanic membrane were the indication for BET. Median hearing threshold was 20 dB HL (95% CI: 0-46 dB). One hundred fifty-five ears (51.8%, 95% CI: 46.1-57.4%) showed a tympanogram type B. Treatment consisted of BET without other interventions ("BET-only") in 70 children, 128 ears. Median length of follow-up for 158 (94.6%) children was 2.6 months (95% CI: 0.3-16.1 mo). After treatment, the tympanic membrane appeared normal in 196 ears (65.6%, 95% CI: 60.0-70.8%, p

Zusammenfassung. Der vorliegende systematische Überblicksartikel basiert auf Vorarbeiten im Rahmen der Erstellung der AWMF-S3-Leitlinien zur Therapie von Autismus-Spektrum-Störungen (ASS). Das Ziel ist, den aktuellen Stand evidenzbasierter Interventionen zur Behandlung der Kernsymptomatik sowie sprachlichen Förderung im Kleinkind- und Vorschulalter für Kinder mit ASS darzustellen. Einschlusskriterien: entwicklungsorientierte oder verhaltenstherapeutisch basierte, manualisierte Intervention für Kinder mit ASS nach DSM-III (R), DSM-IV (TR), DSM-5 oder ICD-10, Alter < 7 Jahre, Publikationsdatum 1.1.2011 bis 31.8.2018. Iterativ-hierarchischer Prozess für den Studieneinschluss: systematisches Review > randomisiert kontrollierte > kontrollierte klinische Studie. Zielgrößen der eingeschlossenen Studien: zentrale autismusspezifische Symptomatik oder entwicklungspsychologisch belegte Vorläuferfertigkeiten oder Verbesserung der sprachlichen Fertigkeiten. Die Interventionen wurden (1) anhand ihrer wöchentlichen Frequenz sowie (2) anhand der therapeutischen Inhalte sortiert. Spezifische Therapieinhalte, wie die Förderung elterlicher Synchronizität sowie kindlicher gemeinsamer Aufmerksamkeit, Symbolspiel und Imitation einerseits oder die umfassende Förderung verschiedener Entwicklungsbereiche andererseits, wurden in den entsprechenden Studien untersucht. Die soziale Interaktion und Kommunikation verbesserte sich langfristig durch das frühe Training elterlicher Synchronizität und kindlicher Reziprozität sowie durch niedrigfrequente, umfassende, entwicklungsorientierte Therapieprogramme, denen das natürliche Lernformat zugrunde liegt. Hochfrequente, am diskreten Lernformat orientierte Programme zeigten diesbezüglich keine Effekte. Sprachliche Fertigkeiten verbesserten sich ebenfalls durch umfassende Förderung. Der Artikel summiert abschließend die Empfehlungen zu der in diesem Artikel untersuchten Fragestellung.

Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.

Abstract. Abstracts: Objective: In current international research, early intervention in children with autism-spectrum disorder (ASD) focuses on naturalistic developmental behavioral interventions (NDBI). The manualized Frankfurt Early Intervention Program for preschool-aged children with ASD (A-FFIP) implements NDBI principles within a low-intensity approach of 2 h intervention/week. The present case-control study established effect sizes of change in autistic symptoms, comorbid behavioral problems as well as IQ after one year. Methodology: An intervention group ( N = 20; age: 3.4–7.9 years) and a treatment-as-usual control group ( N = 20; age: 3.2–7.3 years) of children with ASD were matched for developmental and chronological age. The outcome measures used were the ADOS severity score, the Child Behavior Checklist, and cognitive development. Results: After one year, the A-FFIP group showed a trend towards greater improvement in autistic symptoms (η 2 = .087 [95 %-CI: .000–.159]) and significantly greater improvements in cognitive development (η 2 = .206 [CI: .012–.252]) and global psychopathology (η 2 = .144 [CI: .001–.205]) compared to the control group. Conclusion: The efficacy of A-FFIP should be established in a larger, sufficiently powered, randomized controlled study.

Background Despite numerous studies and meta-analyses the prognostic effect of cardiac rehabilitation is still under debate. This update of the Cardiac Rehabilitation Outcome Study (CROS II) provides a contemporary and practice focused approach including only cardiac rehabilitation interventions based on published standards and core components to evaluate cardiac rehabilitation delivery and effectiveness in improving patient prognosis. Design A systematic review and meta-analysis. Methods Randomised controlled trials and retrospective and prospective controlled cohort studies evaluating patients after acute coronary syndrome, coronary artery bypass grafting or mixed populations with coronary artery disease published until September 2018 were included. Results Based on CROS inclusion criteria out of 7096 abstracts six additional studies including 8671 patients were identified (two randomised controlled trials, two retrospective controlled cohort studies, two prospective controlled cohort studies). In total, 31 studies including 228,337 patients were available for this meta-analysis (three randomised controlled trials, nine prospective controlled cohort studies, 19 retrospective controlled cohort studies; 50,653 patients after acute coronary syndrome 14,583, after coronary artery bypass grafting 163,101, mixed coronary artery disease populations; follow-up periods ranging from 9 months to 14 years). Heterogeneity in design, cardiac rehabilitation delivery, biometrical assessment and potential confounders was considerable. Controlled cohort studies showed a significantly reduced total mortality (primary endpoint) after cardiac rehabilitation participation in patients after acute coronary syndrome (prospective controlled cohort studies: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20–0.69; retrospective controlled cohort studies HR 0.64, 95% CI 0.53–0.76; prospective controlled cohort studies odds ratio 0.20, 95% CI 0.08–0.48), but the single randomised controlled trial fulfilling the CROS inclusion criteria showed neutral results. Cardiac rehabilitation participation was also associated with reduced total mortality in patients after coronary artery bypass grafting (retrospective controlled cohort studies HR 0.62, 95% CI 0.54–0.70, one single randomised controlled trial without fatal events), and in mixed coronary artery disease populations (retrospective controlled cohort studies HR 0.52, 95% CI 0.36–0.77; two out of 10 controlled cohort studies with neutral results). Conclusion CROS II confirms the effectiveness of cardiac rehabilitation participation after acute coronary syndrome and after coronary artery bypass grafting in actual clinical practice by reducing total mortality under the conditions of current evidence-based coronary artery disease treatment. The data of CROS II, however, underscore the urgent need to define internationally accepted minimal standards for cardiac rehabilitation delivery as well as for scientific evaluation.

The performance of statistical methods is often evaluated by means of simulation studies. In case of network meta-analysis of binary data, however, simulations are not currently available for many practically relevant settings. We perform a simulation study for sparse networks of trials under between-trial heterogeneity and including multi-arm trials. Results of the evaluation of two popular frequentist methods and a Bayesian approach using two different prior specifications are presented. Methods are evaluated using coverage, width of intervals, bias, and root mean squared error (RMSE). In addition, deviations from the theoretical surface under the cumulative rankings (SUCRAs) or P-scores of the treatments are evaluated. Under low heterogeneity and when a large number of trials informs the contrasts, all methods perform well with respect to the evaluated performance measures. Coverage is observed to be generally higher for the Bayesian than the frequentist methods. The width of credible intervals is larger than those of confidence intervals and is increasing when using a flatter prior for between-trial heterogeneity. Bias was generally small, but increased with heterogeneity, especially in netmeta. In some scenarios, the direction of bias differed between frequentist and Bayesian methods. The RMSE was comparable between methods but larger in indirectly than in directly estimated treatment effects. The deviation of the SUCRAs or P-scores from their theoretical values was mostly comparable over the methods but differed depending on the heterogeneity and the geometry of the investigated network. Multivariate meta-regression or Bayesian estimation using a half-normal prior scaled to 0.5 seems to be promising with respect to the evaluated performance measures in network meta-analysis of sparse networks.

Individualized therapies for patients with biomarkers are moving more and more into the focus of research interest when developing new treatments. Hereby, the term individualized (or targeted) therapy denotes a treatment specifically developed for biomarker-positive patients. A network meta-analysis model for a binary endpoint combining the evidence for a targeted therapy from individual patient data with the evidence for a non-targeted therapy from aggregate data is presented and investigated. The biomarker status of the patients is either available at patient-level in individual patient data or at study-level in aggregate data. Both types of biomarker information have to be included. The evidence synthesis model follows a Bayesian approach and applies a meta-regression to the studies with aggregate data. In a simulation study, we address three treatment arms, one of them investigating a targeted therapy. The bias and the root-mean-square error of the treatment effect estimate for the subgroup of biomarker-positive patients based on studies with aggregate data are investigated. Thereby, the meta-regression approach is compared to approaches applying alternative solutions. The regression approach has a surprisingly small bias even in the presence of few studies. By contrast, the root-mean-square error is relatively greater. An illustrative example is provided demonstrating implementation of the presented network meta-analysis model in a clinical setting.

Zusammenfassung. Hintergrund: Autismus-Spektrum-Störungen (ASS) umfassen die ICD-10-Diagnosen (International Statistical Classification of Diseases and Related Health Problems) frühkindlicher Autismus, Asperger-Syndrom und atypischer Autismus und zeigen eine Lebenszeitprävalenz von bis zu 1 %. Die S3-Leitlinie der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. hat zum Ziel, evidenzbasierte Diagnostik und Therapie für professionelle Akteure im Gesundheits- und Sozialsystem systematisch zusammenzufassen und klinische Empfehlungen zu konsentieren. Der vorliegende Artikel fasst die wesentlichen Ergebnisse zum Teil Diagnostik zusammen. Methodik: Die Leitliniengruppe besteht aus 14 klinischen und wissenschaftlichen Fachgesellschaften sowie Patienten-/Angehörigen-Vertretern. Die Empfehlungen basieren dabei auf den Ergebnissen systematischer Literatursuche, Datenextraktion, Studienqualitäts-Bewertung sowie metaanalytischer Datenaggregation in Kombination mit der klinischen Expertise der jeweiligen Vertreter. Die Empfehlungen wurden anhand eines nominalen Gruppenprozesses abgestimmt. Ergebnisse: Der aktuelle Forschungsstand zur Diagnostik wird zusammengefasst. Dabei liegt ein besonderer Schwerpunkt auf der Frage der Notwendigkeit und Entbehrlichkeit verschiedener Bestandteile des diagnostischen Prozesses. Nach einer allgemeinen Einführung zum Krankheitsbild werden insbesondere die wesentlichen Aspekte der Anamnese, die sinnvolle Verwendung von Screening- und Diagnostikinstrumenten, die internistisch-neurologische Untersuchung, apparative Diagnostik, testpsychologische Untersuchung, Aufklärung und Beratung sowie sinnvolle Verlaufsdiagnostik detailliert dargestellt. Schlussfolgerung: Die ASS-Leitlinie gibt evidenzbasierte, klinisch konsentierte Empfehlungen zum Prozess der Diagnostik von ASS im Kindes-, Jugend- und Erwachsenenalter. Sie bietet Anwendern zudem die Möglichkeit, sich in kurzer Zeit über die Hintergründe der Störung sowie verschiedene diagnostische Instrumente zu informieren.

Background Current guidelines recommend neoadjuvant therapy for patients with stage II or III rectal cancer. The addition of platinum derivatives to fluoropyrimidine-based chemoradiotherapy has been frequently investigated, but their role in this setting remains controversial. Methods PubMed, Cochrane Library, and Web of Science were systematically searched for randomized trials comparing chemoradiotherapy with or without platinum agents in stage II or III rectal cancer. Main outcome parameters were overall and disease-free survival, additional outcomes included pathological complete response, isolated local recurrence, distant recurrence, toxicity, and perioperative morbidity. Time-to-event data were pooled as hazard ratios (HRs) by the inverse variance method and binary outcomes as odds ratios (ORs) by the Peto method with their respective 95% confidence interval (CI). All statistical tests were two-sided. Results Ten randomized controlled trials with data on 5599 patients were included in the meta-analysis. Platinum derivatives did not statistically significantly improve overall survival (HR = 0.93, 95% CI = 0.82 to 1.05, P = .23), disease-free survival (HR = 0.91, 95% CI = 0.83 to 1.01, P = .07), or local recurrence (OR = 0.83, 95% CI = 0.66 to 1.05, P = .12). However, it led to a statistically significant increase of pathological complete response (OR = 1.31, 95% CI = 1.10 to 1.55, P = .002) and a statistically significant reduction of distant recurrence (OR = 0.78, 95% CI = 0.66 to 0.92, P = .004). Benefits were accompanied by higher rates of grade 3 or 4 toxicities. Conclusions Intensified neoadjuvant chemoradiotherapy with the addition of platinum derivatives cannot be recommended routinely because it did not improve overall or disease-free survival and was associated with increased toxicity. It needs to be elucidated whether the benefits in distant recurrence and pathological complete response may be advantageous for selected high-risk patients.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To compare and rank preoperative chemoradiotherapy and chemotherapy treatment modalities for patients with resectable adenocarcinoma of the esophagus and esophagogastric junction, in terms of overall survival and other patient‐relevant outcomes, by conducting a network meta‐analysis.

Background: Although cardiovascular rehabilitation (CR) is well accepted in general, CR-attendance and delivery still considerably vary between the European countries. Moreover, clinical and prognostic effects of CR are not well established for a variety of cardiovascular diseases. Methods: The guidelines address all aspects of CR including indications, contents and delivery. By processing the guidelines, every step was externally supervised and moderated by independent members of the “Association of the Scientific Medical Societies in Germany” (AWMF). Four meta-analyses were performed to evaluate the prognostic effect of CR after acute coronary syndrome (ACS), after coronary bypass grafting (CABG), in patients with severe chronic systolic heart failure (HFrEF), and to define the effect of psychological interventions during CR. All other indications for CR-delivery were based on a predefined semi-structured literature search and recommendations were established by a formal consenting process including all medical societies involved in guideline generation. Results: Multidisciplinary CR is associated with a significant reduction in all-cause mortality in patients after ACS and after CABG, whereas HFrEF-patients (left ventricular ejection fraction

Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients’ groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.

Objective. In evidence synthesis, therapeutic options have to be compared despite the lack of head-to-head trials. Indirect comparisons are then widely used, although little is known about their performance in situations where cross-trial differences or effect modification are present. Methods. We contrast the matching adjusted indirect comparison (MAIC), simulated treatment comparison (STC), and the method of Bucher using a simulation study. The different methods are evaluated according to their power and type I error rate as well as with respect to the coverage, bias, and the root mean squared error (RMSE) of the effect estimate for practically relevant scenarios using binary and time-to-event endpoints. In addition, we investigate how the power planned for the head-to-head trials influences the actual power of the indirect comparison. Results. Indirect comparisons are considerably underpowered. None of the methods had substantially superior performance. In situations without cross-trial differences and effect modification, MAIC and Bucher led to similar results, while Bucher has the advantage of preserving the within-study randomization. MAIC and STC could enhance power in some scenarios but at the cost of a potential type I error inflation. Adjusting MAIC and STC for confounders that did not modify the effect led to higher bias and RMSE. Conclusion. The choice of effect modifiers in MAIC and STC influences the precision of the indirect comparison. Therefore, a careful selection of effect modifiers is warranted. In addition, missed differences between trials may lead to low power and partly high bias for all considered methods, and thus, results of indirect comparisons should be interpreted with caution.

Empirically based developmental and behavioral intervention programs targeting the core symptoms and language development in toddlers and preschool children with autism spectrum disorder

BACKGROUND: People with urothelial carcinoma of the bladder are at risk for recurrence and progression following transurethral resection of a bladder tumour (TURBT). Mitomycin C (MMC) and Bacillus Calmette‐Guérin (BCG) are commonly used, competing forms of intravesical therapy for intermediate‐ or high‐risk non‐muscle invasive (Ta and T1) urothelial bladder cancer but their relative merits are somewhat uncertain. OBJECTIVES: To assess the effects of BCG intravesical therapy compared to MMC intravesical therapy for treating intermediate‐ and high‐risk Ta and T1 bladder cancer in adults. SEARCH METHODS: We performed a systematic literature search in multiple databases (CENTRAL, MEDLINE, Embase, Web of Science, Scopus, LILACS), as well as in two clinical trial registries. We searched reference lists of relevant publications and abstract proceedings. We applied no language restrictions. The latest search was conducted in September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared intravesical BCG with intravesical MMC therapy for non‐muscle invasive urothelial bladder cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the literature, extracted data, assessed risk of bias and rated the quality of evidence according to GRADE per outcome. In the meta‐analyses, we used the random‐effects model. MAIN RESULTS: We identified 12 RCTs comparing BCG versus MMC in participants with intermediate‐ and high‐risk non‐muscle invasive bladder tumours (published from 1995 to 2013). In total, 2932 participants were randomised. Time to death from any cause: BCG may make little or no difference on time to death from any cause compared to MMC (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.79 to 1.20; participants = 1132, studies = 5; 567 participants in the BCG arm and 565 in the MMC arm; low‐certainty evidence). This corresponds to 6 fewer deaths (40 fewer to 36 more) per 1000 participants treated with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Serious adverse effects: 12/577 participants treated with BCG experienced serious non‐fatal adverse effects compared to 4/447 participants in the MMC group. The pooled risk ratio (RR) is 2.31 (95% CI 0.82 to 6.52; participants = 1024, studies = 5; low‐certainty evidence). Therefore, BCG may increase the risk for serious adverse effects compared to MMC. This corresponds to nine more serious adverse effects (one fewer to 37 more) with BCG. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Time to recurrence: BCG may reduce the time to recurrence compared to MMC (HR 0.88, 95% CI 0.71 to 1.09; participants = 2616, studies = 11, 1273 participants in the BCG arm and 1343 in the MMC arm; low‐certainty evidence). This corresponds to 41 fewer recurrences (104 fewer to 29 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations, imprecision and inconsistency. Time to progression: BCG may make little or no difference on time to progression compared to MMC (HR 0.96, 95% CI 0.73 to 1.26; participants = 1622, studies = 6; 804 participants in the BCG arm and 818 in the MMC arm; low‐certainty evidence). This corresponds to four fewer progressions (29 fewer to 27 more) with BCG at five years. We downgraded the certainty of the evidence two levels due to study limitations and imprecision. Quality of life: we found very limited data for this outcomes and were unable to estimate an effect size. AUTHORS' CONCLUSIONS: Based on our findings, BCG may reduce the risk of recurrence over time although the Confidence Intervals include the possibility of no difference. It may have no effect on either the risk of progression or risk of death from any cause over time. BCG may cause more serious adverse events although the Confidence Intervals once again include the possibility of no difference. We were unable to determine the impact on quality of life. The certainty of the evidence was consistently low, due to concerns that include possible selection bias, performance bias, given the lack of blinding in these studies, and imprecision.

Objective To systematically evaluate evidence on prognostic factors for tumor recurrence in patients with clinical stage I seminoma undergoing surveillance. Methods Systematic literature search conducted of Medline, Web of Science, Cochrane Library, and the conference proceedings of the ASCO, AUA, and EAU meetings (last search: October 2016), according to our prospectively registered protocol (PROSPERO registration number CRD42014009434). Identified records were reviewed according to the Cochrane Method Group of Prognosis Reviews recommendations and the PRISMA reporting guideline. Study quality was appraised with the Quality in Prognosis Studies (QUIPS) tool. Results Nineteen studies reporting on 26 potential prognostic factors were included in our analysis. Among the most frequently reported factors, tumor size (continuous or dichotomized) was significantly associated with relapse in 10/14 studies with a hazard ratio (HR) ranging from 1.33 (95% confidence interval [CI]: 1.14–1.56) to 3.17 (95% CI: 1.08–9.26). Rete testis invasion was significantly associated with relapse in only 4/13 studies with a HR ranging from 1.18 (95% CI: 0.92–1.51) to 1.36 (95% CI: 0.81–2.28). Lymphovascular invasion, young age, and preoperative HCG level had no association with relapse. Our findings are limited by heterogeneity of study designs, potential reporting bias, and moderate-to-poor study quality. Conclusion In stage I seminoma, tumor size is the most valuable prognostic factor on which to base relapse risk and to counsel patients about adjuvant treatment. Large tumor size was defined quite inhomogenously among the included studies, so no distinct cutoff value for tumor size can be recommended. Other potential prognostic factors including rete testis invasion play a minor role in stage I seminoma.

Traditional visualization in meta-analysis uses forest plots to illustrate the combined treatment effect, along with the respective results from primary trials. While the purpose of visualization is clear in the pairwise setting, additional treatments broaden the focus and extend the results to be illustrated in network meta-analysis. The complexity increases further in situations where all potential contrasts in the network are compared to a predefined fixed value of interest, such as the 95% coverage evaluated against the nominal value of 95% in simulation studies. We propose utilizing radar graphs to illustrate results from network meta-analysis in cases where the interest lies in the comparison of estimated results (after fitting a network meta-analysis in a specific data set) or a performance measure (simulation study) to a pre-defined fixed reference value. Accounting for the complex high-dimensional data structure, the general picture of the full network is captured at once without increasing the space needed for visualization. Especially in large simulation studies, where multiple scenarios need to be visually combined to gain an overview on different scenarios, this type of illustration facilitates the discussion of results. Further properties, such as the expected variation due to the Monte-Carlo error or the differentiation between directly and indirectly estimated treatment contrasts in simulation studies, as well as the indication of well-connected and sparsely connected treatments in an applied network meta-analysis, can additionally be included in the visualization. While we used the radar-graph mainly for a simulation study, other applications are suitable whenever relative contributions of treatment (contrasts) are of interest.

SummaryBackground Ultrasound measurements of the airway are useful for determining correctly sized, uncuffed endotracheal tubes in children. Aims The primary objective of this study was to evaluate the influence of ventilation pressure on the sonographically measured tracheal diameter at different levels. Methods A total of 100 patients (under 7 years) were enrolled in this study. Six sonographic measurements of minimal transverse diameters at 3 locations (vocal chords, cricoid cartilage, and proximal trachea) and at 2 different ventilation pressures (0 and 15 mbar) were performed before the intubation procedure. The intubating anesthesiologists were blinded to the results of the ultrasound measurements. The rate of agreement of the outer diameter of the correctly sized endotracheal tube (reference) with the 6 sonographic diameters was determined. In addition, the correct tube sizes were compared with the results of traditional prediction methods (Penlington's and Cole's formula in children ≥1 year and a decision table in children

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, which goes along with increased risk for sudden cardiac death (SCD). Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. We retrieved PubMed/Medline literatures on genotype–phenotype associations in patients with HCM and mutations in MYBPC3, MYH7, TNNT2, and TNNI3. Altogether, 51 studies with 7675 HCM patients were included in our meta-analysis. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 mutation positive patients was the beginning of the fourth decade, significantly earlier than patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3 (62%) and mutation negative group (64%). Cardiac conduction disease, ventricular arrhythmia and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p

Background Recurrence of colorectal liver metastases after a first hepatectomy is common (4–48% of patients). This review investigates the utility of repeated hepatic resection of colorectal liver metastases. Methods A systematic search of the literature was performed in the Cochrane Library, MEDLINE, EMBASE, and trial registers. All studies comparing repeated hepatic resection for colorectal liver metastases with patients who underwent only one hepatectomy were eligible. Outcome criteria were safety parameters and survival rates. Data were analyzed using the random-effects model. Results In eight observational clinical studies, 450 patients with repeated hepatic resection were compared with 2669 single hepatic resections. Morbidity such as hepatic insufficiency (OR [95% CI] 1.46 [0.69; 3.08], p = 0.32) and biliary leakage and fistula (OR [95% CI] 1.22 [0.80; 1.85], p = 0.35) was comparable between the two groups. Mortality (OR [95% CI] 1.13 [0.46; 2.74], p = 0.79) and overall survival (HR [95% CI] 1.00 [0.63; 1.60], p = 0.99) were not significantly different between the two groups. Discussion Repeated hepatic resection for colorectal liver metastases is safe in selected patients. A prospective, multicenter high-quality trial or register study of repeated hepatic resection will be required to clarify patient-oriented outcomes such as overall survival and quality of life.

Background: Naturalistic developmental behavioural interventions (NDBI) have been shown to improve autism-specific symptoms in young children with Autism Spectrum Disorder (ASD). NDBI approaches, such as the ASD-specific Frankfurt Early Intervention Program for ASD (A-FFIP), are based on ASD-specific developmental and learning aspects. A-FFIP is a low-intensity intervention which can easily be implemented in the local health care / social welfare system. The aim of the present study is to establish one-year efficacy of the manualised early intervention program A-FFIP in toddlers and preschool children with ASD. It is hypothesized that A-FFIP will result in improved ASD-specific symptoms compared to early intervention as usual (EIAU). Child and family specific secondary outcomes, as well as moderators and mediators of outcome will be explored. Methods/design: A prospective multi-centre, parallel-group, randomized, controlled, phase-III trial comparing A-FFIP versus EIAU. A total of 134 children (A-FFIP: 67, EIAU: 67) aged 24–66 months at baseline assessment meeting criteria for ASD (DSM-5) will be included. The primary outcome is the absolute change of the total score of the Brief Observation of Social Communication Change (BOSCC-AT) between baseline (T2) and one-year follow-up (T6). The treatment effect will be tested adjusted for relevant covariates applying a mixed model for repeated measures. Secondary outcomes are BOSCC social communication and repetitive behaviour scores, single ASD symptoms, language, cognition, psychopathology, parental well-being and family quality of life. Predictors, moderators and mediating mechanisms will be explored. Discussion: If efficacy of the manualised A-FFIP early intervention is established, the current study has the potential to change clinical practice strongly towards the implementation of low-intensity, evidence based, natural early intervention in ASD. Early intervention in ASD requires specialist training, which subsequently needs to be developed or included into current training curricula.

Introduction Pancreatic surgery is a large and complex field of research. Several evidence gaps exist for specific diseases or surgical procedures. An overview on existing knowledge is needed to plan and prioritise future research. The aim of this project is to create a systematic and living evidence map of pancreatic surgery. Methods and analysis A systematic literature search in MEDLINE (via PubMed), Web of Science and Cochrane Central Register of Controlled Trials will be performed searching for all randomised controlled trials (RCT) and systematic reviews (SR) on pancreatic surgery. RCT and SR will be grouped in research topics. Baseline and outcome data from RCT will be extracted, presented and effect sizes meta-analysed. Data from SR will be used to identify evidence gaps. A freely accessible web-based evidence map in the format of a mind map will be created. The evidence map and meta-analyses will be updated periodically. Dissemination After completion of the project, a permanently updated evidence map of pancreatic surgery will be available to patients, physicians, researchers and funding bodies via www.evidencemap.surgery. Its use will allow clinical decision-making based on primary data and prioritisation of future research endeavours. PROSPERO registration number CRD42019133444.

Background Patients with non-ischemic dilated cardiomyopathy (NIDCM) are at increased risk of ventricular arrhythmias and sudden cardiac death (SCD). However, identifying patients at high risk for life-threatening ventricular arrhythmia (LTVA) who may benefit from an implantable cardioverter defibrillator (ICD) remains challenging. Methods We searched MEDLINE and EMBASE for prognostic studies describing predictors of LTVA (defined as sustained ventricular tachycardia (VT), haemodynamically unstable VT, ventricular fibrillation, (aborted) SCD or appropriate ICD intervention) in patients with NIDCM. We excluded articles with composite heart failure and arrhythmic endpoints but lacking (subgroup) analysis for LTVA. Study quality and risk of bias was assessed using the QUIPS-tool, and articles with high risk of bias in ≥2 areas were excluded from analysis. Univariable hazard ratios of reported predictors were pooled from the remaining studies in a meta-analysis using a random-effects model and presented with 95% confidence interval (CI). Results Out of 1996 unique citations, 51 studies were included comprising 9798 patients with 1493 arrhythmic events. 28 studies were pooled for meta-analysis (mean age 55±4.1 years, 72% male) with a mean follow-up of 3.7±1.9 years. Crude event rate was 4.3% (95% CI 4.02–4.57) per year. From our meta-analysis, hypertension (HR 1.95; CI [1.26–3.00]), history of out of hospital cardiac arrest or sustained VT (HR 4.15; CI [1.32–13.02]), T-wave alternans (HR 6.50; CI [2.46–17.14]), LVEDV per 10ml/m2 increase (HR 1.10; CI [1.10–1.10]), LVESV per 10ml/m2 increase (HR 1.10; CI [1.00–1.22]) and delayed gadolinium enhancement (HR 5.55; CI [4.02–7.67]) were significantly associated with LTVA (figure). The quality of evidence was moderate and there was significant heterogeneity (median i2 57%; IQR 76%) among studies. Additionally from data that could not be pooled, decreased LVEF, history of nsVT and decreased heart rate variability were significantly associated with LTVA. Summary of meta-analysis results Conclusion The risk of LTVA in NIDCM is 4.3% per year and is considerably higher in patients with hypertension, history of LTVA, decreased LVEF, high LVEDV, high LVESV, T-wave alternans, history of nsVT, decreased heart rate variability and delayed gadolinium enhancement. These results may help determine appropriate candidates for ICD implantation. The high heterogeneity in reported results indicate the need for future multicentre studies to further improve risk stratification in NIDCM. Acknowledgement/Funding ERA-CVD JTC2016: DETECTIN-HF, 680969 & Dutch Heart Foundation (2016T096)

BACKGROUND Standard androgen suppression therapy (AST) using surgical or medical castration is considered a mainstay of advanced hormone-sensitive prostate cancer treatment. AST can be initiated early when disease is asymptomatic or deferred when patients suffer symptoms of disseminated prostate cancer. OBJECTIVES To assess the effects of early versus deferred standard AST for advanced hormone-sensitive prostate cancer. SEARCH METHODS For this Cochrane Review update, we performed a comprehensive search of multiple databases (CENTRAL, MEDLINE, Embase, Web of Science; last searched November 2018) and two clinical trial registers, with no restrictions on the language of publication or publication status. We also searched bibliographies of included studies and conference proceedings (last searched January 2019). SELECTION CRITERIA We included all randomised controlled trials (RCTs) with a direct comparison of early versus deferred standard AST. We excluded all other study designs. Participants included had advanced hormone-sensitive prostate cancer receiving surgical or medical castration. DATA COLLECTION AND ANALYSIS Two review authors independently classified studies and abstracted data. The primary outcomes were time to death of any cause and serious adverse events. Secondary outcomes were time to disease progression, time to death from prostate cancer, adverse events and quality of life. We performed statistical analyses using a random-effects model and assessed the certainty of evidence according to GRADE. We performed subgroup analyses for advanced but non-metastatic disease (T2-4/N+ M0), metastatic disease (M1), and prostate-specific antigen (PSA) relapse. MAIN RESULTS We identified seven new RCTs since publication of the original review in 2002. In total, we included 10 RCTs.Primary outcomesEarly AST probably reduces the risk of death from any cause over time (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.75 to 0.90; moderate-certainty evidence; 4767 participants). This corresponds to 57 fewer deaths (95% CI 80 fewer to 31 fewer) per 1000 participants at 5 years for the moderate risk group and 23 fewer deaths (95% CI 32 fewer to 13 fewer) per 1000 participants at 5 years in the low risk group. We downgraded for study limitations. Early versus deferred AST may have little or no effect on serious adverse events (risk ratio (RR) 1.05, 95% CI 0.95 to 1.16; low-certainty evidence; 10,575 participants) which corresponds to 6 more serious adverse events (6 fewer to 18 more) per 1000 participants. We downgraded the certainty of evidence for study limitations and selective reporting.Secondary outcomesEarly AST probably reduces the risk of death from prostate cancer over time (HR 0.69, 95% CI 0.57 to 0.84; moderate-certainty evidence). This corresponds to 62 fewer prostate cancer deaths per 1000 (95% CI 87 fewer to 31 fewer) at 5 years for the moderate risk group and 24 fewer death from prostate cancer (95% CI 34 fewer to 12 fewer) per 1000 men at 5 years in the low risk group. We downgraded the certainty of evidence for study limitations.Early AST may decrease the rate of skeletal events (RR 0.37, 95% CI 0.17 to 0.80; low-certainty evidence) corresponding to 23 fewer skeletal events per 1000 (95% CI 31 fewer to 7 fewer). We downgraded for study limitations and imprecision. It may also increase fatigue (RR 1.41, 95% CI 1.23 to 1.62; low-certainty evidence), corresponding to 31 more men with this complaint per 1000 (95% CI 18 more to 48 more). We downgraded for study limitations and imprecision. It may increase the risk of heart failure (RR 1.90, 95% CI 1.09 to 3.33; low-certainty evidence) corresponding to 27 more events per 1000 (95% CI 3 more to 69 more). We downgraded the certainty of evidence for study limitations and imprecision.Global quality of life is probably similar after two years as assessed with the EORTC QLQ-C30 (version 3.0) questionnaire (mean difference -1.56, 95% CI -4.50 to 1.38; moderate-certainty evidence) with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. AUTHORS' CONCLUSIONS Early AST probably extends time to death of any cause and time to death from prostate cancer. It may slightly decrease the rate of skeletal events. Rates of serious adverse events and quality of life may be similar. It may increase fatigue and may increase the risk of heart failure. Better quality trials would be particularly important to better understand the outcomes related to possible treatment-related harm, for which we only found low-certainty evidence.

Background Exercise-based cardiac rehabilitation (ebCR) often includes various psychological interventions for lifestyle change or distress management. However, the additional benefit of specific psychological interventions on depression, anxiety, quality of life, cardiac morbidity and cardiovascular or total mortality is not well investigated. Design Systematic review and meta-analysis. Methods Randomized controlled trials and controlled cohort trials published between January 1995 and October 2017 comparing ebCR with or without pre-specified psychosocial interventions were selected and evaluated on the basis of predefined inclusion and outcome criteria. Results Out of 15,373 records, 20 studies were identified, including 4450 patients with coronary artery disease (88.5%) or congestive heart failure (11.5%), respectively. Studies were of low to moderate quality and methodological heterogeneity was high. As compared with ebCR alone, additional psychological interventions for lifestyle change or distress management showed a trend to reduce depressive symptoms (standardized mean difference –0.13, 95% confidence interval (CI) –0.30; 0.05). Furthermore, during a follow-up of five years, distress management was associated with a trend to reduce cardiac morbidity (risk ratio 0.74, 95% CI 0.51; 1.07). There was no evidence for an additional impact of either psychological lifestyle change interventions or distress management on anxiety, quality of life, cardiovascular or total mortality. Conclusions Specific psychological interventions offered during ebCR may contribute to a reduction of depressive symptoms and cardiac morbidity, but there remains considerable uncertainty under which conditions these interventions exert their optimal effects. (CRD42015025920).

IntroductionCardiac arrest is a leading cause of death in industrialised countries. Cardiopulmonary resuscitation (CPR) guidelines follow the principles of closed chest compression as described for the first time in 1960. Mechanical CPR devices are designed to improve chest compression quality, thus considering the improvement of resuscitation outcomes. This protocol outlines a systematic review and meta-analysis methodology to assess trials investigating the therapeutic effect of automated mechanical CPR devices at the rate of return of spontaneous circulation, neurological state and secondary endpoints (including short-term and long-term survival, injuries and surrogate parameters for CPR quality) in comparison with manual chest compressions in adults with cardiac arrest.Methods and analysisA sensitive search strategy will be employed in established bibliographic databases from inception until the date of search, followed by forward and backward reference searching. We will include randomised and quasi-randomised trials in qualitative analysis thus comparing mechanical to manual CPR. Studies reporting survival outcomes will be included in quantitative analysis. Two reviewers will assess independently publications using a predefined data collection form. Standardised tools will be used for data extraction, risks of bias and quality of evidence. If enough studies are identified for meta-analysis, the measures of association will be calculated by dint of bivariate random-effects models. Statistical heterogeneity will be evaluated by I2-statistics and explored through sensitivity analysis. By comprehensive subgroup analysis we intend to identify subpopulations who may benefit from mechanical or manual CPR techniques. The reporting follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Ethics and disseminationNo ethical approval will be needed because data from previous studies will be retrieved and analysed. Most resuscitation studies are conducted under an emergency exception for informed consent. This publication contains data deriving from a dissertation project. We will disseminate the results through publication in a peer-reviewed journal and at scientific conferences.PROSPERO registration numberCRD42017051633.

BACKGROUND: The prognostic effect of multi-component cardiac rehabilitation (CR) in the modern era of statins and acute revascularisation remains controversial. Focusing on actual clinical practice, the aim was to evaluate the effect of CR on total mortality and other clinical endpoints after an acute coronary event. DESIGN: Structured review and meta-analysis. METHODS: Randomised controlled trials (RCTs), retrospective controlled cohort studies (rCCSs) and prospective controlled cohort studies (pCCSs) evaluating patients after acute coronary syndrome (ACS), coronary artery bypass grafting (CABG) or mixed populations with coronary artery disease (CAD) were included, provided the index event was in 1995 or later. RESULTS: Out of n = 18,534 abstracts, 25 studies were identified for final evaluation (RCT: n = 1; pCCS: n = 7; rCCS: n = 17), including n = 219,702 patients (after ACS: n = 46,338; after CABG: n = 14,583; mixed populations: n = 158,781; mean follow-up: 40 months). Heterogeneity in design, biometrical assessment of results and potential confounders was evident. CCSs evaluating ACS patients showed a significantly reduced mortality for CR participants (pCCS: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20-0.69; rCCS: HR 0.64, 95% CI 0.49-0.84; odds ratio 0.20, 95% CI 0.08-0.48), but the single RCT fulfilling Cardiac Rehabilitation Outcome Study (CROS) inclusion criteria showed neutral results. CR participation was also associated with reduced mortality after CABG (rCCS: HR 0.62, 95% CI 0.54-0.70) and in mixed CAD populations. CONCLUSIONS: CR participation after ACS and CABG is associated with reduced mortality even in the modern era of CAD treatment. However, the heterogeneity of study designs and CR programmes highlights the need for defining internationally accepted standards in CR delivery and scientific evaluation.

Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. We retrieved PubMed/Medline literature on genotype–phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with TTN mutations. The average frequency of mutations in the investigated genes was between 1 and 5 %. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in LMNA mutation carriers (27 %), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 % of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50 %) and PLN (43 %) mutations was significantly higher. The penetrance of DCM phenotype in subjects with TTN truncating variants increased with age and reached 100 % by age of 70. A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in LMNA and PLN mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.

Network meta-analysis is becoming a common approach to combine direct and indirect comparisons of several treatment arms. In recent research, there have been various developments and extensions of the standard methodology. Simultaneously, cluster randomized trials are experiencing an increased popularity, especially in the field of health services research, where, for example, medical practices are the units of randomization but the outcome is measured at the patient level. Combination of the results of cluster randomized trials is challenging. In this tutorial, we examine and compare different approaches for the incorporation of cluster randomized trials in a (network) meta-analysis. Furthermore, we provide practical insight on the implementation of the models. In simulation studies, it is shown that some of the examined approaches lead to unsatisfying results. However, there are alternatives which are suitable to combine cluster randomized trials in a network meta-analysis as they are unbiased and reach accurate coverage rates. In conclusion, the methodology can be extended in such a way that an adequate inclusion of the results obtained in cluster randomized trials becomes feasible. Copyright © 2016 John Wiley & Sons, Ltd.

Incisional hernias are one of the most common long-term complications associated with open abdominal surgery. The aim of this review and meta-analysis was to systematically assess laparoscopic versus open abdominal surgery as a general surgical strategy in all available indications in terms of incisional hernia occurrence. A systematic literature search was performed to identify randomized controlled trials comparing incisional hernia rates after laparoscopic versus open abdominal surgery in all indications. Random effects meta-analyses were calculated and presented as risk differences (RD) with their corresponding 95 % confidence intervals (CI). 24 trials (3490 patients) were included. Incisional hernias were significantly reduced in the laparoscopic group (RD −0.06, 95 % CI [−0.09, −0.03], p = 0.0002, I 2 = 75). The advantage of the laparoscopic procedure persisted in the subgroup of total-laparoscopic interventions (RD −0.14, 95 % CI [−0.22, −0.06], p = 0.001, I 2 = 87 %), whereas laparoscopically assisted procedures did not show a significant reduction of incisional hernias compared to open surgery (RD −0.01, 95 % CI [−0.03, 0.01], p = 0.31, I 2 = 35 %). Wound infections were significantly reduced in the laparoscopic group (RD −0.06, 95 % CI [−0.09, −0.03], p

The performance of statistical methods is frequently evaluated by means of simulation studies. In case of network meta-analysis of binary data, however, available data-generating models (DGMs) are restricted to either inclusion of two-armed trials or the fixed-effect model. Based on data-generation in the pairwise case, we propose a framework for the simulation of random-effect network meta-analyses including multiarm trials with binary outcome. The only one of the common DGMs used in the pairwise case, which is directly applicable to a random-effects network setting uses strongly restrictive assumptions. To overcome these limitations, we modify this approach and derive a related simulation procedure using odds ratios as effect measure. The performance of this procedure is evaluated with synthetic data and in an empirical example.

Background: Network meta-analysis is an extension of the classical pairwise meta-analysis and allows to compare multiple interventions based on both head-to-head comparisons within trials and indirect comparisons across trials. Bayesian or frequentist models are applied to obtain effect estimates with credible or confidence intervals. Furthermore, p-values or similar measures may be helpful for the comparison of the included arms but related methods are not yet addressed in the literature. In this article, we discuss how hypothesis testing can be done in a Bayesian network meta-analysis. Methods: An index is presented and discussed in a Bayesian modeling framework. Simulation studies were performed to evaluate the characteristics of this index. The approach is illustrated by a real data example. Results: The simulation studies revealed that the type I error rate is controlled. The approach can be applied in a superiority as well as in a non-inferiority setting. Conclusions: Test decisions can be based on the proposed index. The index may be a valuable complement to the commonly reported results of network meta-analyses. The method is easy to apply and of no (noticeable) additional computational cost.

BACKGROUND Biomarkers are well established for diagnosis of myocardial infarction [cardiac troponins, high-sensitivity cardiac troponins (hs-cTn)], exclusion of acute and chronic heart failure [B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)] and venous thromboembolism (d-dimers). Several studies have demonstrated acute increases in cardiac biomarkers and altered cardiac function after strenuous sports that can pretend a cardiovascular emergency and interfere with state-of-the-art clinical assessment. METHODS We performed a systematic review and metaanalysis of biomarker and cardiovascular imaging changes after endurance exercise. We searched for observational studies published in the English language from 1997 to 2014 that assessed these biomarkers or cardiac function and morphology directly after endurance exercise. Of 1787 identified abstracts, 45 studies were included. RESULTS Across all studies cardiac troponin T (cTnT) exceeded the cutoff value (0.01 ng/mL) in 51% (95% CI, 37%–64%) of participants. The measured pooled changes from baseline for high-sensitivity cTnT (hs-cTnT) were +26 ng/L (95% CI, 5.2–46.0), for cTnI +40 ng/L (95% CI, 21.4; 58.0), for BNP +10 ng/L (95% CI, 4.3; 16.6), for NT-proBNP +67 ng/L (95% CI, 49.9; 84.7), and for d-dimer +262 ng/mL (95% CI, 165.9; 358.7). Right ventricular end diastolic diameter increased and right ventricular ejection fraction as well as the ratio of the early to late transmitral flow velocities decreased after exercise, while no significant changes were observed in left ventricular ejection fraction. CONCLUSIONS Current cardiovascular biomarkers (cTnT, hs-cTnT, BNP, NT-proBNP, and d-dimer) that are used in clinical diagnosis of pulmonary embolism, acute coronary syndrome, and heart failure are prone to alterations due to strenuous exercise. Hence, it is necessary to take previous physical exercise into account when a cardiac emergency is suspected.

Background Neoadjuvant chemotherapy improves prognosis of patients with locally advanced gastroesophageal adenocarcinoma. The aim of this study was to identify predictors for postoperative survival following neoadjuvant therapy. These could be useful in deciding about postoperative continuation of chemotherapy. Methods This meta-analysis used IPD from RCTs comparing neoadjuvant chemotherapy with surgery alone for gastroesophageal adenocarcinoma. Trials providing IPD on age, sex, performance status, pT/N stage, resection status, overall and recurrence-free survival were included. Survival was calculated in the entire study population and subgroups stratified by supposed predictors and compared using the log-rank test. Multivariable Cox models were used to identify independent survival predictors. Results Four RCTs providing IPD from 553 patients fulfilled the inclusion criteria. (y)pT and (y)pN stage and resection status strongly predicted postoperative survival both after neoadjuvant therapy and surgery alone. Patients with R1 resection after neoadjuvant therapy survived longer than those with R1 resection after surgery alone. Patients with stage pN0 after surgery alone had better prognosis than those with ypN0 after neoadjuvant therapy. Patients with stage ypT3/4 after neoadjuvant therapy survived longer than those with stage pT3/4 after surgery alone. Multivariable regression identified resection status and (y)pN stage as predictors of survival in both groups. (y)pT stage predicted survival only after surgery alone. Conclusion After neoadjuvant therapy for gastroesophageal adenocarcinoma, survival is determined by the same factors as after surgery alone. However, ypT stage is not an independent predictor. These results can facilitate the decision about postoperative continuation of chemotherapy in pretreated patients.

Summary Objective To compare the efficacy and safety of different pivmecillinam (PIV) regimes for uncomplicated lower urinary tract infections (UTIs). Methods The MEDLINE, Embase, and Cochrane Library databases were searched. Randomized controlled clinical trials (RCTs) involving adults or children with symptoms suggestive of uncomplicated UTI and that compared different PIV regimes or PIV versus other antibiotics were included. Meta-analyses were conducted to obtain direct and indirect efficacy estimates. PIV regimes were categorized into high total dosage, moderate total dosage, and low total dosage. The risk of bias was evaluated using the Cochrane tool. Results Twenty-four RCTs were identified. No difference in clinical cure was found for the high vs. moderate (short-term: risk ratio (RR) 1.01, p =0.813; long term: RR 1.09, p =0.174) or high vs. low dosage comparisons (mean difference 0, 95% confidence interval −0.44 to 0.45, p =1). For bacteriological cure, comparisons of high vs. moderate dosage (short term: RR 1.05, p =0.056; long term: RR 1.05, p =0.131) and high vs. low dosage (short term: RR 1.02, p =0.759; long term: RR 1.13, p =0.247) showed a trend in favor of the high dosage treatment. Results for relapse, re-infection, and failure were inconclusive and not statistically significant. Patients treated with high dosages were 40% ( p =0.062) and 44% ( p =0.293) more likely to report mild to moderate adverse events. Conclusions There is insufficient evidence to support the use of an optimal combination of dosage, frequency, and duration of PIV therapy for the treatment of uncomplicated lower UTI. Evidence is limited due to the high risk of bias, poor reporting, and heterogeneous study data.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine if the omission of postoperative whole breast radiation therapy (WBRT) in selected postmenopausal women with early, favourable breast cancer, results in clinically acceptable, low local recurrence rates compared to women who receive postoperative WBRT.

Background Overexpression of the human papillomavirus (HPV) oncogenes E6 and E7 is necessary for the development of distinct lower genital tract cancers. However, secondary cellular genomic alterations are mandatory to promote progression of HPV-induced premalignant stages. We aimed at identifying the chromosomal regions most frequently gained and lost and the disease stage at which the latter occurs. These regions might be relevant for carcinogenesis and could serve as diagnostic markers to identify premalignant lesions with high progression risk towards invasive cancer. Methods We performed a systematic literature review and meta-analysis of studies listed in PubMed that analysed chromosomal copy number alterations by comparative genomic hybridisation (CGH) in HPV-positive and -negative cancers or premalignant lesions of the anogenital tract (cervix, anus, vagina, penis and vulva). Findings Data were extracted and analysed from 32 studies. The most common alterations in cervical squamous cell carcinoma (SCC) (12 studies, 293 samples) were gains at 3q with a rate of 0.55 (95% confidence interval (CI) 0.43–0.70), losses at 3p (0.36, 95%CI 0.27–0.48) and losses at 11q (0.33, 95%CI 0.26–0.43). Gains at 3q were particularly frequent in HPV16-positive cervical SCC (0.84, 95%CI 0.78–0.90). Also more than one quarter of high grade cervical intraepithelial neoplasia (CIN) harboured gains of 3q (0.27, 95%CI 0.20–0.36), but the rate in low grade CIN was low (0.02, 95%CI 0.00–0.09). For HPV-associated vulvar SCC (four studies, 30 samples) the same common alterations as in cervical SCC were reported. Studies on non-cervical and non-vulvar SCC and premalignant lesions of the lower genital tract are scarce. Interpretation 3q gains were most frequently found in HPV16-positive cervical SCC. The results suggest the selection of HPV-transformed cell clones harbouring 3q gains in high grade premalignant lesions, while alterations in low grade lesions are rare.

This systematic review was performed to investigate the ethical justification, methodological quality, validity and safety of placebo controls in randomized placebo-controlled surgical trials. Central, MEDLINE, and EMBASE were systematically searched to identify randomized controlled trials comparing a surgical procedure to a placebo. “Surgical procedure” was defined as a medical procedure involving an incision with instruments. Placebo was defined as a blinded sham operation involving no change to the structural anatomy and without an expectable physiological response in the target body compartment. Ten randomized placebo-controlled controlled surgical trials were included, all of them published in high-ranking medical journals (mean impact factor: 20.1). Eight of 10 failed to show statistical superiority of the experimental intervention. Serious adverse events did not differ between the groups (rate ratio [RR] 1.38, 95% confidence interval [CI]: 0.92–2.06, P = 0.46). None of the trials had a high risk of bias in any domain. The ethical justification for the use of a placebo control remained unclear in 2 trials. Placebo-controlled surgical trials are feasible and provide high-quality data on efficacy of surgical treatments. The surgical placebo entails a considerable risk for study participants. Consequently, a placebo should be used only if justified by the clinical question and by methodological necessity. Based on the current evidence, a pragmatic proposal for the use of placebo controls in future randomized controlled surgical trials is made.

This protocol for a Cochrane Diagnostic Test Accuracy Review has been withdrawn from publication by the Editorial Team due to a lack of progress.

Hintergrund: Taglich werden im Bereich Medizin und Gesundheitsinterventionen ca. 75 klinische Studien und 11 systematische Ubersichtsarbeiten veroffentlicht. Diese stetig wachsende Zahl an Publikationen erschwert deren zeitnahe Wahrnehmung. Dadurch kann sich die Umsetzung von neuen wirksamen Diagnostik- und Therapieverfahren in die klinische Routine verzogern. Umgekehrt kommen moglicherweise unwirksame oder gar schadliche Verfahren weiterhin zum Einsatz. Die evidenzbasierte Medizin (EBM) verlangt bei der Entscheidungsfindung fur den individuellen Patienten die Berucksichtigung aktueller hochwertiger Evidenz. Randomisiert-kontrollierte Studien (RCTs) zum Nachweis der Wirksamkeit und Sicherheit von chirurgischen Interventionen stellen in der patientenorientierten Forschung den „Goldstandard“ dar. Systematische Ubersichtsarbeiten (Systematic Reviews) bundeln die Ergebnisse einzelner Studien zu einer bestimmten Fragestellung. Zum Auffinden relevanter Publikationen sind Grundkenntnisse der systematischen Literatursuche notwendig und hilfreich. Material und Methoden: Der vorliegende Artikel illustriert anhand von bebilderten Anleitungen verschiedene Moglichkeiten der Literatursuche in der Datenbank Medline zum Auffinden von klinischen Studien und Systematic Reviews. Ergebnisse und Schlussfolgerung: Abhangig vom Thema und dem Ziel der Literatursuche konnen Zeit und Aufwand variieren. Im Praxisalltag ist eine systematische Literatursuche meist unrealistisch. Kliniker, die sich einen schnellen Einblick uber die aktuelle Evidenz zu einem klinischen Problem verschaffen mochten, konnen dazu auf aktuelle systematische Ubersichtsarbeiten zuruckgreifen. Wahrend einer systematischen Literatursuche konnen mehrere Herangehensweisen und verschiedene Strategien notig sein.

Summary Background: It is often difficult to determine the correct size of endotracheal tubes (ETT) needed for intubating pediatric patients. Therefore, we evaluated the role of ultrasound in pediatric patients to compare the correct size of an uncuffed (ETT) with the minimal transverse diameter of the subglottic airway (MTDSA) measured by ultrasound and with tube size predicted by different age-related formulas. Methods: A total of 50 pediatric patients ≤5 years were enrolled. As a standard, we defined the adequate ETT size with no audible leakage below a ventilation pressure of 15 mbar and with an audible leakage above 25 mbar. The maximum allowed difference between the prediction method result and the ETT that fit was defined as 0.3 mm. Ultrasound was performed before the intubation procedure; the intubating anesthesiologists were blinded to the results of the ultrasound measurement. Agreement between the two age-based formulas most commonly used at our department and MTDSA with the correct ETT size (standard) was analyzed using a Bland–Altman plot. Correlation and regression analyses were performed and the numbers of correct intubation trials recorded. Results: The frequency of bias ≤0.3 mm between each method and the correct ETT in the first attempt was