Efficacy and safety of pharmacological treatments for Lyme neuroborreliosis: An updated systematic review.

BACKGROUND: Evidence-based recommendations for treatment of Lyme neuroborreliosis (LNB) should rely on the available literature. As new data emerges, close review and evaluation of the recent literature is needed to build evidence-based recommendations to inform clinical practice and management of LNB. We performed an update of a previous systematic review on treatment of LNB. METHODS: A systematic literature search of Medline and CENTRAL was performed for published studies from 2015 to 2023 to update a previous systematic review. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools for RCTs; NRS were assessed using the ROBINS-I-tool. Quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Data were integrated into an existing meta-analysis of the available literature. RESULTS: After screening 1530 records, two RCTs and five NRS with new and relevant data were additionally identified. Meta-analysis showed no statistically significant difference between doxycycline and beta-lactam antibiotics regarding residual neurological symptoms after 12 months. Meta-analysis showed no benefit of extended antibiotic treatment of LNB. Three NRS show no benefit for additional steroid use in LNB with facial palsy. DISCUSSION: Additional incorporated recent research corroborates existing guideline recommendations for treatment of LNB. New RCTs add to the certainty of previous analysis showing similar efficacy for doxycycline and beta-lactam antibiotics in LNB. Available evidence shows no benefit for extended antibiotic treatment in LNB. NRS do not suggest a role for steroids in facial palsy due to LNB.

An empirical comparison of the harmful effects for randomized controlled trials and non-randomized studies of interventions.

Introduction: Randomized controlled trials (RCTs) are the gold standard to evaluate the efficacy of interventions (e.g., drugs and vaccines), yet the sample size of RCTs is often limited for safety assessment. Non-randomized studies of interventions (NRSIs) had been proposed as an important alternative source for safety assessment. In this study, we aimed to investigate whether there is any difference between RCTs and NRSIs in the evaluation of adverse events. Methods: We used the dataset of systematic reviews with at least one meta-analysis including both RCTs and NRSIs and collected the 2 × 2 table information (i.e., numbers of cases and sample sizes in intervention and control groups) of each study in the meta-analysis. We matched RCTs and NRSIs by their sample sizes (ratio: 0.85/1 to 1/0.85) within a meta-analysis. We estimated the ratio of the odds ratios (RORs) of an NRSI against an RCT in each pair and used the inverse variance as the weight to combine the natural logarithm of ROR (lnROR). Results: We included systematic reviews with 178 meta analyses, from which we confirmed 119 pairs of RCTs and NRSIs. The pooled ROR of NRSIs compared to that of RCTs was estimated to be 0.96 (95% confidence interval: 0.87 and 1.07). Similar results were obtained with different sample size subgroups and treatment subgroups. With the increase in sample size, the difference in ROR between RCTs and NRSIs decreased, although not significantly. Discussion: There was no substantial difference in the effects between RCTs and NRSIs in safety assessment when they have similar sample sizes. Evidence from NRSIs might be considered a supplement to RCTs for safety assessment.

Transportal Tibiotalocalcaneal Nail Ankle Arthrodesis: A Systematic Review of Initial Series.

Background: There is currently a scarcity of information and consensus for transportal (arthroscopic or fluoroscopic) joint preparation during tibiotalocalcaneal (TTC) fusion, and therefore this review aims to summarize the available techniques and to evaluate the outcomes after this procedure. Methods: A systematic electronic search of MEDLINE, EMBASE, and Web of Science was performed for all English-language studies published from their inception to April 4, 2022. All articles addressing arthroscopy in TTC nailing were eligible for inclusion. The PRISMA Checklist guided the reporting and data abstraction. Descriptive statistics are presented. Result: A total of 5 studies with 65 patients were included for analysis. All studies used arthroscopic portals for tibiotalar and subtalar joint preparation (in 4 studies) prior to TTC nailing, with 4 studies using an arthroscope and 1 study using fluoroscopy. The overall major complication rate was 13.8%; however, there was only 1 instance of deep wound infection (1.5%) and 4 instances of surgical site infections (6.2%). Full fusion was achieved in 86% of patients with an average time to fusion of 12.9 weeks. The mean American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score preoperatively was 34.0 and postoperatively was 70.5. Conclusion: Although limited by the number of studies, transportal joint preparation during TTC nail ankle fusion is associated with good rates of complications and successful fusion. Level of Evidence: Level III, systematic review of Level III-IV studies.

Waterpipe Use and Its Cardiovascular Effects: A Systematic Review and Meta-Analysis of Case-Control, Cross-Sectional, and Non-Randomized Studies.

Approximately 100 million people globally smoke cigarettes, making it a significant and quickly spreading global tobacco epidemic. Substance use disorders are frequently evaluated by non-randomized studies. Tobacco use and its impacts on the cardiovascular system were the subjects of a comprehensive search across five electronic databases: Cochrane, MEDLINE, Scopus, Embase, and PubMed. The findings demonstrated that waterpipe smokers in comparison to non-smokers have immediate elevations in heart rate and blood pressure, lower levels of high-density lipoprotein, higher levels of low-density lipoprotein, higher levels of triglycerides, higher levels of fasting blood glucose, and a higher heart rate. Users of waterpipes and cigarettes had similar average heart rates, blood pressure, and lipid levels, with the exception that waterpipe smokers had greater total cholesterol. Smoking a waterpipe has significant negative effects on the cardiovascular system comparable to cigarette smoking, and non-randomized studies proved to yield substantial evidence related to its cardiovascular effects. Such study designs can be used to evaluate substance use and its cardiovascular impact.

Empirical evaluation of the methods used in systematic reviews including observational studies and randomized trials.

OBJECTIVES: To examine the methodological characteristics of systematic reviews and meta-analyses including observational studies (OSs) and randomized controlled trials (RCTs), in various medical disciplines. STUDY DESIGN AND SETTING: We searched Medline via PubMed to identify systematic reviews of interventions including RCTs and OSs published in 110 journals from 2015 to 2019. We extracted in duplicate general and methodological characteristics of the systematic review. RESULTS: We identified 402 systematic reviews. Only 39% (n = 160) of them reported the availability of a pre-established protocol. A rationale for including observational data in the systematic review was clearly reported in 25% (n = 102) of the systematic reviews. Thirty two percent (n = 130) of the reviews reported a search strategy intending to identify published and unpublished data for RCTs and OSs. The risk of bias of the individual studies was assessed in 89% (n = 359) of the systematic reviews. In 74% (n = 266) it was assessed for both RCTs and OSs; 180 (50%) used different tools. Information about confounding factors was reported in only 11% of systematic reviews and the type of effect estimates (crude or adjusted) used was specified in only 22% of the systematic reviews. Among the 385 systematic reviews that performed data synthesis, only 132 (33%) pooled OSs and RCTs in the same meta-analysis. CONCLUSION: Including OSs in systematic reviews of interventions could provide useful information but such an approach could also be misleading; thus, several methodological details are needed to ensure appropriate handling of OS and valid results. Our study revealed, although, that substantial methodological information is missing in reports published in high-impact factor general and specialty journals.

Does computer-assisted navigation improve baseplate screw configuration in reverse shoulder arthroplasty? A systematic review and meta-analysis of comparative studies.

Introduction: Navigation technologies have improved accuracy and precision in positioning glenoid components during shoulder arthroplasty. The influence of navigation on baseplate screw placement has not been independently investigated. This study aimed to evaluate and synthesize the best scientific evidence on the influence of intraoperative navigation on the length and number of screws for primary baseplate fixation in reverse total shoulder arthroplasty procedures. Methods: In August 2022, PubMed, Scopus, and Embase databases were accessed. We analyzed the screw purchase length, the number of screws required for the fixation of the baseplate, and the proportion of cases fixed with two screws in all clinical trials, comparing navigation to standard instrumentation for reverse shoulder arthroplasty. Following an evaluation of the heterogeneity of the studies, DerSimonian-Laird random-effects models were utilized to merge data from separate studies. Results: The systematic search revealed a total of 2034 articles. After excluding duplicates and irrelevant studies, 633 shoulder arthroplasties from 6 trials were included in the analysis. The pooled mean difference in screw purchase length was 5.839 mm (95 %CI 4.496 to 7. 182) in favor of navigation (P < .001). In addition, significant differences were also found in the number of screws per case (- 0.547, 95 %CI -0.890 to -0.203, P = .002) and in the proportion of cases fixed with two screws (Odds Ratio 3.182 95 %CI 1.057 to 9.579, P = .040) in favor of the navigation group. Conclusions: Intraoperative navigation improves the baseplate screw placement, allowing for a greater screw purchase length and fewer screws to achieve primary fixation of the glenoid component during reverse shoulder arthroplasty. It is unclear whether these improvements will increase the longevity of the prosthesis or the clinical outcomes of the patients.

A methodologic survey on use of the GRADE approach in evidence syntheses published in high-impact factor urology and nephrology journals.

BACKGROUND: To identify and describe the use of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for rating the certainty of systematic reviews (SRs) evidence published in urology and nephrology journals. METHODS: SRs that were published in the top ten "urology and nephrology" journals with the highest impact factor according to the 2020 Journal Citation Reports (covering 2016-2020) were systematically searched and evaluated using the GRADE approach. RESULTS: A total of 445 SRs were researched. Sixty SRs of randomized control trials (RCTs) and/or non-randomized studies (NRSs) were evaluated using the GRADE approach. Forty-nine SRs (11%) rated the outcome-specific certainty of evidence (n = 29 in 2019-2020). We identified 811 certainty of evidence outcome ratings (n = 544 RCT ratings) as follows: very low (33.0%); low (32.1%); moderate (24.5%); and high (10.4%). Very low and high certainty of evidence ratings accounted for 55.0% and 0.4% of ratings in SRs of NRSs compared to 23.0% and 15.3% in SRs of RCTs. The certainty of evidence for RCTs and NRSs was downgraded most often for risk of bias and imprecision. CONCLUSIONS: We recommend increased emphasis on acceptance of the GRADE approach, as well as optimal use of the GRADE approach, in the synthesis of urinary tract evidence.

Research Quality and Impact of Cardiac Rehabilitation in Cancer Survivors: A Systematic Review and Meta-Analysis.

Background: Cardiac rehabilitation (CR) is endorsed to improve cardiovascular outcomes in cancer survivors. The quality of CR-based research in oncology has not been assessed. Objectives: The aim of this study was to evaluate the quality of reporting and evidence from CR-based intervention studies in oncology and to explore associations between intervention participation and outcomes. Methods: Systematic searches of 5 databases were conducted (January 2020) and updated (September 2021). Randomized and nonrandomized studies evaluating CR-based interventions in adult cancer survivors during and after treatment were eligible. Independent reviewers extracted data using 2 reporting guidelines (Template for Intervention Description and Replication and Consolidated Standards for Reporting Trials Harms extension), risk of bias (ROB) assessment tools (Cochrane ROB 2.0 and Cochrane Risk of Bias in Non-Randomized Studies of Interventions), and a combined inventory (Tool for the Assessment of Study Quality and reporting in Exercise). A meta-analysis was used to explore pre-intervention/post-intervention differences for commonly assessed outcomes. Results: Ten studies involving data from 685 survivors were included. The mean quality scores for intervention reporting (Template for Intervention Description and Replication) and harms (Consolidated Standards for Reporting Trials Harms extension) were 62% and 17%, respectively. There was moderate-to-high ROB across nonrandomized (Cochrane Risk of Bias in Non-Randomized Studies of Interventions score: 25%) and randomized (ROB 2.0 score: 50%) studies. The mean standardized cardiorespiratory fitness was higher (0.42; 95% CI: 0.27-0.57), fatigue was lower (-0.45; 95% CI: -0.55 to -0.34), and percent body fat (0.07; 95% CI: -0.23 to 0.38) was not different in survivors completing CR compared with those not completing CR. Conclusions: CR-based studies in oncology have low-to-moderate reporting quality and moderate-to-high ROB limiting interpretation, reproducibility, and translation of this evidence into practice.

Combining individual patient data from randomized and non-randomized studies to predict real-world effectiveness of interventions.

Meta-analysis of randomized controlled trials is generally considered the most reliable source of estimates of relative treatment effects. However, in the last few years, there has been interest in using non-randomized studies to complement evidence from randomized controlled trials. Several meta-analytical models have been proposed to this end. Such models mainly focussed on estimating the average relative effects of interventions. In real-life clinical practice, when deciding on how to treat a patient, it might be of great interest to have personalized predictions of absolute outcomes under several available treatment options. This paper describes a general framework for developing models that combine individual patient data from randomized controlled trials and non-randomized study when aiming to predict outcomes for a set of competing medical interventions applied in real-world clinical settings. We also discuss methods for measuring the models' performance to identify the optimal model to use in each setting. We focus on the case of continuous outcomes and illustrate our methods using a data set from rheumatoid arthritis, comprising patient-level data from three randomized controlled trials and two registries from Switzerland and Britain.

Confounders and co-interventions identified in non-randomized studies of interventions.

OBJECTIVES: To identify potential confounders and co-interventions systematically to optimise control of confounding for three non-randomized studies of interventions (NRSI) designed to quantify bleeding in populations exposed to different dual antiplatelet therapy (DAPT). STUDY DESIGN AND SETTING: Systematic review, interviews, and surveys with clinicians. We searched Ovid Medline, Ovid Embase, and the Cochrane Library to identify randomized-controlled trials and cohort studies of DAPT interventions. Two researchers independently screened citations, identified eligible studies and extracted data. We conducted individual semi-structured interviews with six cardiologists and six cardiac surgeons to elicit factors clinicians consider when they prescribe DAPT. We administered two online surveys for members of professional cardiology and cardiac surgery organisations. RESULTS: We screened 2,544 records, identified 322 eligible studies, and extracted data from 47. We identified 10 co-interventions and 70 potential confounders: review 31 (91%); interviews 19 (56%); surveys 31 (91%). 16/34 (47%) were identified by all three methods while, 3/34 (9%) were picked up by one method only. CONCLUSION: The review identified the majority of factors, but the interviews identified hard-to-measure factors such as perceived patient adherence and local prescribing culture. The methods could, in principle, be widely applied when designing or reviewing non-randomized studies of interventions (NRSI).

Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies.

Background: In non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC). Methods: For the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA. Results: Ten of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score. Conclusion: ANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

GRADE guidance 24 optimizing the integration of randomized and non-randomized studies of interventions in evidence syntheses and health guidelines.

BACKGROUND AND OBJECTIVE: This is the 24th in the ongoing series of articles describing the GRADE approach for assessing the certainty of a body of evidence in systematic reviews and health technology assessments and how to move from evidence to recommendations in guidelines. METHODS: Guideline developers and authors of systematic reviews and other evidence syntheses use randomized controlled studies (RCTs) and non-randomized studies of interventions (NRSI) as sources of evidence for questions about health interventions. RCTs with low risk of bias are the most trustworthy source of evidence for estimating relative effects of interventions because of protection against confounding and other biases. However, in several instances, NRSI can still provide valuable information as complementary, sequential, or replacement evidence for RCTs. RESULTS: In this article we offer guidance on the decision regarding when to search for and include either or both types of studies in systematic reviews to inform health recommendations. CONCLUSION: This work aims to help methodologists in review teams, technology assessors, guideline panelists, and anyone conducting evidence syntheses using GRADE.

Integrating sex and gender in studies of cardiac resynchronization therapy: a systematic review.

AIMS: To examine the prevalence, temporal changes, and impact of the National Institute of Health (NIH) Sex as a Biological Variable (SABV) policy on sex and gender reporting and analysis in cardiac resynchronization therapy (CRT) cohort studies. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and Web of Science for cohort studies reporting the effectiveness and safety of CRT in heart failure patients from January 2000 to June 2020, with no language restrictions. Segmented regression analysis was used for policy analysis. We included 253 studies. Fourteen per cent considered sex in the study design. Outcome data disaggregated by sex were only reported in 17% of the studies. Of the studies with statistical models (n = 173), 57% were adjusted for sex. Sixty-eight per cent of those reported an effect size for sex on the outcome. Sex-stratified analyses were conducted in 13% of the studies. Temporal analysis shows an increase in sex reporting in background, statistical models, study design, and discussion. Besides statistical models, NIH SABV policy analysis showed no significant change in the reporting of sex in study sections. Gender was not reported or analysed in any study. CONCLUSIONS: There is a need to improve the study design, analysis, and completeness of reporting of sex in CRT cohort studies. Inadequate sex integration in study design and analysis may potentially hinder progress in understanding sex disparities in CRT. Deficiencies in the integration of sex in studies could be overcome by implementing guidance that already exists.

High-dimensional generalized propensity score with application to omics data.

Propensity score (PS) methods are popular when estimating causal effects in non-randomized studies. Drawing causal conclusion relies on the unconfoundedness assumption. This assumption is untestable and is considered more plausible if a large number of pre-treatment covariates are included in the analysis. However, previous studies have shown that including unnecessary covariates into PS models can lead to bias and efficiency loss. With the ever-increasing amounts of available data, such as the omics data, there is often little prior knowledge of the exact set of important covariates. Therefore, variable selection for causal inference in high-dimensional settings has received considerable attention in recent years. However, recent studies have focused mainly on binary treatments. In this study, we considered continuous treatments and proposed the generalized outcome-adaptive LASSO (GOAL) to select covariates that can provide an unbiased and statistically efficient estimation. Simulation studies showed that when the outcome model was linear, the GOAL selected almost all true confounders and predictors of outcome and excluded other covariates. The accuracy and precision of the estimates were close to ideal. Furthermore, the GOAL is robust to model misspecification. We applied the GOAL to seven DNA methylation datasets from the Gene Expression Omnibus database, which covered four brain regions, to estimate the causal effects of epigenetic aging acceleration on the incidence of Alzheimer's disease.

Cochrane's risk of bias tool for non-randomized studies (ROBINS-I) is frequently misapplied: A methodological systematic review.

OBJECTIVES: We aimed to review how 'Risk of Bias In Non-randomized Studies-of Interventions' (ROBINS-I), a Cochrane risk of bias assessment tool, has been used in recent systematic reviews. STUDY DESIGN AND SETTING: Database and citation searches were conducted in March 2020 to identify recently published reviews using ROBINS-I. Reported ROBINS-I assessments and data on how ROBINS-I was used were extracted from each review. Methodological quality of reviews was assessed using AMSTAR 2 ('A MeaSurement Tool to Assess systematic Reviews'). RESULTS: Of 181 hits, 124 reviews were included. Risk of bias was serious/critical in 54% of assessments on average, most commonly due to confounding. Quality of reviews was mostly low, and modifications and incorrect use of ROBINS-I were common, with 20% reviews modifying the rating scale, 20% understating overall risk of bias, and 19% including critical-risk of bias studies in evidence synthesis. Poorly conducted reviews were more likely to report low/moderate risk of bias (predicted probability 57% [95% CI: 47-67] in critically low-quality reviews, 31% [19-46] in high/moderate-quality reviews). CONCLUSION: Low-quality reviews frequently apply ROBINS-I incorrectly, and may thus inappropriately include or give too much weight to uncertain evidence. Readers should be aware that such problems can lead to incorrect conclusions in reviews.

Comparison of statistical methodologies used to estimate the treatment effect on time-to-event outcomes in observational studies.

The use of real-world data became more and more popular in the pharmaceutical industry. The impact of real-world evidence is now well emphasized by the regulatory authorities. Indeed, the analysis of this type of data can play a key role for treatment efficacy and safety. The aim of this work is to assess various methods and give guidance on the comparisons of drugs, mostly with respect to time-to-event data, in non-randomized studies with potentially confounding variables. For that purpose, several statistical methodologies are compared based on simulation studies. These methodologies belong to family classes of methods that are widely used for this type of problem: regression, matching, weighting and subclassification methods. The evaluation criteria used to compare methods performances are the relative bias, the mean square error, the coverage probability and the width of the confidence interval. In this paper, we consider different scenarios of dataset features in order to study the effect of the sample size, the number of covariates and the magnitude of the treatment effect on the statistical methodologies performances. These statistical analyses are conducted within a proportional hazard model framework. Furthermore, we highlight the advantage of using techniques to identify relevant covariates for time-to-event outcomes by comparing two variable selection methods under a frequentist and a Bayesian inference. Based on simulation results, recommendations on each of the family of methods are provided to guide decision making.

Effect of real-time and post-event feedback in out-of-hospital cardiac arrest attended by EMS - A systematic review and meta-analysis.

OBJECTIVES: A systematic review to determine if cardiopulmonary resuscitation (CPR) guided by either real-time or post-event feedback could improve CPR quality or patient outcome compared to unguided CPR in out-of-hospital cardiac arrest (OHCA). METHODS: Four databases were searched; PubMed, Embase, CINAHL, and Cochrane Library in August 2020 for post 2010 literature on OHCA in adults. Critical outcomes were chest compression depth, rate and fraction. Important outcomes were any return of spontaneous circulation, survival to hospital and survival to discharge. RESULTS: A total of 9464 studies were identified with 61 eligibility for full text screening. A total of eight studies was included in the meta-analysis. Five studies investigated real-time feedback and three investigated post-event feedback. Meta-analysis revealed that real-time feedback statistically improves compression depth and rate while post-event feedback improved depth and fraction. Feedback did not statistically improve patient outcome but an improvement in absolute numbers revealed a clinical effect of feedback. Heterogenity varied from "might not be important" to "considerable". CONCLUSION: To significantly improve CPR quality real-time and post-event feedback should be combined. Neither real-time nor post event feedback could statistically be associated with patient outcome however, a clinical effect was detected. The conclusions reached were based on few studies of low to very low quality. PROSPERO REGISTRATION: CRD42019133881.

Sex differences in CRT device implantation rates, efficacy, and complications following implantation: protocol for a systematic review and meta-analysis of cohort studies.

INTRODUCTION: There is abundant evidence for sex differences in the diagnosis, implantation, and outcomes for cardiac resynchronization therapy (CRT) devices. Controversial data suggesting women are less likely to receive the device regardless of the greater benefit. The aim of this review is to assess sex differences in the implantation rate, clinical effectiveness, and safety of patients receiving CRT devices. METHODS: We will conduct a systematic literature search of MEDLINE, Embase, and Web of Science to identify cohort studies that meet our eligibility criteria. Title and full text screening will be conducted in duplicate independently. Eligible studies report clinical effectiveness or safety of patients receiving CRT device while providing sex-disaggregated data. Implantation rate will be extracted from the baseline characteristics tables of the studies. The effectiveness outcomes include the following: all-cause death, hospitalization, peak oxygen consumption (pVO2), quality of life (QoL), 6-min walk test, NYHA class reduction, LVEF, and heart failure hospitalization. The complication outcomes include the following: contrast-induced nephropathy, pneumothorax, pocket-related hematoma, pericardial tamponade, phrenic nerve stimulation, device infection, death, pulmonary edema, electrical storm, cardiogenic shock, and hypotension requiring resuscitation. Description of included studies will be reported in detail and outcomes will be meta-analyzed and presented using forest plots when feasible. Risk of bias will be assessed using the Newcastle-Ottawa Scale (NOS) by two review authors independently. GRADE approach will be used to assess the certainty of evidence. DISCUSSION: The aim of this review is to determine the presence of differences in CRT implantation between women and men as well as differences in clinical effectiveness and safety of CRT after device implantation. Results from this systematic review will provide important insights into sex differences in CRT devices that could contribute to the development of sex-specific recommendations and inform policy. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020204804.

Customized guidance/training improved the psychometric properties of methodologically rigorous risk of bias instruments for non-randomized studies.

OBJECTIVES: To evaluate the impact of guidance and training on the inter-rater reliability (IRR), inter-consensus reliability (ICR) and evaluator burden of the Risk of Bias (RoB) in Non-randomized Studies (NRS) of Interventions (ROBINS-I) tool, and the RoB instrument for NRS of Exposures (ROB-NRSE). STUDY DESIGN AND SETTING: In a before-and-after study, seven reviewers appraised the RoB using ROBINS-I (n = 44) and ROB-NRSE (n = 44), before and after guidance and training. We used Gwet's AC1 statistic to calculate IRR and ICR. RESULTS: After guidance and training, the IRR and ICR of the overall bias domain of ROBINS-I and ROB-NRSE improved significantly; with many individual domains showing either a significant (IRR and ICR of ROB-NRSE; ICR of ROBINS-I), or nonsignificant improvement (IRR of ROBINS-I). Evaluator burden significantly decreased after guidance and training for ROBINS-I, whereas for ROB-NRSE there was a slight nonsignificant increase. CONCLUSION: Overall, there was benefit for guidance and training for both tools. We highly recommend guidance and training to reviewers prior to RoB assessments and that future research investigate aspects of guidance and training that are most effective.

Decomposition analysis as a framework for understanding heterogeneity of treatment effects in non-randomized health care studies.

This paper uses the decomposition framework from the economics literature to examine the statistical structure of treatment effects estimated with observational data compared to those estimated from randomized studies. It begins with the estimation of treatment effects using a dummy variable in regression models and then presents the decomposition method from economics which estimates separate regression models for the comparison groups and recovers the treatment effect using bootstrapping methods. This method shows that the overall treatment effect is a weighted average of structural relationships of patient features with outcomes within each treatment arm and differences in the distributions of these features across the arms. In large randomized trials, it is assumed that the distribution of features across arms is very similar. Importantly, randomization not only balances observed features but also unobserved. Applying high dimensional balancing methods such as propensity score matching to the observational data causes the distributional terms of the decomposition model to be eliminated but unobserved features may still not be balanced in the observational data. Finally, a correction for non-random selection into the treatment groups is introduced via a switching regime model. Theoretically, the treatment effect estimates obtained from this model should be the same as those from a randomized trial. However, there are significant challenges in identifying instrumental variables that are necessary for estimating such models. At a minimum, decomposition models are useful tools for understanding the relationship between treatment effects estimated from observational versus randomized data.