A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E).

BACKGROUND: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies. OBJECTIVE: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome. METHODS AND RESULTS: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias. CONCLUSION: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference.

Methodological review of NMA bias concepts provides groundwork for the development of a list of concepts for potential inclusion in a new risk of bias tool for network meta-analysis (RoB NMA Tool).

INTRODUCTION: Network meta-analyses (NMAs) have gained popularity and grown in number due to their ability to provide estimates of the comparative effectiveness of multiple treatments for the same condition. The aim of this study is to conduct a methodological review to compile a preliminary list of concepts related to bias in NMAs. METHODS AND ANALYSIS: We included papers that present items related to bias, reporting or methodological quality, papers assessing the quality of NMAs, or method papers. We searched MEDLINE, the Cochrane Library and unpublished literature (up to July 2020). We extracted items related to bias in NMAs. An item was excluded if it related to general systematic review quality or bias and was included in currently available tools such as ROBIS or AMSTAR 2. We reworded items, typically structured as questions, into concepts (i.e. general notions). RESULTS: One hundred eighty-one articles were assessed in full text and 58 were included. Of these articles, 12 were tools, checklists or journal standards; 13 were guidance documents for NMAs; 27 were studies related to bias or NMA methods; and 6 were papers assessing the quality of NMAs. These studies yielded 99 items of which the majority related to general systematic review quality and biases and were therefore excluded. The 22 items we included were reworded into concepts specific to bias in NMAs. CONCLUSIONS: A list of 22 concepts was included. This list is not intended to be used to assess biases in NMAs, but to inform the development of items to be included in our tool.

HIGHLIGHTS: • Our research aimed to develop a preliminary list of concepts related to bias with the goal of developing the first tool for assessing the risk of bias in the results and conclusions of a network meta-analysis (NMA).• We followed the methodology proposed by Whiting (2017) and Sanderson (2007) for creating systematically developed lists of quality items, as a first step in the development of a risk of bias tool for network meta-analysis (RoB NMA Tool).• We included items related to biases in NMAs and excluded items that are equally applicable to all systematic reviews as they are covered by other tools (e.g. ROBIS, AMSTAR 2).• Fifty-seven studies were included generating 99 items, which when screened, yielded 22 included items. These items were then reworded into concepts in preparation for a Delphi process for further vetting by external experts.• A limitation of our study is the challenge in retrieving methods studies as methods collections are not regularly updated.

Meta-regression of genome-wide association studies to estimate age-varying genetic effects.

Fixed-effect meta-analysis has been used to summarize genetic effects on a phenotype across multiple Genome-Wide Association Studies (GWAS) assuming a common underlying genetic effect. Genetic effects may vary with age (or other characteristics), and not allowing for this in a GWAS might lead to bias. Meta-regression models between study heterogeneity and allows effect modification of the genetic effects to be explored. The aim of this study was to explore the use of meta-analysis and meta-regression for estimating age-varying genetic effects on phenotypes. With simulations we compared the performance of meta-regression to fixed-effect and random -effects meta-analyses in estimating (i) main genetic effects and (ii) age-varying genetic effects (SNP by age interactions) from multiple GWAS studies under a range of scenarios. We applied meta-regression on publicly available summary data to estimate the main and age-varying genetic effects of the FTO SNP rs9939609 on Body Mass Index (BMI). Fixed-effect and random-effects meta-analyses accurately estimated genetic effects when these did not change with age. Meta-regression accurately estimated both main genetic effects and age-varying genetic effects. When the number of studies or the age-diversity between studies was low, meta-regression had limited power. In the applied example, each additional minor allele (A) of rs9939609 was inversely associated with BMI at ages 0 to 3, and positively associated at ages 5.5 to 13. Our findings challenge the assumption that genetic effects are consistent across all ages and provide a method for exploring this. GWAS consortia should be encouraged to use meta-regression to explore age-varying genetic effects.

Heat impacts on human health in the Western Pacific Region: an umbrella review.

Background: High temperatures and heatwaves are occurring more frequently and lasting longer because of climate change. A synthesis of existing evidence of heat-related health impacts in the Western Pacific Region (WPR) is lacking. This review addresses this gap. Methods: The Scopus and PubMed databases were searched for reviews about heat impacts on mortality, cardiovascular morbidity, respiratory morbidity, dehydration and heat stroke, adverse birth outcomes, and sleep disturbance. The last search was conducted in February 2023 and only publications written in English were included. Primary studies and reviews that did not include specific WPR data were excluded. Data were extracted from 29 reviews. Findings: There is strong evidence of heat-related mortality in the WPR, with the evidence concentrating on high-income countries and China. Associations between heat and cardiovascular or respiratory morbidity are not robust. There is evidence of heat-related dehydration and stroke, and preterm and still births in high-income countries in the WPR. Some evidence of sleep disturbance from heat is found for Australia, Japan and China. Interpretation: Mortality is by far the most studied and robust health outcome of heat. Future research should focus on morbidity, and lower income countries in continental Asia and Pacific Island States, where there is little review-level evidence. Funding: Funded by the World Health Organization WPR Office.

The influence of climate change on mental health in populations of the western Pacific region: An umbrella scoping review.

The Western Pacific Region (WPR) is on the front line of climate change challenges. Understanding how these challenges affect the WPR populations' mental health is essential to design effective prevention and care policies. Thus, the present study conducted an umbrella scoping review that examined the influence of climate change on mental health in the WPR, using review articles as a source of information. Ten review articles were selected according to eligibility criteria, and the findings were synthesized according to the socio-economic status of the countries identified: Australia, the Republic of Korea, the Philippines, Vietnam, the Pacific Islands (broadly), and China. The findings revealed that each country and sub-region has its own unique profile of climate change-related challenges and vulnerable populations, highlighting the need for specific approaches to mental health care. Specifically, the influence of climate-related challenges differed according to populations' region (e.g., rural populations), demographic characteristics (e.g., age and gender), culture (e.g., traditional tights to land), and employment (e.g., farmers and fishers). The most frequently reported mental health outcomes in response to climate change-related challenges such as droughts, floods, storms, tornadoes, typhoons, and climate-related migration were the decline in mental well-being and the increase in post-traumatic stress disorder symptoms. In addition, using the GRADE framework for assessing the certainty of the findings, we identified that the number of articles discussing associations between a given climate change challenge and a mental health outcome was overall limited. Based on our findings and findings on a global scale, we identified several key research gaps in WPR and provided recommendations for future research and policy strategies.

Genomic landscape and actionable mutations of brain metastases derived from non-small cell lung cancer: A systematic review.

Background: Brain metastases derived from non-small cell lung cancer (NSCLC) represent a significant clinical problem. We aim to characterize the genomic landscape of brain metastases derived from NSCLC and assess clinical actionability. Methods: We searched Embase, MEDLINE, Web of Science, and BIOSIS from inception to 18/19 May 2022. We extracted information on patient demographics, smoking status, genomic data, matched primary NSCLC, and programmed cell death ligand 1 expression. Results: We found 72 included papers and data on 2346 patients. The most frequently mutated genes from our data were EGFR (n = 559), TP53 (n = 331), KRAS (n = 328), CDKN2A (n = 97), and STK11 (n = 72). Common missense mutations included EGFR L858R (n = 80) and KRAS G12C (n = 17). Brain metastases of ever versus never smokers had differing missense mutations in TP53 and EGFR, except for L858R and T790M in EGFR, which were seen in both subgroups. Of the top 10 frequently mutated genes that had primary NSCLC data, we found 37% of the specific mutations assessed to be discordant between the primary NSCLC and brain metastases. Conclusions: To our knowledge, this is the first systematic review to describe the genomic landscape of brain metastases derived from NSCLC. These results provide a comprehensive outline of frequently mutated genes and missense mutations that could be clinically actionable. These data also provide evidence of differing genomic landscapes between ever versus never smokers and primary NSCLC compared to the BM. This information could have important consequences for the selection and development of targeted drugs for these patients.

A new approach to evaluating loop inconsistency in network meta-analysis.

In network meta-analysis, studies evaluating multiple treatment comparisons are modeled simultaneously, and estimation is informed by a combination of direct and indirect evidence. Network meta-analysis relies on an assumption of consistency, meaning that direct and indirect evidence should agree for each treatment comparison. Here we propose new local and global tests for inconsistency and demonstrate their application to three example networks. Because inconsistency is a property of a loop of treatments in the network meta-analysis, we locate the local test in a loop. We define a model with one inconsistency parameter that can be interpreted as loop inconsistency. The model builds on the existing ideas of node-splitting and side-splitting in network meta-analysis. To provide a global test for inconsistency, we extend the model across multiple independent loops with one degree of freedom per loop. We develop a new algorithm for identifying independent loops within a network meta-analysis. Our proposed models handle treatments symmetrically, locate inconsistency in loops rather than in nodes or treatment comparisons, and are invariant to choice of reference treatment, making the results less dependent on model parameterization. For testing global inconsistency in network meta-analysis, our global model uses fewer degrees of freedom than the existing design-by-treatment interaction approach and has the potential to increase power. To illustrate our methods, we fit the models to three network meta-analyses varying in size and complexity. Local and global tests for inconsistency are performed and we demonstrate that the global model is invariant to choice of independent loops.

A narrative review of recent tools and innovations toward automating living systematic reviews and evidence syntheses.

Living reviews are an increasingly popular research paradigm. The purpose of a 'living' approach is to allow rapid collation, appraisal and synthesis of evolving evidence on an important research topic, enabling timely influence on patient care and public health policy. However, living reviews are time- and resource-intensive. The accumulation of new evidence and the possibility of developments within the review's research topic can introduce unique challenges into the living review workflow. To investigate the potential of software tools to support living systematic or rapid reviews, we present a narrative review informed by an examination of tools contained on the Systematic Review Toolbox website. We identified 11 tools with relevant functionalities and discuss the important features of these tools with respect to different steps of the living review workflow. Four tools (NestedKnowledge, SWIFT-ActiveScreener, DistillerSR, EPPI-Reviewer) covered multiple, successive steps of the review process, and the remaining tools addressed specific components of the workflow, including scoping and protocol formulation, reference retrieval, automated data extraction, write-up and dissemination of data. We identify several ways in which living reviews can be made more efficient and practical. Most of these focus on general workflow management, or automation through artificial intelligence and machine-learning, in the screening process. More sophisticated uses of automation mostly target living rapid reviews to increase the speed of production or evidence maps to broaden the scope of the map. We use a case study to highlight some of the barriers and challenges to incorporating tools into the living review workflow and processes. These include increased workload, the need for organisation, ensuring timely dissemination and challenges related to the development of bespoke automation tools to facilitate the review process. We describe how current end-user tools address these challenges, and which knowledge gaps remain that could be addressed by future tool development. Dedicated web presences for automatic dissemination of in-progress evidence updates, rather than solely relying on peer-reviewed journal publications, help to make the effort of a living evidence synthesis worthwhile. Despite offering basic living review functionalities, existing end-user tools could be further developed to be interoperable with other tools to support multiple workflow steps seamlessly, to address broader automatic evidence retrieval from a larger variety of sources, and to improve dissemination of evidence between review updates.

Immunogenicity and seroefficacy of 10-valent and 13-valent pneumococcal conjugate vaccines: a systematic review and network meta-analysis of individual participant data.

Background: Vaccination of infants with pneumococcal conjugate vaccines (PCV) is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Methods: In this systematic-review and network meta-analysis, we searched the Cochrane Library, Embase, Global Health, Medline, clinicaltrials.gov and trialsearch.who.int up to February 17, 2023 with no language restrictions. Studies were eligible if they presented data comparing the immunogenicity of either PCV7, PCV10 or PCV13 in head-to-head randomised trials of young children under 2 years of age, and provided immunogenicity data for at least one time point after the primary vaccination series or the booster dose. Publication bias was assessed via Cochrane's Risk Of Bias due to Missing Evidence tool and comparison-adjusted funnel plots with Egger's test. Individual participant level data were requested from publication authors and/or relevant vaccine manufacturers. Outcomes included the geometric mean ratio (GMR) of serotype-specific IgG and the relative risk (RR) of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Seroefficacy was defined as the RR of seroinfection. We also estimated the relationship between the GMR of IgG one month after priming and the RR of seroinfection by the time of the booster dose. The protocol is registered with PROSPERO, ID CRD42019124580. Findings: 47 studies were eligible from 38 countries across six continents. 28 and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. GMRs comparing PCV13 vs PCV10 favoured PCV13 for serotypes 4, 9V, and 23F at 1 month after primary vaccination series, with 1.14- to 1.54- fold significantly higher IgG responses with PCV13. Risk of seroinfection prior to the time of booster dose was lower for PCV13 for serotype 4, 6B, 9V, 18C and 23F than for PCV10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Two-fold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (RR 0.46, 95% CI 0.23-0.96). Interpretation: Serotype-specific differences were found in immunogenicity and seroefficacy between PCV13 and PCV10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These findings could be used to compare PCVs and optimise vaccination strategies. Funding: The NIHR Health Technology Assessment Programme.

Tools for assessing quality and risk of bias in Mendelian randomization studies: a systematic review.

BACKGROUND: The use of Mendelian randomization (MR) in epidemiology has increased considerably in recent years, with a subsequent increase in systematic reviews of MR studies. We conducted a systematic review of tools designed for assessing risk of bias and/or quality of evidence in MR studies and a review of systematic reviews of MR studies. METHODS: We systematically searched MEDLINE, Embase, the Web of Science, preprints servers and Google Scholar for articles containing tools for assessing, conducting and/or reporting MR studies. We also searched for systematic reviews and protocols of systematic reviews of MR studies. From eligible articles we collected data on tool characteristics and content, as well as details of narrative description of bias assessment. RESULTS: Our searches retrieved 2464 records to screen, from which 14 tools, 35 systematic reviews and 38 protocols were included in our review. Seven tools were designed for assessing risk of bias/quality of evidence in MR studies and evaluation of their content revealed that all seven tools addressed the three core assumptions of instrumental variable analysis, violation of which can potentially introduce bias in MR analysis estimates. CONCLUSION: We present an overview of tools and methods to assess risk of bias/quality of evidence in MR analysis. Issues commonly addressed relate to the three standard assumptions of instrumental variables analyses, the choice of genetic instrument(s) and features of the population(s) from which the data are collected (particularly in two-sample MR), in addition to more traditional non-MR-specific epidemiological biases. The identified tools should be tested and validated for general use before recommendations can be made on their widespread use. Our findings should raise awareness about the importance of bias related to MR analysis and provide information that is useful for assessment of MR studies in the context of systematic reviews.

Statistical power in clinical trials of interventions for mood, anxiety, and psychotic disorders.

BACKGROUND: Previous research has suggested that statistical power is suboptimal in many biomedical disciplines, but it is unclear whether power is better in trials for particular interventions, disorders, or outcome types. We therefore performed a detailed examination of power in trials of psychotherapy, pharmacotherapy, and complementary and alternative medicine (CAM) for mood, anxiety, and psychotic disorders. METHODS: We extracted data from the Cochrane Database of Systematic Reviews (Mental Health). We focused on continuous efficacy outcomes and estimated power to detect predetermined effect sizes (standardized mean difference [SMD] = 0.20-0.80, primary SMD = 0.40) and meta-analytic effect sizes (ESMA). We performed meta-regression to estimate the influence of including underpowered studies in meta-analyses. RESULTS: We included 256 reviews with 10 686 meta-analyses and 47 384 studies. Statistical power for continuous efficacy outcomes was very low across intervention and disorder types (overall median [IQR] power for SMD = 0.40: 0.32 [0.19-0.54]; for ESMA: 0.23 [0.09-0.58]), only reaching conventionally acceptable levels (80%) for SMD = 0.80. Median power to detect the ESMA was higher in treatment-as-usual (TAU)/waitlist-controlled (0.49-0.63) or placebo-controlled (0.12-0.38) trials than in trials comparing active treatments (0.07-0.13). Adequately-powered studies produced smaller effect sizes than underpowered studies (B = -0.06, p ⩽ 0.001). CONCLUSIONS: Power to detect both predetermined and meta-analytic effect sizes in psychiatric trials was low across all interventions and disorders examined. Consistent with the presence of reporting bias, underpowered studies produced larger effect sizes than adequately-powered studies. These results emphasize the need to increase sample sizes and to reduce reporting bias against studies reporting null results to improve the reliability of the published literature.

The impact of the COVID-19 pandemic on presentations to health services following self-harm: systematic review.

BACKGROUND: Evidence on the impact of the pandemic on healthcare presentations for self-harm has accumulated rapidly. However, existing reviews do not include studies published beyond 2020. AIMS: To systematically review evidence on presentations to health services following self-harm during the COVID-19 pandemic. METHOD: A comprehensive search of databases (WHO COVID-19 database; Medline; medRxiv; Scopus; PsyRxiv; SocArXiv; bioRxiv; COVID-19 Open Research Dataset, PubMed) was conducted. Studies published from 1 January 2020 to 7 September 2021 were included. Study quality was assessed with a critical appraisal tool. RESULTS: Fifty-one studies were included: 57% (29/51) were rated as 'low' quality, 31% (16/51) as 'moderate' and 12% (6/51) as 'high-moderate'. Most evidence (84%, 43/51) was from high-income countries. A total of 47% (24/51) of studies reported reductions in presentation frequency, including all six rated as high-moderate quality, which reported reductions of 17-56%. Settings treating higher lethality self-harm were overrepresented among studies reporting increased demand. Two of the three higher-quality studies including study observation months from 2021 reported reductions in self-harm presentations. Evidence from 2021 suggests increased numbers of presentations among adolescents, particularly girls. CONCLUSIONS: Sustained reductions in numbers of self-harm presentations were seen into the first half of 2021, although this evidence is based on a relatively small number of higher-quality studies. Evidence from low- and middle-income countries is lacking. Increased numbers of presentations among adolescents, particularly girls, into 2021 is concerning. Findings may reflect changes in thresholds for help-seeking, use of alternative sources of support and variable effects of the pandemic across groups.

SARS-CoV-2 Infection and the Risk of Suicidal and Self-Harm Thoughts and Behaviour: A Systematic Review.

OBJECTIVE: The COVID-19 pandemic has had a complex impact on risks of suicide and non-fatal self-harm worldwide with some evidence of increased risk in specific populations including women, young people, and people from ethnic minority backgrounds. This review aims to systematically address whether SARS-CoV-2 infection and/or COVID-19 disease confer elevated risk directly. METHOD: As part of a larger Living Systematic Review examining self-harm and suicide during the pandemic, automated daily searches using a broad list of keywords were performed on a comprehensive set of databases with data from relevant articles published between January 1, 2020 and July 18, 2021. Eligibility criteria for our present review included studies investigating suicide and/or self-harm in people infected with SARS-CoV-2 with or without manifestations of COVID-19 disease with a comparator group who did not have infection or disease. Suicidal and self-harm thoughts and behaviour (STBs) were outcomes of interest. Studies were excluded if they reported data for people who only had potential infection/disease without a confirmed exposure, clinical/molecular diagnosis or self-report of a positive SARS-CoV-2 test result. Studies of news reports, treatment studies, and ecological studies examining rates of both SARS-CoV-2 infections and suicide/self-harm rates across a region were also excluded. RESULTS: We identified 12 studies examining STBs in nine distinct samples of people with SARS-CoV-2. These studies, which investigated STBs in the general population and in subpopulations, including healthcare workers, generally found positive associations between SARS-CoV-2 infection and/or COVID-19 disease and subsequent suicidal/self-harm thoughts and suicidal/self-harm behaviour. CONCLUSIONS: This review identified some evidence that infection with SARS-CoV-2 and/or COVID-19 disease may be associated with increased risks for suicidal and self-harm thoughts and behaviours but a causal link cannot be inferred. Further research with longer follow-up periods is required to confirm these findings and to establish whether these associations are causal.

Tenets for the Proper Conduct and Use of Meta-Analyses: A Practical Guide for Neurosurgeons.

Neurosurgeons today are inundated with rapidly amassing neurosurgical research publications. Systematic reviews and meta-analyses have consequently surged in popularity because, when executed properly, they constitute a high level of evidence and may save busy neurosurgeons many hours of combing and reviewing the literature for relevant articles. Meta-analysis refers to the quantitative (and discretionary) component of systematic reviews. It involves applying statistical techniques to combine effect sizes from multiple studies, which might offer more actionable insights than a systematic review without meta-analysis. Well-executed meta-analyses may prove instructive for clinical practice, but poorly conducted ones sow confusion and have the potential to cause harm. Unfortunately, recent audits have found the conduct and reporting of meta-analyses in neurosurgery (but also other surgical disciplines) to be relatively lackluster in methodologic rigor and compliance to established guidelines. Some of these deficiencies can be easily remedied through better awareness and adherence to prescribed standards-which will be reviewed in this article-but others stem from inherent problems with the source data (e.g., poor reporting of original research) as well as unique constraints faced by surgery as a field (e.g., lack of equipoise for randomized trials, or existence of learning curves for novel surgical procedures, which can lead to temporal heterogeneity), which may require unconventional tools (e.g., cumulative meta-analysis) to address. Therefore, it is also our goal to take stock of the unique issues encountered by surgeons who do meta-analysis and to highlight various techniques-some of which less well-known-to address such challenges.

Investigating the transparency of reporting in two-sample summary data Mendelian randomization studies using the MR-Base platform.

BACKGROUND: Two-sample Mendelian randomization (2SMR) is an increasingly popular epidemiological method that uses genetic variants as instruments for making causal inferences. Clear reporting of methods employed in such studies is important for evaluating their underlying quality. However, the quality of methodological reporting of 2SMR studies is currently unclear. We aimed to assess the reporting quality of studies that used MR-Base, one of the most popular platforms for implementing 2SMR analysis. METHODS: We created a bespoke reporting checklist to evaluate reporting quality of 2SMR studies. We then searched Web of Science Core Collection, PsycInfo, MEDLINE, EMBASE and Google Scholar citations of the MR-Base descriptor paper to identify published MR studies that used MR-Base for any component of the MR analysis. Study screening and data extraction were performed by at least two independent reviewers. RESULTS: In the primary analysis, 87 studies were included. Reporting quality was generally poor across studies, with a mean of 53% (SD = 14%) of items reported in each study. Many items required for evaluating the validity of key assumptions made in MR were poorly reported: only 44% of studies provided sufficient details for assessing if the genetic variant associates with the exposure ('relevance' assumption), 31% for assessing if there are any variant-outcome confounders ('independence' assumption), 89% for the assessing if the variant causes the outcome independently of the exposure ('exclusion restriction' assumption) and 32% for assumptions of falsification tests. We did not find evidence of a change in reporting quality over time or a difference in reporting quality between studies that used MR-Base and a random sample of MR studies that did not use this platform. CONCLUSIONS: The quality of reporting of two-sample Mendelian randomization studies in our sample was generally poor. Journals and researchers should consider using the STROBE-MR guidelines to improve reporting quality.

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).

Diagnostic accuracy of 1p/19q codeletion tests in oligodendroglioma: A comprehensive meta-analysis based on a Cochrane systematic review.

Codeletion of chromosomal arms 1p and 19q, in conjunction with a mutation in the isocitrate dehydrogenase 1 or 2 gene, is the molecular diagnostic criterion for oligodendroglioma, IDH mutant and 1p/19q codeleted. 1p/19q codeletion is a diagnostic marker and allows prognostication and prediction of the best drug response within IDH-mutant tumours. We performed a Cochrane review and simple economic analysis to establish the most sensitive, specific and cost-effective techniques for determining 1p/19q codeletion status. Fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) test methods were considered as reference standard. Most techniques (FISH, chromogenic in situ hybridisation [CISH], PCR, real-time PCR, multiplex ligation-dependent probe amplification [MLPA], single nucleotide polymorphism [SNP] array, comparative genomic hybridisation [CGH], array CGH, next-generation sequencing [NGS], mass spectrometry and NanoString) showed good sensitivity (few false negatives) for detection of 1p/19q codeletions in glioma, irrespective of whether FISH or PCR-based LOH was used as the reference standard. Both NGS and SNP array had a high specificity (fewer false positives) for 1p/19q codeletion when considered against FISH as the reference standard. Our findings suggest that G banding is not a suitable test for 1p/19q analysis. Within these limits, considering cost per diagnosis and using FISH as a reference, MLPA was marginally more cost-effective than other tests, although these economic analyses were limited by the range of available parameters, time horizon and data from multiple healthcare organisations.

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

BACKGROUND: Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development. METHODS: Our systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response. RESULTS: Based on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45-89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48-64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23-54%], ganglioglioma (GG): 40% [33-46%], and anaplastic ganglioglioma (aGG): 46% [18-76%]. Prevalence in astroblastoma was 24% [8-43%], desmoplastic infantile astrocytoma (DIA): 16% [0-57%], subependymal giant cell astrocytoma (SEGA): 8% [0-37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0-11%], diffuse astrocytoma (DA): 3% [0-9%], and pilocytic astrocytoma (PA): 3% [2-5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively. CONCLUSIONS: BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

Suicide and self-harm in low- and middle- income countries during the COVID-19 pandemic: A systematic review.

There is widespread concern over the potential impact of the COVID-19 pandemic on suicide and self-harm globally, particularly in low- and middle-income countries (LMIC) where the burden of these behaviours is greatest. We synthesised the evidence from the published literature on the impact of the pandemic on suicide and self-harm in LMIC. This review is nested within a living systematic review (PROSPERO ID CRD42020183326) that continuously identifies published evidence (all languages) through a comprehensive automated search of multiple databases (PubMed; Scopus; medRxiv, PsyArXiv; SocArXiv; bioRxiv; the WHO COVID-19 database; and the COVID-19 Open Research Dataset by Semantic Scholar (up to 11/2020), including data from Microsoft Academic, Elsevier, arXiv and PubMed Central.) All articles identified by the 4th August 2021 were screened. Papers reporting on data from a LMIC and presenting evidence on the impact of the pandemic on suicide or self-harm were included. Methodological quality was assessed using an appropriate tool, and a narrative synthesis presented. A total of 22 studies from LMIC were identified representing data from 12 countries. There was an absence of data from Africa, the Pacific, and the Caribbean. The reviewed studies mostly report on the early months of COVID-19 and were generally methodologically poor. Few studies directly assessed the impact of the pandemic. The most robust evidence, from time-series studies, indicate either a reduction or no change in suicide and self-harm behaviour. As LMIC continue to experience repeated waves of the virus and increased associated mortality, against a backdrop of vaccine inaccessibility and limited welfare support, continued efforts are needed to track the indirect impact of the pandemic on suicide and self-harm in these countries.