Lack of Evidence for Ribavirin Treatment of Lassa Fever in Systematic Review of Published and Unpublished Studies1.

Ribavirin has been used widely to treat Lassa fever in West Africa since the 1980s. However, few studies have systematically appraised the evidence for its use. We conducted a systematic review of published and unpublished literature retrieved from electronic databases and gray literature from inception to March 8, 2022. We identified 13 studies of the comparative effectiveness of ribavirin versus no ribavirin treatment on mortality outcomes, including unpublished data from a study in Sierra Leone provided through a US Freedom of Information Act request. Although ribavirin was associated with decreased mortality rates, results of these studies were at critical or serious risk for bias when appraised using the ROBINS-I tool. Important risks for bias related to lack of control for confounders, immortal time bias, and missing outcome data. Robust evidence supporting the use of ribavirin in Lassa fever is lacking. Well-conducted clinical trials to elucidate the effectiveness of ribavirin for Lassa fever are needed.

Ensuring Prevention Science Research is Synthesis-Ready for Immediate and Lasting Scientific Impact.

When seeking to inform and improve prevention efforts and policy, it is important to be able to robustly synthesize all available evidence. But evidence sources are often large and heterogeneous, so understanding what works, for whom, and in what contexts can only be achieved through a systematic and comprehensive synthesis of evidence. Many barriers impede comprehensive evidence synthesis, which leads to uncertainty about the generalizability of intervention effectiveness, including inaccurate titles/abstracts/keywords terminology (hampering literature search efforts), ambiguous reporting of study methods (resulting in inaccurate assessments of study rigor), and poorly reported participant characteristics, outcomes, and key variables (obstructing the calculation of an overall effect or the examination of effect modifiers). To address these issues and improve the reach of primary studies through their inclusion in evidence syntheses, we provide a set of practical guidelines to help prevention scientists prepare synthesis-ready research. We use a recent mindfulness trial as an empirical example to ground the discussion and demonstrate ways to ensure the following: (1) primary studies are discoverable; (2) the types of data needed for synthesis are present; and (3) these data are readily synthesizable. We highlight several tools and practices that can aid authors in these efforts, such as using a data-driven approach for crafting titles, abstracts, and keywords or by creating a repository for each project to host all study-related data files. We also provide step-by-step guidance and software suggestions for standardizing data design and public archiving to facilitate synthesis-ready research.

[The PRISMA 2020 statement: an updated guideline for reporting systematic reviewsDeclaración PRISMA 2020: una guía actualizada para la publicación de revisiones sistemáticas]. / A declaração PRISMA 2020: diretriz atualizada para relatar revisões sistemáticas.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

La declaración PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses), publicada en 2009, se diseñó para ayudar a los autores de revisiones sistemáticas a documentar de manera transparente el porqué de la revisión, qué hicieron los autores y qué encontraron. Durante la última década, ha habido muchos avances en la metodología y terminología de las revisiones sistemáticas, lo que ha requerido una actualización de esta guía. La declaración PRISMA 2020 sustituye a la declaración de 2009 e incluye una nueva guía de presentación de las publicaciones que refleja los avances en los métodos para identificar, seleccionar, evaluar y sintetizar estudios. La estructura y la presentación de los ítems ha sido modificada para facilitar su implementación. En este artículo, presentamos la lista de verificación PRISMA 2020 con 27 ítems, y una lista de verificación ampliada que detalla las recomendaciones en la publicación de cada ítem, la lista de verificación del resumen estructurado PRISMA 2020 y el diagrama de flujo revisado para revisiones sistemáticas.

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

Matthew Page and co-authors describe PRISMA 2020, an updated reporting guideline for systematic reviews and meta-analyses.

The validity of dementia diagnoses in routinely collected electronic health records in the United Kingdom: A systematic review.

PURPOSE: The purpose of the study is to assess the validity of codes or algorithms used to identify dementia in UK electronic health record (EHR) primary care and hospitalisation databases. METHODS: Relevant studies were identified by searching the MEDLINE/EMBASE databases from inception to June 2018, hand-searching reference lists, and consulting experts. The search strategy included synonyms for "Dementia", "Europe", and "EHR". Studies were included if they validated dementia diagnoses in UK primary care or hospitalisation databases, irrespective of validation method used. The Quality Assessment for Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess risk of bias. RESULTS: From 1469 unique records, 14 relevant studies were included. Thirteen validated individual diagnoses against a reference standard, reporting high estimates of validity. Most reported only the positive predictive value (PPV), with estimates ranging between 0.09 and 1.0 and 0.62 and 0.85 in primary care and hospitalisation databases, respectively. One study performed a rate comparison, indicating good generalisability of dementia diagnoses in The Health Improvement Network (THIN) database to the UK population. Studies were of low methodological quality. As studies were not comparable, no summary validity estimates were produced. CONCLUSION: While heterogenous across studies, reported validity estimates were generally high. However, the credibility of these estimates is limited by the methodological quality of studies, primarily resulting from insufficient blinding of researchers interpreting the reference test. Inadequate reporting, particularly of the specific codes validated, hindered comparison of estimates across studies. Future validation studies should make use of more robust reference tests, follow established reporting guidelines, and calculate all measures of validity.

Cannabis use and the risk of tuberculosis: a systematic review.

BACKGROUND: Cannabis has been identified as a possible risk factor in some tuberculosis (TB) outbreaks. As the most widely used (largely) illegal substance in Western countries this may be an important public health concern. We aim to systematically review the evidence on the association between cannabis use and TB (latent infection and active disease) to inform ongoing and future TB prevention and control strategies. METHODS: We conducted a systematic review. We searched Ovid Medline, Embase and PsycInfo, together with the World Health Organization website and Google Scholar, for all years to January 2018. Reference lists and conference abstracts were hand-searched, a forward citation search was conducted on the Web of Science, and experts were contacted. Two authors independently screened studies for inclusion, extracted data and assessed risk of bias using an adapted version of ROBINS-I ("Risk of Bias in Non-randomised Studies - of Interventions"). Data were narratively synthesised. RESULTS: Of 377 records identified, 11 studies were eligible. Study designs were heterogeneous. Six studies utilised a relevant comparator group. Four of these investigated the association between cannabis use and latent TB infection; all provided some evidence of an association, although only two of these had adjusted for confounders. The remaining two comparator studies investigated the association between cannabis use and active TB disease; neither found evidence of an association after adjusting for confounding. All six studies were at "Serious" risk of bias. The five studies which did not utilise a relevant comparator group were all indicative of TB outbreaks occurring among cannabis users, but the quality of the evidence was very weak. CONCLUSIONS: Evidence for an association between cannabis use and TB acquisition is weak. The topic warrants further robust primary research including the collection of consistent and accurate exposure information, including cannabis use practices, dose and frequency, and adjustment for confounders.

Has increasing public health awareness influenced the size of testicular tumours among adult populations over the last 40 years?

Background: Testicular cancer is the commonest malignancy in young men. Improvements in survival rates have led to campaigns to raise awareness in at-risk men. We assessed the changing size of testicular tumours given the public health initiatives promoting testicular self-examination (TSE). Methods: Retrospective analysis of men (≥16 years) undergoing orchidectomy for testicular cancer at our institution over two time periods (1975-85 and 2007-12) were identified using our cancer registry. Histopathology reports were used to record testicular tumour size as the maximum measured dimension. Significance was indicated by P < 0.05. Results: Of 305 orchidectomies performed, 215 had histopathology reports available. Median age was 34 years (16-75 years). Mean tumour size was 7.2 cm in 1975-85 and 4.1 cm in 2007-12 showing a significant reduction (P = 0.02). Significant reduction was seen in all age groups except >60 years. Furthermore there was a significant increase in proportion of men presenting in the youngest age group (16-29 years) in the 2007-12 cohort (43 versus 29%, P = 0.02). Conclusion: The trend in reduction of tumour size at presentation and increased proportion of younger men presenting with testicular cancer supports an increased awareness. Promotion of TSE and public education should remain important initiatives given the increasing incidence of testicular cancer. Awareness still needs addressing in older men.

PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis.

Background: Reporting standards, such as PRISMA aim to ensure that the methods and results of systematic reviews are described in sufficient detail to allow full transparency. Flow diagrams in evidence syntheses allow the reader to rapidly understand the core procedures used in a review and examine the attrition of irrelevant records throughout the review process. Recent research suggests that use of flow diagrams in systematic reviews is poor and of low quality and called for standardised templates to facilitate better reporting in flow diagrams. The increasing options for interactivity provided by the Internet gives us an opportunity to support easy-to-use evidence synthesis tools, and here we report on the development of a tool for the production of PRISMA 2020-compliant systematic review flow diagrams. Methods and Findings: We developed a free-to-use, Open Source R package and web-based Shiny app to allow users to design PRISMA flow diagrams for their own systematic reviews. Our tool allows users to produce standardised visualisations that transparently document the methods and results of a systematic review process in a variety of formats. In addition, we provide the opportunity to produce interactive, web-based flow diagrams (exported as HTML files), that allow readers to click on boxes of the diagram and navigate to further details on methods, results or data files. We provide an interactive example here; https://prisma-flowdiagram.github.io/. Conclusions: We have developed a user-friendly tool for producing PRISMA 2020-compliant flow diagrams for users with coding experience and, importantly, for users without prior experience in coding by making use of Shiny (https://estech.shinyapps.io/prisma_flowdiagram/). This free-to-use tool will make it easier to produce clear and PRISMA 2020-compliant systematic review flow diagrams. Significantly, users can also produce interactive flow diagrams for the first time, allowing readers of their reviews to smoothly and swiftly explore and navigate to further details of the methods and results of a review. We believe this tool will increase use of PRISMA flow diagrams, improve the compliance and quality of flow diagrams, and facilitate strong science communication of the methods and results of systematic reviews by making use of interactivity. We encourage the systematic review community to make use of the tool, and provide feedback to streamline and improve their usability and efficiency.

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.

Systematic review and meta-analyses: What has the application of Mendelian randomization told us about the causal effect of adiposity on health outcomes?

Mendelian randomization (MR) is increasingly used for generating estimates of the causal impact of exposures on outcomes. Evidence suggests a causal role of excess adipose tissue (adiposity) on many health outcomes. However, this body of work has not been systematically appraised. We systematically reviewed and meta-analysed results from MR studies investigating the association between adiposity and health outcomes prior to the SARS-CoV-2/COVID-19 pandemic (PROSPERO: CRD42018096684). We searched Medline, EMBASE, and bioRxiv up to February 2019 and obtained data on 2,214 MR analyses from 173 included articles. 29 meta-analyses were conducted using data from 34 articles (including 66 MR analyses) and results not able to be meta-analysed were narratively synthesised. Body mass index (BMI) was the predominant exposure used and was primarily associated with an increase in investigated outcomes; the largest effect in the meta-analyses was observed for the association between BMI and polycystic ovary syndrome (estimates reflect odds ratios (OR) per standard deviation change in each adiposity measure): OR = 2.55; 95% confidence interval (CI) = 1.22-5.33. Only colorectal cancer was investigated with two exposures in the meta-analysis: BMI (OR = 1.18; 95% CI = 1.01-1.37) and waist-hip ratio (WHR; OR = 1.48; 95% CI = 1.08-2.03). Broadly, results were consistent across the meta-analyses and narrative synthesis. Consistent with many observational studies, this work highlights the impact of adiposity across a broad spectrum of health outcomes, enabling targeted follow-up analyses. However, missing and incomplete data mean results should be interpreted with caution.

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.

A descriptive analysis of the data availability statements accompanying medRxiv preprints and a comparison with their published counterparts.

OBJECTIVE: To determine whether medRxiv data availability statements describe open or closed data-that is, whether the data used in the study is openly available without restriction-and to examine if this changes on publication based on journal data-sharing policy. Additionally, to examine whether data availability statements are sufficient to capture code availability declarations. DESIGN: Observational study, following a pre-registered protocol, of preprints posted on the medRxiv repository between 25th June 2019 and 1st May 2020 and their published counterparts. MAIN OUTCOME MEASURES: Distribution of preprinted data availability statements across nine categories, determined by a prespecified classification system. Change in the percentage of data availability statements describing open data between the preprinted and published versions of the same record, stratified by journal sharing policy. Number of code availability declarations reported in the full-text preprint which were not captured in the corresponding data availability statement. RESULTS: 3938 medRxiv preprints with an applicable data availability statement were included in our sample, of which 911 (23.1%) were categorized as describing open data. 379 (9.6%) preprints were subsequently published, and of these published articles, only 155 contained an applicable data availability statement. Similar to the preprint stage, a minority (59 (38.1%)) of these published data availability statements described open data. Of the 151 records eligible for the comparison between preprinted and published stages, 57 (37.7%) were published in journals which mandated open data sharing. Data availability statements more frequently described open data on publication when the journal mandated data sharing (open at preprint: 33.3%, open at publication: 61.4%) compared to when the journal did not mandate data sharing (open at preprint: 20.2%, open at publication: 22.3%). CONCLUSION: Requiring that authors submit a data availability statement is a good first step, but is insufficient to ensure data availability. Strict editorial policies that mandate data sharing (where appropriate) as a condition of publication appear to be effective in making research data available. We would strongly encourage all journal editors to examine whether their data availability policies are sufficiently stringent and consistently enforced.

Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments.

Despite a major increase in the range and number of software offerings now available to help researchers produce evidence syntheses, there is currently no generic tool for producing figures to display and explore the risk-of-bias assessments that routinely take place as part of systematic review. However, tools such as the R programming environment and Shiny (an R package for building interactive web apps) have made it straightforward to produce new tools to help in producing evidence syntheses. We present a new tool, robvis (Risk-Of-Bias VISualization), available as an R package and web app, which facilitates rapid production of publication-quality risk-of-bias assessment figures. We present a timeline of the tool's development and its key functionality.

Systematic review of the impact of the COVID-19 pandemic on suicidal behaviour amongst health and social care workers across the world.

BACKGROUND: The COVID-19 pandemic has had an impact on the mental health of healthcare and social care workers, and its potential effect on suicidal thoughts and behaviour is of particular concern. METHODS: This systematic review identified and appraised the published literature that has reported on the impact of COVID-19 on suicidal thoughts and behaviour and self-harm amongst healthcare and social care workers worldwide up to May 31, 2021. RESULTS: Out of 37 potentially relevant papers identified, ten met our eligibility criteria. Our review has highlighted that the impact of COVID-19 has varied as a function of setting, working relationships, occupational roles, and psychiatric comorbidities. LIMITATIONS: There have been no completed cohort studies comparing pre- and post-pandemic suicidal thoughts and behaviours. It is possible some papers may have been missed in the search. CONCLUSIONS: The current quality of evidence pertaining to suicidal behaviour in healthcare workers is poor, and evidence is entirely absent for those working in social care. The clinical relevance of this work is to bring attention to what evidence exists, and to encourage, in practice, proactive approaches to interventions for improving healthcare and social care worker mental health.

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

The PRISMA 2020 statement: An updated guideline for reporting systematic reviews.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. / Declaración PRISMA 2020: una guía actualizada para la publicación de revisiones sistemáticas.

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews. Full English text available from:www.revespcardiol.org/en.

Data extraction methods for systematic review (semi)automation: A living review protocol.

Background: Researchers in evidence-based medicine cannot keep up with the amounts of both old and newly published primary research articles. Conducting and updating of systematic reviews is time-consuming. In practice, data extraction is one of the most complex tasks in this process. Exponential improvements in computational processing speed and data storage are fostering the development of data extraction models and algorithms. This, in combination with quicker pathways to publication, led to a large landscape of tools and methods for data extraction tasks. Objective: To review published methods and tools for data extraction to (semi)automate the systematic reviewing process. Methods: We propose to conduct a living review. With this methodology we aim to do monthly search updates, as well as bi-annual review updates if new evidence permits it. In a cross-sectional analysis we will extract methodological characteristics and assess the quality of reporting in our included papers. Conclusions: We aim to increase transparency in the reporting and assessment of machine learning technologies to the benefit of data scientists, systematic reviewers and funders of health research. This living review will help to reduce duplicate efforts by data scientists who develop data extraction methods. It will also serve to inform systematic reviewers about possibilities to support their data extraction.

Treatment interventions to maintain abstinence from alcohol in primary care: systematic review and network meta-analysis.

OBJECTIVE: To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization's International Clinical Trials Registry Platform. STUDY SELECTION: Randomised controlled trials comparing two or more interventions that could be used in primary care. The population was patients with alcohol dependency diagnosed by standardised clinical tools and who became detoxified within four weeks. DATA EXTRACTION: Outcomes of interest were continuous abstinence from alcohol (effectiveness) and all cause dropouts (as a proxy for acceptability) at least 12 weeks after start of intervention. RESULTS: 64 trials (43 interventions) were included. The median probability of abstinence across placebo arms was 25%. Compared with placebo, the only intervention associated with increased probability of abstinence and moderate certainty evidence was acamprosate (odds ratio 1.86, 95% confidence interval 1.49 to 2.33, corresponding to an absolute probability of 38%). Of the 62 included trials that reported all cause dropouts, interventions associated with a reduced number of dropouts compared with placebo (probability 50%) and moderate certainty of evidence were acamprosate (0.73, 0.62 to 0.86; 42%), naltrexone (0.70, 0.50 to 0.98; 41%), and acamprosate-naltrexone (0.30, 0.13 to 0.67; 17%). Acamprosate was the only intervention associated with moderate confidence in the evidence of effectiveness and acceptability up to 12 months. It is uncertain whether other interventions can help maintain abstinence and reduce dropouts because of low confidence in the evidence. CONCLUSIONS: Evidence is lacking for benefit from interventions that could be implemented in primary care settings for alcohol abstinence, other than for acamprosate. More evidence from high quality randomised controlled trials is needed, as are strategies using combined interventions (combinations of drug interventions or drug and psychosocial interventions) to improve treatment of alcohol dependency in primary care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049779.

Synthesising quantitative evidence in systematic reviews of complex health interventions.

Public health and health service interventions are typically complex: they are multifaceted, with impacts at multiple levels and on multiple stakeholders. Systematic reviews evaluating the effects of complex health interventions can be challenging to conduct. This paper is part of a special series of papers considering these challenges particularly in the context of WHO guideline development. We outline established and innovative methods for synthesising quantitative evidence within a systematic review of a complex intervention, including considerations of the complexity of the system into which the intervention is introduced. We describe methods in three broad areas: non-quantitative approaches, including tabulation, narrative and graphical approaches; standard meta-analysis methods, including meta-regression to investigate study-level moderators of effect; and advanced synthesis methods, in which models allow exploration of intervention components, investigation of both moderators and mediators, examination of mechanisms, and exploration of complexities of the system. We offer guidance on the choice of approach that might be taken by people collating evidence in support of guideline development, and emphasise that the appropriate methods will depend on the purpose of the synthesis, the similarity of the studies included in the review, the level of detail available from the studies, the nature of the results reported in the studies, the expertise of the synthesis team and the resources available.