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Abstract Background Leptospirosis is an underdiagnosed infectious disease with non-specific clinical presentation that requires laboratory confirmation for diagnosis. The serologic reference standard remains the microscopic agglutination test (MAT) on paired serum samples. However, reported estimates of MAT’s sensitivity vary. We evaluated the accuracy of four index tests, MAT on paired samples as well as alternative standards for leptospirosis diagnosis: MAT on single acute-phase samples, polymerase chain reaction (PCR) with the target gene Lfb1, and ELISA IgM with Leptospira fainei serovar Hurstbridge as an antigen. Methods We performed a systematic review of studies reporting results of leptospirosis diagnostic tests. We searched eight electronic databases and selected studies that tested human blood samples and compared index tests with blood culture and/or PCR and/or MAT (comparator tests). For MAT selection criteria we defined a threshold for single acute-phase samples according to a national classification of leptospirosis endemicity. We used a Bayesian random-effect meta-analysis to estimate the sensitivity and specificity of MAT in single acute-phase and paired samples separately, and assessed risk of bias using the Quality Assessment of Studies of Diagnostic Accuracy Approach- 2 (QUADAS-2) tool. Results For the MAT accuracy evaluation, 15 studies were included, 11 with single acute-phase serum, and 12 with paired sera. Two included studies used PCR targeting the Lfb1 gene, and one included study used IgM ELISA with Leptospira fainei serovar Hurstbridge as antigen. For MAT in single acute-phase samples, the pooled sensitivity and specificity were 14% (95% credible interval [CrI] 3–38%) and 86% (95% CrI 59–96%), respectively, and the predicted sensitivity and specificity were 14% (95% CrI 0–90%) and 86% (95% CrI 9–100%). Among paired MAT samples, the pooled sensitivity and specificity were 68% (95% CrI 32–92%) and 75% (95% CrI 45–93%) respectively, and the predicted sensitivity and specificity were 69% (95% CrI 2–100%) and 75% (2–100%). Conclusions Based on our analysis, the accuracy of MAT in paired samples was not high, but it remains the reference standard until a more accurate diagnostic test is developed. Future studies that include larger numbers of participants with paired samples will improve the certainty of accuracy estimates.

Abstract Background Parasitological investigation of bone marrow, splenic or lymph node aspirations is the gold standard for the diagnosis of visceral leishmaniasis (VL). However, this invasive test requires skilled clinical and laboratory staff and adequate facilities, and sensitivity varies depending on the tissue used. The direct agglutination test (DAT) is a serological test that does not need specialised staff, with just minimal training required. While previous meta-analysis has shown DAT to have high sensitivity and specificity when using parasitology as the reference test for diagnosis, meta-analysis of DAT compared to other diagnostic techniques, such as PCR and ELISA, that are increasingly used in clinical and research settings, has not been done. Methods We conducted a systematic review to determine the diagnostic performance of DAT compared to all available tests for the laboratory diagnosis of human VL. We searched electronic databases including Medline, Embase, Global Health, Scopus, WoS Science Citation Index, Wiley Cochrane Central Register of Controlled Trials, Africa-Wide Information, LILACS and WHO Global Index. Three independent reviewers screened reports and extracted data from eligible studies. A meta-analysis estimated the diagnostic sensitivity and specificity of DAT. Results Of 987 titles screened, 358 were selected for full data extraction and 78 were included in the analysis, reporting on 32,822 participants from 19 countries. Studies included were conducted between 1987–2020. Meta-analysis of studies using serum and DAT compared to any other test showed pooled sensitivity of 95% (95%CrI 90–98%) and pooled specificity of 95% (95%CrI 88–98%). Results were similar for freeze-dried DAT and liquid DAT when analysed separately. Sensitivity was lower for HIV-positive patients (90%, CrI 59–98%) and specificity was lower for symptomatic patients (70%, CrI 43–89%). When comparing different geographical regions, the lowest median sensitivity (89%, CrI 67–97%) was in Western Asia (five studies). Conclusions This systematic review and meta-analysis demonstrates high estimated pooled sensitivity and specificity of DAT for diagnosis of VL, although sensitivity and specificity were lower for different patient groups and geographical locations. This review highlights the lack of standardisation of DAT methods and preparations, and the lack of data from some important geographical locations. Future well-reported studies could provide better evidence to inform test implementation for different patient populations and use cases. PROSPERO registration CRD42021240830

Background Whole-school interventions modify the school environment to promote health. A subset of these interventions promotes student commitment to school to prevent substance (tobacco, alcohol, other drugs) use and/or violence. A previous review identified the theory of human functioning and school organisation as a comprehensive theory of such interventions, and found evidence that these interventions reduce substance use and/or violence. Objectives The objectives were to search for, appraise and synthesise evidence to address the following questions: (1) What whole-school interventions promoting student commitment to school to prevent substance use and/or violence have been evaluated, what intervention subtypes are apparent and how closely do these align with the theory of human functioning and school organisation? (2) What factors relating to setting, population and intervention affect implementation? (3) What are the effects on student substance use, violence and educational attainment? (4) What is the cost-effectiveness of such interventions? (5) Are intervention effects mediated by student commitment to school or moderated by setting or population? Data sources A total of 56 information sources were searched (in January 2020), then an updated search of 48 of these was carried out (in May 2021). Reference lists were also searched and experts were contacted. Review methods Eligible studies were process/outcome evaluations of whole-school interventions to reduce student violence or substance use among students aged 5–18 years attending schools, via actions aligning with the theory of human functioning and school organisation: modifying teaching to increase engagement, enhancing student–staff relationships, revising school policies, encouraging volunteering or increasing parental involvement. Data extraction and quality assessments used existing tools. Theory and process reports were synthesised qualitatively. Outcome and economic data were synthesised narratively; outcome data were meta-analysed. Results Searches retrieved 63 eligible reports on 27 studies of 22 interventions. We identified four intervention subtypes focused on student participation in school-wide decisions, improving staff–student relationships, increasing engagement in learning and involving parents. The theories of change of most intervention subtypes aligned closely with the theory of human functioning and school organisation, and informed refinement of an intervention theory of change. Theories of change for interventions increasing learning engagement did not align with this theory, aiming instead to increase school commitment primarily via social skills curricula. Factors influencing the implementation included whether or not interventions were tailorable, workable and well explained. Interventions with action groups comprising staff/students, etc. and providing local data were well implemented. Implementation was also affected by whether or not schools accepted the need for change and staff had the resources for delivery. Meta-analyses suggest small, but significant, intervention effects in preventing violence victimisation and perpetration, and substance use. There was sparse and inconsistent evidence of moderation and some evidence of mediation by student commitment to school. Two economic evaluations suggested that there is the potential for the interventions to be cost-effective. Limitations The quality of the studies was variable and the economic synthesis was limited to two studies. Conclusions Whole-school interventions aiming to promote student commitment to school share similar theories of change and factors affecting implementation. They have the potential to contribute to preventing violence and substance use among young people. Future trials should aim to optimise intervention effectiveness by better theorisation, and assess implementation and effect moderators and mediators. Study registration This study is registered as PROSPERO CRD42019154334. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/151/05) and is published in full in Public Health Research; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information. Plain language summary Whole-school health interventions aim to modify how schools are run, to promote students’ health. Some aim to promote student commitment to school to prevent the important interlinked outcomes of substance (tobacco, alcohol, other drugs) use and violence. We searched for all evaluations of such interventions. We summarised what this research said about the sorts of interventions used, how they are meant to work, what factors affect delivery, whether or not they reduce violence and substance use and whether or not they are worth the money. We found 63 reports on 27 studies of 22 interventions. We identified four subtypes of interventions. These aimed to involve students in school decisions, improve staff–student relationships, increase engagement in learning or involve parents. Most of these interventions were intended to work by making sure schools focused on student needs, or by improving relationships between staff and students, between different areas of learning or between schools and communities. This aimed to make students feel committed to school and therefore avoid violence or substance use. A few aimed to work mostly by teaching students how to avoid violence and substance use. We found that interventions were well implemented if they were tailored for each school and had good materials and support. Interventions were well delivered if they were led by action groups (comprising staff, students, etc.) or provided schools with information on students’ needs. Implementation was affected by whether or not schools accepted the need for change and whether or not staff had the necessary time and money to do the work. These interventions appear to have small, but significant, intervention impacts in preventing violence and substance use among young people. There was not consistent evidence of different effects for different students. A small number of studies suggest that such interventions might show economic benefit, but this would need further research. Future research should focus on interventions that are refined to make sure that they can be well delivered. Scientific summary Background and rationale Substance use and violence are important interconnected outcomes often associated with disengagement from school. Whole-school interventions aiming to modify the school environment to promote student commitment to school might be an effective way to prevent these outcomes. This review synthesised evidence on such interventions. According to a previous review, the theory of human functioning and school organisation provides the most comprehensive theory of how schools can influence student commitment to school and health behaviours. This proposes that promoting student commitment to school can decrease involvement in risk behaviours by promoting student practical reasoning and positive peer affiliations. Schools can promote commitment by reframing provision on student needs and eroding boundaries between staff and students, between different areas of learning and between schools and local communities. We used this theory to define our initial theory of change and inclusion criteria, and as a starting point for categorising interventions and synthesising theories of change. Aim and review questions The aim was to search systematically for, appraise and synthesise evidence to address the following questions: What whole-school interventions promoting student commitment to school to prevent student substance use and/or violence have been evaluated, what subtypes are apparent and how closely do these align with the theory of human functioning and school organisation? What factors influence implementation of such interventions? Overall and by intervention subtype, what are the effects of such interventions on student substance use, violence and educational attainment? What is the cost-effectiveness of such interventions? Are the effects of such interventions on student substance use and/or violence mediated by student commitment to school, or moderated by setting or population? Methods Inclusion criteria Eligible studies were process or experimental/quasi-experimental outcome evaluations of whole-school interventions aiming to reduce violence or substance (tobacco, alcohol, other drug) use among students aged 5–18 years in schools, by modifying teaching to increase engagement in learning, enhancing student–staff relationships, revising school policies, encouraging student volunteering or involving parents in school. Searching information sources The search strategy included terms covering population, intervention and evaluation design. We initially searched 21 databases, 3 trial registries and 32 websites (16–27 January 2020), and updated the search across 14 databases, 2 trial registries and 32 websites (11–25 May 2021). We searched reference lists and contacted subject experts. Information management and study selection Citations identified by our searches were de-duplicated before being uploaded to EPPI-Reviewer 4.0 software (Evidence for Policy and Practice Information and Co-ordinating Centre, University of London, London, UK). Two reviewers double-screened batches of 50 references. Disagreements were resolved by discussion. After reaching an agreement rate of ≥ 90% on these batches, each subsequent reference was single-screened on title/abstract. If references were considered likely to be eligible based on the title/abstract, the full report was reviewed using a similar process. Data extraction Two reviewers independently extracted data using existing tools. Disagreements were resolved by discussion. For intervention descriptions, date were extracted on domains included in a standard framework. For theory reports, we extracted data on constructs, mechanisms and contextual contingencies affecting these. For empirical studies, we extracted data on basic study details, methods, interventions and findings. Assessments of quality and risk of bias The quality of each report was assessed independently by two reviewers using existing tools. The reviewers met to compare assessments and resolve any differences through discussion. Theory reports were assessed on the basis of whether or not this described the path from intervention to outcomes, clarity of constructs, clarity of inter-relationships between constructs, whether or not the underlying mechanisms were explained, and whether or not the theory considered how mechanisms and outcomes might vary by context. Process evaluations were assessed on the basis of rigour of sampling, data collection and data analysis; the extent to which findings were grounded in data; whether or not the study privileged the perspectives of students; and breadth/depth of findings. Outcome studies were assessed for risk of bias on the basis of sequence generation, allocation concealment, blinding of participants or personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting and other sources of bias. Economic evaluations were assessed using an adapted version of an existing tool. Data analysis To create a categorisation of intervention subtypes, we drew on descriptions of interventions and theories of change, using these to refine an initial categorisation informed by the theory of human functioning and school organisation. Reviewers grouped interventions into discrete categories and subcategories. To synthesise theories of change, we used best-fit framework synthesis. We defined a priori themes based on the theory of human functioning and school organisation and then coded data from included studies against these. When concepts from the included studies could not be coded with these, we coded inductively. This coding was then used to refine the existing theory of change by intervention subtype. We synthesised qualitative and quantitative elements of process evaluation reports using thematic synthesis methods. We conducted a narrative synthesis of outcome evaluations ordered by outcome then, within this, by intervention subtype, follow-up time and study design. Outcomes were categorised into violence, use of tobacco, alcohol and other drugs, and academic attainment. We produced forest plots for different outcomes and follow-up times. Plots included point estimates and standard errors for each study, expressed as standardised mean differences (Cohen’s d) to ensure comparability across reports. When data allowed, we calculated pooled effect sizes within each pairwise comparison, accounting for the extent of heterogeneity among the studies, estimating separate models for each outcome. We regarded follow-up times of up to 1 year and > 1 year post baseline as different outcomes, pooling first by follow-up times and, when appropriate, overall across follow-up times. We used the Grading of Recommendations Assessment, Development and Evaluation to present the quality of evidence. For synthesising economic evaluations, measures of costs, indirect resource use and cost-effectiveness were summarised in a table and adjusted for currency and inflation to the then-current UK context. These data were used to inform a narrative synthesis of economic evidence. Stakeholder consultation We consulted policy and practice stakeholders once during the review. In October 2021, stakeholders reviewed slides summarising the main findings. We asked stakeholders to advise on interpretation, implications and knowledge exchange. Ethics approval The research involved no human participants and drew solely on evidence in the public realm, so ethics approval was not required. Results Included studies The original searches retrieved 62,742 unique references and 56 eligible reports. The updated search retrieved 9709 unique references and 9 eligible reports. In total, 63 reports on 27 studies of 22 interventions were included: 63 on theories of change, 16 on process evaluations, 48 on outcome evaluations and 3 on economic evaluations. Of the included interventions, 10 addressed violence (with 2 of these also addressing educational attainment), 3 addressed substance use (with 1 of these also addressing educational attainment) and 9 addressed violence and substance use (with 1 of these also addressing educational attainment). What interventions have been evaluated and what intervention subtypes are apparent? We identified four intervention subtypes, focused on the following: developing student participation in school-wide decisions, improving staff–student relationships, increasing student engagement in learning and increasing parental involvement in school. How closely do intervention theories of change align with the theory of human functioning and school organisation? We synthesised interventions developing student participation, enhancing staff–student relationships and involving parents together because of commonalities in theories of change. Despite only one intervention being explicitly informed by the theory of human functioning and school organisation, theories of change aligned closely with this theory, with recurrent themes that reciprocally translated with this theory and each other. Inductive coding suggested a number of refinements to the starting theory, for example relating to how school organisation, learning, discipline and school–community links were reframed. Interventions aimed not only to reduce risk behaviours but to promote positive overall development via increasing commitment to school. The theories of change for interventions developing student engagement in learning aligned much less with the theory of human functioning and school organisation. These interventions were theorised to increase students’ school engagement primarily through social skills curricula, with whole-school elements secondary. What factors relating to setting, population and intervention influence the implementation of these interventions? Evaluations suggested that school staff were more likely to understand what was required to implement an intervention when provided with good materials and support. Whether or not staff would commit to delivery was influenced by whether interventions could be integrated with existing practices, locally tailored or built on existing work. Interventions providing local data helped build buy-in. Staff were more likely to commit when external providers were credible and experienced. Students were more likely to commit if an intervention offered opportunities for active roles or expressing their views. School leaders were more likely to commit to an intervention that addressed an issue they were already interested in tackling and when there was already a recognition of the need for change. To ensure those in schools worked together to deliver interventions, interventions needed to be locally workable, fitting with timetables and providing clear guidance. Interventions that included ‘action groups’ (consisting of staff, students, etc.) helped build collective action. Interventions with synergistic components were implemented more successfully. Whether or not staff could come together to deliver interventions also depended on having the time, budgets, authority and connections to support this. Action groups enabled members to reflexively monitor implementation and assess what else was needed. This could give participants the permission and resources to try different things, persisting with what worked. What are the effects on student substance use, violence and educational attainment of whole-school interventions aiming to promote student commitment? Overall, meta-analyses suggested that interventions led to a small, but statistically significant, reduction in violence perpetration at up to 1 year post baseline [odds ratio (OR) 0.85, 95% confidence interval (CI) 0.76 to 0.96] and > 1 year post baseline (OR 0.79, 95% CI 0.65 to 0.98). Considering intervention subtypes, meta-analyses suggested possible, but inconsistent, impacts on violence perpetration of interventions promoting student participation in school policy decisions and student relationships with teachers at up to 1 year post baseline and at > 1 year post baseline. Meta-analyses suggested that interventions promoting student engagement in learning and parental involvement were unlikely to affect violence perpetration up to 1 year post baseline and at > 1 year post baseline. Overall, meta-analyses suggested that interventions led to small, but statistically significant, reductions in violence victimisation at up to 1 year post baseline (OR 0.84, 95% CI 0.72 to 0.98) and > 1 year post baseline (OR 0.85, 95% CI 0.73 to 0.99). Considering subtypes, evidence suggested possible but inconsistent impacts of interventions promoting student participation in decisions and student relationships with teachers on violence victimisation at up to 1 year post baseline and > 1 year post baseline. Studies suggested that interventions promoting parental involvement were unlikely to affect violence victimisation up to 1 year post baseline and > 1 year post baseline. Studies of intervention effects on observed violence were not meta-analysed owing to heterogeneity of study designs, but evidence suggested that interventions promoting student participation in decisions significantly reduced observed violence at > 1 year post baseline. Interventions promoting parental involvement significantly reduced observed violence at up to 1 year post baseline and at > 1 year post baseline. Overall, meta-analyses suggested that interventions led to small, but statistically significant, reductions in substance use at up to 1 year post baseline (OR 0.83, 95% CI 0.70 to 0.97) and at > 1 year post baseline (OR 0.79, 95% CI 0.62 to 0.998). Meta-analyses of such interventions suggested small and statistically non-significant reductions in measures of specific outcomes (alcohol, smoking, illicit drugs, general substance use) at up to 1 year post baseline and at > 1 year post baseline. Considering subtypes, the evidence suggested possible, but inconsistent, impacts of interventions promoting student participation in decisions in reducing substance use at up to 1 year post baseline and at > 1 year post baseline, with similar findings for alcohol outcomes and illicit drug use outcomes separately. There was less evidence of impact on tobacco outcomes. An analysis of omnibus substance use outcomes suggested a larger, but still substantially heterogeneous and non-significant, effect. One trial reported on the effects of an intervention promoting student–teacher relationships: up to 1 year post baseline, there were no significant effects on alcohol or cannabis outcomes, and no significant effects on any reported lifetime smoking, but there was a significant effect on regular smoking; at > 1 year post baseline, there were no significant effects on alcohol use, tobacco smoking or cannabis use outcomes. Findings from two randomised trials suggested possible, but inconsistent, impacts of interventions promoting student engagement in learning in reducing substance use, but a non-significant impact on reducing alcohol use at up to 1 year post baseline. Evidence suggested possible, but inconsistent, impacts of interventions promoting student engagement in learning in reducing substance use at > 1 year post baseline, and a non-significant impact of such interventions on reducing alcohol use at > 1 year post baseline. Our syntheses of effects on academic attainment are exploratory. All such studies were of interventions promoting student participation in decisions and reporting attainment at > 1 year post baseline. Findings did not suggest clear evidence of impact on academic attainment. Are the effects of whole-school interventions on student substance use and violence mediated by student commitment to school, or moderated by setting or population? Evidence was sparse and inconsistent across trials for moderation of effects on all outcomes by population and school characteristics. Three studies examined mediation of intervention effects by student commitment to school. All focused on interventions promoting student participation in decisions. There was some evidence that student commitment to school mediated intervention effects on violence and substance use outcomes. What is the cost-effectiveness of such interventions, overall and by intervention subtype? Economic evidence was sparse but suggested that two interventions aiming to involve students in decision-making were cost-effective. Conclusions Whole-school interventions aiming to promote student commitment to school to prevent violence and substance use can be categorised into those promoting (1) student participation in decision-making, (2) staff–student relationships, (3) engagement in learning and (4) parental involvement in school. Despite not generally being explicitly informed by the theory of human functioning and school organisation, most interventions are underpinned by theories of change closely aligning with this. Factors influencing implementation include whether or not interventions were tailorable, workable, well explained and had synergistic components. Implementation was also affected by whether or not schools accepted the need for school transformation and whether or not staff had the necessary time, budgets, authority and connections for delivery. Interventions were effective in preventing violence victimisation and perpetration and substance use, although effects are small. Such interventions may contribute to broader efforts to reduce violence and substance use among young people but are unlikely to achieve large population impacts alone. Future trials should aim to optimise intervention effectiveness by better theorisation, and assess implementation and effect moderators and mediators. Study registration This study is registered as PROSPERO CRD42019154334. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/151/05) and is published in full in Public Health Research; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information.

Abstract Background The incidence of cryptococcosis amongst HIV-negative persons is increasing. Whilst the excellent performance of the CrAg testing in people living with HIV is well described, the diagnostic performance of the CrAg LFA has not been systematically evaluated in HIV-negative cohorts on serum or cerebrospinal fluid. Methods We performed a systematic review to characterise the diagnostic performance of IMMY CrAg® LFA in HIV-negative populations on serum and cerebrospinal fluid. A systematic electronic search was performed using Medline, Embase, Global Health, CENTRAL, WoS Science Citation Index, SCOPUS, Africa-Wide Information, LILACS and WHO Global Health Library. Studies were screened and data extracted from eligible studies by two independent reviewers. A fixed effect meta-analysis was used to estimate the diagnostic sensitivity and specificity. Results Of 447 records assessed for eligibility, nine studies met our inclusion criteria, including 528 participants overall. Amongst eight studies that evaluated the diagnostic performance of the IMMY CrAg® LFA on serum, the pooled median sensitivity was 96% (95% Credible Interval (CrI) 68–100%) with a pooled specificity estimate of 96% (95%CrI 84–100%). Amongst six studies which evaluated the diagnostic performance of IMMY CrAg® LFA on CSF, the pooled median sensitivity was 99% (95%CrI 95–100%) with a pooled specificity median of 99% (95%CrI 95–100%). Conclusions This review demonstrates a high pooled sensitivity and specificity for the IMMY CrAg® LFA in HIV-negative populations, in keeping with findings in HIV-positive individuals. The review was limited by the small number of studies. Further studies using IMMY CrAg® LFA in HIV-negative populations would help to better determine the diagnostic value of this test.

Abstract Background Whole-school interventions go beyond classroom health education to modify the school environment to promote health. A sub-set aim to promote student commitment to school to reduce substance use and violence (outcomes associated with low commitment). It is unclear what factors influence implementation of such interventions. Methods We conducted a systematic review including synthesis of evidence from process evaluations examining what factors affect implementation. Meta-ethnographic synthesis was informed by May’s General Theory of Implementation. Results Sixteen reports, covering 13 studies and 10 interventions were included in our synthesis. In terms of May’s concept of ‘sense-making’, we found that school staff were more likely to understand what was required in implementing an intervention when provided with good-quality materials and support. Staff could sometimes wilfully or unintentionally misinterpret interventions. In terms of May’s concept of ‘cognitive participation’, whereby staff commit to implementation, we found that lack of intervention adaptability could in particular undermine implementation of whole-school elements. Interventions providing local data were reported as helping build staff commitment. School leaders were more likely to commit to an intervention addressing an issue they already intended to tackle. Collaborative planning groups were reported as useful in ensuring staff ‘collective action’ (May’s term for working together) to enact interventions. Collective action was also promoted by the presence of sufficient time, leadership and relationships. Implementation of whole-school interventions took time to build. Considering May’s concept of ‘reflexive monitoring’ (formal or informal review of progress), this was important in assessing and enhancing implementation. ‘Quick wins’ could help maintain collective impetus to implement further intervention activities. Conclusion We identified novel factors influencing implementation of whole-school elements such as: local adaptability of interventions; providing local data to build commitment; interventions addressing an issue already on school leaders’ agenda; collaborative planning groups; and ‘reflexive monitoring’ as an explicit intervention component.

Abstract Respiratory syncytial virus (RSV) and influenza viruses are important global causes of morbidity and mortality. We evaluated the diagnostic accuracy of the Luminex NxTAG respiratory pathogen panels (RPPs)™ (index) against other RPPs (comparator) for detection of RSV and influenza viruses. Studies comparing human clinical respiratory samples tested with the index and at least one comparator test were included. A random-effect latent class meta-analysis was performed to assess the specificity and sensitivity of the index test for RSV and influenza. Risk of bias was assessed using the QUADAS-2 tool and certainty of evidence using GRADE. Ten studies were included. For RSV, predicted sensitivity was 99% (95% credible interval [CrI] 96–100%) and specificity 100% (95% CrI 98–100%). For influenza A and B, predicted sensitivity was 97% (95% CrI 89–100) and 98% (95% CrI 88–100) respectively; specificity 100% (95% CrI 99–100) and 100% (95% CrI 99–100), respectively. Evidence was low certainty. Although index sensitivity and specificity were excellent, comparators’ performance varied. Further research with clear patient recruitment strategies could ascertain performance across different populations. Protocol Registration: Prospero CRD42021272062.

Background: Effective and rapid actions are required to achieve global goals for climate change mitigation, and there is an opportunity to ensure that the actions taken are also positive for human health. However, little is known about the relative magnitude of the health co-benefits that can be achieved from mitigation actions, so robust and comprehensive syntheses of the evidence on the nature and effects of relevant actions are required. This paper presents a protocol for an interdisciplinary and cross-sectoral umbrella review of systematic reviews, synthesising modelled and empirical evidence on such actions. Methods: Nine bibliographic databases will be searched, capturing literature across a wide range of disciplines and sectors. Unique records retrieved by the searches will be screened by two independent reviewers. The quality of all the included systematic reviews will be assessed using A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) 2 critical appraisal tool. Data will be extracted on methodological and thematic characteristics of the reviews, nature of the actions, and their effects on greenhouse gas emission reduction, health, and its determinants, as well as any other reported effects and interactions across different actions. Results: Narrative and quantitative synthesis methods will be used to create a typology of relevant actions, map pathways to their impacts on health, compare the magnitude of health and greenhouse gas (GHG) emission reduction impacts by selected characteristics of the actions and the nature of the evidence, as well as to identify gaps in evidence syntheses. Conclusion: This review will identify the most effective actions for global climate change mitigation and health based on the best available scientific evidence. This protocol has been registered in PROSPERO, Reg No.: CRD42021239292.

Abstract Background Sexual risk, substance use, and mental ill health constitute a syndemic of co-occurring, mutually reinforcing epidemics amongst men who have sex with men (MSM). Developed since 1995, e-health interventions offer accessible, anonymous support and can be effective in addressing these outcomes, suggesting the potential value of developing e-health interventions that address these simultaneously amongst MSM. We conducted a systematic review of e-health interventions addressing one or more of these outcomes amongst MSM and in this paper describe the theories of change underpinning relevant interventions, what these offer and how they might complement each other. Methods We identified eligible reports via expert requests, reference-checking and database and Google searches. Results were screened for reports published in 1995 or later; focused on MSM; reporting on e-health interventions providing ongoing support to prevent HIV/STIs, sexual risk behaviour, substance use, anxiety or depression; and describing intervention theories of change. Reviewers assessed report quality, extracted intervention and theory of change data, and developed a novel method of synthesis using diagrammatic representations of theories of change. Results Thirty-three reports on 22 intervention theories of change were included, largely of low/medium-quality. Inductively grouping these theories according to their core constructs, we identified three distinct groupings of theorised pathways. In the largest, the ‘cognitive/skills’ grouping, interventions provide information and activities which are theorised to influence behaviour via motivation/intention and self-efficacy/perceived control. In the ‘self-monitoring’ grouping, interventions are theorised to trigger reflection, self-reward/critique and self-regulation. In the ‘cognitive therapy’ grouping, the theory of change is rooted in cognitive therapy techniques, aiming to reframe negative emotions to improve mental health. Conclusions The synthesised theories of change provide a framework for developing e-health interventions that might holistically address syndemic health problems amongst MSM. Improving reporting on theories of change in primary studies of e-health interventions would enable a better understanding of how they are intended to work and the evidence supporting this. The novel diagrammatic method of theory of change synthesis used here could be used for future reviews where interventions are driven by existing well-defined behaviour and behaviour change theories. Systematic review registration PROSPERO CRD42018110317

BackgroundMen who have sex with men experience disproportionately high levels of HIV and other sexually transmitted infections (STIs), sexual risk behavior, substance use, and mental ill-health. These experiences are interrelated, and these interrelations are potentiated by structural conditions of discrimination, stigma, and unequal access to appropriate health services, and they magnify each other and have intersecting causal pathways, worsening both risk for each condition and risk for the negative sequelae of each condition. eHealth interventions could address these issues simultaneously and thus have wide-ranging and greater effects than would be for any 1 outcome alone. ObjectiveWe systematically reviewed the evidence for the effectiveness of eHealth interventions in addressing these outcomes separately or together. MethodsWe searched 19 databases for randomized trials of interactive or noninteractive eHealth interventions delivered via mobile phone apps, internet, or other electronic media to populations consisting entirely or principally of men who have sex with men to prevent HIV, STIs, sexual risk behavior, alcohol and drug use, or common mental illnesses. We extracted data and appraised each study, estimated meta-analyses where possible by using random effects and robust variance estimation, and assessed the certainty of our findings (closeness of the estimated effect to the true effect) by using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). ResultsWe included 14 trials, of which 13 included active versus control comparisons; none reported mental health outcomes, and all drew from 12 months or less of follow-up postintervention. Findings for STIs drew on low numbers of studies and did not suggest consistent short-term (

Background: Human immunodeficiency virus/sexually transmitted infections, sexual risk, substance (alcohol and other legal and illegal drugs) use and mental ill health constitute a ‘syndemic’ of mutually reinforcing epidemics among men who have sex with men. Electronic health (e-health) interventions addressing these epidemics among men who have sex with men might have multiplicative effects. To our knowledge, no systematic review has examined the effectiveness of such interventions on these epidemics among men who have sex with men. Objective: The objective was to synthesise evidence addressing the following: (1) What approaches and theories of change do existing e-health interventions employ to prevent human immunodeficiency virus/sexually transmitted infections, sexual risk, alcohol/drug use or mental ill health among men who have sex with men? (2) What factors influence implementation? (3) What are the effects of such interventions on the aforementioned epidemics? (4) Are such interventions cost-effective? Data sources: A total of 24 information sources were searched initially (October–November 2018) [the following sources were searched: ProQuest Applied Social Sciences Index and Abstracts; Campbell Library; EBSCO Cumulative Index to Nursing and Allied Health Literature Plus, Wiley Online Library The Cochrane Library; Centre for Reviews and Dissemination databases (the Database of Abstracts of Reviews of Effects and the NHS Economic Evaluation Database); the Health Technology Assessment database; Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) database of health promotion research (Bibliomap); ProQuest Dissertations & Theses Global; OvidSP EconLit; OvidSP EMBASE; OvidSP Global Health; OvidSP Health Management Information Consortium; ProQuest International Bibliography of the Social Sciences; Ovid MEDLINE ALL; OvidSP PsycINFO; Web of Science Science Citation Index Expanded; Elsevier Scopus; OvidSP Social Policy & Practice; Web of Science Social Sciences Citation Index Expanded; ProQuest Sociological Abstracts; ClinicalTrials.gov; World Health Organization International Clinical Trials Registry Platform; EPPI-Centre Trials Register of Promoting Health Interventions; and the OpenGrey database], and an updated search of 19 of these was conducted in April 2020. Reference lists of included reports were searched and experts were contacted. Review methods: Eligible reports presented theories of change and/or process, outcome and/or economic evaluations of e-health interventions offering ongoing support to men who have sex with men to prevent human immunodeficiency virus/sexually transmitted infections, sexual risk behaviour, alcohol/drug use and/or common mental illnesses. References were screened by title/abstract, then by full text. Data extraction and quality assessments used existing tools. Theory and process reports were synthesised using qualitative methods. Outcome and economic data were synthesised narratively; outcome data were meta-analysed. Results: Original searches retrieved 27 eligible reports. Updated searches retrieved 10 eligible reports. Thirty-seven reports on 28 studies of 23 interventions were included: 33 on theories of change, 12 on process evaluations, 16 on outcome evaluations and one on an economic evaluation. Research question 1: five intervention types were identified – ‘online modular’, ‘computer games’ and ‘non-interactive’ time-limited/modular interventions, and open-ended interventions with ‘content organised by assessment’ and ‘general content’. Three broad types of intervention theories of change were identified, focusing on ‘cognitive/skills’, ‘self-monitoring’ and ‘cognitive therapy’. Research question 2: individual tailoring based on participant characteristics was particularly acceptable, and participants valued intervention content reflecting their experiences. Research question 3: little evidence was available of effects on human immunodeficiency virus or sexually transmitted infections. The analysis did not suggest that interventions were effective in reducing instances of human immunodeficiency virus or sexually transmitted infections. The overall meta-analysis for sexually transmitted infections reported a small non-significant increase in sexually transmitted infections in the intervention group, compared with the control group. Meta-analyses found a significant impact on sexual risk behaviour. The findings for drug use could not be meta-analysed because of study heterogeneity. Studies addressing this outcome did not present consistent evidence of effectiveness. Trials did not report effects on alcohol use or mental health. Research question 4: evidence on cost-effectiveness was limited. Limitations: The quality of the eligible reports was variable and the economic synthesis was limited to one eligible study. Conclusions: There is commonality in intervention theories of change and factors affecting receipt of e-health interventions. Evidence on effectiveness is limited. Future work: Future trials should assess the impact of interventions on multiple syndemic factors, among them sexual risk, substance use and mental health; incorporate sufficient follow-up and sample sizes to detect the impact on human immunodeficiency virus/sexually transmitted infections; and incorporate rigorous process and economic evaluations. Study registration: This study is registered as PROSPERO CRD42018110317. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 4. See the NIHR Journals Library website for further project information.

Abstract Objectives This protocol outlines a systematic review methodology, aiming to assess the recent evidence-base for the impact of testing strategies and approaches on access to testing, testing coverage, and linkage to care for populations at risk for specific curable sexually transmitted infections (STIs) (chlamydia, gonorrhoea, syphilis, trichomoniasis, and Mycoplasma genitalium infections). Data sources These include MEDLINE, Embase, PsycINFO, Global Health, Cochrane Database, Epistemonikos, CINAHL Plus, and Web of Science Core Collection. Review methods Papers reporting primary data from 1 January 2012 onwards will be included. Titles, abstracts, and full texts will be reviewed for inclusion, and data will be extracted using a pre-specified and piloted data extraction form, by two independent reviewers. Experts in the field will be contacted and interviewed for further information about ongoing or unpublished studies. A narrative synthesis of the findings will be conducted. Discussion Outcomes of this study will inform policy makers, national and international programme coordinators, public health and clinical experts, and civil society organisations involved in STI prevention and control in EU/EEA countries and elsewhere. The review will provide a direction for future researchers and programmers seeking to improve STI testing services among key populations at high risk for STIs. Systematic review registration In accordance with guidelines outlined in the PRISMA-P methodology, this protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 30 January 2019: CRD42019118261 .

Objectives: Genital Ulcer Disease (GUD) carries a significant disease burden globally. With limited access to diagnostics, the 2001 World Health Organization (WHO) sexually transmitted illnesses (STI) guidelines proposed a syndromic management algorithm that required a clinical decision to determine the management of GUD. We assessed the diagnostic accuracy of this algorithm.Methods: We conducted a systematic review (Prospero: CRD42020153294) using eight databases for publications between 1995 and January 2021 that reported primary data on the diagnostic accuracy of clinical diagnosis to identify aetiological agents of GUD. Titles and abstracts were independently assessed for eligibility, and data were extracted from full texts for sensitivity/specificity. A hierarchical logistic regression model was used to derive pooled sensitivity and specificity. We used GRADE to evaluate the certainty of evidence.Results: Of 24,857 articles, 151 full texts were examined and 29 included in the analysis. The majority were from middle-income countries [(14/29 (48%) lower middle, 10/29 (34%) upper middle)]. We pooled studies where molecular testing was using to confirm the aetiology of GUD: 9 studies (12 estimates) for herpes, 4 studies (7 estimates) for syphilis, and 7 studies (10 estimates) for chancroid. The pooled sensitivity and specificity of GUD for the detection of herpes was 43.5% [95% confidence interval (CI): 26.2–62.4], and 88.0% (95% CI: 67.0–96.3), respectively (high certainty evidence); and for syphilis were 52.8% (95% CI: 23.0–80.7), and 72.1% (95% CI: 28.0–94.5) (moderate certainty evidence); and for chancroid were 71.9% (95% CI: 45.9–88.5) and 53.1% (95% CI: 36.6–68.9) (moderate certainty evidence), respectively.Conclusion: Algorithms requiring a clinical diagnosis to determine and treat the aetiology of GUD have poor sensitivities for syphilis and herpes simplex virus, resulting in significant numbers of missed cases. There is an urgent need to improve access to affordable and efficient diagnostics (e.g., point-of-care tests) to be incorporated into GUD algorithms to better guide appropriate management.Systematic Review Registration: PROSPERO, identifier: CRD42020153294.

Fibroblast-like synoviocytes (FLS) play an important role in maintaining joint homeostasis and orchestrating local inflammatory processes. When activated during injury or inflammation, FLS undergo transiently increased bioenergetic and biosynthetic demand. We aimed to identify metabolic changes which occur early in inflammatory disease pathogenesis which might support sustained cellular activation in persistent inflammation. We took primary human FLS from synovial biopsies of patients with very early rheumatoid arthritis (veRA) or resolving synovitis, and compared them with uninflamed control samples from the synovium of people without arthritis. Metabotypes were compared using NMR spectroscopy-based metabolomics and correlated with serum C-reactive protein levels. We measured glycolysis and oxidative phosphorylation by Seahorse analysis and assessed mitochondrial morphology by immunofluorescence. We demonstrate differences in FLS metabolism measurable after ex vivo culture, suggesting that disease-associated metabolic changes are long-lasting. We term this phenomenon ‘metabolic memory’. We identify changes in cell metabolism after acute TNFα stimulation across disease groups. When compared to FLS from patients with early rheumatoid arthritis, FLS from patients with resolving synovitis have significantly elevated mitochondrial respiratory capacity in the resting state, and less fragmented mitochondrial morphology after TNFα treatment. Our findings indicate the potential to restore cell metabotypes by modulating mitochondrial function at sites of inflammation, with implications for treatment of RA and related inflammatory conditions in which fibroblasts play a role.

BackgroundTwo weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment.Methods and findingsFor the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation.ConclusionsThis systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment.Trial registrationSystematic review registration: PROSPERO 85226.

Abstract Background Although direct-acting antivirals can achieve sustained virological response rates greater than 90% in Hepatitis C Virus (HCV) infected persons, at present the majority of HCV-infected individuals remain undiagnosed and therefore untreated. While there are a wide range of HCV serological tests available, there is a lack of formal assessment of their diagnostic performance. We undertook a systematic review and meta-analysis to evaluate he diagnostic accuracy of available rapid diagnostic tests (RDT) and laboratory based EIA assays in detecting antibodies to HCV. Methods We used the PRISMA checklist and Cochrane guidance to develop our search protocol. The search strategy was registered in PROSPERO (CRD42015023567). The search focused on hepatitis C, diagnostic tests, and diagnostic accuracy within eight databases (MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, SCOPUS, Literatura Latino-Americana e do Caribe em Ciências da Saúde and WHO Global Index Medicus. Studies were included if they evaluated an assay to determine the sensitivity and specificity of HCV antibody (HCV Ab) in humans. Two reviewers independently extracted data and performed a quality assessment of the studies using the QUADAS tool. We pooled test estimates using the DerSimonian-Laird method, by using the software R and RevMan. 5.3. Results A total of 52 studies were identified that included 52,673 unique test measurements. Based on five studies, the pooled sensitivity and specificity of HCV Ab rapid diagnostic tests (RDTs) were 98% (95% CI 98-100%) and 100% (95% CI 100-100%) compared to an enzyme immunoassay (EIA) reference standard. High HCV Ab RDTs sensitivity and specificity were observed across screening populations (general population, high risk populations, and hospital patients) using different reference standards (EIA, nucleic acid testing, immunoblot). There were insufficient studies to undertake subanalyses based on HIV co-infection. Oral HCV Ab RDTs also had excellent sensitivity and specificity compared to blood reference tests, respectively at 94% (95% CI 93-96%) and 100% (95% CI 100-100%). Among studies that assessed individual oral RDTs, the eight studies revealed that OraQuick ADVANCE® had a slightly higher sensitivity (98%, 95% CI 97-98%) compared to the other oral brands (pooled sensitivity: 88%, 95% CI 84-92%). Conclusions RDTs, including oral tests, have excellent sensitivity and specificity compared to laboratory-based methods for HCV antibody detection across a wide range of settings. Oral HCV Ab RDTs had good sensitivity and specificity compared to blood reference standards.

Abstract Background Chronic Hepatitis B Virus (HBV) infection is characterised by the persistence of hepatitis B surface antigen (HBsAg). Expanding HBV diagnosis and treatment programmes into low resource settings will require high quality but inexpensive rapid diagnostic tests (RDTs) in addition to laboratory-based enzyme immunoassays (EIAs) to detect HBsAg. The purpose of this review is to assess the clinical accuracy of available diagnostic tests to detect HBsAg to inform recommendations on testing strategies in 2017 WHO hepatitis testing guidelines. Methods The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines using 9 databases. Two reviewers independently extracted data according to a pre-specified plan and evaluated study quality. Meta-analysis was performed. HBsAg diagnostic accuracy of rapid diagnostic tests (RDTs) was compared to enzyme immunoassay (EIA) and nucleic-acid test (NAT) reference standards. Subanalyses were performed to determine accuracy among brands, HIV-status and specimen type. Results Of the 40 studies that met the inclusion criteria, 33 compared RDTs and/or EIAs against EIAs and 7 against NATs as reference standards. Thirty studies assessed diagnostic accuracy of 33 brands of RDTs in 23,716 individuals from 23 countries using EIA as the reference standard. The pooled sensitivity and specificity were 90.0% (95% CI: 89.1, 90.8) and 99.5% (95% CI: 99.4, 99.5) respectively, but accuracy varied widely among brands. Accuracy did not differ significantly whether serum, plasma, venous or capillary whole blood was used. Pooled sensitivity of RDTs in 5 studies of HIV-positive persons was lower at 72.3% (95% CI: 67.9, 76.4) compared to that in HIV-negative persons, but specificity remained high. Five studies evaluated 8 EIAs against a chemiluminescence immunoassay reference standard with a pooled sensitivity and specificity of 88.9% (95% CI: 87.0, 90.6) and 98.4% (95% CI: 97.8, 98.8), respectively. Accuracy of both RDTs and EIAs using a NAT reference were generally lower, especially amongst HIV-positive cohorts. Conclusions HBsAg RDTs have good sensitivity and excellent specificity compared to laboratory immunoassays as a reference standard. Sensitivity of HBsAg RDTs may be lower in HIV infected individuals.

Background: This project examines the organisation and delivery of health improvement activities by and within general practice and the primary health-care team. The project was designed to examine who delivers these interventions, where they are located, what approaches are developed in practices, how individual practices and the primary health-care team organise such public health activities, and how these contribute to health improvement. Our focus was on health promotion and ill-health prevention activities. Aims: The aim of this scoping exercise was to identify the current extent of knowledge about the health improvement activities in general practice and the wider primary health-care team. The key objectives were to provide an overview of the range and type of health improvement activities, identify gaps in knowledge and areas for further empirical research. Our specific research objectives were to map the range and type of health improvement activity undertaken by general practice staff and the primary health-care team based within general practice; to scope the literature on health improvement in general practice or undertaken by health-care staff based in general practice and identify gaps in the evidence base; to synthesise the literature and identify effective approaches to the delivery and organisation of health improvement interventions in a general practice setting; and to identify the priority areas for research as defined by those working in general practice. Methods: We undertook a comprehensive search of the literature. We followed a staged selection process involving reviews of titles and abstracts. This resulted in the identification of 1140 papers for data extraction, with 658 of these papers selected for inclusion in the review, of which 347 were included in the evidence synthesis. We also undertook 45 individual and two group interviews with primary health-care staff. Findings: Many of the research studies reviewed had some details about the type, process or location, or who provided the intervention. Generally, however, little attention is paid in the literature to examining the impact of the organisational context on the way services are delivered or how this affects the effectiveness of health improvement interventions in general practice. We found that the focus of attention is mainly on individual prevention approaches, with practices engaging in both primary and secondary prevention. The range of activities suggests that general practitioners do not take a population approach but focus on individual patients. However, it is clear that many general practitioners see health promotion as an integral part of practice, whether as individual approaches to primary or secondary health improvement or as a practice-based approach to improving the health of their patients. Our key conclusion is that there is currently insufficient good evidence to support many of the health improvement interventions undertaken in general practice and primary care more widely. Future Research: Future research on health improvement in general practice and by the primary health-care team needs to move beyond clinical research to include delivery systems and be conducted in a primary care setting. More research needs to examine areas where there are chronic disease burdens – cancer, dementia and other disabilities of old age. Reviews should be commissioned that examine the whole prevention pathway for health problems that are managed within primary care drawing together research from general practice, pharmacy, community engagement, etc. Funding: The National Institute for Health Research Health Services and Delivery Research programme.

Background. Angina is a common chronic condition, largely managed in primary care in the UK. Mortality data are predominately from population or hospital studies with little known about the prognosis of angina in general practice settings.Objective. To describe the prognosis of angina in patients identified in primary care.MethodsDesign. Systematic review of cohort studies of angina in primary care.Data sources. Medline, PsycINFO, EMBASE, CINAHL, HMIC, WOS, IBSS, UK National Research Register, notification via JISC, CHAIN.Review methodsSelection criteria. Cohort studies of patients with angina, with >12 months of follow-up, recruited within primary care.Validity assessment. Database searches and abstracts were reviewed independently by two authors. Papers were assessed according to criteria derived from the cohort methodological literature.Data abstraction. Data were abstracted by two reviewers.Data synthesis. Narrative summary. A quantitative synthesis was planned.Main outcome measures. Total and cardiovascular death; non-fatal myocardial infarction (MI).Results. Six studies fulfilled our selection criteria. The annual total mortality rate is 2.8–6.6%, an annual cardiovascular death rate of 1.4–6.5% and an annual non-fatal MI rate of 0.3–5.5%. A quantitative synthesis was not possible, because the studies were clinically heterogeneous.Conclusions. The primary studies have value in determining the prognosis of patients with angina recruited in general practice; however, the studies are old, have small numbers of events and are clinically heterogeneous. The contemporary prognosis of angina in primary care remains a key question, and further research is, therefore, required to estimate the prognosis of angina in this setting and its determinants. [ABSTRACT FROM AUTHOR]