Search

Background Identifying new, eligible studies for integration into living systematic reviews and maps usually relies on conventional Boolean updating searches of multiple databases and manual processing of the updated results. Automated searches of one, comprehensive, continuously updated source, with adjunctive machine learning, could enable more efficient searching, selection and prioritisation workflows for updating (living) reviews and maps, though research is needed to establish this. Microsoft Academic Graph (MAG) is a potentially comprehensive single source which also contains metadata that can be used in machine learning to help efficiently identify eligible studies. This study sought to establish whether: (a) MAG was a sufficiently sensitive single source to maintain our living map of COVID-19 research; and (b) eligible records could be identified with an acceptably high level of specificity. Methods We conducted an eight-arm cost-effectiveness analysis to assess the costs, recall and precision of semi-automated workflows, incorporating MAG with adjunctive machine learning, for continually updating our living map. Resource use data (time use) were collected from information specialists and other researchers involved in map production. Our systematic review software, EPPI-Reviewer, was adapted to incorporate MAG and associated machine learning workflows, and also used to collect data on recall, precision, and manual screening workload. Results The semi-automated MAG-enabled workflow dominated conventional workflows in both the base case and sensitivity analyses. At one month our MAG-enabled workflow with machine learning, active learning and fixed screening targets identified 469 additional, eligible articles for inclusion in our living map, and cost £3,179 GBP per week less, compared with conventional methods relying on Boolean searches of Medline and Embase. Conclusions We were able to increase recall and coverage of a large living map, whilst reducing its production costs. This finding is likely to be transferrable to OpenAlex, MAG’s successor database platform.

Abstract Background This systematic overview was commissioned by England’s Department of Health and Social Care (DHSC) to assess the evidence on direct (previously ‘novel’) oral anticoagulants (OACs), compared with usual care, in adults, to prevent stroke related to atrial fibrillation (AF), and to prevent and treat venous thromboembolism (VTE). Specifically, to assess efficacy and safety, genotyping, self-monitoring, and patient and clinician experiences of OACs. Methods We searched MEDLINE, Embase, ASSIA, and CINAHL, in October, 2017, updated in November 2021. We included systematic reviews, published from 2014, in English, assessing OACs, in adults. We rated review quality using AMSTAR2 or the JBI checklist. Two reviewers extracted and synthesised the main findings from the included reviews. Results We included 49 systematic reviews; one evaluated efficacy, safety, and cost-effectiveness, 17 assessed genotyping, 23 self-monitoring or adherence, and 15 experiences (seven assessed two topics). Generally, the direct OACs, particularly apixaban (5 mg twice daily), were more effective and safer than warfarin in preventing AF-related stroke. For VTE, there was little evidence of differences in efficacy between direct OACs and low-molecular-weight heparin (prevention), warfarin (treatment), and warfarin or aspirin (secondary prevention). The evidence suggested that some direct OACs may reduce the risk of bleeding, compared with warfarin. One review of genotype-guided warfarin dosing assessed AF patients; no significant differences in stroke prevention were reported. Education about OACs, in patients with AF, could improve adherence. Pharmacist management of coagulation may be better than primary care management. Patients were more adherent to direct OACs than warfarin. Drug efficacy was highly valued by patients and most clinicians, followed by safety. No other factors consistently affected patients’ choice of anticoagulant and adherence to treatment. Patients were more satisfied with direct OACs than warfarin. Conclusions For stroke prevention in AF, direct OACs seem to be more effective and safer than usual care, and apixaban (5 mg twice daily) had the best profile. For VTE, there was no strong evidence that direct OACs were better than usual care. Education and pharmacist management could improve coagulation control. Both clinicians and patients rated efficacy and safety as the most important factors in managing AF and VTE. Systematic review registration PROSPERO CRD42017084263—one deviation; efficacy and safety were from one review.

Aims: This systematic review places a recently completed multicentre randomized controlled trial (RCT), UK FROST, in the context of existing randomized evidence for the management of primary frozen shoulder. UK FROST compared the effectiveness of pre-specified physiotherapy techniques with a steroid injection (PTSI), manipulation under anaesthesia (MUA) with a steroid injection, and arthroscopic capsular release (ACR). This review updates a 2012 review focusing on the effectiveness of MUA, ACR, hydrodilatation, and PTSI. Methods: MEDLINE, Embase, PEDro, Science Citation Index, Clinicaltrials.gov, CENTRAL, and the World Health Organization (WHO) International Clinical Trials Registry were searched up to December 2018. Reference lists of included studies were screened. No language restrictions applied. Eligible studies were RCTs comparing the effectiveness of MUA, ACR, PTSI, and hydrodilatation against each other, or supportive care or no treatment, for the management of primary frozen shoulder. Results: Nine RCTs were included. The primary outcome of patient-reported shoulder function at long-term follow-up (> 6 months and ≤ 12 months) was reported for five treatment comparisons across four studies. Standardized mean differences (SMD) were: ACR versus MUA: 0.21 (95% confidence interval (CI) 0.00 to 0.42), ACR versus supportive care: -0.13 (95% CI -1.10 to 0.83), and ACR versus PTSI: 0.33 (95% CI 0.07 to 0.59) and 0.25 (95% CI -0.34 to 0.85), all favouring ACR; MUA versus supportive care: 0 (95% CI -0.44 to 0.44) not favouring either; and MUA versus PTSI: 0.12 (95% CI -0.14 to 0.37) favouring MUA. None of these differences met the threshold of clinical significance agreed for the UK FROST and most confidence intervals included zero. Conclusion: The findings from a recent multicentre RCT provided the strongest evidence that, when compared with each other, neither PTSI, MUA, nor ACR are clinically superior. Evidence from smaller RCTs did not change this conclusion. The effectiveness of hydrodilatation based on four RCTs was inconclusive and there remains an evidence gap. Cite this article: Bone Jt Open 2021;2(9):773–784.

Abstract Background Young people’s use of pornography and participation in sexting are commonly viewed as harmful behaviours. This paper reports findings from a ‘review of reviews’, which aimed to systematically identify and synthesise the evidence on pornography and sexting amongst young people. Here, we focus specifically on the evidence relating to young people’s use of pornography; involvement in sexting; and their beliefs, attitudes, behaviours and wellbeing to better understand potential harms and benefits, and identify where future research is required. Methods We searched five health and social science databases; searches for grey literature were also performed. Review quality was assessed and findings synthesised narratively. Results Eleven reviews of quantitative and/or qualitative studies were included. A relationship was identified between pornography use and more permissive sexual attitudes. An association between pornography use and stronger gender-stereotypical sexual beliefs was also reported, but not consistently. Similarly, inconsistent evidence of an association between pornography use and sexting and sexual behaviour was identified. Pornography use has been associated with various forms of sexual violence, aggression and harassment, but the relationship appears complex. Girls, in particular, may experience coercion and pressure to engage in sexting and suffer more negative consequences than boys if sexts become public. Positive aspects to sexting were reported, particularly in relation to young people’s personal relationships. Conclusions We identified evidence from reviews of varying quality that linked pornography use and sexting amongst young people to specific beliefs, attitudes and behaviours. However, evidence was often inconsistent and mostly derived from observational studies using a cross-sectional design, which precludes establishing any causal relationship. Other methodological limitations and evidence gaps were identified. More rigorous quantitative studies and greater use of qualitative methods are required.

Background: People with severe mental illness die 15–20 years earlier than the general population. Reasons why include that people with severe mental illness are more likely to smoke and be physically inactive as a result of social inequalities. Objectives: (1) Evaluate the clinical effectiveness of multiple risk behaviour interventions on behaviour change (e.g. smoking abstinence), and outcomes affected by behaviours (e.g. weight loss). (2) Compare the clinical effectiveness of interventions targeting multiple and single risk behaviours. (3) Examine the factors affecting outcomes (e.g. intervention content). (4) Assess the factors affecting experiences of interventions (e.g. barriers and facilitators). Data sources: The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE™ (Elsevier, Amsterdam, the Netherlands), MEDLINE, PsycInfo® (American Psychological Association, Washington, DC, USA) and Science Citation Index (Clarivate Analytics, Philadelphia, PA, USA) were searched from inception to October 2018, and an updated search was conducted in March 2020. An Applied Social Sciences Index and Abstracts (ASSIA) search and an updated Cochrane Central Register of Controlled Trials search were undertaken in September 2020. Study selection: Randomised controlled trials targeting single or multiple health risk behaviours among people with severe mental illness were included. Qualitative evidence on factors affecting the effectiveness of risk behaviour interventions was included. Study appraisal: Network meta-analyses were conducted to compare the effectiveness of multiple and single risk behaviour interventions. The mean differences were estimated for continuous outcomes; if this was not possible, standardised mean differences were calculated. Thematic syntheses of qualitative studies were conducted. Results: A total of 101 studies (67 randomised controlled trials and 34 qualitative studies) were included. Most outcomes were smoking abstinence, weight and body mass index. Just over half of studies were rated as having a high overall risk of bias. Trials focusing on smoking alone led to greater abstinence than targeting smoking and other behaviours. However, heterogeneity means that other explanations cannot be ruled out. For weight loss and body mass index, single risk behaviour (e.g. physical activity alone) and multiple risk behaviour (e.g. diet and physical activity) interventions had positive but modest benefits. For example, any risk behaviour intervention led to a 2 kg greater weight loss (–2.10 kg, 95% credible interval –3.14 to –1.06 kg) and approximately half a point (i.e. 0.5 kg/m2) greater body mass index reduction (–0.49 kg/m2, 95% credible interval –0.97 to –0.01 kg/m2) than treatment as usual. There were potential synergies for targeting multiple health behaviours for reduction in systolic and diastolic blood pressure. No evidence was found of a deterioration in mental health for people with severe mental illness engaging in interventions to reduce health risk behaviours. Qualitative studies found that people with severe mental illness favoured interventions promoting physical and mental health together, and that took their condition into account. However, trials focused mainly on promoting physical health. Limitations: Most quantitative studies focused on weight and body mass index; few assessed behavioural outcomes. Qualitative studies often addressed different aims. Conclusions: Multiple and single risk behaviour interventions were associated with positive but modest benefits on most outcomes. Interventions seeking to promote physical health were not associated with deterioration in mental health. There was a lack of overlap between quantitative and qualitative studies. Future work: Further research is needed to investigate whether or not health behaviour changes are maintained long term; tailoring weight-loss interventions for people with severe mental illness; and in terms of methods, co-production and mixed-methods approaches in future trials. Study registration: This study is registered as PROSPERO CRD42018104724. Funding: This project was funded by the National Institute for Health Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 6. See the NIHR Journals Library website for further project information.

Background: Chronic heart failure is a debilitating condition that accounts for an annual NHS spend of £2.3B. Low levels of endogenous coenzyme Q10 may exacerbate chronic heart failure. Coenzyme Q10 supplements might improve symptoms and slow progression. As statins are thought to block the production of coenzyme Q10, supplementation might be particularly beneficial for patients taking statins. Objectives: To assess the clinical effectiveness and cost-effectiveness of coenzyme Q10 in managing chronic heart failure with a reduced ejection fraction. Methods: A systematic review that included randomised trials comparing coenzyme Q10 plus standard care with standard care alone in chronic heart failure. Trials restricted to chronic heart failure with a preserved ejection fraction were excluded. Databases including MEDLINE, EMBASE and CENTRAL were searched up to March 2020. Risk of bias was assessed using the Cochrane Risk of Bias tool (version 5.2). A planned individual participant data meta-analysis was not possible and meta-analyses were mostly based on aggregate data from publications. Potential effect modification was examined using meta-regression. A Markov model used treatment effects from the meta-analysis and baseline mortality and hospitalisation from an observational UK cohort. Costs were evaluated from an NHS and Personal Social Services perspective and expressed in Great British pounds at a 2019/20 price base. Outcomes were expressed in quality-adjusted life-years. Both costs and outcomes were discounted at a 3.5% annual rate. Results: A total of 26 trials, comprising 2250 participants, were included in the systematic review. Many trials were reported poorly and were rated as having a high or unclear risk of bias in at least one domain. Meta-analysis suggested a possible benefit of coenzyme Q10 on all-cause mortality (seven trials, 1371 participants; relative risk 0.68, 95% confidence interval 0.45 to 1.03). The results for short-term functional outcomes were more modest or unclear. There was no indication of increased adverse events with coenzyme Q10. Meta-regression found no evidence of treatment interaction with statins. The base-case cost-effectiveness analysis produced incremental costs of £4878, incremental quality-adjusted life-years of 1.34 and an incremental cost-effectiveness ratio of £3650. Probabilistic sensitivity analyses showed that at thresholds of £20,000 and £30,000 per quality-adjusted life-year coenzyme Q10 had a high probability (95.2% and 95.8%, respectively) of being more cost-effective than standard care alone. Scenario analyses in which the population and other model assumptions were varied all found coenzyme Q10 to be cost-effective. The expected value of perfect information suggested that a new trial could be valuable. Limitations: For most outcomes, data were available from few trials and different trials contributed to different outcomes. There were concerns about risk of bias and whether or not the results from included trials were applicable to a typical UK population. A lack of individual participant data meant that planned detailed analyses of effect modifiers were not possible. Conclusions: Available evidence suggested that, if prescribed, coenzyme Q10 has the potential to be clinically effective and cost-effective for heart failure with a reduced ejection fraction. However, given important concerns about risk of bias, plausibility of effect sizes and applicability of the evidence base, establishing whether or not coenzyme Q10 is genuinely effective in a typical UK population is important, particularly as coenzyme Q10 has not been subject to the scrutiny of drug-licensing processes. Stronger evidence is needed before considering its prescription in the NHS. Future work: A new independent, well-designed clinical trial of coenzyme Q10 in a typical UK heart failure with a reduced ejection fraction population may be warranted. Study registration: This study is registered as PROSPERO CRD42018106189. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 4. See the NIHR Journals Library website for further project information.

Background: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. Methods: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. Results: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. Conclusions: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. Further research: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.

Background: QAngio® XA 3D/QFR® (three-dimensional/quantitative flow ratio) imaging software (Medis Medical Imaging Systems BV, Leiden, the Netherlands) and CAAS® vFFR® (vessel fractional flow reserve) imaging software (Pie Medical Imaging BV, Maastricht, the Netherlands) are non-invasive technologies to assess the functional significance of coronary stenoses, which can be alternatives to invasive fractional flow reserve assessment. Objectives: The objectives were to determine the clinical effectiveness and cost-effectiveness of QAngio XA 3D/QFR and CAAS vFFR. Methods: We performed a systematic review of all evidence on QAngio XA 3D/QFR and CAAS vFFR, including diagnostic accuracy, clinical effectiveness, implementation and economic analyses. We searched MEDLINE and other databases to January 2020 for studies where either technology was used and compared with fractional flow reserve in patients with intermediate stenosis. The risk of bias was assessed with quality assessment of diagnostic accuracy studies. Meta-analyses of diagnostic accuracy were performed. Clinical and implementation outcomes were synthesised narratively. A simulation study investigated the clinical impact of using QAngio XA 3D/QFR. We developed a de novo decision-analytic model to estimate the cost-effectiveness of QAngio XA 3D/QFR and CAAS vFFR relative to invasive fractional flow reserve or invasive coronary angiography alone. Scenario analyses were undertaken to explore the robustness of the results to variation in the sources of data used to populate the model and alternative assumptions. Results: Thirty-nine studies (5440 patients) of QAngio XA 3D/QFR and three studies (500 patients) of CAAS vFFR were included. QAngio XA 3D/QFR had good diagnostic accuracy to predict functionally significant fractional flow reserve (≤ 0.80 cut-off point); contrast-flow quantitative flow ratio had a sensitivity of 85% (95% confidence interval 78% to 90%) and a specificity of 91% (95% confidence interval 85% to 95%). A total of 95% of quantitative flow ratio measurements were within 0.14 of the fractional flow reserve. Data on the diagnostic accuracy of CAAS vFFR were limited and a full meta-analysis was not feasible. There were very few data on clinical and implementation outcomes. The simulation found that quantitative flow ratio slightly increased the revascularisation rate when compared with fractional flow reserve, from 40.2% to 42.0%. Quantitative flow ratio and fractional flow reserve resulted in similar numbers of subsequent coronary events. The base-case cost-effectiveness results showed that the test strategy with the highest net benefit was invasive coronary angiography with confirmatory fractional flow reserve. The next best strategies were QAngio XA 3D/QFR and CAAS vFFR (without fractional flow reserve). However, the difference in net benefit between this best strategy and the next best was small, ranging from 0.007 to 0.012 quality-adjusted life-years (or equivalently £140–240) per patient diagnosed at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. Limitations: Diagnostic accuracy evidence on CAAS vFFR, and evidence on the clinical impact of QAngio XA 3D/QFR, were limited. Conclusions: Quantitative flow ratio as measured by QAngio XA 3D/QFR has good agreement and diagnostic accuracy compared with fractional flow reserve and is preferable to standard invasive coronary angiography alone. It appears to have very similar cost-effectiveness to fractional flow reserve and, therefore, pending further evidence on general clinical benefits and specific subgroups, could be a reasonable alternative. The clinical effectiveness and cost-effectiveness of CAAS vFFR are uncertain. Randomised controlled trial evidence evaluating the effect of quantitative flow ratio on clinical and patient-centred outcomes is needed. Future work: Studies are required to assess the diagnostic accuracy and clinical feasibility of CAAS vFFR. Large ongoing randomised trials will hopefully inform the clinical value of QAngio XA 3D/QFR. Study registration: This study is registered as PROSPERO CRD42019154575. Funding: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 56. See the NIHR Journals Library website for further project information.

Background: Advance care planning (ACP) can be defined as a voluntary process of discussion about future care between an individual and their care providers, irrespective of discipline. An ACP discussion might include an individual’s concerns and wishes, their important values or personal goals for care, their understanding about their illness and prognosis, preferences and wishes for types of care or treatment in the future and the availability of such treatment. Objective(s): To undertake a systematic mapping review of the evidence. It was not the aim of this work to extract, evaluate and synthesise findings from individual publications, rather it was to assess the methodological rigour and scope of the existing evidence. Participants: Adults with any progressive life-limiting condition approaching end of life or likelihood of loss of mental capacity at some time; or their family members and carers; or health and/or social care practitioners involved in delivering care and support to such adults. Interventions: Any form of intervention addressing ACP. Interventions solely addressing Advance Directives or Living Wills were excluded. Main outcome measures: Any relevant to effectiveness, cost-effectiveness or process and implementation. Data sources and study designs: Comprehensive searches were conducted to identify evidence syntheses, cost-effectiveness studies and recent primary studies. No language or geographical restrictions were applied. Review methods: An evidence map was constructed, descriptive statistics were produced for key characteristics. Ongoing reviews, and reviews that failed to meet minimum methodological criteria were referenced. Results: We included 76 evidence syntheses: 28 evaluating effectiveness, 37 process and implementation, 10 evaluating both, and one guideline. Three reviews of cost-effectiveness and nine primary studies were included. We identified 406 recent primary studies published between 2017 and October 2019.: Reviews encompassed a range of methodologies and included a diversity of study designs. There was significant variation in the methodological quality and clarity of reporting. Most reviews combined studies of patients with various conditions. Some reviews did focus on patients with specific conditions such as dementia, cancer, heart disease, or kidney disease. Most of the reviews included studies across a range of settings.: Reporting of patient-centred outcomes was sporadic, few reviews reported congruence between patient wishes and care received. Outcomes for carers or family members was often lacking. Many of the high quality, well reported reviews provided a clear commentary on the limitations of the included studies and made recommendations for future research to address these concerns. There was a lack of UK-based cost-effectiveness studies; identified studies were highly heterogeneous and had methodological limitations. Limitations: Despite comprehensive searches some potentially relevant studies may have been missed. Primary study summaries were based on information from the titles and abstracts only. It is unclear to what extent findings from reviews of studies conducted in other countries are generalisable to the UK. Conclusions: This systematic mapping review has identified a large number of existing reviews looking at the effectiveness, cost-effectiveness and process and implementation of ACP. The evidence is heterogeneous and of mixed methodological quality. There appear to be increasing numbers of primary studies and reviews, but currently these do not address the questions of interest to stakeholders. Recommendations for future research are discussed. Registration details: Research Registry unique identifying number: reviewregistry800 (https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/5e25c1ba4d5c41001713af47/) Funding details: National Institute of Health Research: Health Service and Delivery Research (project no.16/47/11)

Background: People with a history of complex traumatic events typically experience trauma and stressor disorders and additional mental comorbidities. It is not known if existing evidence-based treatments are effective and acceptable for this group of people. Objective: To identify candidate psychological and non-pharmacological treatments for future research. Design: Mixed-methods systematic review. Participants: Adults aged ≥ 18 years with a history of complex traumatic events. Interventions: Psychological interventions versus control or active control; pharmacological interventions versus placebo. Main outcome measures: Post-traumatic stress disorder symptoms, common mental health problems and attrition. Data sources: Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1937 onwards); Cochrane Central Register of Controlled Trials (CENTRAL) (from inception); EMBASE (1974 to 2017 week 16); International Pharmaceutical Abstracts (1970 onwards); MEDLINE and MEDLINE Epub Ahead of Print and In-Process & Other Non-Indexed Citations (1946 to present); Published International Literature on Traumatic Stress (PILOTS) (1987 onwards); PsycINFO (1806 to April week 2 2017); and Science Citation Index (1900 onwards). Searches were conducted between April and August 2017. Review methods: Eligible studies were singly screened and disagreements were resolved at consensus meetings. The risk of bias was assessed using the Cochrane risk-of-bias tool and a bespoke version of a quality appraisal checklist used by the National Institute for Health and Care Excellence. A meta-analysis was conducted across all populations for each intervention category and for population subgroups. Moderators of effectiveness were assessed using metaregression and a component network meta-analysis. A qualitative synthesis was undertaken to summarise the acceptability of interventions with the relevance of findings assessed by the GRADE-CERQual checklist. Results: One hundred and four randomised controlled trials and nine non-randomised controlled trials were included. For the qualitative acceptability review, 4324 records were identified and nine studies were included. The population subgroups were veterans, childhood sexual abuse victims, war affected, refugees and domestic violence victims. Psychological interventions were superior to the control post treatment for reducing post-traumatic stress disorder symptoms (standardised mean difference –0.90, 95% confidence interval –1.14 to –0.66; number of trials = 39) and also for associated symptoms of depression, but not anxiety. Trauma-focused therapies were the most effective interventions across all populations for post-traumatic stress disorder and depression. Multicomponent and trauma-focused interventions were effective for negative self-concept. Phase-based approaches were also superior to the control for post-traumatic stress disorder and depression and showed the most benefit for managing emotional dysregulation and interpersonal problems. Only antipsychotic medication was effective for reducing post-traumatic stress disorder symptoms; medications were not effective for mental comorbidities. Eight qualitative studies were included. Interventions were more acceptable if service users could identify benefits and if they were delivered in ways that accommodated their personal and social needs. Limitations: Assessments about long-term effectiveness of interventions were not possible. Studies that included outcomes related to comorbid psychiatric states, such as borderline personality disorder, and populations from prisons and humanitarian crises were under-represented. Conclusions: Evidence-based psychological interventions are effective and acceptable post treatment for reducing post-traumatic stress disorder symptoms and depression and anxiety in people with complex trauma. These interventions were less effective in veterans and had less of an impact on symptoms associated with complex post-traumatic stress disorder. Future work: Definitive trials of phase-based versus non-phase-based interventions with long-term follow-up for post-traumatic stress disorder and associated mental comorbidities. Study registration: This study is registered as PROSPERO CRD42017055523. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 43. See the NIHR Journals Library website for further project information.

BackgroundComplex traumatic events associated with armed conflict, forcible displacement, childhood sexual abuse, and domestic violence are increasingly prevalent. People exposed to complex traumatic events are at risk of not only posttraumatic stress disorder (PTSD) but also other mental health comorbidities. Whereas evidence-based psychological and pharmacological treatments are effective for single-event PTSD, it is not known if people who have experienced complex traumatic events can benefit and tolerate these commonly available treatments. Furthermore, it is not known which components of psychological interventions are most effective for managing PTSD in this population. We performed a systematic review and component network meta-analysis to assess the effectiveness of psychological and pharmacological interventions for managing mental health problems in people exposed to complex traumatic events.Methods and findingsWe searched CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Published International Literature on Traumatic Stress, PsycINFO, and Science Citation Index for randomised controlled trials (RCTs) and non-RCTs of psychological and pharmacological treatments for PTSD symptoms in people exposed to complex traumatic events, published up to 25 October 2019. We adopted a nondiagnostic approach and included studies of adults who have experienced complex trauma. Complex-trauma subgroups included veterans; childhood sexual abuse; war-affected; refugees; and domestic violence. The primary outcome was reduction in PTSD symptoms. Secondary outcomes were depressive and anxiety symptoms, quality of life, sleep quality, and positive and negative affect. We included 116 studies, of which 50 were conducted in hospital settings, 24 were delivered in community settings, seven were delivered in military clinics for veterans or active military personnel, five were conducted in refugee camps, four used remote delivery via web-based or telephone platforms, four were conducted in specialist trauma clinics, two were delivered in home settings, and two were delivered in primary care clinics; clinical setting was not reported in 17 studies. Ninety-four RCTs, for a total of 6,158 participants, were included in meta-analyses across the primary and secondary outcomes; 18 RCTs for a total of 933 participants were included in the component network meta-analysis. The mean age of participants in the included RCTs was 42.6 ± 9.3 years, and 42% were male. Nine non-RCTs were included. The mean age of participants in the non-RCTs was 40.6 ± 9.4 years, and 47% were male. The average length of follow-up across all included studies at posttreatment for the primary outcome was 11.5 weeks. The pairwise meta-analysis showed that psychological interventions reduce PTSD symptoms more than inactive control (k = 46; n = 3,389; standardised mean difference [SMD] = -0.82, 95% confidence interval [CI] -1.02 to -0.63) and active control (k-9; n = 662; SMD = -0.35, 95% CI -0.56 to -0.14) at posttreatment and also compared with inactive control at 6-month follow-up (k = 10; n = 738; SMD = -0.45, 95% CI -0.82 to -0.08). Psychological interventions reduced depressive symptoms (k = 31; n = 2,075; SMD = -0.87, 95% CI -1.11 to -0.63; I2 = 82.7%, p = 0.000) and anxiety (k = 15; n = 1,395; SMD = -1.03, 95% CI -1.44 to -0.61; p = 0.000) at posttreatment compared with inactive control. Sleep quality was significantly improved at posttreatment by psychological interventions compared with inactive control (k = 3; n = 111; SMD = -1.00, 95% CI -1.49 to -0.51; p = 0.245). There were no significant differences between psychological interventions and inactive control group at posttreatment for quality of life (k = 6; n = 401; SMD = 0.33, 95% CI -0.01 to 0.66; p = 0.021). Antipsychotic medicine (k = 5; n = 364; SMD = -0.45; -0.85 to -0.05; p = 0.085) and prazosin (k = 3; n = 110; SMD = -0.52; -1.03 to -0.02; p = 0.182) were effective in reducing PTSD symptoms. Phase-based psychological interventions that included skills-based strategies along with trauma-focused strategies were the most promising interventions for emotional dysregulation and interpersonal problems. Compared with pharmacological interventions, we observed that psychological interventions were associated with greater reductions in PTSD and depression symptoms and improved sleep quality. Sensitivity analysis showed that psychological interventions were acceptable with lower dropout, even in studies rated at low risk of attrition bias. Trauma-focused psychological interventions were superior to non-trauma-focused interventions across trauma subgroups for PTSD symptoms, but effects among veterans and war-affected populations were significantly reduced. The network meta-analysis showed that multicomponent interventions that included cognitive restructuring and imaginal exposure were the most effective for reducing PTSD symptoms (k = 17; n = 1,077; mean difference = -37.95, 95% CI -60.84 to -15.16). Our use of a non-diagnostic inclusion strategy may have overlooked certain complex-trauma populations with severe and enduring mental health comorbidities. Additionally, the relative contribution of skills-based intervention components was not feasibly evaluated in the network meta-analysis.ConclusionsIn this systematic review and meta-analysis, we observed that trauma-focused psychological interventions are effective for managing mental health problems and comorbidities in people exposed to complex trauma. Multicomponent interventions, which can include phase-based approaches, were the most effective treatment package for managing PTSD in complex trauma. Establishing optimal ways to deliver multicomponent psychological interventions for people exposed to complex traumatic events is a research and clinical priority.

Background: Early intensive applied behaviour analysis-based interventions are intensive interventions for autistic children that are often delivered on a one-to-one basis for 20–50 hours per week. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of early intensive applied behaviour analysis-based interventions for autistic children, based on current evidence. Methods: A systematic review and individual participant data meta-analysis were conducted to evaluate the clinical effectiveness of an early intensive applied behaviour analysis-based intervention for autistic children. An economic analysis included a review of existing analyses and the development of a new model. Results: Twenty studies were included in the clinical review. Individual participant data were retrieved from 15 of these studies. Results favoured the interventions when assessing adaptive behaviour after 2 years compared with treatment as usual/eclectic interventions (mean difference 7.00, 95% confidence interval 1.95 to 12.06). In analyses of cognitive ability (intelligence quotient), results favoured the interventions by approximately 10 points after 1 year (mean difference 9.16, 95% confidence interval 4.38 to 13.93) and 2 years (mean difference 14.13, 95% confidence interval 9.16 to 19.10). Evidence for other outcomes was limited and meta-analyses were generally inconclusive. There was no evidence that the effect of the interventions varied with characteristics of the children, but data were limited. Adopting a £30,000 per quality-adjusted life-year threshold, the results of the cost-effectiveness analysis indicate that early intensive applied behaviour analysis-based interventions would need to generate larger benefits or cost savings to be cost-effective. Adopting a public sector perspective and making pessimistic assumptions about long-term effects, the incremental cost-effectiveness ratio for early intensive applied behaviour analysis-based therapy compared with treatment as usual is £189,122 per quality-adjusted life-year. When optimistic assumptions are made, the incremental cost-effectiveness ratio is £46,768 per quality-adjusted life-year. Scenario analyses indicated that these interventions can potentially be cost-effective if long-term improvements persist into adulthood, or if they have significant impact on educational placement. Care should be taken when interpreting these scenarios owing to the limited data. Limitations: All included studies were at risk of bias, there was substantial heterogeneity and effects varied considerably across studies. The effect of intervention on autism symptom severity, language development and school placement remains uncertain because of the limited data. The long-term effects are unclear owing to a lack of follow-up data. Conclusions: This review found limited evidence that early intensive applied behaviour analysis-based interventions may improve cognitive ability and adaptive behaviour, but the long-term impact of the interventions remains unknown. The economic analysis is constrained by the limited effectiveness evidence, but suggests that these interventions are unlikely to be cost-effective unless clear long-term benefits, or a substantial change in which schools children attend, can be identified. Future work: Further studies into the effectiveness of early intensive applied behaviour analysis-based interventions may be warranted if they include well-defined, alternative interventions as comparators and collect relevant outcomes. Consideration should be given to future studies that not only address whether or not early intensive applied behaviour analysis-based interventions are clinically effective, but also aim to identify which components of early intensive applied behaviour analysis-based interventions might drive effectiveness. Study registration: This study is registered as PROSPERO CRD42017068303. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 35. See the NIHR Journals Library website for further project information.

Background: The health and well-being of staff working in the NHS is a significant issue for UK health care. We sought to identify research relevant to the promotion of healthy lifestyles among NHS staff on behalf of NHS England. Objectives: To map existing reviews on workplace-based interventions to promote health and well-being, and to assess the scope for further evidence synthesis work. Design: Rapid and responsive scoping search and evidence map. Participants: Adult employees in any occupational setting and in any role. Interventions: Any intervention aimed at promoting or maintaining physical or mental health and well-being. Early intervention initiatives and those addressing violence against staff, workplace bullying or harassment were also included. Main outcome measures: Any outcome related to the effectiveness, cost-effectiveness or implementation of interventions. Data sources: A scoping search of nine databases was conducted to identify systematic reviews on health and well-being at work. Searches were limited by publication date (2000 to January/February 2019). Review methods: The titles and abstracts of over 8241 records were screened and a total of 408 potentially relevant publications were identified. Information on key characteristics were extracted from the titles and abstracts of all potentially relevant publications. Descriptive statistics (counts and percentages) for key characteristics were generated and data from reviews and ‘reviews of reviews’ were used to produce the evidence map. Results: Evidence related to a broad range of physical and mental health issues was identified across 12 ‘reviews of reviews’ and 312 other reviews, including 16 Cochrane reviews. There also exists National Institute for Health and Care Excellence guidance addressing multiple issues of potential relevance. A large number of reviews focused on mental health, changing lifestyle behaviour, such as physical activity, or on general workplace health/health promotion. Most of the reviews that focused only on health-care staff addressed mental health issues, and stress/burnout in particular. Limitations: The scoping search process was extensive and clearly effective at identifying relevant publications, but the strategy used may not have identified every potentially relevant review. Owing to the large number of potentially relevant reviews identified from the scoping search, it was necessary to produce the evidence map using information from the titles and abstracts of reviews only. Conclusions: It is doubtful that further evidence synthesis work at this stage would generate substantial new knowledge, particularly within the context of the NHS Health and Wellbeing Framework[NHS England. Workforce Health and Wellbeing Framework. 2018. URL: www.nhsemployers.org/-/media/Employers/Publications/Health-and-wellbeing/NHS-Workforce-HWB-Framework_updated-July-18.pdf (accessed 10 January 2019)] published in 2018. Additional synthesis work may be useful if it addressed an identifiable need and it was possible to identify one of the following: (1) a specific and focused research question arising from the current evidence map; it may then be appropriate to focus on a smaller number of reviews only, and provide a more thorough and critical assessment of the available evidence; and (2) a specific gap in the literature (i.e. an issue not already addressed by existing reviews or guidance); it may then be possible to undertake further literature searching and conduct a new evidence review. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 18. See the NIHR Journals Library website for further project information.

Abstract Background Preterm birth is the most common cause of death and harm to newborn babies. Babies that are born early may have difficulties at birth and experience health problems during early childhood. Despite extensive study, there is still uncertainty about the effectiveness of progestogen (medications that are similar to the natural hormone progesterone) in preventing or delaying preterm birth, and in improving birth outcomes. The Evaluating Progestogen for Prevention of Preterm birth International Collaborative (EPPPIC) project aims to reduce uncertainty about the specific conditions in which progestogen may (or may not) be effective in preventing or delaying preterm birth and improving birth outcomes. Methods The design of the study involves international collaborative individual participant data meta-analysis comprising systematic review, re-analysis, and synthesis of trial datasets. Inclusion criteria are as follows: randomized controlled trials comparing progestogen versus placebo or non-intervention, or comparing different types of progestogen, in asymptomatic women at risk of preterm birth. Main outcomes are as follows; fetal/infant death, preterm birth or fetal death (

Abstract Background Most countries recommend that healthcare workers (HCWs) are vaccinated seasonally against influenza in order to protect themselves and patients. However, in many cases coverage remains low. A range of strategies have been implemented to increase uptake. Qualitative evidence can help in understanding the context of interventions, including why interventions may fail to achieve the desired effect. This study aimed to synthesise evidence on HCWs’ perceptions and experiences of vaccination for seasonal influenza. Methods Systematic review of qualitative evidence. We searched MEDLINE, EMBASE and CINAHL and included English-language studies which reported substantive qualitative data on the vaccination of HCWs for seasonal influenza. Findings were synthesised thematically. Results Twenty-five studies were included in the review. HCWs may be motivated to accept vaccination to protect themselves and their patients against infection. However, a range of beliefs may act as barriers to vaccine uptake, including concerns about side-effects, scepticism about vaccine effectiveness, and the belief that influenza is not a serious illness. HCWs value their autonomy and professional responsibility in making decisions about vaccination. The implementation of interventions to promote vaccination uptake may face barriers both from HCWs’ personal beliefs and from the relationships between management and employees within the targeted organisations. Conclusions HCWs’ vaccination behaviour needs to be understood in the context of HCWs’ relationships with each other, with management and with patients. Interventions to promote vaccination should take into account both the individual beliefs of targeted HCWs and the organisational context within which they are implemented.

Abstract Background The police and others in occupations where they come into close contact with people experiencing/with mental ill health, often have to manage difficult and complex situations. Training is needed to equip them to recognise and assist when someone has a mental health issue or learning/intellectual disability. We undertook a systematic review of the effectiveness of training programmes aimed at increasing knowledge, changing behaviour and/or attitudes of the trainees with regard to mental ill health, mental vulnerability, and learning disabilities. Methods Databases searched from 1995 onwards included: ASSIA, Cochrane Central Register of Controlled Clinical Trials (CENTRAL), Criminal Justice Abstracts, Embase, ERIC, MEDLINE, PsycINFO, Social Science Citation Index. Courses, training, or learning packages aimed at helping police officers and others who interact with the public in a similar way to deal with people with mental health problems were included. Primary outcomes were change in practice and change in outcomes for the groups of people the trainees come into contact with. Systematic reviews, randomised controlled trials (RCTs) and non- randomised controlled trials (non-RCTs) were included and quality assessed. In addition non-comparative evaluations of training for police in England were included. Results From 8578 search results, 19 studies met the inclusion criteria: one systematic review, 12 RCTs, three prospective non-RCTs, and three non-comparative studies. The training interventions identified included broad mental health awareness training and packages addressing a variety of specific mental health issues or conditions. Trainees included police officers, teachers and other public sector workers. Some short term positive changes in behaviour were identified for trainees, but for the people the trainees came into contact with there was little or no evidence of benefit. Conclusions A variety of training programmes exist for non-mental health professionals who come into contact with people who have mental health issues. There may be some short term change in behaviour for the trainees, but longer term follow up is needed. Research evaluating training for UK police officers is needed in which a number of methodological issues need to be addressed. Trial registration Protocol registration number: PROSPERO: CRD42015015981 .

Abstract Background Risk behaviours, such as smoking and physical inactivity account for up to two-thirds of all cardiovascular deaths, and are associated with substantial increased mortality in many conditions including cancer and diabetes. As risk behaviours are thought to co-occur in individuals we conducted a systematic review of studies addressing clustering or co-occurrence of risk behaviours and their predictors. As the main aim of the review was to inform public health policy in England we limited inclusion to studies conducted in the UK. Methods Key databases were searched from 1990 to 2016. We included UK based cross-sectional and longitudinal studies that investigated risk behaviours such as smoking, physical inactivity, unhealthy diet. High heterogeneity precluded meta-analyses. Results Thirty-seven studies were included in the review (32 cross-sectional and five longitudinal). Most studies investigated unhealthy diet, physical inactivity, alcohol misuse, and smoking. In general adult populations, there was relatively strong evidence of clustering between alcohol misuse and smoking; and unhealthy diet and smoking. For young adults, there was evidence of clustering between sexual risk behaviour and smoking, sexual risk behaviour and illicit drug use, and sexual risk behaviour and alcohol misuse. The strongest associations with co-occurrence and clustering of multiple risk behaviours were occupation (up to 4-fold increased odds in lower SES groups) and education (up to 5-fold increased odds in those with no qualifications). Conclusions Among general adult populations, alcohol misuse and smoking was the most commonly identified risk behaviour cluster. Among young adults, there was consistent evidence of clustering found between sexual risk behaviour and substance misuse. Socio-economic status was the strongest predictor of engaging in multiple risk behaviours. This suggests the potential for interventions targeting multiple risk behaviours either sequentially or concurrently particularly where there is evidence of clustering. In addition, there is potential for intervening at the social or environmental level due to the strong association with socio-economic status.

Background: There is uncertainty about the most appropriate ways to manage non-respiratory sleep disturbances in children with neurodisabilities (NDs). Objective: To assess the clinical effectiveness and safety of NHS-relevant pharmacological and non-pharmacological interventions to manage sleep disturbance in children and young people with NDs, who have non-respiratory sleep disturbance. Data sources: Sixteen databases, including The Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE, were searched up to February 2017, and grey literature searches and hand-searches were conducted. Review methods: For pharmacological interventions, only randomised controlled trials (RCTs) were included. For non-pharmacological interventions, RCTs, non-randomised controlled studies and before-and-after studies were included. Data were extracted and quality assessed by two researchers. Meta-analysis and narrative synthesis were undertaken. Data on parents’ and children’s experiences of receiving a sleep disturbance intervention were collated into themes and reported narratively. Results: Thirty-nine studies were included. Sample sizes ranged from 5 to 244 participants. Thirteen RCTs evaluated oral melatonin. Twenty-six studies (12 RCTs and 14 before-and-after studies) evaluated non-pharmacological interventions, including comprehensive parent-directed tailored (n = 9) and non-tailored (n = 8) interventions, non-comprehensive parent-directed interventions (n = 2) and other non-pharmacological interventions (n = 7). All but one study were reported as having a high or unclear risk of bias, and studies were generally poorly reported. There was a statistically significant increase in diary-reported total sleep time (TST), which was the most commonly reported outcome for melatonin compared with placebo [pooled mean difference 29.6 minutes, 95% confidence interval (CI) 6.9 to 52.4 minutes; p = 0.01]; however, statistical heterogeneity was extremely high (97%). For the single melatonin study that was rated as having a low risk of bias, the mean increase in TST was 13.2 minutes and the lower CI included the possibility of reduced sleep time (95% CI –13.3 to 39.7 minutes). There was mixed evidence about the clinical effectiveness of the non-pharmacological interventions. Sixteen studies included interventions that investigated the feasibility, acceptability and/or parent or clinician views of sleep disturbance interventions. The majority of these studies reported the ‘family experience’ of non-pharmacological interventions. Limitations: Planned subgroup analysis was possible in only a small number of melatonin trials. Conclusions: There is some evidence of benefit for melatonin compared with placebo, but the degree of benefit is uncertain. There are various types of non-pharmacological interventions for managing sleep disturbance; however, clinical and methodological heterogeneity, few RCTs, a lack of standardised outcome measures and risk of bias means that it is not possible to draw conclusions with regard to their effectiveness. Future work should include the development of a core outcome, further evaluation of the clinical effectiveness and cost-effectiveness of pharmacological and non-pharmacological interventions and research exploring the prevention of, and methods for identifying, sleep disturbance. Research mapping current practices and exploring families’ understanding of sleep disturbance and their experiences of obtaining help may facilitate service provision development. Study registration: This study is registered as PROSPERO CRD42016034067. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Hyperhidrosis is uncontrollable excessive sweating that occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. The management of hyperhidrosis is uncertain and variable. Objective: To establish the expected value of undertaking additional research to determine the most effective interventions for the management of refractory primary hyperhidrosis in secondary care. Methods: A systematic review and economic model, including a value-of-information (VOI) analysis. Treatments to be prescribed by dermatologists and minor surgical treatments for hyperhidrosis of the hands, feet and axillae were reviewed; as endoscopic thoracic sympathectomy (ETS) is incontestably an end-of-line treatment, it was not reviewed further. Fifteen databases (e.g. CENTRAL, PubMed and PsycINFO), conference proceedings and trial registers were searched from inception to July 2016. Systematic review methods were followed. Pairwise meta-analyses were conducted for comparisons between botulinum toxin (BTX) injections and placebo for axillary hyperhidrosis, but otherwise, owing to evidence limitations, data were synthesised narratively. A decision-analytic model assessed the cost-effectiveness and VOI of five treatments (iontophoresis, medication, BTX, curettage, ETS) in 64 different sequences for axillary hyperhidrosis only. Results and conclusions: Fifty studies were included in the effectiveness review: 32 randomised controlled trials (RCTs), 17 non-RCTs and one large prospective case series. Most studies were small, rated as having a high risk of bias and poorly reported. The interventions assessed in the review were iontophoresis, BTX, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland (e.g. laser, microwave). There is moderate-quality evidence of a large statistically significant effect of BTX on axillary hyperhidrosis symptoms, compared with placebo. There was weak but consistent evidence for iontophoresis for palmar hyperhidrosis. Evidence for other interventions was of low or very low quality. For axillary hyperhidrosis cost-effectiveness results indicated that iontophoresis, BTX, medication, curettage and ETS was the most cost-effective sequence (probability 0.8), with an incremental cost-effectiveness ratio of £9304 per quality-adjusted life-year. Uncertainty associated with study bias was not reflected in the economic results. Patients and clinicians attending an end-of-project workshop were satisfied with the sequence of treatments for axillary hyperhidrosis identified as being cost-effective. All patient advisors considered that the Hyperhidrosis Quality of Life Index was superior to other tools commonly used in hyperhidrosis research for assessing quality of life. Limitations: The evidence for the clinical effectiveness and safety of second-line treatments for primary hyperhidrosis is limited. This meant that there was insufficient evidence to draw conclusions for most interventions assessed and the cost-effectiveness analysis was restricted to hyperhidrosis of the axilla. Future work: Based on anecdotal evidence and inference from evidence for the axillae, participants agreed that a trial of BTX (with anaesthesia) compared with iontophoresis for palmar hyperhidrosis would be most useful. The VOI analysis indicates that further research into the effectiveness of existing medications might be worthwhile, but it is unclear that such trials are of clinical importance. Research that established a robust estimate of the annual incidence of axillary hyperhidrosis in the UK population would reduce the uncertainty in future VOI analyses. Study registration: This study is registered as PROSPERO CRD42015027803. Funding: The National Institute for Health Research Health Technology Assessment programme.

BackgroundWe performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events.Methods and findingsStudies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published.ConclusionsThere is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events.

Background: Crisis Concordat was established to improve outcomes for people experiencing a mental health crisis. The Crisis Concordat sets out four stages of the crisis care pathway: (1) access to support before crisis point; (2) urgent and emergency access to crisis care; (3) quality treatment and care in crisis; and (4) promoting recovery. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of the models of care for improving outcomes at each stage of the care pathway. Data sources: Electronic databases were searched for guidelines, reviews and, where necessary, primary studies. The searches were performed on 25 and 26 June 2014 for NHS Evidence, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database, and the Health Technology Assessment (HTA) and PROSPERO databases, and on 11 November 2014 for MEDLINE, PsycINFO and the Criminal Justice Abstracts databases. Relevant reports and reference lists of retrieved articles were scanned to identify additional studies. Study selection: When guidelines covered a topic comprehensively, further literature was not assessed; however, where there were gaps, systematic reviews and then primary studies were assessed in order of priority. Study appraisal and synthesis methods: Systematic reviews were critically appraised using the Risk Of Bias In Systematic reviews assessment tool, trials were assessed using the Cochrane risk-of-bias tool, studies without a control group were assessed using the National Institute for Health and Care Excellence (NICE) prognostic studies tool and qualitative studies were assessed using the Critical Appraisal Skills Programme quality assessment tool. A narrative synthesis was conducted for each stage of the care pathway structured according to the type of care model assessed. The type and range of evidence identified precluded the use of meta-analysis. Results and limitations: One review of reviews, six systematic reviews, nine guidelines and 15 primary studies were included. There was very limited evidence for access to support before crisis point. There was evidence of benefits for liaison psychiatry teams in improving service-related outcomes in emergency departments, but this was often limited by potential confounding in most studies. There was limited evidence regarding models to improve urgent and emergency access to crisis care to guide police officers in their Mental Health Act responsibilities. There was positive evidence on clinical effectiveness and cost-effectiveness of crisis resolution teams but variability in implementation. Current work from the Crisis resolution team Optimisation and RElapse prevention study aims to improve fidelity in delivering these models. Crisis houses and acute day hospital care are also currently recommended by NICE. There was a large evidence base on promoting recovery with a range of interventions recommended by NICE likely to be important in helping people stay well. Conclusions and implications: Most evidence was rated as low or very low quality, but this partly reflects the difficulty of conducting research into complex interventions for people in a mental health crisis and does not imply that all research was poorly conducted. However, there are currently important gaps in research for a number of stages of the crisis care pathway. Particular gaps in research on access to support before crisis point and urgent and emergency access to crisis care were found. In addition, more high-quality research is needed on the clinical effectiveness and cost-effectiveness of mental health crisis care, including effective components of inpatient care, post-discharge transitional care and Community Mental Health Teams/intensive case management teams. Study registration: This study is registered as PROSPERO CRD42014013279. Funding: The National Institute for Health Research HTA programme.

BACKGROUND:Modifiable lifestyle risk behaviours such as smoking, unhealthy diet, physical inactivity and alcohol misuse are the leading causes of major, non-communicable diseases worldwide. It is increasingly being recognised that interventions which target more than one risk behaviour may be an effective and efficient way of improving people's lifestyles. To date, there has been no attempt to summarise the global evidence base for interventions targeting multiple risk behaviours. OBJECTIVE:To identify and map the characteristics of studies evaluating multiple risk behaviour change interventions targeted at adult populations in any country. METHODS:Seven bibliographic databases were searched between January, 1990, and January/ May, 2013. Authors of protocols, conference abstracts, and other relevant articles were contacted. Study characteristics were extracted and inputted into Eppi-Reviewer 4. RESULTS:In total, 220 studies were included in the scoping review. Most were randomised controlled trials (62%) conducted in the United States (49%), and targeted diet and physical activity (56%) in people from general populations (14%) or subgroups of general populations (45%). Very few studies had been conducted in the Middle East (2%), Africa (0.5%), or South America (0.5%). There was also a scarcity of studies conducted among young adults (1%), or racial and minority ethnic populations (4%) worldwide. CONCLUSIONS:Research is required to investigate the interrelationships of lifestyle risk behaviours in varying cultural contexts around the world. Cross-cultural development and evaluation of multiple risk behaviour change interventions is also needed, particularly in populations of young adults and racial and minority ethnic populations.

Background: Crime and fear of crime may impact negatively on health and well-being. Interventions to reduce crime and fear of crime, particularly interventions in the physical environment, may be a promising way to improve population-level well-being. Project components: (1) Mapping review of theories and pathways; (2) systematic review of effectiveness; (3) systematic review of UK qualitative data; and (4) focus groups and interviews with stakeholders. Methods: (1) The mapping review was a pragmatic non-systematic review focusing on theoretical literature and observational quantitative studies and development of a theoretical model of pathways. (2 and 3) The systematic reviews followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. In total, 18 databases including EMBASE, MEDLINE, PsycINFO and Science Citation Index were searched from inception to 2010. Studies presenting data on the built environment and the fear of crime were included. Quality assessment was conducted. Data synthesis was conducted narratively for the intervention review, with harvest plots to synthesise data on inequalities, and by thematic analysis for the review of qualitative evidence. (4) Semistructured interviews with nine stakeholders working in community safety and two focus groups with members of the public were conducted to inform the methods of the project and the dissemination of findings. Data were analysed thematically. Results: (1) There are complex and often indirect links between crime, fear of crime, environment, and health and well-being at both individual and population levels. Fear of crime is associated with poorer health outcomes. There is considerable debate about the measurement of fear of crime. Both fear of crime and crime are associated with a range of environmental factors. (2) A total of 12,093 references were screened on abstract for the two systematic reviews. Of these, 47 effectiveness studies (22 controlled and 25 uncontrolled) were included in the systematic review of effectiveness, with 36 conducted in the UK, 10 in the USA and one in the Netherlands. There is some evidence that home security improvements and non-crime-related environmental improvements may improve some fear of crime outcomes. There is little evidence that the following reduce fear of crime: street lighting improvements, closed-circuit television, multicomponent environmental crime prevention programmes or regeneration programmes. The evidence on housing improvement is mixed. Very few data on the health and well-being outcomes of crime reduction interventions were located and the study quality overall is poor. (3) A total of 39 studies were included in the systematic review of qualitative data. Several factors in the physical environment are perceived to impact on fear of crime. However, factors in the local social environment appear to be more important as drivers of fear of crime. There is considerable evidence for limitations on physical activity as a result of fear of crime, but less for mental health impacts. (4) Stakeholders see fear of crime as harder to address than crime and as linked to health and well-being. Environmental interventions, such as Secured by Design, are widely used and positively regarded. Limitations: The review is relatively restricted in its scope and a number of relevant interventions and themes are excluded. The underlying evidence base is of limited quality, particularly for the effectiveness review, and is heterogeneous. Conclusions: Broader social interventions appear more promising than crime-focused environmental interventions as a means of improving fear of crime, health and well-being. The qualitative evidence suggests that fear of crime may impact on physical activity. More broadly, crime and fear of crime appear to be linked to health and well-being mainly as aspects of socioeconomic disadvantage. This review indicates the following gaps in the literature: evaluation research on the health impacts of crime reduction interventions; more robust research on interventions to reduce fear of crime; systematic reviews of non-environmental interventions to reduce fear of crime and systematic reviews of qualitative evidence on other crime-related topics. Funding: The National Institute for Health Research Public Health Research programme.

Objectives: To determine which class of non-opioid analgesics – paracetamol (acetaminophen), NSAIDs or COX-2 inhibitors – is the most effective at reducing morphine consumption and associated adverse effects when used as part of multimodal analgesia following major surgery. Data sources: A systematic literature review was conducted using MEDLINE, EMBASE and CENTRAL databases, searched from January 2003 to February 2009 and updating an earlier review. Review methods: Randomised controlled trials comparing paracetamol, NSAIDs or COX-2 inhibitors to each other or placebo, in adults receiving patient-controlled analgesia (PCA) with morphine following major surgery, were included. The COX-2 inhibitors rofecoxib and valdecoxib were excluded. Only trials that reported 24-hour morphine consumption were included. Other outcomes of interest were morphine-related adverse effects and adverse effects related to the non-opioids. Adequacy of randomisation, concealment of allocation, double blinding, and the flow of patients within the trial was assessed. The main analysis was a mixed treatment comparison (MTC) evaluating the relative effects of the four treatment classes. Four main outcomes were prioritised: 24-hour morphine consumption, sedation, nausea and vomiting, and surgical bleeding. Studies reporting nausea alone were pooled with studies reporting postoperative nausea and vomiting (PONV). Comparisons were described as statistically significant (at 5% level) when the credibility interval (CrI) did not cross 1 for odds ratio (OR) and zero for mean difference (MD). Trials making direct comparisons between the active interventions were also pooled in a meta-analysis using a random effects model. Sensitivity analyses were performed to assess the effects of study quality, individual drugs, and baseline morphine consumption. Results: Sixty relevant studies were identified. When paracetamol, NSAIDs or COX-2 inhibitors were added to PCA morphine, there was a statistically significant reduction in morphine consumption: paracetamol (MD –6.34 mg; 95% CrI –9.02 to –3.65); NSAIDs (MD –10.18; 95% CrI –11.65 to –8.72); and COX-2 inhibitors (MD –10.92; 95% CrI –12.77 to –9.08). NSAIDs and COX-2 inhibitors were both significantly better than paracetamol, and there was no significant difference between NSAIDs and COX-2 inhibitors (MD –0.74; 95% CrI –3.03 to 1.56). There was a significant reduction in nausea and PONV with NSAIDs compared to placebo (OR 0.70; 95% CrI 0.53 to 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared to paracetamol or COX-2 inhibitors. Conclusions: 24-hour morphine consumption decreased by 6.3 mg to 10.9 mg, compared to placebo, when paracetamol, NSAID or COX-2 inhibitors were added to PCA morphine following surgery. Differences in effect between the three drug classes were small and unlikely to be of clinical significance. There does not appear to be a strong case for recommending routine addition of any of the three non-opioids to PCA morphine in the 24 hours immediately after surgery, or for favouring one drug class above the others.