Coenzyme Q10 to manage chronic heart failure with a reduced ejection fraction: a systematic review and economic evaluation.

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.

People living with chronic heart failure suffer from shortness of breath, ankle swelling, tiredness, frequent stays in hospital and reduced quality of life and have shorter lives. The NHS spends over £2 billion each year managing chronic heart failure. Coenzyme Q10 is a vitamin-like substance made by the body that helps cells produce energy. Low levels of coenzyme Q10 in heart muscle may lead to, or exacerbate, chronic heart failure. Taking coenzyme Q10 supplements might improve symptoms or slow deterioration. To the best of our knowledge, we found all randomised clinical trials of coenzyme Q10 in patients with the type of chronic heart failure caused by muscle weakness (i.e. heart failure with reduced ejection fraction, where the heart's pumping function is weaker than normal). We asked the research groups responsible for these trials to provide the patient data that they had collected in their trials. Most research groups did not share their data and so we mainly used information from published trial reports. This limited our planned analyses. We found that taking coenzyme Q10 alongside usual treatment for heart failure with reduced ejection fraction potentially reduced deaths by approximately one-third and reduced readmission to hospital by around 40%. However, these results were uncertain. Side effects were not increased. We had some concerns about how reliable the data were, and it is not clear how well the results apply to UK patients. We also worked out what the benefits and costs to the NHS would be if coenzyme Q10 became available on prescription for patients with heart failure with reduced ejection fraction. Our model found that prescription could be worthwhile; however, a new trial is needed first to make sure that coenzyme Q10 improves outcomes for patients. A new trial would be particularly important because coenzyme Q10 has not been assessed in the same way as prescribed medicines. A new trial could make sure that there is better evidence about whether or not prescribing would be a good use of NHS resources.

Cost Effectiveness of Digital Interventions for Generalised Anxiety Disorder: A Model-Based Analysis.

BACKGROUND: Digital interventions (DIs) are increasingly being used in mental health care, despite limited evidence regarding their value for money. This study aimed to evaluate the cost effectiveness of DIs for generalised anxiety disorder (GAD), in comparison with alternative care options, from the perspective of the UK health care system. METHODS: An open-source decision analytic cohort model was used to extrapolate the results of a network meta-analysis over a patient's lifetime and estimate the costs and outcomes (quality-adjusted life-years) of DIs and their comparators. The net monetary benefit (NMB) and probability of cost effectiveness was estimated for each comparator, and we conducted a Value of Information analysis to evaluate the scale and drivers of uncertainty. RESULTS: DIs were associated with lower NMB compared with medication and with group therapy, but greater NMB compared with non-therapeutic controls and with usual care. DIs that were supported by a clinician, an assistant or a lay person had higher delivery costs than purely patient-self-directed DIs, yielding a greater NMB when opportunity cost was above £3000/QALY. There was considerable uncertainty in the findings driven largely by uncertainty in the estimated treatment effects. The value of further research to establish the effectiveness of DIs for GAD was substantial, at least £12.9 billion. CONCLUSIONS: The high uncertainty about these results does not allow for recommendations based on the cost effectiveness of DIs. However, the analysis highlights areas for future research, and demonstrates that apparent cost savings associated with DIs can be offset by reduced effectiveness.

Reducing lifestyle risk behaviours in disadvantaged groups in high-income countries: A scoping review of systematic reviews.

High prevalence of risk behaviours may exacerbate existing poor health in disadvantaged groups. We aimed to identify and bring together systematic reviews with a focus on reducing risk behaviours in disadvantaged groups and highlight where evidence is lacking. We searched MEDLINE and Embase up to October 2020, with supplementary searching in Epistemonikos and Health Systems Evidence. We included systematic reviews that reported behavioural outcomes and targeted smoking, excessive alcohol use, unhealthy diet, or physical inactivity in groups with the following characteristics: low income or low socio-economic status (SES), unemployed people, homeless people, care leavers, prisoners, refugees or asylum seeker, Gypsies, Travellers, or Roma, people with learning disabilities and people living in disadvantaged areas. Reviews that included primary studies from any high-income country were eligible. Reviews were mapped based on the disadvantaged group(s) and behaviour(s) targeted. Ninety-two reviews were included, with the majority (n = 63) focusing on people with low income or low SES. We identified gaps in the evidence for care leavers; Gypsies, Travellers, and Roma and limited evidence for refugees and unemployed people. Few reviews targeted alcohol use. There was limited evidence on barriers and facilitators to behaviour change. This suggests there is insufficient evidence to inform policy and practice and new reviews or primary studies may be required.

Non-invasive imaging software to assess the functional significance of coronary stenoses: a systematic review and economic evaluation.

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.

Stable angina is a type of chest pain; left untreated, it can lead to heart failure, heart attack and sudden death. To avoid these outcomes, patients may require surgical intervention to open obstructed arteries, known as 'revascularisation'. Patients who might need revascularisation undergo tests to identify blocked arteries. The last line of testing is called invasive fractional flow reserve assessment. This is an invasive measurement of blood flow that involves inserting a wire into an artery after the patient has taken drugs to dilate the artery. It carries some risks and may have side effects. Non-invasive tests have been proposed to precede or replace invasive fractional flow reserve assessments. These include QAngio^® XA 3D/QFR^® (three-dimensional/quantitative flow ratio) (Medis Medical Imaging Systems BV, Leiden, the Netherlands) and CAAS^® vFFR^® (vessel fractional flow reserve) (Pie Medical Imaging BV, Maastricht, the Netherlands) imaging software. This project investigated whether or not these technologies can provide accurate assessments of blood pressure, and if they are a reasonable use of NHS resources. A thorough review of all the literature on the technologies was performed. All data were combined and re-analysed to determine whether or not the tests accurately predict the need for revascularisation and to consider their clinical benefits. An economic analysis was conducted to investigate whether or not using either of these technologies is economically viable. The project found that QAngio XA 3D/QFR can accurately measure blood flow, may be a reasonable alternative to fractional flow reserve, pending more evidence on benefits to patients' health, and is a reasonable use of NHS resources. The current evidence for CAAS vFFR is too limited to draw any firm conclusions.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

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.

In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.

Cost-effectiveness of Microsoft Academic Graph with machine learning for automated study identification in a living map of coronavirus disease 2019 (COVID-19) research.

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.

Interventions for adults with a history of complex traumatic events: the INCiTE mixed-methods systematic review.

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.

Traumatic events that happen often and that are difficult to escape from, such as childhood abuse, are sometimes known as complex traumatic events. People who have a history of complex traumatic events can develop post-traumatic stress disorder and can also suffer from other mental health problems. It is not known if people who experience complex traumatic events can benefit from existing psychological treatments or medications, or if these treatments are acceptable. This review aimed to find out which treatments are most effective and acceptable for mental health problems in people with complex trauma histories, and to identify the frontrunners for future research. We searched electronic databases for evidence about treatment effectiveness and acceptability in adults with a history of complex traumatic events. We found 104 randomised controlled trials and nine non-randomised controlled trials that tested the effectiveness of psychological and/or medications, as well as nine studies that used interviews and focus groups to describe the acceptability of psychological treatments. The studies were split across different populations that included veterans, refugees, people who had experienced childhood sexual abuse and domestic violence, and civilians affected by war. We found that psychological treatments that focused on improving symptoms associated with trauma were effective for reducing post-traumatic stress disorder symptoms and depression across all populations and fewer people dropped out of these treatments, suggesting that they are acceptable. However, trauma-focused treatments were less effective among veterans than among other groups and less effective for reducing other psychological symptoms commonly experienced by people with complex trauma histories. Phased treatments that first start with helping people to feel safe before focusing on trauma symptoms might be beneficial for both post-traumatic stress disorder and additional psychological symptoms. There was little evidence that medications, other than antipsychotics, were effective for post-traumatic stress disorder symptoms. Future work should test if phased treatments are more effective than non-phased treatments over the long term.

Interventions based on early intensive applied behaviour analysis for autistic children: a systematic review and cost-effectiveness analysis.

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.

Autism is a lifelong condition that affects how people understand the world and interact with others. Early intensive applied behaviour analysis-based interventions are an approach designed to help young (preschool) autistic children. This approach is often delivered on a one-to-one basis, for 20­50 hours per week, over a period of several years. This project obtained and analysed the original data from studies of early intensive applied behaviour analysis-based interventions, to determine whether or not these interventions are beneficial. It also investigated whether or not the interventions represent good value for money. The results suggest that early intensive applied behaviour analysis-based interventions may improve children's intelligence, communication, social and life skills more than standard approaches. However, some results could be inaccurate or incorrect, and there was no evidence about other important outcomes, such as the severity of autism and where children went to school. Most studies lasted for around 2 years, which means that it is not known if early intensive applied behaviour analysis-based interventions have meaningful long-term benefits. It was not possible to fully assess whether or not these interventions provided value for money, as the benefits of early intensive applied behaviour analysis-based interventions were unclear, although the available evidence suggested that they did not. Early intensive applied behaviour analysis-based interventions may, however, provide value for money if their effects were to last into adulthood, or if receiving early intensive applied behaviour analysis had a large impact on the type of school children attended. Future studies of early interventions may be helpful, but should consider looking at which components of early applied behaviour analysis-based interventions are the most important, rather than at whether or not they work better than other interventions. Future studies should also follow best current research practice and evaluate outcomes that matter to autistic people and their families.

Assessment of C-Reactive Protein Diagnostic Test Accuracy for Late-Onset Infection in Newborn Infants: A Systematic Review and Meta-analysis.

Importance: Rapid and accurate diagnosis of late-onset infection in newborn infants could inform treatment decisions and avoid unnecessary administration of antibiotics. Objective: To compare the accuracy of serum C-reactive protein (CRP) with that of microbiological blood culture for diagnosing late-onset infection in newborns. Data Sources: MEDLINE (1946-2019), Embase (1946-2019), and Science Citation Index (1900-2019) databases were searched for references (any language). The MeSH search terms included were "exp infant, newborn/" or "premature birth/" plus free text synonyms; and "C-reactive protein/" plus free text synonyms; and "exp sepsis/" or "exp bacterial infections/" plus free text synonyms. The proceedings from relevant conferences and references of identified papers were scrutinized. Authors were contacted to request missing data. Study Selection: Cohort and cross-sectional studies were included that compared the accuracy of serum CRP levels with microbiological culture results to diagnose late-onset (>72 hours after birth) infection in newborns (any gestational age) hospitalized after birth. Two reviewers assessed study eligibility. Among 10 394 records, 148 studies were assessed as full texts. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline extension for Diagnostic Test Accuracy (DTA) reviews was followed. Two reviewers assessed the method quality of each study using guidance from the Cochrane Screening and Diagnostic Test Methods Group (adapted from the Quality Assessment of Diagnostic Accuracy Studies 2). Main Outcomes and Measures: The primary meta-analysis outcome was diagnostic test accuracy of serum CRP level taken at initial investigation of an infant with suspected late-onset infection. The median specificity (proportion of true-negative results) and calculated pooled sensitivity (proportion of true-positive results) were determined by generating hierarchical summary receiver characteristic operating curves. Results: In total, 22 studies with 2255 infants were included (sample size range, 11-590 infants). Participants in most studies were preterm (<37 weeks) or very low-birth weight (<1500 g) infants. Two studies additionally enrolled infants born at term. Most studies (16) used a prespecified CRP level cutoff for a "positive" index test (5-10 mg/L), and most studies (17) used the culture of a pathogenic microorganism from blood as the reference standard. Risk of bias was low with independent assessment of index and reference tests. At median specificity (0.74), pooled sensitivity was 0.62 (95% CI, 0.50-0.72). Adding serum CRP level to the assessment of an infant with a 40% pretest probability of late-onset infection (the median for the included studies) generated posttest probabilities of 26% for a negative test result and 61% for a positive test result. Conclusions and Relevance: The findings suggest that determination of serum CRP level at initial evaluation of an infant with suspected late-onset infection is unlikely to aid early diagnosis or to select infants to undergo further investigation or treatment with antimicrobial therapy or other interventions.

The development of search filters for adverse effects of medical devices in medline and embase.

BACKGROUND: Objectively derived search filters for adverse drug effects and complications in surgery have been developed but not for medical device adverse effects. OBJECTIVE: To develop and validate search filters to retrieve evidence on medical device adverse effects from ovid medline and embase. METHODS: We identified systematic reviews from Epistemonikos and the Health Technology Assessment (hta) database. Included studies within these reviews that reported on medical device adverse effects were randomly divided into three test sets and one validation set of records. Using word frequency analysis from one test set, we constructed a sensitivity maximising search strategy. This strategy was refined using two other test sets, then validated. RESULTS: From 186 systematic reviews which met our inclusion criteria, 1984 unique included studies were available from medline and 1986 from embase. Generic adverse effects searches in medline and embase achieved 84% and 83% sensitivity. Recall was improved to over 90%, however, when specific adverse effects terms were added. CONCLUSION: We have derived and validated novel search filters that retrieve over 80% of records with medical device adverse effects data in medline and embase. The addition of specific adverse effects terms is required to achieve higher levels of sensitivity.

Ceritinib for Untreated Anaplastic Lymphoma Kinase-Positive Advanced Non-Small-Cell Lung Cancer: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the company that manufactures ceritinib (Zykadia®, Novartis) to submit evidence on the clinical and cost effectiveness of the drug, as a first-line treatment for adults with anaplastic lymphoma kinase (ALK)-positive (+) advanced non-small-cell lung cancer (NSCLC), as part of the Institute's single technology appraisal (STA) process. The CRD (Centre for Reviews and Dissemination) and CHE (Centre for Health Economics) Technology Assessment Group at the University of York was commissioned to act as the Evidence Review Group (ERG). This paper describes the Company's submission (CS), the ERG review and NICE's subsequent decisions. The evidence submitted in support of ceritinib, as the first-line treatment in ALK+ advanced NSCLC, was a phase III, international, multicentre, open-label randomised controlled trial (RCT) comparing ceritinib with pemetrexed/cisplatin plus pemetrexed maintenance therapy (chemotherapy [CT] group). The results indicated that ceritinib prolonged progression-free survival (PFS) compared with CT. The only comparator considered in the CS was crizotinib. The evidence selected in support of crizotinib was PROFILE 1014, an open-label RCT of crizotinib, compared with pemetrexed/cisplatin CT (without maintenance therapy), in previously untreated advanced or metastatic ALK+ NSCLC. The design and population of PROFILE 1014 was similar to that of ASCEND-4, though there were some differences between the trials. The Company considered it not possible to perform an 'anchor-based' analysis of first-line ceritinib and crizotinib, and presented a Matching-Adjusted Indirect Comparison (MAIC) of ceritinib and crizotinib using only the ALK inhibitor arm of ASCEND-4 and PROFILE 1014. The indirect comparison suggests that ceritinib may be more effective in prolonging PFS than crizotinib. The ERG agreed that an indirect comparison using only the ALK inhibitor arm of the trials was the only option available in the present assessment; however, a number of limitations and potential bias were identified in this analysis. The Company's model estimated that ceritinib was cost effective when compared with crizotinib. However, the ERG highlighted several concerns with the Company's analysis; the ERG's preferred base case estimated an incremental cost-effectiveness ratio of £69,255 per quality-adjusted life-year (no patient access scheme [PAS] included). The ERG considered the economic analysis to be sensitive to changes in assumption used, partly due to the due to the immaturity of the overall survival data from trials, which leads to uncertainty around the extrapolation used. The NICE Appraisal Committee concluded that ceritinib is recommended, within its marketing authorisation, as an option for untreated ALK+ advanced NSCLC in adults, if the Company provides it with the discount agreed in the PAS.

Brodalumab for the Treatment of Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence single technology appraisal process, brodalumab was assessed to determine the clinical and cost effectiveness of its use in the treatment of moderate-to-severe plaque psoriasis. The Centre for Reviews and Dissemination and the Centre for Health Economics Technology Assessment Group at the University of York were commissioned to act as the independent Evidence Review Group. This article provides a summary of the Evidence Review Group's review of the company's submission, the Evidence Review Group report and the National Institute for Health and Care Excellence Appraisal Committee's subsequent guidance issued in March 2018. The main clinical effectiveness data were derived from three well-conducted, multicentre, double-blind randomised controlled trials. The trials demonstrated that brodalumab statistically significantly reduced the severity of psoriasis and its impact on health-related quality of life, compared with placebo, at 12 weeks. In comparison with ustekinumab, statistically significantly more patients taking brodalumab had reduced psoriasis severity at 12 weeks. Psoriasis severity and quality of life also appeared improved at 52 weeks, although statistical significance was not assessed. Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab. A network meta-analysis was presented, comparing brodalumab with other therapies available at the same point in the treatment pathway (i.e. in patients for whom standard systemic therapy or phototherapy is inadequately effective, not tolerated or contraindicated). The network meta-analysis ranked treatments in order of effectiveness, in terms of achieving different levels of Psoriasis Area and Severity Index response. The results indicated that brodalumab had a similar probability of response to ixekizumab, secukinumab and infliximab and a higher probability of response than ustekinumab, adalimumab, etanercept, apremilast, dimethyl fumarate and placebo. The company's economic model compared nine treatment sequences that included three lines of active therapy, consisting of brodalumab and other comparators recommended by the National Institute for Health and Care Excellence, followed by best supportive care. The sequence with brodalumab in the first-line position dominated sequences that started with adalimumab, infliximab, secukinumab and ustekinumab. The incremental cost-effectiveness ratio of the brodalumab sequence compared to less effective and non-dominated sequences ranged from £7145 (vs. the etanercept sequence) to £13,353 (vs. the dimethyl fumarate sequence) per quality-adjusted life-year gained. The incremental cost-effectiveness ratio for the more costly and effective ixekizumab sequence was £894,010 per quality-adjusted life-year gained compared to the brodalumab sequence. At a threshold of £20,000 per quality-adjusted life-year gained, the brodalumab sequence had the highest probability of being cost effective (96%). The main limitation of the company's economic model was the restrictive nature of the sequences compared. Twelve separate scenarios based on key uncertainties were explored by the Evidence Review Group. The only scenarios where brodalumab was ranked lower than first were not considered to be more appropriate or plausible than the assumptions or scenarios included in the company's base case. The treatment rankings identified in the Evidence Review Group's alternative base case were identical to those derived from the company's base case model. At the first National Institute for Health and Care Excellence Appraisal Committee meeting, the Committee concluded that brodalumab appears to be as effective as other anti-interleukin-17 agents and is cost effective, based on the discount agreed in the patient access scheme. Brodalumab is recommended as an option for treating adults with severe plaque psoriasis (defined by a total Psoriasis Area and Severity Index score of 10 or more and a Dermatology Life Quality Index score of more than 10) who have not responded to other systemic non-biological therapies. Brodalumab should be stopped at 12 weeks if the psoriasis has not responded adequately.

Pharmacological and non-pharmacological interventions for non-respiratory sleep disturbance in children with neurodisabilities: a systematic review.

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.

Support for adults with autism spectrum disorder without intellectual impairment: Systematic review.

Adults with autism spectrum disorder without intellectual impairment may benefit from a range of support services. This article presents the results of a systematic review assessing the effectiveness of supportive interventions for adults with autism spectrum disorder without intellectual impairment. A total of 32 studies were included; most focused on younger male participants. Although evidence was lacking for most types of intervention, employment programmes and social skills training were found to be effective for more proximal outcomes such as social skills. Evidence that any intervention improves mental health or well-being was very limited. Most interventions focused on mitigating specific deficits, rather than on providing broader support. Further research is needed on the effectiveness of supportive interventions such as advocacy and mentoring.

Interventions for hyperhidrosis in secondary care: a systematic review and value-of-information analysis.

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.

Social prescribing: less rhetoric and more reality. A systematic review of the evidence.

OBJECTIVES: Social prescribing is a way of linking patients in primary care with sources of support within the community to help improve their health and well-being. Social prescribing programmes are being widely promoted and adopted in the UK National Health Service and so we conducted a systematic review to assess the evidence for their effectiveness. SETTING/DATA SOURCES: Nine databases were searched from 2000 to January 2016 for studies conducted in the UK. Relevant reports and guidelines, websites and reference lists of retrieved articles were scanned to identify additional studies. All the searches were restricted to English language only. PARTICIPANTS: Systematic reviews and any published evaluation of programmes where patient referral was made from a primary care setting to a link worker or facilitator of social prescribing were eligible for inclusion. Risk of bias for included studies was undertaken independently by two reviewers and a narrative synthesis was performed. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes of interest were any measures of health and well-being and/or usage of health services. RESULTS: We included a total of 15 evaluations of social prescribing programmes. Most were small scale and limited by poor design and reporting. All were rated as a having a high risk of bias. Common design issues included a lack of comparative controls, short follow-up durations, a lack of standardised and validated measuring tools, missing data and a failure to consider potential confounding factors. Despite clear methodological shortcomings, most evaluations presented positive conclusions. CONCLUSIONS: Social prescribing is being widely advocated and implemented but current evidence fails to provide sufficient detail to judge either success or value for money. If social prescribing is to realise its potential, future evaluations must be comparative by design and consider when, by whom, for whom, how well and at what cost. TRIAL REGISTRATION NUMBER: PROSPERO Registration: CRD42015023501.

A systematic review on the clustering and co-occurrence of multiple risk behaviours.

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.

The Clinical and Cost Effectiveness of Vortioxetine for the Treatment of a Major Depressive Episode in Patients With Failed Prior Antidepressant Therapy: A Critique of the Evidence.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of vortioxetine (Lundbeck) to submit clinical and cost-effectiveness evidence for vortioxetine for the treatment of major depressive episodes (MDEs), as part of the Institute's Single Technology Appraisal (STA) process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA367 issued in November 2015. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. Two phase III randomised controlled trials for a second-line population involving vortioxetine were identified-REVIVE and TAK318. These two trials represent only 972 of over 7000 patients included in trials of vortioxetine. In REVIVE, there was a statistically significant difference in depression scores favouring vortioxetine compared with agomelatine [mean Montgomery-Åsberg Depression Rating Scale (MADRS) score difference of 2.16 points; 95 % confidence interval 0.81-3.51]. The ERG concluded that, based on all the evidence, rather than the substantially restricted subset of evidence originally considered by the manufacturer, vortioxetine is likely to be similar in efficacy to other analysed antidepressants [citalopram, sertraline, escitalopram and venlafaxine extended release (XR)], and may be more efficacious than agomelatine and inferior to duloxetine. The ERG concluded that vortioxetine may be more tolerable than other analysed antidepressants (sertraline, venlafaxine XR and bupropion), although the limited data prevent firm conclusions. The base-case incremental cost-effectiveness ratio (ICER) of vortioxetine reported by the manufacturer was £378 per quality-adjusted life-year (QALY) compared with venlafaxine. Given considerable concerns about the indirect treatment comparison undertaken by the manufacturer, the use of only a restrictive subset of the available evidence, and concerns regarding comparators and structural model assumptions, the ERG believes that this is not a valid estimate of the cost effectiveness of vortioxetine. Following corrections made to the model made by the ERG, the estimated cost effectiveness of vortioxetine was sensitive to the source of evidence used, in addition to whether certain comparators were excluded. The NICE thus asked the manufacturer to provide a revised economic model, which incorporated the broader evidence base and considered the cost effectiveness of vortioxetine as a third-line treatment. Assuming equal efficacy, vortioxetine was shown to be less costly and generate a higher QALY gain than relevant comparators at the third-line of treatment owing to its tolerability and adverse event profile. The NICE Appraisal Committee recommended vortioxetine as an option for treating MDEs in adults whose condition has responded inadequately to two antidepressants within the current episode.

Improving outcomes for people in mental health crisis: a rapid synthesis of the evidence for available models of care.

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.

Fear of crime and the environment: systematic review of UK qualitative evidence.

BACKGROUND: The fear of crime may have negative consequences for health and wellbeing. It is influenced by factors in the physical and social environment. This study aimed to review and synthesize qualitative evidence from the UK on fear of crime and the environment. METHODS: Eighteen databases were searched, including crime, health and social science databases. Qualitative studies conducted in the UK which presented data on fear of crime and the environment were included. Quality was assessed using Hawker et al.'s framework. Data were synthesized thematically. RESULTS: A total of 40 studies were included in the review. Several factors in the physical environment are perceived to impact on fear of crime, including visibility and signs of neglect. However, factors in the local social environment appear to be more important as drivers of fear of crime, including social networks and familiarity. Broader social factors appear to be of limited relevance. There is considerable evidence for limitations on physical activity as a result of fear of crime, but less for mental health impacts. CONCLUSIONS: Fear of crime represents a complex set of responses to the environment. It may play a role in mediating environmental impacts on health and wellbeing.