Oral anticoagulants: a systematic overview of reviews on efficacy and safety, genotyping, self-monitoring, and stakeholder experiences.

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.

Biomarkers of systemic treatment response in people with psoriasis: a scoping review.

BACKGROUND: Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. OBJECTIVES: To perform a scoping review to identify and catalogue candidate biomarkers of systemic treatment response in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with systemic treatment response. The main outcomes were any measure of systemic treatment efficacy or safety. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise and mapped to relevant cellular and molecular pathways. RESULTS: Of 71 included studies (67 studying effectiveness outcomes and eight safety outcomes; four studied both), most reported genomic or proteomic biomarkers associated with response to biologics (48 studies). Methodological or reporting limitations frequently compromised the interpretation of findings, including inadequate control for key covariates, lack of adjustment for multiple testing, and selective outcome reporting. We identified candidate biomarkers of efficacy to tumour necrosis factor inhibitors [variation in CARD14, CDKAL1, IL1B, IL12B and IL17RA loci, and lipopolysaccharide-induced phosphorylation of nuclear factor (NF)-κB in type 2 dendritic cells] and ustekinumab (HLA-C*06:02 and variation in an IL1B locus). None were supported by sufficient evidence for clinical use without further validation studies. Candidate biomarkers were found to be involved in the immune cellular crosstalk implicated in psoriasis pathogenesis, most notably antigen presentation, T helper (Th)17 cell differentiation, positive regulation of NF-κB, and Th17 cell activation. CONCLUSIONS: This comprehensive catalogue provides a key resource for researchers and reveals a diverse range of biomarker types and outcomes in the included studies. The candidate biomarkers identified require further evaluation in methodologically robust studies to establish potential clinical utility. Future studies should aim to address the common methodological limitations highlighted in this review to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? Responses to the systemic treatments commonly used to treat psoriasis vary. Biomarkers that accurately predict effectiveness and safety would enable targeted treatment selection, improved patient outcomes and more cost-effective healthcare. What does this study add? This review provides a comprehensive catalogue of investigated biomarkers of systemic treatment response in psoriasis. A diverse range of biomarker types and outcomes was found in the included studies, serving as a key resource for the translational research community.

Biomarkers of disease progression in people with psoriasis: a scoping review.

BACKGROUND: Identification of those at risk of more severe psoriasis and/or associated morbidities offers opportunity for early intervention, reduced disease burden and more cost-effective healthcare. Prognostic biomarkers of disease progression have thus been the focus of intense research, but none are part of routine practice. OBJECTIVES: To identify and catalogue candidate biomarkers of disease progression in psoriasis for the translational research community. METHODS: A systematic search of CENTRAL, Embase, LILACS and MEDLINE was performed for relevant articles published between 1990 and December 2021. Eligibility criteria were studies involving patients with psoriasis (any age, n ≥ 50) reporting biomarkers associated with disease progression. The main outcomes were any measure of skin severity or any prespecified psoriasis comorbidity. Data were extracted by one reviewer and checked by a second; studies meeting minimal quality criteria (longitudinal design and/or use of methods to control for confounding) were formally assessed for bias. Candidate biomarkers were identified by an expert multistakeholder group using a majority voting consensus exercise, and mapped to relevant cellular and molecular pathways. RESULTS: Of 181 included studies, most investigated genomic or proteomic biomarkers associated with disease severity (n = 145) or psoriatic arthritis (n = 30). Methodological and reporting limitations compromised interpretation of findings, most notably a lack of longitudinal studies, and inadequate control for key prognostic factors. The following candidate biomarkers with future potential utility were identified for predicting disease severity: LCE3D, interleukin (IL)23R, IL23A, NFKBIL1 loci, HLA-C*06:02 (genomic), IL-17A, IgG aHDL, GlycA, I-FABP and kallikrein 8 (proteomic), tyramine (metabolomic); psoriatic arthritis: HLA-C*06:02, HLA-B*27, HLA-B*38, HLA-B*08, and variation at the IL23R and IL13 loci (genomic); IL-17A, CXCL10, Mac-2 binding protein, integrin b5, matrix metalloproteinase-3 and macrophage-colony stimulating factor (proteomic) and tyramine and mucic acid (metabolomic); and type 2 diabetes mellitus: variation in IL12B and IL23R loci (genomic). No biomarkers were supported by sufficient evidence for clinical use without further validation. CONCLUSIONS: This review provides a comprehensive catalogue of investigated biomarkers of disease progression in psoriasis. Future studies must address the common methodological limitations identified herein to expedite discovery and validation of biomarkers for clinical use. What is already known about this topic? The current treatment paradigm in psoriasis is reactive. There is a need to develop effective risk-stratified management approaches that can proactively attenuate the substantial burden of disease. Prognostic biomarkers of disease progression have therefore been the focus of intense research. What does this study add? This review is the first to scope, collate and catalogue research investigating biomarkers of disease progression in psoriasis. The review identifies potentially promising candidate biomarkers for further investigation and highlights common important limitations that should be considered when designing and conducting future studies in this area.

Development of a core outcome set for multimorbidity trials in low/middle-income countries (COSMOS): study protocol.

INTRODUCTION: 'Multimorbidity' describes the presence of two or more long-term conditions, which can include communicable, non-communicable diseases, and mental disorders. The rising global burden from multimorbidity is well documented, but trial evidence for effective interventions in low-/middle-income countries (LMICs) is limited. Selection of appropriate outcomes is fundamental to trial design to ensure cross-study comparability, but there is currently no agreement on a core outcome set (COS) to include in trials investigating multimorbidity specifically in LMICs. Our aim is to develop international consensus on two COSs for trials of interventions to prevent and treat multimorbidity in LMIC settings. METHODS AND ANALYSIS: Following methods recommended by the Core Outcome Measures in Effectiveness Trials initiative, the development of these two COSs will occur in parallel in three stages: (1) generation of a long list of potential outcomes for inclusion; (2) two-round online Delphi surveys and (3) consensus meetings. First, to generate an initial list of outcomes, we will conduct a systematic review of multimorbidity intervention and prevention trials and interviews with people living with multimorbidity and their caregivers in LMICs. Outcomes will be classified using an outcome taxonomy. Two-round Delphi surveys will be used to elicit importance scores for these outcomes from people living with multimorbidity, caregivers, healthcare professionals, policy makers and researchers in LMICs. Finally, consensus meetings including all of these stakeholders will be held to agree outcomes for inclusion in the two COSs. ETHICS AND DISSEMINATION: The study has been approved by the Research Governance Committee of the Department of Health Sciences, University of York, UK (HSRGC/2020/409/D:COSMOS). Each participating country/research group will obtain local ethics board approval. Informed consent will be obtained from all participants. We will disseminate findings through peer-reviewed open access publications, and presentations at global conferences selected to reach a wide range of LMIC stakeholders. PROSPERO REGISTATION NUMBER: CRD42020197293.

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.

Effectiveness of interventions for the management of primary frozen shoulder : a systematic review of randomized trials.

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.

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.

Intensive behavioural interventions based on applied behaviour analysis for young children with autism: An international collaborative individual participant data meta-analysis.

LAY ABSTRACT: Early intensive applied behaviour analysis-based interventions are designed to support young autistic children's learning and development. Unfortunately, the available evidence about the effectiveness of these interventions remains unclear. Several reviews have focused on the published findings rather than contacting the authors to collect and analyse data about the individual participants in the original studies. Also, most of the studies were carried out by groups involved in delivering the interventions leading to the potential bias in interpreting the results. Our research team (supported by an international advisory group) carried out an independent individual patient data review by collecting the original participant data from the authors of the studies, to examine the effectiveness of these interventions. The results suggested that early intensive applied behaviour analysis-based interventions might lead to some changes in children's cognitive ability (intelligence quotient) and everyday life skills after 2 years, compared with standard treatments. However, all the studies had problems with the way they were designed. Also, few of the studies looked at outcomes that have been described as most important to autistic people or followed children beyond 2 years. We think that further systematic reviews of the existing evidence are unlikely to add to the findings of our review. Furthermore, we recommend that future research should investigate which types of supports and interventions are most effective for children and families, prioritising outcomes measures that are meaningful for the autism community and include, wherever possible, longer-term follow-up.

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.

Pornography use and sexting amongst children and young people: a systematic overview of reviews.

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.

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.

Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: Systematic review and component network meta-analysis.

BACKGROUND: Complex 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 FINDINGS: We 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. CONCLUSIONS: In 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.

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.

Specialist paediatric palliative care for children and young people with cancer: A mixed-methods systematic review.

BACKGROUND: Specialist paediatric palliative care services are promoted as an important component of palliative care provision, but there is uncertainty about their role for children with cancer. AIM: To examine the impact of specialist paediatric palliative care for children and young people with cancer and explore factors affecting access. DESIGN: A mixed-methods systematic review and narrative synthesis (PROSPERO Registration No. CRD42017064874). DATA SOURCES: Database (CINAHL, Cochrane Database of Systematic Reviews, Embase, MEDLINE, PsycINFO) searches (2000-2019) identified primary studies of any design exploring the impact of and/or factors affecting access to specialist paediatric palliative care. Study quality was assessed using The Mixed Methods Appraisal Tool. RESULTS: An evidence base of mainly low- and moderate-quality studies (n = 42) shows that accessing specialist paediatric palliative care is associated with less intensive care at the end of life, more advance care planning and fewer in-hospital deaths. Current evidence cannot tell us whether these services improve children's symptom burden or quality of life. Nine studies reporting provider or family views identified uncertainties about what specialist paediatric palliative care offers, concerns about involving a new team, association of palliative care with end of life and indecision about when to introduce palliative care as important barriers to access. There was evidence that children with haematological malignancies are less likely to access these services. CONCLUSION: Current evidence suggests that children and young people with cancer receiving specialist palliative care are cared for differently. However, little is understood about children's views, and research is needed to determine whether specialist input improves quality of life.

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.

Interventions for female drug-using offenders.

BACKGROUND: This review represents one in a family of three reviews focusing on the effectiveness of interventions in reducing drug use and criminal activity for offenders. OBJECTIVES: To assess the effectiveness of interventions for female drug-using offenders in reducing criminal activity, or drug use, or both. SEARCH METHODS: We searched 12 electronic bibliographic databases up to February 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 13 trials with 2560 participants. Interventions were delivered in prison (7/13 studies, 53%) and community (6/13 studies, 47%) settings. The rating of bias was affected by the lack of clear reporting by authors, and we rated many items as 'unclear'. In two studies (190 participants) collaborative case management in comparison to treatment as usual did not reduce drug use (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.20 to 2.12; 1 study, 77 participants; low-certainty evidence), reincarceration at nine months (RR 0.71, 95% CI 0.32 to 1.57; 1 study, 77 participants; low-certainty evidence), and number of subsequent arrests at 12 months (RR 1.11, 95% CI 0.83 to 1.49; 1 study, 113 participants; low-certainty evidence). One study (36 participants) comparing buprenorphine to placebo showed no significant reduction in self-reported drug use at end of treatment (RR 0.57, 95% CI 0.27 to 1.20) and three months (RR 0.58, 95% CI 0.25 to 1.35); very low-certainty evidence. No adverse events were reported. One study (38 participants) comparing interpersonal psychotherapy to a psychoeducational intervention did not find reduction in drug use at three months (RR 0.67, 95% CI 0.30 to 1.50; low-certainty evidence). One study (31 participants) comparing acceptance and commitment therapy (ACT) to a waiting list showed no significant reduction in self-reported drug use using the Addiction Severity Index (mean difference (MD) -0.04, 95% CI -0.37 to 0.29) and abstinence from drug use at six months (RR 2.89, 95% CI 0.73 to 11.43); low-certainty evidence. One study (314 participants) comparing cognitive behavioural skills to a therapeutic community programme and aftercare showed no significant reduction in self-reported drug use (RR 0.86, 95% CI 0.58 to 1.27), re-arrest for any type of crime (RR 0.73, 95% CI 0.52 to 1.03); criminal activity (RR 0.80, 95% CI 0.63 to 1.03), or drug-related crime (RR 0.95, 95% CI 0.68 to 1.32). A significant reduction for arrested (not for parole) violations at six months follow-up was significantly in favour of cognitive behavioural skills (RR 0.43, 95% CI 0.25 to 0.77; very low-certainty evidence). A second study with 115 participants comparing cognitive behavioural skills to an alternative substance abuse treatment showed no significant reduction in reincarceration at 12 months (RR 0.70, 95% CI 0.43 to 1.12; low certainty-evidence. One study (44 participants) comparing cognitive behavioural skills and standard therapy versus treatment as usual showed no significant reduction in Addiction Severity Index (ASI) drug score at three months (MD 0.02, 95% CI -0.05 to 0.09) and six months (MD -0.02, 95% CI -0.09 to 0.05), and incarceration at three months (RR 0.46, 95% CI 0.04 to 4.68) and six months (RR 0.51, 95% CI 0.20 to 1.27); very low-certainty evidence. One study (171 participants) comparing a single computerised intervention versus case management showed no significant reduction in the number of days not using drugs at three months (MD -0.89, 95% CI -4.83 to 3.05; low certainty-evidence). One study (116 participants) comparing dialectic behavioural therapy and case management (DBT-CM) versus a health promotion intervention showed no significant reduction at six months follow-up in positive drug testing (RR 0.67, 95% CI 0.43 to 1.03), number of people not using marijuana (RR 1.23, 95% CI 0.95 to 1.59), crack (RR 1.00, 95% CI 0.87 to 1.14), cocaine (RR 1.02, 95% CI 0.93 to 1.12), heroin (RR 1.05, 95% CI 0.98 to 1.13), methamphetamine (RR 1.02, 95% CI 0.87 to 1.20), and self-reported drug use for any drug (RR 1.20, 95% CI 0.92 to 1.56); very low-certainty evidence. One study (211 participants) comparing a therapeutic community programme versus work release showed no significant reduction in marijuana use at six months (RR 1.03, 95% CI 0.19 to 5.65), nor 18 months (RR 1.00, 95% CI 0.07 to 14.45), heroin use at six months (RR 1.59, 95% CI 0.49 to 5.14), nor 18 months (RR 1.92, 95% CI 0.24 to 15.37), crack use at six months (RR 2.07, 95% CI 0.41 to 10.41), nor 18 months (RR 1.64, 95% CI 0.19 to 14.06), cocaine use at six months (RR 1.09, 95% CI 0.79 to 1.50), nor 18 months (RR 0.93, 95% CI 0.64 to 1.35). It also showed no significant reduction in incarceration for drug offences at 18 months (RR 1.45, 95% CI 0.87 to 2.42); with overall very low- to low-certainty evidence. One study (511 participants) comparing intensive discharge planning and case management versus prison only showed no significant reduction in use of marijuana (RR 0.79, 95% CI 0.53 to 1.16), hard drugs (RR 1.12, 95% CI 0.88 to 1.43), crack cocaine (RR 1.08, 95% CI 0.75 to 1.54), nor positive hair testing for marijuana (RR 0.75, 95% CI 0.55 to 1.03); it found a significant reduction in arrests (RR 0.19, 95% CI 0.04 to 0.87), but no significant reduction in drug charges (RR 1.07, 95% CI 0.75 to 1.53) nor incarceration (RR 1.09, 95% CI 0.86 to 1.39); moderate-certainty evidence. One narrative study summary (211 participants) comparing buprenorphine pre- and post-release from prison showed no significant reduction in drug use at 12 months post-release; low certainty-evidence. No adverse effects were reported. AUTHORS' CONCLUSIONS: The studies showed a high degree of heterogeneity for types of comparisons, outcome measures and small samples. Descriptions of treatment modalities are required. On one outcome of arrest (no parole violations), we identified a significant reduction when cognitive behavioural therapy (CBT) was compared to a therapeutic community programme. But for all other outcomes, none of the interventions were effective. Larger trials are required to increase the precision of confidence about the certainty of evidence.

Interventions for drug-using offenders with co-occurring mental health problems.

BACKGROUND: This review represents one from a family of three reviews focusing on interventions for drug-using offenders. Many people under the care of the criminal justice system have co-occurring mental health problems and drug misuse problems; it is important to identify the most effective treatments for this vulnerable population. OBJECTIVES: To assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems in reducing criminal activity or drug use, or both.This review addresses the following questions.• Does any treatment for drug-using offenders with co-occurring mental health problems reduce drug use?• Does any treatment for drug-using offenders with co-occurring mental health problems reduce criminal activity?• Does the treatment setting (court, community, prison/secure establishment) affect intervention outcome(s)?• Does the type of treatment affect treatment outcome(s)? SEARCH METHODS: We searched 12 databases up to February 2019 and checked the reference lists of included studies. We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials designed to prevent relapse of drug use and/or criminal activity among drug-using offenders with co-occurring mental health problems. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane . MAIN RESULTS: We included 13 studies with a total of 2606 participants. Interventions were delivered in prison (eight studies; 61%), in court (two studies; 15%), in the community (two studies; 15%), or at a medium secure hospital (one study; 8%). Main sources of bias were unclear risk of selection bias and high risk of detection bias.Four studies compared a therapeutic community intervention versus (1) treatment as usual (two studies; 266 participants), providing moderate-certainty evidence that participants who received the intervention were less likely to be involved in subsequent criminal activity (risk ratio (RR) 0.67, 95% confidence interval (CI) 0.53 to 0.84) or returned to prison (RR 0.40, 95% CI 0.24 to 0.67); (2) a cognitive-behavioural therapy (one study; 314 participants), reporting no significant reduction in self-reported drug use (RR 0.78, 95% CI 0.46 to 1.32), re-arrest for any type of crime (RR 0.69, 95% CI 0.44 to 1.09), criminal activity (RR 0.74, 95% CI 0.52 to 1.05), or drug-related crime (RR 0.87, 95% CI 0.56 to 1.36), yielding low-certainty evidence; and (3) a waiting list control (one study; 478 participants), showing a significant reduction in return to prison for those people engaging in the therapeutic community (RR 0.60, 95% CI 0.46 to 0.79), providing moderate-certainty evidence.One study (235 participants) compared a mental health treatment court with an assertive case management model versus treatment as usual, showing no significant reduction at 12 months' follow-up on an Addictive Severity Index (ASI) self-report of drug use (mean difference (MD) 0.00, 95% CI -0.03 to 0.03), conviction for a new crime (RR 1.05, 95% CI 0.90 to 1.22), or re-incarceration to jail (RR 0.79, 95% CI 0.62 to 1.01), providing low-certainty evidence.Four studies compared motivational interviewing/mindfulness and cognitive skills with relaxation therapy (one study), a waiting list control (one study), or treatment as usual (two studies). In comparison to relaxation training, one study reported narrative information on marijuana use at three-month follow-up assessment. Researchers reported a main effect < .007 with participants in the motivational interviewing group, showing fewer problems than participants in the relaxation training group, with moderate-certainty evidence. In comparison to a waiting list control, one study reported no significant reduction in self-reported drug use based on the ASI (MD -0.04, 95% CI -0.37 to 0.29) and on abstinence from drug use (RR 2.89, 95% CI 0.73 to 11.43), presenting low-certainty evidence at six months (31 participants). In comparison to treatment as usual, two studies (with 40 participants) found no significant reduction in frequency of marijuana use at three months post release (MD -1.05, 95% CI -2.39 to 0.29) nor time to first arrest (MD 0.87, 95% CI -0.12 to 1.86), along with a small reduction in frequency of re-arrest (MD -0.66, 95% CI -1.31 to -0.01) up to 36 months, yielding low-certainty evidence; the other study with 80 participants found no significant reduction in positive drug screens at 12 months (MD -0.7, 95% CI -3.5 to 2.1), providing very low-certainty evidence.Two studies reported on the use of multi-systemic therapy involving juveniles and families versus treatment as usual and adolescent substance abuse therapy. In comparing treatment as usual, researchers found no significant reduction up to seven months in drug dependence on the Drug Use Disorders Identification Test (DUDIT) score (MD -0.22, 95% CI -2.51 to 2.07) nor in arrests (RR 0.97, 95% CI 0.70 to 1.36), providing low-certainty evidence (156 participants). In comparison to an adolescent substance abuse therapy, one study (112 participants) found significant reduction in re-arrests up to 24 months (MD 0.24, 95% CI 0.76 to 0.28), based on low-certainty evidence.One study (38 participants) reported on the use of interpersonal psychotherapy in comparison to a psychoeducational intervention. Investigators found no significant reduction in self-reported drug use at three months (RR 0.67, 95% CI 0.30 to 1.50), providing very low-certainty evidence. The final study (29 participants) compared legal defence service and wrap-around social work services versus legal defence service only and found no significant reductions in the number of new offences committed at 12 months (RR 0.64, 95% CI 0.07 to 6.01), yielding very low-certainty evidence. AUTHORS' CONCLUSIONS: Therapeutic community interventions and mental health treatment courts may help people to reduce subsequent drug use and/or criminal activity. For other interventions such as interpersonal psychotherapy, multi-systemic therapy, legal defence wrap-around services, and motivational interviewing, the evidence is more uncertain. Studies showed a high degree of variation, warranting a degree of caution in interpreting the magnitude of effect and the direction of benefit for treatment outcomes.