Objectives Systematic reviews (SRs) provide the highest level of evidence for clinical and policy decision-making but quickly become outdated as new studies emerge. Updated systematic reviews (USRs) and living systematic reviews (LSRs) offer 2 frameworks to maintain currency; however, statistical approaches for repeated updates of pairwise meta-analyses (PMAs) and network meta-analyses (NMA) remain heterogeneous. This scoping review aimed to identify, categorize, and summarize existing methods for conducting updated meta-analyses (primarily PMAs and, subject to available evidence, NMAs) in the context of USRs and LSRs, highlighting their properties, as well as their reported advantages and limitations. Methods A scoping review was conducted to identify studies that described or compared methods for updating PMAs or NMAs within USRs or LSRs. We followed the 2020 Joanna Briggs Institute methodology and searched across major bibliographic databases (MEDLINE, Embase, the Cochrane Library, Cochrane CENTRAL, the Cochrane Methodology Register, ERIC, and PsycINFO) from inception to March 6, 2024. Gray literature and expert recommendations supplemented our literature search. Two reviewers independently screened records, extracted data, and categorized methods. Results Of 2710 records identified, 51 studies and 1 companion report met the inclusion criteria. The studies were grouped into 9 methodological categories: Traditional/Cumulative Meta-analysis, Law of Iterated Logarithm, Shuster Sequential Method, Sequential Meta-Analysis, Trial Sequential Analysis, Stochastic Curtailment, Adaptive Design, Likelihood Ratio Test, and Bayesian meta-analysis. Most studies focused on USRs (72.5%) and PMAs (98%). Trial Sequential Analysis was the most frequently encountered approach (46/51), while only 1 study described an extension to NMA. Methods varied widely in error control and ability to adjust for heterogeneity. While most approaches addressed type I error, fewer considered type II error or heterogeneity. Conclusion This scoping review provides the first comprehensive mapping of methods for updated and living meta-analyses. Despite a range of available approaches, no single method demonstrated superiority across contexts. Further research should compare methods empirically, develop accessible software to support reliable, continuously updated evidence synthesis, and extend frameworks to NMA, especially as only a single methodological study was found for NMA.

Background:Skin cancers are some of the most common types of cancer. Dermatology services receive about 1.2 million referrals a year, but only a small minority are confirmed skin cancer. Artificial intelligence may be helpful in the diagnosis of skin cancer by identifying lesions that are or are not cancerous. Objectives:To investigate the clinical and cost-effectiveness of two artificial intelligence technologies: DERM (Deep Ensemble for Recognition of Malignancy, Skin Analytics) and Moleanalyzer Pro (FotoFinder), as decision aids following a primary care referral. Methods:A rapid systematic review of evidence on the two technologies was conducted. A narrative synthesis was performed, with a meta-analysis of diagnostic accuracy data. Published and unpublished cost-effectiveness evidence on the named technologies, as well as other diagnostic technologies were reviewed. A conceptual model was developed that could form the basis of a full economic evaluation. Results:Four studies of DERM and two of Moleanalyzer Pro were subject to full synthesis. DERM had a sensitivity of 96.1% to detect any malignant lesion (95% confidence interval 95.4 to 96.8); at a specificity of 65.4% (95% confidence interval 64.7 to 66.1). For detecting benign lesions, the sensitivity was 71.5% (95% confidence interval 70.7 to 72.3) for a specificity of 86.2% (95% confidence interval 85.4 to 87.0). Moleanalyzer Pro had lower sensitivity, but higher specificity for detecting melanoma than face-to-face dermatologists. DERM might lead to around half of all patients being discharged without assessment by a dermatologist, but a small number of malignant lesions would be missed. Patient and clinical opinions showed substantial resistance to using artificial intelligence without any assessment of lesions by a dermatologist. No published assessments of the cost-effectiveness of the technologies were identified; three assessments related to skin cancer more broadly in a National Health Service setting were identified. These studies employed similar model structures, but the mechanism by which diagnostic accuracy influenced costs and health outcomes differed. An unpublished cost-utility model was provided by Skin Analytics. Several issues with the modelling approach were identified, particularly the mechanisms by which value is driven and how diagnostic accuracy evidence was used. The conceptual model presents an alternative approach, which aligns more closely with the National Institute for Health and Care Excellence reference case and which more appropriately characterises the long-term consequences of basal cell carcinoma. Limitations:The rapid review approach meant that some relevant material may have been missed, and capacity for synthesis was limited. The proposed conceptual model does not capture non-cash benefits associated with demand on dermatologist time. An assessment of the likely budget impact and resource use could not be provided. Conclusions:DERM shows promising diagnostic accuracy for triage and diagnosis of suspicious cancer lesions in selected patients referred from primary care. Its impact on the diagnostic pathway and patient care is, however, uncertain. Moleanalyzer Pro shows promising accuracy for diagnosing melanoma, but its evidence base is limited. Future work:While artificial intelligence has the potential to be cost-effective for the identification of benign lesions, further research addressing the limitations in the diagnostic accuracy evidence is necessary. Without comparative evidence on the diagnostic accuracy of artificial intelligence technologies, their value will remain uncertain. Study registration:This study is registered as PROSPERO CRD42023475705. Funding:This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR136014) and is published in full in Health Technology Assessment; Vol. 30, No. 10. See the NIHR Funding and Awards website for further award information.

Abstract Background Statins and ezetimibe are the preferred lipid-lowering therapies (LLTs) for children with heterozygous familial hypercholesterolaemia (HeFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are newer add-on therapies for individuals not achieving low-density lipoprotein-cholesterol (LDL-C) targets. We evaluated the efficacy and safety of PCSK9i in children aged <18 years with HeFH. Methods Systematic review and pairwise meta-analyses of randomised-controlled trials (RCTs) of evolocumab, alirocumab and inclisiran. Comprehensive bibliographic searches were conducted in February 2026. Risk of bias was assessed with Cochrane RoB 2. Results Of 2798 unique records screened, three RCTs were included (n=451, mean age 13 years, follow-up 24 to 47 weeks). Each trial evaluated either evolocumab, alirocumab or inclisiran against placebo as add-on to baseline LLT. Participants had elevated LDL-C (>3.4 mmol/L [130 mg/dL]) despite stable LLT. Overall risk of bias was low. PCSK9i reduced LDL-C by an average of 35.44% (95% CI −41.74 to −29.14, I 2 =50.8%) and by 1.63 mmol/L [62.93 mg/dL] (95% CI −1.86 to −1.39, I 2 =18.6%) compared with placebo. There was no evidence of differences between PCSK9i and placebo in tolerability, growth and maturation, and overall incidence of adverse events. Conclusions PCSK9i add-on therapy leads to substantial reductions in LDL-C in paediatric patients with HeFH failing to achieve LDL-C targets with standard LLT. While the findings of this review support the use of PCSK9i in a subset of children and young people with HeFH, limited trial numbers and short follow-up periods underscore the need for future high-quality studies evaluating long-term safety, effectiveness and cost-effectiveness. Abstract Figure GRAPHICAL ABSTRACT PCSK9 inhibitors for children and adolescents with HeFH

Objective:The objective of this scoping review is to describe existing guidance documents or studies reporting on the conduct of meta-analyses in updated systematic reviews (USRs) or living systematic reviews (LSRs).Introduction:The rapid increase in the medical literature poses a substantial challenge in keeping systematic reviews up to date. In LSRs, a review is updated with a pre-specified frequency or when some other signalling criterion is triggered. While the LSR framework is well-established, there is uncertainty regarding the most appropriate methods for conducting repeated meta-analyses over time, which may result in sub-optimal decision-making.Inclusion criteria:Studies of any design (including commentaries, books, manuals) providing guidance on conducting meta-analysis in USRs or LSRs.Methods:This review will use the JBI methodology for scoping reviews. We will search multiple medical bibliographic databases (Cochrane Library, Embase, ERIC, MEDLINE, JBI Evidence Synthesis, and PsycINFO), statistical and mathematics databases (COBRA, Current Index to Statistics, MathSciNet, Project Euclid Complete, and zbMATH), pre print archives (Arvix, BioRxiv, and MedRxiv), and unpublished (or gray) literature sources. Two reviewers will independently screen titles, abstracts, and full-text documents, and extract data. Characteristics of recommendations for meta-analysis in USRs and LSRs will be presented using descriptive statistics and categorized concepts.Review registration:Open Science Framework https://osf.io/9c27g

Background and aims Statins, ezetimibe and statins-ezetimibe combination therapy are recommended lipid-lowering therapies (LLTs) in children with heterozygous familial hypercholesterolaemia (HeFH). However, their relative effectiveness is not well understood. We aimed to compare the safety and efficacy of these therapies using direct and indirect comparisons. Methods We conducted systematic review, pairwise and network meta-analyses (NMAs) of randomised-controlled trials (RCTs) of statins, ezetimibe and statins-ezetimibe combination therapy in people <18 years with HeFH. Comprehensive bibliographic searches were conducted in December 2022, and a Medline update in January 2024. NMA models accounted for drug class, statin type and dosage. Results Thirteen RCTs were included (n = 1649, median age 13 years, follow-up 6 weeks-2 years). All LLTs reduced low-density lipoprotein cholesterol (LDL-C) and total cholesterol; statins led to increases in high-density lipoprotein cholesterol and reductions in triglycerides. Statins reduced LDL-C by 33.61 % against placebo (95 % CI 27.58 to 39.63, I-2 = 83 %). Adding ezetimibe to statins reduced LDL-C by an additional 15.85 % (95 % CI 11.91 to 19.79). NMAs showed intermediate-dose statins reduced LDL-C by an additional 4.77 % compared with lower-doses statins (95 % CrI -11.22 to 1.05); higher-dose statins and intermediate-dose statins + ezetimibe may be similarly effective and are probably superior to ezetimibe, intermediate-and lower-dose statins. There was no evidence of differences in maturation, safety or tolerability between LLTs and placebo. Conclusions Statins, ezetimibe and statins-ezetimibe are all effective treatments for children with HeFH, but the magnitude of LDL-C reductions varies and may depend on treatment dosage and combination. No safety or tolerability issues were found. Longer-term safety and effectiveness are uncertain.

INTRODUCTION:Inhaled corticosteroids (ICS) can improve clinical outcomes in patients with chronic obstructive pulmonary disease (COPD) and eosinophilic airway inflammation, but they also increase the risk of side effects like pneumonia. Blood eosinophils guide ICS use, though evidence is limited. The predictors of treatment REsponse to ICS in COPD: a randomised controlled trials (RCTs) individual participant Data re-Evaluation (ICS-RECODE) research programme will leverage data from large RCTs to identify patients who benefit most from ICS with minimal risk. This protocol details an individual participant data (IPD) meta-analysis, assessing ICS safety, efficacy and treatment×covariate interactions to identify predictors of treatment response. METHODS AND ANALYSIS:This meta-analysis will adhere to Cochrane, IPD handbook and Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance. We will conduct a two-stage IPD meta-analysis of RCTs evaluating the addition of ICS to maintenance COPD treatments. Only RCTs with at least 500 participants across all eligible arms will be included, to allow for treatment×covariate interaction evaluation. Primary outcomes are severe and moderate or severe exacerbation rates; secondary outcomes assess both safety and efficacy. Data from each RCT will be reanalysed using rigorous, consistent statistical methods. Treatment×covariate interactions will be assessed at the RCT level. Trial treatment effects and the coefficients of treatment×covariate interaction analyses will be pooled using random effects model meta-analysis. Risk of bias will be appraised using RoB-2 informed by IPD, and certainty of evidence will be assessed with GRADE and the Instrument to assess the Credibility of Effect Modification Analyses.The ICS-RECODE IPD meta-analysis will make use of the best available data to define evidence-based, precision medicine approaches for ICS use in COPD. ETHICS AND DISSEMINATION:The Health Research Authority approved the ICS-RECODE study, exempting it from ethics review (HRA UK, Reference: 24/HRA/0460). Our findings will be published in peer-reviewed journals and shared with the scientific and broader stakeholder communities. PROSPERO REGISTRATION NUMBER:CRD42024508286.

This article consists of a citation of a published article describing research funded by the Health Technology Assessment programme under project number NIHR132948, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/j.jval.2024.03.007 This study aimed to evaluate the cost-effectiveness of anti–vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of −0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties. This publication was funded by the Health Technology Assessment programme as a part of award number NIHR132948. This article reports on one component of the research award Anti-VEGF drugs compared with laser photocoagulation for the treatment of diabetic retinopathy: a systematic review and economic analysis. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR132948] https://doi.org/10.1016/j.jval.2024.03.007

Background Non-proliferative and proliferative diabetic retinopathy are common complications of diabetes and a major cause of sight loss. Anti-vascular endothelial growth factor drugs represent a treatment option for people with diabetic retinopathy and are routinely used to treat various other eye conditions. However, anti-vascular endothelial growth factor drugs are expensive relative to current care options, and it is unclear whether this additional cost is justified when the immediate risk of vision loss is lower compared to patients with more aggressive ophthalmological conditions. Objective To systematically review the evidence supporting the cost-effectiveness of alternative treatments for diabetic retinopathy. Methods A systematic review of all comparative cost-effectiveness studies evaluating any treatment for diabetic retinopathy was conducted. Bibliographic searches were carried out to identify studies reporting on the cost-effectiveness of treatments for diabetic retinopathy; the latest searches were conducted on 28 April 2023. Included studies were synthesised narratively and evaluated with reference to UK decision-making. Studies were grouped by population into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. Results The review identified five studies in the proliferative diabetic retinopathy population, all of which examined the cost-effectiveness of anti-vascular endothelial growth factor treatments compared to pan-retinal photocoagulation. Results of these studies suggest that anti-vascular endothelial growth factor treatments offer some additional benefits in terms of preserved visual acuity but also incur substantial additional costs relative to pan-retinal photocoagulation. Most authors agreed that the additional costs outweigh the limited benefits, especially in certain patient subgroups without pre-existing oedema. As most of the identified evidence considered a US perspective, it is unclear how these results would translate to a UK setting. Two studies were identified in the non-proliferative diabetic retinopathy population. There was limited evidence to support the early use of anti-vascular endothelial growth factor treatment. However, one UK study suggested that early treatment of non-proliferative diabetic retinopathy with pan-retinal photocoagulation is cost-effective compared to delayed pan-retinal photocoagulation. Conclusions Overall, there is a dearth of cost-effectiveness evidence considering the UK context. The identified studies raised doubts about the cost-effectiveness of anti-vascular endothelial growth factor treatments for proliferative diabetic retinopathy. No conclusions can be made regarding the cost-effectiveness of anti-vascular endothelial growth factor treatments for non-proliferative diabetic retinopathy. Future research should focus on developing rigorous model-based cost-effectiveness analyses integrating all available evidence. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.

Background:Proliferative diabetic retinopathy is a major cause of sight loss in people with diabetes, with a high risk of vitreous haemorrhage, tractional retinal detachment and other complications. Panretinal photocoagulation is the primary established treatment for proliferative diabetic retinopathy. Anti-vascular endothelial growth factor drugs are used to treat various eye conditions and may be beneficial for people with proliferative diabetic retinopathy. Objective:To investigate the efficacy and safety of anti-vascular endothelial growth factor therapy for the treatment of proliferative diabetic retinopathy when compared to panretinal photocoagulation. Methods:A systematic review and network meta-analysis of randomised controlled trials comparing anti-vascular endothelial growth factor (alone or in combination) to panretinal photocoagulation in people with proliferative diabetic retinopathy. The database searches were updated in May 2023. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Key outcomes were best corrected visual acuity, diabetic macular oedema and vitreous haemorrhage. Individual participant data were obtained and analysed for three large, high-quality trials in combination with published data from other trials. Network meta-analyses of best corrected visual acuity and meta-analyses of other outcomes combined individual participant data with published data from other trials; regression analyses against patient covariates used just the individual participant data. Results:Twelve trials were included: one of aflibercept, five of bevacizumab and six of ranibizumab. Individual participant data were available from 1 aflibercept and 2 ranibizumab trials, representing 624 patients (33% of the total). When considered together, anti-vascular endothelial growth factors produced a modest, but not clinically meaningful, benefit over panretinal photocoagulation in best corrected visual acuity, after 1 year of follow-up (mean difference in logarithm of the minimum angle of resolution -0.116, 95% credible interval -0.183 to -0.038). There was no clear evidence of a difference in effectiveness between the anti-vascular endothelial growth factors. The benefit of anti-vascular endothelial growth factor appears to decline over time. Analysis of the individual participant data trials suggested that anti-vascular endothelial growth factor therapy may be more effective in people with poorer visual acuity, in those who have vitreous haemorrhage and, possibly, in people with poorer vision generally. Anti-vascular endothelial growth factor was superior to panretinal photocoagulation at preventing macular oedema after 1 year (relative risk 0.48, 95% confidence interval 0.28 to 0.83) and possibly at preventing vitreous haemorrhage (relative risk 0.72, 95% confidence interval 0.47 to 1.10). Anti-vascular endothelial growth factor reduced the incidence of retinal detachment when compared to panretinal photocoagulation (relative risk 0.41, 95% confidence interval 0.22 to 0.77). Data on other adverse events were generally too limited to identify any differences between anti-vascular endothelial growth factor and panretinal photocoagulation. Conclusions:Anti-vascular endothelial growth factor has no clinically meaningful benefit over panretinal photocoagulation for preserving visual acuity. However, anti-vascular endothelial growth factor therapy appears to delay or prevent progression to macular oedema and vitreous haemorrhage. The possibility that anti-vascular endothelial growth factor therapy may be more effective in patients with poorer health and poorer vision merits further clinical investigation. The long-term effectiveness and safety of anti-vascular endothelial growth factor treatment are unclear, particularly as additional panretinal photocoagulation and anti-vascular endothelial growth factor treatment will be required over time. Funding:This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.

Background:Diabetic retinopathy is a major cause of sight loss in people with diabetes. The most severe form, proliferative diabetic retinopathy, carries a high risk of vision loss, vitreous haemorrhage, macular oedema and other harms. Panretinal photocoagulation is the primary treatment for proliferative diabetic retinopathy. Anti-vascular endothelial growth factor drugs are used to treat various eye conditions and may be beneficial for people with diabetic retinopathy. Objective:To investigate the efficacy and safety of anti-vascular endothelial growth factor therapy for the treatment of diabetic retinopathy when compared to panretinal photocoagulation. Methods:A systematic review and network meta-analysis of all published randomised controlled trials comparing anti-vascular endothelial growth factor (alone or in combination with panretinal photocoagulation) to panretinal photocoagulation in people with diabetic retinopathy. The database searches were updated in May 2023. Trials where the primary focus was treatment of macular oedema or vitreous haemorrhage were excluded. Results:A total of 14 trials were included: 3 of aflibercept, 5 of bevacizumab and 6 of ranibizumab. Two trials were of patients with non-proliferative diabetic retinopathy; all others were in proliferative diabetic retinopathy. Overall, anti-vascular endothelial growth factor was slightly better than panretinal photocoagulation at preventing vision loss, measured as best corrected visual acuity, at up to 2 years follow-up [mean difference in the logarithm of the minimum angle of resolution -0.089 (or 3.6 Early Treatment Diabetic Retinopathy Study letters), 95% confidence interval -0.180 to -0.019]. There was no clear evidence of any difference between the anti-vascular endothelial growth factors, but the potential for bias complicated the comparison. One trial found no benefit of anti-vascular endothelial growth factor over panretinal photocoagulation after 5 years. Anti-vascular endothelial growth factor was superior to panretinal photocoagulation at preventing macular oedema (relative risk 0.29, 95% confidence interval 0.18 to 0.49) and vitreous haemorrhage (relative risk 0.77, 95% confidence interval 0.61 to 0.99). There was no clear evidence that the effectiveness of anti-vascular endothelial growth factor varied over time. Conclusions:Anti-vascular endothelial growth factor injections reduce vision loss when compared to panretinal photocoagulation, but the benefit is small and unlikely to be clinically meaningful. Anti-vascular endothelial growth factor may have greater benefits for preventing complications such as macular oedema. Observational studies extending follow-up beyond the 1-year duration of most trials are needed to investigate the longer-term effects of repeated anti-vascular endothelial growth factor injections. Funding:This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.

Objectives: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. Methods: A discrete event simulation model was developed, informed by individual participant data meta -analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. Results: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer qualityadjusted life -years at an additional cost of 3688 pound, with a net health benefit of 20.214 at a 20 pound 000 willingness -to -pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. Conclusions: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real -world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision -threatening complications may be beneficial in resolving uncertainties.

Background: Parkinson's disease is a brain condition causing a progressive loss of co ordination and movement problems. Around 145,500 people have Parkinson's disease in the United Kingdom. Levodopa is the most prescribed treatment for managing motor symptoms in the early stages. Patients should be monitored by a specialist every 6-12 months for disease progression and treatment of adverse effects. Wearable devices may provide a novel approach to management by directly monitoring patients for bradykinesia, dyskinesia, tremor and other symptoms. They are intended to be used alongside clinical judgement. Objectives: To determine the clinical and cost-effectiveness of five devices for monitoring Parkinson's disease: Personal KinetiGraph, Kinesia 360, KinesiaU, PDMonitor and STAT-ON. Methods: We performed systematic reviews of all evidence on the five devices, outcomes included: diagnostic accuracy, impact on decision-making, clinical outcomes, patient and clinician opinions and economic outcomes. We searched MEDLINE and 12 other databases/trial registries to February 2022. Risk of bias was assessed. Narrative synthesis was used to summarise all identified evidence, as the evidence was insufficient for meta-analysis. One included trial provided individual-level data, which was re-analysed. A de novo decision-analytic model was developed to estimate the cost-effectiveness of Personal KinetiGraph and Kinesia 360 compared to standard of care in the UK NHS over a 5-year time horizon. The base-case analysis considered two alternative monitoring strategies: one-time use and routine use of the device. Results: Fifty-seven studies of Personal KinetiGraph, 15 of STAT-ON, 3 of Kinesia 360, 1 of KinesiaU and 1 of PDMonitor were included. There was some evidence to suggest that Personal KinetiGraph can accurately measure bradykinesia and dyskinesia, leading to treatment modification in some patients, and a possible improvement in clinical outcomes when measured using the Unified Parkinson's Disease Rating Scale. The evidence for STAT-ON suggested it may be of value for diagnosing symptoms, but there is currently no evidence on its clinical impact. The evidence for Kinesia 360, KinesiaU and PDMonitor is insufficient to draw any conclusions on their value in clinical practice. The base-case results for Personal KinetiGraph compared to standard of care for one-time and routine use resulted in incremental cost-effectiveness ratios of 67,856 pound and 57,877 pound per quality-adjusted lifeyear gained, respectively, with a beneficial impact of the Personal KinetiGraph on Unified Parkinson's Disease Rating Scale domains III and IV. The incremental cost-effectiveness ratio results for Kinesia 360 compared to standard of care for one-time and routine use were 38,828 pound and 67,203 pound per quality adjusted life-year gained, respectively. Limitations: The evidence was limited in extent and often low quality. For all devices, except Personal KinetiGraph, there was little to no evidence on the clinical impact of the technology. Conclusions: Personal KinetiGraph could reasonably be used in practice to monitor patient symptoms and modify treatment where required. There is too little evidence on STAT-ON, Kinesia 360, KinesiaU or PDMonitor to be confident that they are clinically useful. The cost-effectiveness of remote monitoring appears to be largely unfavourable with incremental cost-effectiveness ratios in excess of 30,000 pound per quality-adjusted life-year across a range of alternative assumptions. The main driver of cost-effectiveness was the durability of improvements in patient symptoms.

Whilst teacher violence against children at school is a significant global issue, it remains a form of child abuse that is rarely explored. The aim of this study was to systematically review the global literature on the effectiveness of school-based interventions to reduce teacher violence against children. MEDLINE, Embase, ASSIA, CINAHL Complete, ERIC and clinical databases were searched from inception to 21 April 2022. Four cluster randomised controlled trials were retrieved from Uganda, Tanzania and Jamaica. The number of schools per study (cluster size) varied from 8 to 42 schools with between 55 and 591 teachers and 220-4789 students. The average student age was between 7 and 15 years old and, on average, the teachers were between 30 and 42 years old. The interventions aimed to reduce teacher violence against children and incorporated teacher training workshops that targeted teacher-student relationships by promoting positive discipline techniques and nurturing learning environments. The use of teacher violence was significantly reduced among intervention groups. This suggests that these interventions may effectively decrease teacher violence against children and therefore should be advocated more widely.

Abstract Background & Aims Non‐surgical therapies are frequently used for patients with early or very early hepatocellular carcinoma (HCC). The aim of this systematic review and network meta‐analysis (NMA) was to evaluate and compare the effectiveness of ablative and non‐surgical therapies for patients with small HCC. Methods Nine databases were searched (March 2021) along with clinical trial registries. Randomised controlled trials (RCTs) of any ablative or non‐surgical therapy versus any comparator in patients with HCC ≤3 cm were eligible. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. The effectiveness of therapies was compared using NMA. Threshold analysis was undertaken to identify which NMA results had less robust evidence. Results Thirty‐seven eligible RCTs were included (including over 3700 patients). Most were from China (n = 17) or Japan (n = 7). Sample sizes ranged from 30 to 308 patients. The majority had a high RoB or some RoB concerns. No RCTs were identified for some therapies and no RCTs reported quality of life outcomes. The results of the NMA and treatment effectiveness rankings were very uncertain. However, the evidence demonstrated that percutaneous ethanol injection was worse than radiofrequency ablation for overall survival (hazard ratio [HR]: 1.45, 95% credible interval [CrI]: 1.16–1.82), progression‐free survival (HR: 1.36, 95% CrI: 1.11–1.67), overall recurrence (relative risk [RR]: 1.19, 95% CrI: 1.02–1.39) and local recurrence (RR: 1.80, 95% CrI: 1.19–2.71). The threshold analysis suggested that robust evidence was lacking for some comparisons. Conclusions It is unclear which treatment is most effective for patients with small HCC because of limitations in the evidence base. It is also not known how these treatments would impact on quality of life. Further high quality RCTs are needed to provide robust evidence but may be difficult to undertake.

Background The economic and social costs of autism are significant. This study evaluates the cost-effectiveness of early intensive Applied Behaviour Analysis (ABA)-based interventions for autistic pre-school children in the UK. Methods A de novo economic analysis was developed in Microsoft Excel comparing early intensive ABA-based interventions compared with treatment as usual (TAU). The analysis used 15.5-year time horizon, with costs and benefits discounted a 3.5%. The model structure was based on cohort structure to capture changes in adaptive behaviour and cognitive ability over time. The analysis was informed by an individual patient data (IPD) meta-analysis of available evidence. Results Adopting a public sector perspective, early intensive ABA-based therapies were associated with greater incremental costs and greater benefits. When pessimistic assumptions were made regarding the long-term effects of treatment incremental costs were £46,103 and incremental quality-adjusted life years (QALYs) were 0.24, resulting in an incremental cost-effectiveness ratio (ICER) of £189,122 per quality-adjusted life year (QALY). When optimistic assumptions were made about long-term effects, incremental costs were £39,233 with incremental benefits of 0.84 QALYs. The resulting ICER was £46,768 per QALY. Scenario analyses emphasised the importance of assumptions made regarding adult outcomes and type of school attended, both of which significantly affect the results of the analysis. Conclusions The results of this economic analysis suggest that early intensive ABA-based interventions are unlikely to represent value for money, based on a £20,000 to £30,000 per QALY threshold typically adopted to inform UK healthcare funding decisions. However, important gaps in the available evidence, limit the strength of the conclusions that can be drawn from the presented analysis. Further research, focusing on the trajectory of autistic children following intervention is likely to be highly beneficial to resolving some of these uncertainties.

BACKGROUNDChronic 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.OBJECTIVESTo assess the clinical effectiveness and cost-effectiveness of coenzyme Q10 in managing chronic heart failure with a reduced ejection fraction.METHODSA 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.RESULTSA 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.LIMITATIONSFor 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.CONCLUSIONSAvailable 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 WORKA 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 REGISTRATIONThis study is registered as PROSPERO CRD42018106189.FUNDINGThis 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.

Systematic reviews are difficult to keep up to date, but failure to do so leads to poor review currency and accuracy. "Living systematic review" (LSR) is an approach that aims to continually update a review, incorporating relevant new evidence as it becomes available. LSRs may be particularly important in fields where research evidence is emerging rapidly, current evidence is uncertain, and new research may change policy or practice decisions.This chapter describes the concept and processes of living systematic reviews. It describes the general principles of LSRs, when they might be of particular value, and how their procedures differ from conventional systematic reviews. The chapter focuses particularly on two methods of sequential meta-analysis that may be particularly useful for LSRs: Trial Sequential Analysis and Sequential Meta-Analysis, which both control for Type I error, Type II error (failing to detect a genuine effect) and take account of heterogeneity.

Introduction Threshold analysis is a novel statistical approach which can be used to investigate which direct comparisons in a network meta-analysis (NMA) have estimated relative effects that may not be robust to changes in the evidence, either due to possible bias, sampling variation, or relevance. Methods In a health technology assessment of the clinical effectiveness of ablative and non-invasive therapies for patients with early hepatocellular carcinoma (HCC), we conducted a threshold analysis to identify treatment comparisons that would be sensitive to changes in the randomized controlled trial (RCT) evidence used in the NMAs, potentially leading to a change in the recommended treatment. The results of the threshold analysis were used to guide a targeted systematic review of high-quality, non-randomized, prospective comparative studies that could strengthen the evidence for those comparisons identified as sensitive to change. Results We conducted NMAs of RCT evidence for four outcomes: overall survival (16 RCTs), progression-free survival (6 RCTs), overall recurrence (7 RCTs), and local recurrence (10 RCTs). The results of the NMAs displayed a high level of uncertainty, attributable to the sparse nature of the network, characterised by interventions being mainly compared in small trials. A targeted systematic review was conducted on relevant interventions that were identified as being sensitive to changes in evidence by the threshold analysis. The studies identified in this review were incorporated into a second NMA to support the RCT evidence. Conclusions Threshold analysis has been typically used as a tool to assess how robust comparisons in an NMA are to additional sources of evidence, but it can also be used to guide the search for additional non-randomized evidence when the available RCT evidence is sparse.