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Background Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention. Methods The By-Band study was designed in the UK in 2009-2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux-en- Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation. Results The pilot phase recruited over 13 months in 2013-2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder. Conclusion Adaptation of a two-group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (/). [ABSTRACT FROM AUTHOR]

Several countries include medium-chain acyl- CoA dehydrogenase ( MCAD) deficiency, a rare autosomal recessive disease, in their newborn screening programmes despite prevalence uncertainty. We estimated the frequency of its most common mutation, c. 985A>G, tested for regional differences and compared screening and genotype frequencies. We identified 43 studies reporting the frequency of c. 985A>G over 10 million individuals, and pooled frequency data using a novel Bayesian approach. We found significant variation in the frequency of the mutation across regions supporting a reported founder effect. The proportion of c. 985A>G homozygotes was highest in Western Europe with 4.1 (95% CI: 2.8-5.6) per 100,000 individuals, then the New World (3.2, 95% CI: 2.0-4.7), Southern (1.2, 95% CI: 0.6-2.0) and Eastern European regions (0.9, 95% CI: 0.5-1.7). No cases with the mutation were identified in Asian and Middle Eastern regions. Significant differences were found in some countries between the genotype and screening allele frequency of c. 985A>G. Our predictions could inform the frequency of the mutation by region and our approach could apply to other genetic conditions. [ABSTRACT FROM AUTHOR]

Background: Day surgery for unicompartmental knee replacement (UKR) could potentially reduce hospital costs. We aimed to measure the impact of introducing a day surgery UKR pathway on mean length of stay (LOS) and costs for the UK NHS, compared to an accelerated inpatient pathway. Secondly, the study aimed to compare the magnitude of costs using three costing approaches: top-down costing; simple micro-costing; and real-world costing., Methods: We conducted an observational, before-and-after study of 2,111 UKR patients at one NHS hospital: 1,094 patients followed the day surgery pathway between September 2017 and February 2020; and 1,017 patients followed the accelerated inpatient pathway between September 2013 and February 2016. Top-down costs were estimated using Average NHS Costs. Simple micro-costing used the cost per bed-day. Real-world costs for this centre were estimated by costing actual changes in staffing levels., Results: 532 (48.5%) patients in the day surgery pathway were discharged on the day of surgery compared with 36 (3.5%) patients in the accelerated inpatient pathway. The day surgery pathway reduced the mean LOS by 2.2 (95% CI: 1.81, 2.53) nights and was associated with an 18% decrease in Average NHS Costs (p < 0.001). Mean savings were £1,429 per patient with the Average NHS Costs approach, £905 per patient with the micro-costing approach, and £577 per patient with the "real-world" costing approach. Overall, moving NHS UKR surgeries to a day surgery pathway could save the NHS £8,659,740 per year., Conclusion: Day surgery for UKR could produce substantial cost savings for hospitals and the NHS., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DM has received or will receive benefits for personal or professional use from a commercial party related directly to the subject of this article. The other authors declare that they have no competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity., Methods: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment., Findings: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483)., Interpretation: SRT can reduce ranibizumab treatment burden without compromising vision., Funding: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme., Competing Interests: Declaration of interests Oraya/Zeiss provided free use of the SRT device at the STAR National Treatment Centres. BCR, TP, YW, HAW, JMO, and JP declare no competing interests. TLJ is a consultant or adviser to 2CTech, Alcon, Dutch Ophthalmic Research Centre, iLumen, Opthea, Outlook Therapeutics, Oxurion, and Regeneron. He has received conference support from Roche, and an advisory board payment from Oraya in 2013. TP has participated in advisory boards for Apellis and received investigator initiated research funds paid to her institution from Boehringen Ingelheim; as well as receiving speakers fees from Heidelberg, Zeiss, and Optos. UC serves on a data monitoring committee for Adverum and is a consultant to Apellis, Boehringer Ingelheim, Isarna, Iveric, and Hoffman La Roche. JEN is an adviser to Solvemed, has received lecture fees from Novartis, and has received conference support from Dutch Ophthalmic Research Centre. HD and SW are financially supported in part by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre. CNL has undertaken contracting work for Opthea. TLJ, LR, RD, CNL, CL, PC and JEN's NHS employer receives site fees for patients enrolled on commercial retinal trials of AMD and other conditions., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Importance: Etiologic diagnoses for rare diseases can involve a diagnostic odyssey, with repeated health care interactions and inconclusive diagnostics. Prior studies reported cost savings associated with genome-wide sequencing (GWS) compared with cytogenetic or molecular testing through rapid genetic diagnosis, but there is limited evidence on whether diagnosis from GWS is associated with reduced health care costs., Objective: To measure changes in health care costs after diagnosis from GWS for Canadian and English children with suspected rare diseases., Design, Setting, and Participants: This cohort study was a quasiexperimental retrospective analysis across 3 distinct English and Canadian cohorts, completed in 2023. Mixed-effects generalized linear regression was used to estimate associations between GWS and costs in the 2 years before and after GWS. Difference-in-differences regression was used to estimate associations of genetic diagnosis and costs. Costs are in 2019 US dollars. GWS was conducted in a research setting (Genomics England 100 000 Genomes Project [100KGP] and Clinical Assessment of the Utility of Sequencing and Evaluation as a Service [CAUSES] Research Clinic) or clinical outpatient setting (publicly reimbursed GWS in British Columbia [BC], Canada). Participants were children with developmental disorders, seizure disorders, or both undergoing GWS between 2014 and 2019. Data were analyzed from April 2021 to September 2023., Exposures: GWS and genetic diagnosis., Main Outcomes and Measures: Annual health care costs and diagnostic costs per child., Results: Study cohorts included 7775 patients in 100KGP, among whom 788 children had epilepsy (mean [SD] age at GWS, 11.6 [11.1] years; 400 female [50.8%]) and 6987 children had an intellectual disability (mean [SD] age at GWS, 8.2 [8.4] years; 2750 female [39.4%]); 77 patients in CAUSES (mean [SD] age at GWS, 8.5 [4.4] years; 33 female [42.9%]); and 118 publicly reimbursed GWS recipients from BC (mean [SD] age at GWS, 5.5 [5.2] years; 58 female [49.2%]). GWS diagnostic yield was 143 children (18.1%) for those with epilepsy and 1323 children (18.9%) for those with an intellectual disability in 100KGP, 47 children (39.8%) in the BC publicly reimbursed setting, and 42 children (54.5%) in CAUSES. Mean annual per-patient spending over the study period was $5283 (95% CI, $5121-$5427) for epilepsy and $3373 (95% CI, $3322-$3424) for intellectual disability in the 100KGP, $724 (95% CI, $563-$886) in CAUSES, and $1573 (95% CI, $1372-$1773) in the BC reimbursed setting. Receiving a genetic diagnosis from GWS was not associated with changed costs in any cohort., Conclusions and Relevance: In this study, receiving a genetic diagnosis was not associated with cost savings. This finding suggests that patient benefit and cost-effectiveness should instead drive GWS implementation.

Bacteria are becoming increasingly resistant to antibiotics, reducing our ability to treat infections and threatening to undermine modern health care. Optimising antibiotic use is a key element in tackling the problem. Traditional economic evaluation methods do not capture many of the benefits from improved antibiotic use and the potential impact on resistance. Not capturing these benefits is a major obstacle to optimising antibiotic use, as it fails to incentivise the development and use of interventions to optimise the use of antibiotics and preserve their effectiveness (stewardship interventions). Estimates of the benefits of improving antibiotic use involve considerable uncertainty as they depend on the evolution of resistance and associated health outcomes and costs. Here we discuss how economic evaluation methods might be adapted, in the face of such uncertainties. We propose a threshold-based approach that estimates the minimum resistance-related costs that would need to be averted by an intervention to make it cost-effective. If it is probable that without the intervention costs will exceed the threshold then the intervention should be deemed cost-effective., (© 2024. The Author(s).)

Despite the emerging evidence in recent years, successful implementation of clinical genomic sequencing (CGS) remains limited and is challenged by a range of barriers. These include a lack of standardized practices, limited economic assessments for specific indications, limited meaningful patient engagement in health policy decision-making, and the associated costs and resource demand for implementation. Although CGS is gradually becoming more available and accessible worldwide, large variations and disparities remain, and reflections on the lessons learned for successful implementation are sparse. In this commentary, members of the Global Economics and Evaluation of Clinical Genomics Sequencing Working Group (GEECS) describe the global landscape of CGS in the context of health economics and policy and propose evidence-based solutions to address existing and future barriers to CGS implementation. The topics discussed are reflected as two overarching themes: (1) system readiness for CGS and (2) evidence, assessments, and approval processes. These themes highlight the need for health economics, public health, and infrastructure and operational considerations; a robust patient- and family-centered evidence base on CGS outcomes; and a comprehensive, collaborative, interdisciplinary approach., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Competing Interests: Declaration of interests HVF acknowledges former chairing of the Joint Committee on Genomics in Medicine for the Royal Colleges 2018–22, and royalties from UpToDate (as a Section Editor in Genetics). RL acknowledges membership of the Foetal Maternal and Child Health Group of the UK National Screening Committee. MM acknowledges membership of a steering group for the 2024 St Andrews Evidence Based Early Diagnosis conference. AOMW acknowledges non-remunerated roles on the Science Advisory Committee of Genomics England and the Medical Research Council Molecular and Cellular Medicine Board. SW acknowledges non-financial support from Illumina (outside of the submitted work). All other authors declare no competing interests.

Introduction: Adalimumab is an effective treatment for autoimmune non-infectious uveitis (ANIU), but it is currently only funded for a minority of patients with ANIU in the UK as it is restricted by the National Institute for Health and Care Excellence guidance. Ophthalmologists believe that adalimumab may be effective in a wider range of patients. The Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness (ASTUTE) trial will recruit patients with ANIU who do and do not meet funding criteria and will evaluate the effectiveness and cost-effectiveness of adalimumab versus placebo as an add-on therapy to standard care., Methods and Analysis: The ASTUTE trial is a multicentre, parallel-group, placebo-controlled, pragmatic randomised controlled trial with a 16-week treatment run-in (TRI). At the end of the TRI, only responders will be randomised (1:1) to 40 mg adalimumab or placebo (both are the study investigational medicinal product) self-administered fortnightly by subcutaneous injection. The target sample size is 174 randomised participants. The primary outcome is time to treatment failure (TF), a composite of signs indicative of active ANIU. Secondary outcomes include individual TF components, retinal morphology, adverse events, health-related quality of life, patient-reported side effects and visual function, best-corrected visual acuity, employment status and resource use. In the event of TF, open-label drug treatment will be restarted as per TRI for 16 weeks, and if a participant responds again, allocation will be switched without unmasking and treatment with investigational medicinal product restarted., Ethics and Dissemination: The trial received Research Ethics Committee (REC) approval from South Central - Oxford B REC in June 2020. The findings will be presented at international meetings, by peer-reviewed publications and through patient organisations and newsletters to patients, where available., Trial Registration: ISRCTN31474800. Registered 14 April 2020., Competing Interests: Competing interests: CAR received support from the National Institute for Health and Care Research (NIHR) for the project associated with this manuscript, which was paid to the University of Bristol. KP, MH, LC, MPYL, SB and BCR received support from the NIHR for the project associated with this manuscript, which contributed to their salary. SW, TP, SMS, NAVB and AD received support from the NIHR for the project associated with this manuscript, which was paid to their institution. SMS is the chair of the NIHR Uveitis Clinical Study Group. PAK receives support from UK Research and Innovation and Moorfields Eye Charity. PAK reports payment for consulting for Novartis, Boehringer-Ingleheim, Apellis, Abbvie, Roche and Adecco. PAK reports payment or honoraria for educational events for Novartis, Gyroscope, Bayer, Thea, Boehringer-Ingleheim, Apellis, Abbvie and Alimera. PAK participates on an advisory board for RetinAI, Novartis, Boehringer-Ingleheim, Roche and Abbvie. PAK reports patents for Google US10198832B2 (issued) and Google US20220301152A1 (pending). PAK reports stock with Big Picture Medical (stocks) and Bitfount (stock options). NAVB receives support from Wellcome Trust and recently receives support from Indonesian Endowment Fund for Education paid to their institution. NAVB reports payments for consulting for Roche. NAVB reports payment or honoria for educational events for Alimera Sciences. NAVB is a member of the Scientific Committee of the Royal College of Ophthalmologists. AD receives support from NIHR Biomedical Research Centre, Janssen Pharmaceuticals, Macular Society, MRC Cluster Consortium Awards and Arthritis Research UK, which is paid to his institution. AD receives royalties from The Eye Basic Science in Practice (Elsevier). AD reports payment for consulting for Hovartis, Hubble Htz, Active Bio and Gilead. AD participates on an advisory board for Co-THEIA Randomised Controlled Trial in Spain. AD is a non-executive director at Moorfields NHS Foundation Trust. No other conflicts were reported., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Evidence indicates that a melanoma prevention program using personalized genomic risk provision and genetic counseling can affect prevention behaviors, including reducing sunburns in adults with no melanoma history. This analysis evaluated its longer-term cost-effectiveness from an Australian health system perspective., Methods: The primary outcome was incremental cost effectiveness ratio (ICER) of genomic risk provision (intervention) compared with standard prevention advice. A decision-analytic Markov model was developed using randomized trial data to simulate lifetime cost-effectiveness. All costs were presented in 2018/19 Australian dollars (AUD). The intervention effect on reduced sunburns was stratified by sex and traditional risk, which was calculated through a validated prediction model. Deterministic and probabilistic sensitivity analyses were undertaken for robustness checks., Results: The per participant cost of intervention was AUD$189. Genomic risk provision targeting high-traditional risk individuals produced an ICER of AUD$35,254 (per quality-adjusted life year gained); sensitivity analyses indicated the intervention would be cost-effective in more than 50% of scenarios. When the intervention was extended to low-traditional risk groups, the ICER was AUD$43,746 with a 45% probability of being cost-effective., Conclusion: Genomic risk provision targeted to high-traditional melanoma risk individuals is likely a cost-effective strategy for reducing sunburns and will likely prevent future melanomas and keratinocyte carcinomas., Competing Interests: Conflict of Interest Alexander M. Menzies has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, and QBiotics., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Aim: To explore variations in the cost-effectiveness of entrectinib across different testing strategies and settings. Methods: Four testing strategies where adult cancer patients received entrectinib if they tested positive for NTRK  gene fusions compared with 'no testing' and standard of care (SoC) for all patients were evaluated. Results: Immunohistochemistry for all patients followed by RNA-based next-generation sequencing after a positive result was the optimal strategy in all included countries. However, the incremental net monetary benefit compared with SoC was negative in all countries, ranging between international euros (int€) -206 and -404. In a subgroup analysis with only NTRK -positive patients, the incremental net monetary benefit was int€ 8405 in England, int€ -53,088 in Hungary and int€ 54,372 in The Netherlands. Conclusion: Using the cost-effectiveness thresholds recommended by national guidelines, none of the testing strategies were cost-effective compared with no testing. The implementation of entrectinib is unlikely to become cost-effective in Hungary, due to the large cost difference between the entrectinib and SoC arms, while there might be more potential in England and The Netherlands.

Background: Correct diagnosis of maturity-onset diabetes of the young (MODY), which is often misdiagnosed as Type 1 or 2 diabetes, is important for providing appropriate treatment. Materials & Methods: A diabetes model was adapted to Hungary, the Netherlands, and the UK to analyse the cost-effectiveness and budget impact of different screening strategies for MODY with 20 years time horizon. Results: Compared with no screening, screening with the MODY calculator then genetic testing is considered cost-effective with respect to each country's willingness to pay threshold. The addition of autoantibody testing dominated the no screening strategy. The budget impact of the strategies ranges between 0.001 and 0.025% of annual public healthcare spending. Conclusion: The analysed strategies are considered good value for money with potential cost savings in the long term.