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OBJECTIVES: Anti-vascular endothelial growth factor (VEGF) therapy restores retinal architecture and enhances vision in diabetic macular edema (DME). Bevacizumab is an off-label anti-VEGF drug that effectively treats DME. The safety and efficacy of bevacizumab biosimilars, which are more affordable than the original medication, still need to be established. This study aimed to assess the cost-effectiveness, efficacy, and safety of biosimilars for treating patients with naïve DME across various price ranges that are accessible in the Indian market. MATERIALS AND METHODS: Two biosimilars, BevaciRelTM (Reliance Life Sciences Pvt. Ltd.) and ZyBev (Cadila Healthcare Limited), were compared to their original, Avastin (Roche Products [India] Pvt. Ltd.), in a randomized, control study. Three end-notes were used to assess safety and efficacy: persistence, improvement, and adverse events. Cost-effective analysis was carried out using a decision-tree analysis model. RESULTS: This study included 69 (59%) men and 54 (41%) women with naïve DME. The cohort had an average log MAR visual acuity of 0.87 ± 0.22, and the central retinal thickness at baseline on OCT was 398.5 ± 37.61 µm. The visual acuity showed a similar improvement, and there was a decrease in central retinal thickness as observed on OCT across the groups. The incremental cost-effectiveness ratio was 10.8. CONCLUSIONS: The biosimilars of bevacizumab are safe and efficacious in treating DME in a cost-effective manner.

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Background: We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost-utility analysis. Methods: We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost-utility analysis using methods recommended by The National Institute for Health and Care Excellence. Results: The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons. Limitations: We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges. Conclusions: In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation). Future work: More randomised controlled trials are necessary. Study registration: This study is registered as PROSPERO CRD42019130504. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

Cancers of the bowel, ovary or stomach can spread to the lining of the abdomen ('peritoneal metastases'). Chemotherapy (the use of drugs that aim to kill cancer cells) given by injection or tablets ('systemic chemotherapy') is one of the main treatment options. There is uncertainty about whether adding cytoreductive surgery (cytoreductive surgery; an operation to remove the cancer) and 'hyperthermic intraoperative peritoneal chemotherapy' (warm chemotherapy delivered into the lining of the abdomen during cytoreductive surgery) are beneficial. We reviewed all the information from medical literature published until 14 April 2022, to answer the above uncertainty. We found the following from eight trials, including about 1000 participants. In people with peritoneal metastases from bowel cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably does not provide any benefits and increases harm compared to cytoreductive surgery + systemic chemotherapy, while cytoreductive surgery + systemic chemotherapy appears to increase survival compared to systemic chemotherapy alone. There is uncertainty about the best treatment for people with peritoneal metastases from stomach cancer. In women with peritoneal metastases from ovarian cancer who require systemic chemotherapy before cytoreductive surgery to shrink the cancer to allow surgery ('advanced ovarian cancer'), hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably increases survival compared to cytoreductive surgery + systemic chemotherapy. In people who can withstand a major operation and in whom cancer can be removed, cytoreductive surgery + systemic chemotherapy should be offered to people with peritoneal metastases from bowel cancer, while hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered to women with peritoneal metastases from 'advanced ovarian cancer'. Uncertainty in treatment continues for gastric cancer. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.

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OBJECTIVE: In Malaysia, there is now a dearth of recommendations pertaining to the priority of biologic treatments for the effective management of psoriasis, given the multitude of available therapeutic alternatives. Present analysis reports results of a cost-effectiveness model that determines the most optimal arrangement of biologic treatments, with a particular focus of adding biosimilars to the existing treatment pathway for psoriasis in Malaysia. METHODS: A Markov model was developed to compare the cost effectiveness of various biologic sequential treatments in a hypothetical cohort of moderate to severe psoriasis patient in Malaysia over a lifetime horizon. The model simulated the progression of patients through three lines of active biologic therapy, before transitioning to best supportive care. Costs and effects were discounted annually at a rate of 3%. RESULTS: First line secukinumab has produced lowest incremental cost effectiveness ratios (ICERs) when compared to first line systemic [ICERs value; US$152,474 (first set analysis) and US$110,572 (second set analysis)] and first line phototherapy [ICERs value; US$147,057 (first set analysis) and US$107,616 (second set analysis)]. However, these values were slightly higher than the Malaysian based threshold of three times gross domestic product per capita, US$104,337. A 40% reduction in the unit costs of reference biologics renders most of the evaluated treatment sequences cost-effective. CONCLUSION: Adding biosimilar to the current treatment sequence could achieve cost savings ranging from 4.3% to 10.8% without significant loss of effectiveness. Given the significant impact of comorbidities and the resulting decline in quality of life among individuals with psoriasis, it may be justifiable to establish a threshold of up to US$184,000 per quality-adjusted life year (QALY) for the provision of therapies in the context of Malaysia.

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INTRODUCTION: HIV drug resistance (HIVDR) is an important challenge in the fight against HIV/AIDS and can threaten progress toward achieving the target of HIV elimination by 2030. Genotyping pretreatment HIVDR testing (DRT) has been proposed as a potential solution. However, the cost-effectiveness of this intervention needs to be evaluated to determine its feasibility and potential impact on healthcare systems. This study aimed to assess the cost-effectiveness of DRT among people living with HIV (PLHIV) in Iran. METHODS: 1000 hypothetical PLHIV were simulated in terms of cost and effectiveness based on quality-adjusted life Years (QALY). The Markov Model was developed to calculate incremental cost-effectiveness ratio (ICER) using TreeAge Pro 2020. Deterministic and probabilistic analyses were performed for sensitivity analyses. RESULTS: Results showed that compared to not performing pretreatment HIVDR testing, this intervention gained 0.035999 QALY with an incremental cost of 1,695.32 USD. The ICER was calculated as 47,093.53 USD, indicating that pretreatment DRT was not cost-effective. The probability of opportunistic infection (OI) in people with viral failure, the effectiveness of Dolutegravir in people without drug resistance, and the quality of life (QoL) of people in the AIDS stage were found to be the most important variables affecting ICER. With an increasing willingness to pay more than 53,000 USD, pretreatment DRT testing will become cost-effective. CONCLUSION: Based on our findings, pretreatment HIVDR testing is not currently cost-effective in Iran as it imposes high costs on healthcare systems with few benefits for People living with HIV (PLHIV). However, if resources are available, drug resistance testing can be a valuable tool in generating HIV molecular data and molecular surveillance of HIV.

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BACKGROUND: People with incomplete spinal cord injury (iSCI) often have gait impairments that negatively affect daily life gait performance (i.e., ambulation in the home and community setting) and quality of life. They may benefit from light-weight lower extremity exosuits that assist in walking, such as the Myosuit (MyoSwiss AG, Zurich, Switzerland). A previous pilot study showed that participants with various gait disorders increased their gait speed with the Myosuit in a standardized environment. However, the effect of a soft exosuit on daily life gait performance in people with iSCI has not yet been evaluated. OBJECTIVE: The primary study objective is to test the effect of a soft exosuit (Myosuit) on daily life gait performance in people with iSCI. Second, the effect of Myosuit use on gait capacity and the usability of the Myosuit in the home and community setting will be investigated. Finally, short-term impact on both costs and effects will be evaluated. METHODS: This is a two-armed, open label, randomized controlled trial (RCT). Participants will be randomized (1:1) to the intervention group (receiving the Myosuit program) or control group (initially receiving the conventional program). Thirty-four people with chronic iSCI will be included. The Myosuit program consists of five gait training sessions with the Myosuit at the Sint Maartenskliniek. Thereafter, participants will have access to the Myosuit for home use during 6 weeks. The conventional program consists of four gait training sessions, followed by a 6-week home period. After completing the conventional program, participants in the control group will subsequently receive the Myosuit program. The primary outcome is walking time per day as assessed with an activity monitor at baseline and during the first, third, and sixth week of the home periods. Secondary outcomes are gait capacity (10MWT, 6MWT, and SCI-FAP), usability (D-SUS and D-QUEST questionnaires), and costs and effects (EQ-5D-5L). DISCUSSION: This is the first RCT to investigate the effect of the Myosuit on daily life gait performance in people with iSCI. TRIAL REGISTRATION: Clinicaltrials.gov NCT05605912. Registered on November 2, 2022.

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Cardiovascular disease (CVD) is the leading cause of mortality globally. Low-density lipoprotein (LDL) plays an important role in CVD pathophysiology. Research has shown the safety and efficacy of keeping LDL at very low levels for CVD prevention. Therefore, experts recommend intense LDL-lowering approaches starting at young ages, promoting the mantras "the lower, the better" and "the earlier, the better." This commentary discusses the challenges regarding applying aggressive LDL-lowering approaches in the general population, including pharmacological efficacy and side effects, the cost-effectiveness of interventions, and patient adherence to treatment regimens.

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Importance: Previous research has shown good discrimination of short-term risk using an artificial intelligence (AI) risk prediction model (Mirai). However, no studies have been undertaken to evaluate whether this might translate into economic gains. Objective: To assess the cost-effectiveness of incorporating risk-stratified screening using a breast cancer AI model into the United Kingdom (UK) National Breast Cancer Screening Program. Design, Setting, and Participants: This study, conducted from January 1, 2023, to January 31, 2024, involved the development of a decision analytical model to estimate health-related quality of life, cancer survival rates, and costs over the lifetime of the female population eligible for screening. The analysis took a UK payer perspective, and the simulated cohort consisted of women aged 50 to 70 years at screening. Exposures: Mammography screening at 1 to 6 yearly screening intervals based on breast cancer risk and standard care (screening every 3 years). Main Outcomes and Measures: Incremental net monetary benefit based on quality-adjusted life-years (QALYs) and National Health Service (NHS) costs (given in pounds sterling; to convert to US dollars, multiply by 1.28). Results: Artificial intelligence-based risk-stratified programs were estimated to be cost-saving and increase QALYs compared with the current screening program. A screening schedule of every 6 years for lowest-risk individuals, biannually and triennially for those below and above average risk, respectively, and annually for those at highest risk was estimated to give yearly net monetary benefits within the NHS of approximately £60.4 (US $77.3) million and £85.3 (US $109.2) million, with QALY values set at £20 000 (US $25 600) and £30 000 (US $38 400), respectively. Even in scenarios where decision-makers hesitate to allocate additional NHS resources toward screening, implementing the proposed strategies at a QALY value of £1 (US $1.28) was estimated to generate a yearly monetary benefit of approximately £10.6 (US $13.6) million. Conclusions and Relevance: In this decision analytical model study of integrating risk-stratified screening with a breast cancer AI model into the UK National Breast Cancer Screening Program, risk-stratified screening was likely to be cost-effective, yielding added health benefits at reduced costs. These results are particularly relevant for health care settings where resources are under pressure. New studies to prospectively evaluate AI-guided screening appear warranted.

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BACKGROUND: Duchenne muscular dystrophy (DMD) is a genetic disease resulting in progressive muscle weakness, loss of ambulation, and cardiorespiratory complications. Direct estimation of health-related quality of life for patients with DMD is challenging, highlighting the need for proxy measures. This study aims to catalog and compare existing published health state utility estimates for DMD and related conditions. METHODS: Using two search strategies, relevant utilities were extracted from the Tufts Cost-Effectiveness Analysis Registry, including health states, utility estimates, and study and patient characteristics. Analysis One identified health states with comparable utility estimates to a set of published US patient population utility estimates for DMD. A minimal clinically important difference of ± 0.03 was applied to each DMD utility estimate to establish a range, and the registry was searched to identify other health states with associated utilities that fell within each range. Analysis Two used pre-defined search terms to identify health states clinically similar to DMD. Mapping was based on the degree of clinical similarity. RESULTS: Analysis One identified 4,308 unique utilities across 2,322 cost-effectiveness publications. The health states captured a wide range of acute and chronic conditions; 34% of utility records were extrapolated for US populations (n = 1,451); 1% were related to pediatric populations (n = 61). Analysis Two identified 153 utilities with health states clinically similar to DMD. The median utility estimates varied among identified health states. Health states similar to the early non-ambulatory DMD phase exhibited the greatest difference between the median estimate of the sample (0.39) and the existing estimate from published literature (0.21). CONCLUSIONS: When available estimates are limited, using novel search strategies to identify utilities of clinically similar conditions could be an approach for overcoming the information gap. However, it requires careful evaluation of the utility instruments, tariffs, and raters (proxy or self).

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¼ We aimed to determine the cost-effectiveness of different protocols of extended postoperative antibiotic prophylaxis (E-PAP) following adult spinal surgery.¼ Both stratified (randomized controlled trials only) and nonstratified (all studies) analyses demonstrated that E-PAP has no significant value in reducing the rate of surgical site infection (SSI), deep SSI, or superficial SSI.¼ Notably, the E-PAP protocols were associated with a significant increase in the length of hospital stay, resulting in an additional expenditure of $244.4 per episode for the E-PAP 72 hours protocol compared with PAP 24 hours and $309.8 per episode for the E-PAP >48 hours protocol compared with PAP <48 hours.¼ E-PAP does not demonstrate any significant reduction in the rate of SSIs following spine surgery. However, these extended protocols were significantly associated with an increase in the length of hospital stay and higher overall projected costs.

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In vitro amplification of single-stranded oligonucleotide libraries presents a significant challenge due to the potential for excessive byproduct formation. This phenomenon largely affects the quality of the ssDNAs created using the most commonly used methods, e.g., asymmetric PCR, biotin-streptavidin separation, or lambda exonuclease digestion of dsDNA. Here, we describe an improved protocol that combines primer-blocked asymmetric PCR (PBA-PCR) with emulsion PCR and a cost-effective downstream process that altogether alleviates byproduct formation without distorting the sequence space of the ssDNA library. In PBA-PCR, the reaction mixture is complemented with a 3'-phosphate-blocked limiting primer that decreases mispriming, thus reducing polymerization of DNA byproducts. The downstream process includes mixing of the PBA-PCR product with excess reverse complement of the 3'-phosphate-blocked limiting primer and removal of dsDNA strands via biotin-streptavidin separation, yielding purified ssDNAs. In conclusion, we have devised a universally applicable approach for simple and cost-effective production of ssDNA libraries and unique ssDNA sequences with on-demand labeling. Our protocol could be beneficial for a variety of uses, such as generating aptamer libraries for SELEX, creating unique molecular identifiers for a wide range of sequencing applications, providing donor DNA for CRISPR-Cas9 systems, developing scaffold nanostructures, and enabling DNA-based data storage. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Amplification of ssDNA libraries using PBA-PCR Alternate Protocol 1: Amplification of ssDNA libraries using emulsion PBA-PCR with a simplified extraction of PBA-PCR products Basic Protocol 2: Purification of PBA-PCR products to remove dsDNA and conversion of 3'-blocked primer to double-stranded complexes Alternate Protocol 2: Purification of PBA-PCR products to remove both dsDNA and blocking primers from the reaction mixture Support Protocol: Analysis of PBA-PCR products by gel electrophoresis.

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BACKGROUND AND OBJECTIVES: The primary objective of this study was to evaluate the influence of operating room nurse (ORN) characteristics on the duration of elective neurosurgical procedures in adults. In addition, we conducted a cost-benefit analysis of various strategies for organizing the workflow of ORNs. METHODS: We collected and analyzed operating times for adult elective neurosurgical procedures, categorizing them by surgeon, procedure complexity (dichotomized as technologically complex and simple), and ORN characteristics (dichotomized as ORN dedicated to neurosurgery [dORN] and ORN not dedicated to neurosurgery [ndORN]). The monetary valuation of operating times is based on the unitary cost per minute of the operating room, including opportunity costs of ORN, as well as their training costs and salaries. Cost-benefit analysis adopted the hospital perspective. RESULTS: Analysis of operating times reveals an approximately 20-minute difference for complex procedures when performed with ndORN. However, there is no significant difference in operating times for simple procedures, whether they are conducted by dORN or ndORN. The additional annual cost incurred by complex procedures performed with ndORN is estimated at CHF 68 144.4 for the Geneva University Hospitals. CONCLUSION: Complex neurosurgical procedures exhibit shorter durations when performed by dORNs. We explore several hypotheses to explain this difference. By adapting available human resources and optimizing workflow organization, hospitals can potentially achieve a net benefit.

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BACKGROUND: In the UK, one in four patients are in work at the time of their hip or knee replacement surgery. These patients receive little support about their return to work (RTW). There is a need for an occupational support intervention that encourages safe and sustained RTW which can be integrated into National Health Service practice. We developed a two-arm intervention trial, based on a feasibility study, to assess whether an occupational support intervention (the OPAL (Occupational support for Patients undergoing Arthroplasty of the Lower limb) intervention) is effective in supporting a reduced time to full, sustained RTW compared with usual care in patients undergoing hip and knee replacement. METHODS AND ANALYSIS: This is a multicentre, individually randomised controlled superiority trial comparing the OPAL intervention to usual care. 742 working adults listed for elective primary hip or knee replacement, who intend to RTW, will be randomised to the OPAL intervention or usual care. The intervention comprises: (1) multimedia information resources; and (2) support from a designated RTW coordinator. The primary outcome is time until 'full' sustained RTW without sick leave for a consecutive 4-week period. Secondary outcomes are: time to any RTW, measures of functional recovery, number of 'sick days' between surgery and 'full' sustained RTW and the use of workplace modifications to facilitate their return. A health economic evaluation and a mixed methods process evaluation will assess cost-effectiveness and the implementation, fidelity and acceptability of the intervention, respectively. Outcomes will be collected at baseline, 3, 6, 9 and 12-month follow-up time points, as well as a monthly RTW questionnaire. ETHICS AND DISSEMINATION: Dissemination will focus on supporting the wider adoption and implementation of the intervention (if effective) and will target groups for whom the results will be relevant. This trial was approved by West Midlands-Edgbaston REC 23/WM/0013. TRIAL REGISTRATION NUMBER: ISRCTN13694911.

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BACKGROUND: Acute Rehabilitation following Traumatic anterior shoulder dISlocAtioN (ARTISAN) was a large trial comparing the clinical and cost-effectiveness of two rehabilitation interventions in adults with a first-time traumatic shoulder dislocation. Participants were allocated to receive either a single session of advice (ARTISAN) or a single session of advice and a programme of physiotherapy (ARTISAN plus). Trial results illustrated that additional physiotherapy after an initial session was not superior in improving functional outcomes for participants. OBJECTIVES: In this study, we aim to explore the experiences of a purposive sample of participants from both the ARTISAN and ARTISAN plus groups regarding their rehabilitation journey. DESIGN: This is a semistructured interview-based study. SETTING: The study was conducted in the United Kingdom. PARTICIPANTS: Thirty-one participants of ARTISAN trial: 16 participants from ARTISAN group and 15 from ARTISAN plus group. OUTCOME MEASURES AND ANALYSIS: The study follows the consolidated criteria for reporting qualitative research. The framework analysis was used to synthesise the participants' experiences. The interviews were coded through NVivo 12.6.1. RESULTS: Three dominant and interrelated topics emerged from the interview data: (1) feelings about their shoulder rehabilitation outcome, (2) judgement of ARTISAN rehabilitation materials, (3) assessment of shoulder rehabilitation service provision. CONCLUSION: Both forms of intervention have some merit for some individuals. Thus, it may be appropriate to look at the patients' preference for offering treatment to them. Recognising and facilitating this will be of benefit to both the patients and healthcare as a whole.

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INTRODUCTION: There remains a high unmet need for disease-modifying therapies that can impact disability progression in secondary progressive multiple sclerosis (SPMS). Following positive results of the phase 2 MS-STAT study, the MS-STAT2 phase 3 trial will evaluate the efficacy and cost-effectiveness of repurposed high-dose simvastatin in slowing the progression of disability in SPMS. METHODS AND ANALYSIS: MS-STAT2 will be a multicentre, randomised, placebo-controlled, double-blind trial of participants aged between 25 and 65 (inclusive) who have SPMS with an Expanded Disability Status Scale (EDSS) score of 4.0-6.5 (inclusive). Steady progression rather than relapse must be the major cause of increasing disability in the preceding 2 years.Participants will be allocated to simvastatin or placebo in a 1:1 ratio. The active treatment will be 80 mg daily, after 1 month at 40 mg daily. 31 hospitals across the UK will participate.The primary outcome is (confirmed) disability progression at 6 monthly intervals, measured as change from EDSS baseline score. Recruitment of 1050 participants will be required to achieve a total of 330 progression events, giving 90% power to demonstrate a 30% relative reduction in disability progression versus placebo. The follow-up period is 36 months, extendable by up to 18 months for patients without confirmed progression.Clinician-reported measures include Timed 25 Foot Walk; 9 Hole Peg Test; Single Digit Modalities Test; Sloan Low Contrast Visual Acuity; Relapse assessment; modified Rankin Scale and Brief International Cognitive Assessment For Multiple Sclerosis. Patient-reported outcomes include MS-specific walking, fatigue and impact scales. A health economic analysis will occur. ETHICS AND DISSEMINATION: The protocol was approved by the London-Westminster REC (17/LO/1509). This manuscript is based on protocol version 8.0, 26 February 2024. Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBERS: NCT03387670; ISRCTN82598726.

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Background: Acne is common, can cause significant impact on quality of life and is a frequent reason for long-term antibiotic use. Spironolactone has been prescribed for acne in women for many years, but robust evidence is lacking. Objective: To evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women. Design: Pragmatic, parallel, double-blind, randomised superiority trial. Setting: Primary and secondary healthcare and community settings (community and social media advertising). Participants: Women aged 18 years and older with facial acne persisting for at least 6 months, judged to potentially warrant oral antibiotic treatment. Interventions: Participants were randomised 1 : 1, using an independent web-based procedure, to either 50 mg/day spironolactone or matched placebo until week 6, increasing to 100 mg/day spironolactone or matched placebo until week 24. Participants continued usual topical treatment. Main outcome measures: Primary outcome was the adjusted mean difference in Acne-Specific Quality of Life symptom subscale score at 12 weeks. Secondary outcomes included Acne-Specific Quality of Life total and subscales; participant self-assessed improvement; Investigator's Global Assessment; Participant's Global Assessment; satisfaction; adverse effects and cost-effectiveness. Results: Of 1267 women assessed for eligibility, 410 were randomised (201 intervention, 209 control), 342 in the primary analysis (176 intervention, 166 control). Mean age was 29.2 years (standard deviation 7.2) and 7.9% (28/356) were from non-white backgrounds. At baseline, Investigator's Global Assessment classified acne as mild in 46%, moderate in 40% and severe in 13%. At baseline, 82.9% were using topical treatments. Over 95% of participants in both groups tolerated the treatment and increased their dose. Mean baseline Acne-Specific Quality of Life symptom subscale was 13.0 (standard deviation 4.7) across both groups. Mean scores at week 12 were 19.2 (standard deviation 6.1) for spironolactone and 17.8 (standard deviation 5.6) for placebo [difference favouring spironolactone 1.27 (95% confidence interval 0.07 to 2.46) adjusting for baseline variables]. Mean scores at week 24 were 21.2 (standard deviation 5.9) in spironolactone group and 17.4 (standard deviation 5.8) in placebo group [adjusted difference 3.77 (95% confidence interval 2.50 to 5.03) adjusted]. Secondary outcomes also favoured spironolactone at 12 weeks with greater differences at 24 weeks. Participants taking spironolactone were more likely than those taking placebo to report overall acne improvement at 12 weeks {72.2% vs. 67.9% [adjusted odds ratio 1.16 (95% confidence interval 0.70 to 1.91)]} and at 24 weeks {81.9% vs. 63.3% [adjusted odds ratio 2.72 (95% confidence interval 1.50 to 4.93)]}. Investigator's Global Assessment was judged successful at week 12 for 31/201 (18.5%) taking spironolactone and 9/209 (5.6%) taking placebo [adjusted odds ratio 5.18 (95% confidence interval 2.18 to 12.28)]. Satisfaction with treatment improved in 70.6% of participants taking spironolactone compared with 43.1% taking placebo [adjusted odds ratio 3.12 (95% confidence interval 1.80 to 5.41)]. Adverse reactions were similar between groups, but headaches were reported more commonly on spironolactone (20.4% vs. 12.0%). No serious adverse reactions were reported. Taking account for missing data through multiple imputation gave an incremental cost per quality-adjusted life-year of £27,879 (adjusted) compared to placebo or £2683 per quality-adjusted life-year compared to oral antibiotics. Conclusions: Spironolactone resulted in better participant-reported and investigator-reported outcomes than placebo, with greater differences at week 24 than week 12. Trial registration: This trial is registered as ISRCTN12892056 and EudraCT (2018-003630-33). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/13/02) and is published in full in Health Technology Assessment; Vol. 28, No. 56. See the NIHR Funding and Awards website for further award information.

Acne (or spots) is common and often persists into adulthood. Many people take long courses of antibiotic tablets, but concerns about antibiotic resistance mean alternatives are needed. Spironolactone is a medicine that is sometimes used for acne in women. However, we do not know whether it works. This trial aimed to answer this question. We invited women aged over 18 who had acne on their face for at least 6 months to take part via their general practitioner surgery, hospital or advertising. Women were randomly assigned to two groups: one group was given spironolactone and the other group was given identical-looking placebo ('dummy pill') daily for 24 weeks. Women in both groups could continue using acne treatments applied to the skin (gels/creams/lotions). We asked participants to rate their acne using a questionnaire called Acne-Specific Quality of Life, asked whether they felt their skin had improved and asked skin specialists to assess their skin. Four hundred and ten women took part, many of whom had had acne for a long time. Acne-Specific Quality of Life scores improved in both groups by 12 weeks but improved more in the spironolactone group at 12 and 24 weeks. When asked directly whether their skin had improved, 71% of participants in the spironolactone group said it had, compared with 43% on placebo. Skin specialists were also more likely to report that the acne had improved in the spironolactone group. Side effects were mild and similar in both groups but there were slightly more headaches on spironolactone (20% compared with 12%). Spironolactone is likely to represent value for money for the National Health Service, though this depends on a number of factors including what it is compared to. This trial suggests that spironolactone is a useful additional treatment for women with persistent acne.

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Background: Globally alcohol consumption is a leading risk factor for premature death and disability and is associated with crime, social and economic consequences. Local communities may be able to play a role in addressing alcohol-related issues in their area. Objectives: To evaluate the effectiveness and cost-benefit of an asset-based community development approach to reducing alcohol-related harm and understand the context and factors that enable or hinder its implementation. Design: A mixed-methods evaluation. Area-level quasi-experimental trial analysed using four different evaluation methods (a stepped-wedge design where each area was a control until it entered the intervention, comparison to matched local/national controls and comparison to synthetic controls), alongside process and economic evaluations. Setting: Ten local authorities in Greater Manchester, England. Participants: The outcomes evaluation was analysed at an area level. Ninety-three lay persons representing nineareas completed questionnaires, with 12 follow-up interviews in five areas; 20 stakeholders representing ten areas were interviewed at baseline, with 17 follow-up interviews in eight areas and 26 members of the public from two areas attended focus groups. Interventions: Professionals in a co-ordinator role recruited and supported lay volunteers who were trained to become alcohol health champions. The champion's role was to provide informal, brief alcohol advice to the local population and take action to strengthen restrictions on alcohol availability. Main outcome measures: Numbers of alcohol-related hospital admissions, accident and emergency attendances, ambulance call-outs, street-level crime and antisocial behaviour in the intervention areas (area size: 1600-5500 residents). Set-up and running costs were collected alongside process evaluation data exploring barriers and facilitators. Data sources: Routinely collected quantitative data on outcome measures aggregated at the intervention area and matched control and synthetic control areas. Data from policy documents, licensing registers, meeting notes, invoices, time/cost diaries, training registers, questionnaires, interviews, reflective diaries and focus groups. Results: The intervention rolled out in nine out of ten areas, seven of which ran for a full 12 months. Areas with better-established infrastructure at baseline were able to train more champions. In total, 123 alcohol health champions were trained (95 lay volunteers and 28 professionals): lay volunteers self-reported positive impact. Champions engaged in brief advice conversations more readily than taking action on alcohol availability. There were no consistent differences in the health and crime area-level indicators between intervention areas and controls, as confirmed by using three different analysis methods for evaluating natural experiments. The intervention was not found to be cost-beneficial. Limitations: Although the sequential roll-out order of the intervention was randomised, the selection of the intervention areas was not. Self-reported impact may have been subject to social desirability bias due to the project's high profile. Conclusions: There was no measurable impact on health and crime outcomes. Possible explanations include too few volunteers trained, volunteers being unwilling to get involved in licensing decisions, or that the intervention has no direct impact on the selected outcomes. Future work: Future similar interventions should use a coproduced community outcomes framework. Other natural experiment evaluations should use methodological triangulation to strengthen inferences about effectiveness. Trial registration: This trial is registered as ISRCTN81942890. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/129/03) and is published in full in Public Health Research; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information.

Alcohol consumption puts an individual's health and social relationships at risk of harm. The more a person drinks, the more harmful it is. The harmful effects can place a burden on emergency services and hospitals. We wanted to find out whether community members can make a difference by taking action to address alcohol harm in their local area. Local councils in Greater Manchester developed a project called Communities in Charge of Alcohol, where volunteers in targeted local areas were trained to become 'alcohol health champions'. Alcohol health champions gave alcohol-related brief advice to people to help them drink less. They had a say about when, where and how alcohol is sold by reporting issues to their local council. We compared numbers of alcohol-related hospital admissions, accident and emergency attendances, ambulance call-outs and reports of crime and antisocial behaviour between areas that had alcohol health champions with other similar areas in England that did not. We calculated how much it costs to run and whether Communities in Charge of Alcohol could save society money. Not as many volunteers came forward to become an alcohol health champion as hoped for. Those who did give alcohol-related brief advice to people. They preferred not to report issues about alcohol sales to their local council, either because it was too complicated or because they did not want to be called a 'grass'. We did not find levels of alcohol harm changed in the Communities in Charge of Alcohol areas. Because of this, we could not demonstrate that Communities in Charge of Alcohol could save society money. Getting involved in alcohol licensing decisions needs to be made easier for communities, with more anonymity, through the support of professionals. More work needs to be done to understand whether giving brief advice can reduce alcohol harm in whole communities.

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As the heritability of abdominal aortic aneurysm (AAA) is high and AAA partially shares genetic architecture with other cardiovascular diseases, genetic information could help inform AAA screening strategies. Exploiting pleiotropy and meta-analysing summary data from large studies, we construct a polygenic risk score (PRS) for AAA. Leveraging related traits improves PRS performance (R2) by 22.7%, relative to using AAA alone. Compared with the low PRS tertile, intermediate and high tertiles have hazard ratios for AAA of 2.13 (95%CI 1.61, 2.82) and 3.70 (95%CI 2.86, 4.80) respectively, adjusted for clinical risk factors. Using simulation modelling, we compare PRS- and smoking-stratified screening with inviting men at age 65 and not inviting women (current UK strategy). In a futuristic scenario where genomic information is available, our modelling suggests inviting male current smokers with high PRS earlier than 65 and screening female smokers with high/intermediate PRS at 65 and 70 respectively, may improve cost-effectiveness.

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In September 2023, 10-valent pneumococcal conjugate vaccine (PCV) was replaced by 15-valent PCV (PCV15) in Sweden's pediatric national immunization program. Following European approval of 20-valent PCV (PCV20) in March 2024, we assessed the cost-effectiveness of PCV20 versus PCV15, both under 2 + 1 schedule, among Sweden's pediatric population. A Markov state-transition model evaluated the economic and health benefits of PCV20 versus PCV15 among all ages over a 10-year time horizon. The base case adopted a Swedish payer perspective with an annual cycle length and 3.0% discount rate for costs and outcomes. Country-specific data informed population size, epidemiology, costs, and quality of life estimates. PCV15/PCV20 effect estimates were informed by PCV13 clinical effectiveness and impact studies plus PCV7 efficacy studies. Sensitivity analyses evaluated model robustness, including PCV20 under a 3 + 1 schedule. PCV20 was associated with higher quality-adjusted life year gains versus PCV15, averting an estimated 3,116 invasive pneumococcal disease cases 21,109 inpatient pneumonia cases, 6,618 outpatient pneumonia cases, and 36,209 otitis media cases, plus 3,281 pneumococcal disease-related deaths. PCV20 yielded substantial cost savings exceeding 5.4 billion SEK over a 10-year time horizon, primarily attributed to reduced direct medical costs due to improved health outcomes compared with PCV15. The findings confirmed the dominance of PCV20 in the base case, which remained robust across deterministic and probabilistic sensitivity analyses as well as scenario assessments. PCV20 was the dominant strategy versus PCV15 over 10 years. The broader serotype coverage of PCV20 suggests superior clinical and economic advantages over PCV15, warranting inclusion in Sweden's pediatric immunization program.

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Background: Stress urinary incontinence, fecal incontinence, and pelvic organ prolapse are common forms of pelvic floor dysfunction. Pelvic floor muscle training is used to improve pelvic floor function, through a program of exercises. We conducted a health technology assessment of pelvic floor muscle training for people with stress urinary incontinence, fecal incontinence, or pelvic organ prolapse, which included an evaluation of effectiveness, safety, and the budget impact of publicly funding pelvic floor muscle training, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of included studies using the ROBIS tool, for systematic reviews, and the Cochrane Risk of Bias tool, for randomized controlled trials, and we assessed the quality of the body of evidence according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search but did not conduct a primary economic evaluation. We also analyzed the budget impact of publicly funding pelvic floor muscle training in adults with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse in Ontario. To contextualize the potential value of pelvic floor muscle training as a treatment, we spoke with people with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse. Results: We included 6 studies (4 systematic reviews and 2 randomized controlled trials) in the clinical evidence review. In comparison with no treatment, pelvic floor muscle training significantly improved symptom severity and increased patient satisfaction in women with stress urinary incontinence or pelvic organ prolapse (GRADE: Moderate). For men with stress urinary incontinence after prostatectomy, pelvic floor muscle training yielded mixed results for symptom improvement (GRADE: Very low). For adults with fecal incontinence, pelvic floor muscle training did not improve symptoms in comparison with standard care (GRADE: Very low).In the economic literature review, we included 6 cost-utility analyses that had evaluated the cost-effectiveness of pelvic floor muscle training as a treatment for people with pelvic organ prolapse or urinary incontinence. We did not identify any economic studies on pelvic floor muscle training for women or men with fecal incontinence or men with pelvic organ prolapse. The analyses included in our review found that, for women with stress urinary incontinence, pelvic floor muscle training was likely cost-effective in comparison with other nonsurgical interventions. For men with urinary incontinence after prostate surgery, pelvic floor muscle training was likely not cost-effective in comparison with standard care. For women with pelvic organ prolapse, the cost-effectiveness of pelvic floor muscle training in comparison with no active treatment was uncertain.The average cost of pelvic floor muscle training was approximately $763 per patient. Publicly funding pelvic floor muscle training for women with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse would result in additional costs over 5 years of $185.3 million, $275.6 million, and $85.8 million, respectively. Publicly funding pelvic floor muscle training for men with stress urinary incontinence and fecal incontinence would result in additional costs over 5 years of $10.8 million and $131.1 million, respectively. The people we spoke with reported that stress urinary incontinence, fecal incontinence, and pelvic organ prolapse limited their social and physical activities, taking a huge emotional toll. Many were hesitant or even fearful of surgery, and most people with experience of pelvic floor muscle training reported that it relieved most or all of their symptoms and allowed them to return to normal daily activities. Conclusions: Pelvic floor muscle training is likely more effective (with respect to symptom improvement and patient satisfaction) than no treatment for women with stress urinary incontinence or pelvic organ prolapse. Pelvic floor muscle training may yield mixed results with respect to symptom improvement for men with stress urinary incontinence after prostatectomy and have little to no effect on symptom improvement for adults with fecal incontinence. We estimate that publicly funding pelvic floor muscle training for adults with pelvic floor dysfunction (stress urinary incontinence, fecal incontinence, and pelvic organ prolapse) in Ontario would result in a substantial budget increase over the next 5 years. People with stress urinary incontinence, fecal incontinence, and pelvic organ prolapse shared the negative impact these conditions have on their social and physical life and valued pelvic floor muscle training as a nonsurgical treatment option.

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