Laparoscopic cholecystectomy versus conservative management for adults with uncomplicated symptomatic gallstones: the C-GALL RCT.

Background: Gallstone disease is a common gastrointestinal disorder in industrialised societies. The prevalence of gallstones in the adult population is estimated to be approximately 10-15%, and around 80% remain asymptomatic. At present, cholecystectomy is the default option for people with symptomatic gallstone disease. Objectives: To assess the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in secondary care. Design: Parallel group, multicentre patient randomised superiority pragmatic trial with up to 24 months follow-up and embedded qualitative research. Within-trial cost-utility and 10-year Markov model analyses. Development of a core outcome set for uncomplicated symptomatic gallstone disease. Setting: Secondary care elective settings. Participants: Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting were considered for inclusion. Interventions: Participants were randomised 1: 1 at clinic to receive either laparoscopic cholecystectomy or observation/conservative management. Main outcome measures: The primary outcome was quality of life measured by area under the curve over 18 months using the Short Form-36 bodily pain domain. Secondary outcomes included the Otago gallstones' condition-specific questionnaire, Short Form-36 domains (excluding bodily pain), area under the curve over 24 months for Short Form-36 bodily pain domain, persistent symptoms, complications and need for further treatment. No outcomes were blinded to allocation. Results: Between August 2016 and November 2019, 434 participants were randomised (217 in each group) from 20 United Kingdom centres. By 24 months, 64 (29.5%) in the observation/conservative management group and 153 (70.5%) in the laparoscopic cholecystectomy group had received surgery, median time to surgery of 9.0 months (interquartile range, 5.6-15.0) and 4.7 months (interquartile range 2.6-7.9), respectively. At 18 months, the mean Short Form-36 norm-based bodily pain score was 49.4 (standard deviation 11.7) in the observation/conservative management group and 50.4 (standard deviation 11.6) in the laparoscopic cholecystectomy group. The mean area under the curve over 18 months was 46.8 for both groups with no difference: mean difference -0.0, 95% confidence interval (-1.7 to 1.7); p-value 0.996; n = 203 observation/conservative, n = 205 cholecystectomy. There was no evidence of differences in quality of life, complications or need for further treatment at up to 24 months follow-up. Condition-specific quality of life at 24 months favoured cholecystectomy: mean difference 9.0, 95% confidence interval (4.1 to 14.0), p < 0.001 with a similar pattern for the persistent symptoms score. Within-trial cost-utility analysis found observation/conservative management over 24 months was less costly than cholecystectomy (mean difference -£1033). A non-significant quality-adjusted life-year difference of -0.019 favouring cholecystectomy resulted in an incremental cost-effectiveness ratio of £55,235. The Markov model continued to favour observation/conservative management, but some scenarios reversed the findings due to uncertainties in longer-term quality of life. The core outcome set included 11 critically important outcomes from both patients and healthcare professionals. Conclusions: The results suggested that in the short term (up to 24 months) observation/conservative management may be a cost-effective use of National Health Service resources in selected patients, but subsequent surgeries in the randomised groups and differences in quality of life beyond 24 months could reverse this finding. Future research should focus on longer-term follow-up data and identification of the cohort of patients that should be routinely offered surgery. Trial registration: This trial is registered as ISRCTN55215960. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/192/71) and is published in full in Health Technology Assessment; Vol. 28, No. 26. See the NIHR Funding and Awards website for further award information.

The C-GALL study assessed the benefits, in terms of symptoms, quality of life and costs, of cholecystectomy versus observation (conservative management: by the patient and general practitioner that might include dietary advice and pain management and surgery if needed). Four hundred and thirty-four patients with symptomatic gallstones were randomly allocated surgery or conservative management. The main symptom of ongoing bodily pain and some other quality-of-life measures were assessed over the next 2 years using postal questionnaires. After 2 years, 70% of those allocated to surgery had been operated on and 37% of the observation group either had an operation or were waiting for one. There was no difference in bodily pain or overall quality of life between the groups. However, participants in the surgery group reported fewer ongoing problems related to their gallstone disease or after surgery than those in the conservative management group. Surgery was, however, more costly than conservative management. The C-GALL study has shown that for some patients, a conservative management approach may be a sufficient and less costly way of managing their gallstone symptoms rather than going straight on the waiting list for surgery. More research is needed to identify which patients benefit most from surgery.

Assessment of depth of sedation using Bispectral Index™ monitoring in patients with severe traumatic brain injury in UK intensive care units.

Introduction: Severe traumatic brain injury affects ∼4500 per year across the UK. Most patients undergo a period of sedation to prevent secondary brain injury, however the optimal sedation target is unclear. This study aimed to assess the relationship between the electroencephalogram (EEG)-based Bispectral Index™ (BIS™) value and the clinical sedation score, along with other clinical outcomes. Methods: Patients with severe traumatic brain injury in four UK ICUs were recruited to have blinded BIS data collected for a 24-h period while sedated on the ICU. Drug, physiological, and outcome data were recorded from the ICU record. Sedation management was at the discretion of the ICU clinical team. Results: Twenty-six participants were recruited to the study. The mean BIS was 38 (inter-quartile range 29-44) and there was poor correlation between BIS and sedation score as a group (correlation coefficient 0.17, 95% confidence interval 0.08-0.26), however the spread in BIS values increased with decreasing sedation score. There was no statistically significant relationship between BIS and intracranial pressure, vasopressor use, osmotherapy use, or need for an additional sedative. Conclusion: This study supports previous work showing that BIS decreases with decreasing sedation score. However, the variation in BIS values increased with deeper levels of clinical sedation. Patients may not be benefiting from the full potential of sedation in traumatic brain injury and further studies of sedation titrated to an EEG-based parameter are needed. Clinical trial registration: NCT03575169.

Text Messages With Financial Incentives for Men With Obesity: A Randomized Clinical Trial.

Importance: Effective weight loss interventions are needed for men with obesity. Objective: To determine whether an intervention that combined text messaging with financial incentives attained significant weight loss at the 12-month follow-up compared with the control group and whether an intervention of text messaging alone attained significant weight loss at the 12-month follow-up compared with the control group. Design, Setting, and Participants: An assessor-blinded randomized clinical trial conducted in Belfast, Bristol, and Glasgow areas in the UK. A total of 585 men with body mass index (BMI) of 30 or more were enrolled between July 2021 and May 2022. Final follow-up occurred June 2023. Interventions: Participants were randomly assigned to 12 months of behavioral focused text messages combined with financial incentives (n = 196), 12 months of behavioral focused text messages alone (n= 194), or a waiting list (control group; n= 195). The financial incentive consisted of a monetary reward that was lost if weight loss targets were not met. All participants received weight management information and a pedometer at baseline. Main Outcomes and Measures: The 2 primary comparisons were the 12-month comparison of within-participant weight change between the text messaging with financial incentive group and the control group and the comparison between the text messaging alone group and the control group (minimum clinically important difference, 3%). The P value defined for statistical significance was P < .025 for each comparison. Results: Of the 585 men (mean [SD] age, 50.7 [13.3] years; mean weight, 118.5 [19.9] kg; mean BMI, 37.7 [5.7]; 525 [90%] White), 227 (39%) lived in postal code areas with lower socioeconomic status, and 426 (73%) completed the 12-month follow-up. At the 12-month follow-up, compared with the control group, the mean percent weight change was significantly greater in the text messaging with financial incentive group (mean difference, -3.2%; 97.5% CI, -4.6% to -1.9%; P < .001) but was not significantly greater in the text messaging alone group (mean difference, -1.4%; 97.5% CI, -2.9% to 0.0, P = .05). The mean (SD) weight changes were -5.7 (7.4) kg for the text messaging with financial incentives group, -3.0 (7.5) kg for the text messaging alone group, and -1.5 (6.6) kg for the control group. The 12-month mean (SD) percentage weight changes from baseline were -4.8% (6.1%) for the text messaging with financial incentives group, -2.7% (6.3%) for text messaging alone group, and -1.3% (5.5%) for the control group. Of 366 adverse events reported, the most common were infections (83 [23%]). Of the 23 serious adverse events (6.3%), 12 (52%) occurred in the text messaging with financial incentives group, 5 (22%) in the texts messaging alone group, and 6 (26%) in the control group. None were considered related to participating in a trial group. Conclusion and Relevance: Among men with obesity, an intervention with text messaging with financial incentive significantly improved weight loss compared with a control group, whereas text messaging alone was not significantly better than the control condition. These findings support text messaging combined with financial incentives to attain weight loss in men with obesity. Trial Registration: isrctn.org Identifier: ISRCTN91974895.

Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that ß-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306.

SFX-01 in hospitalised patients with community-acquired pneumonia during the COVID-19 pandemic: a double-blind, randomised, placebo-controlled trial.

Introduction: Sulforaphane can induce the transcription factor, Nrf2, promoting antioxidant and anti-inflammatory responses. In this study, hospitalised patients with community-acquired pneumonia (CAP) were treated with stabilised synthetic sulforaphane (SFX-01) to evaluate impact on clinical status and inflammation. Methods: Double-blind, randomised, placebo-controlled trial of SFX-01 (300 mg oral capsule, once daily for 14 days) conducted in Dundee, UK, between November 2020 and May 2021. Patients had radiologically confirmed CAP and CURB-65 (confusion, urea >7 mmol·L-1, respiratory rate ≥30 breaths·min-1, blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) score ≥1. The primary outcome was the seven-point World Health Organization clinical status scale at day 15. Secondary outcomes included time to clinical improvement, length of stay and mortality. Effects on Nrf2 activity and inflammation were evaluated on days 1, 8 and 15 by measurement of 45 serum cytokines and mRNA sequencing of peripheral blood leukocytes. Results: The trial was terminated prematurely due to futility with 133 patients enrolled. 65 patients were randomised to SFX-01 treatment and 68 patients to placebo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the cause of CAP in 103 (77%) cases. SFX-01 treatment did not improve clinical status at day 15 (adjusted OR 0.87, 95% CI 0.41-1.83; p=0.71), time to clinical improvement (adjusted hazard ratio (aHR) 1.02, 95% CI 0.70-1.49), length of stay (aHR 0.84, 95% CI 0.56-1.26) or 28-day mortality (aHR 1.45, 95% CI 0.67-3.16). The expression of Nrf2 targets and pro-inflammatory genes, including interleukin (IL)-6, IL-1ß and tumour necrosis factor-α, was not significantly changed by SFX-01 treatment. At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p<0.05, log2FC >1). Conclusion: SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.

Three-year cost utility analysis of mini versus standard slings: A trial based economic evaluation.

Objective: To report on the cost-effectiveness of adjustable anchored single-incision mini-slings (mini-slings) compared with tension-free standard mid-urethral slings (standard slings) in the surgical management of female stress urinary incontinence (SUI). Patients and Methods: Data on resource use and quality were collected from women aged ≥18 years with predominant SUI undergoing mid-urethral sling procedures in 21 UK hospitals. Resource use and quality of life (QoL) data were prospectively collected alongside the Single-Incision Mini-Slings versus standard synthetic mid-urethral slings Randomised Control Trial (SIMS RCT), for surgical treatment of SUI in women. A health service provider's (National Health Service [NHS]) perspective with 3-year follow-up was adopted to estimate the costs of the intervention and all subsequent resource use. A generic instrument, EuroQol EQ-5D-3L, was used to estimate the QoL. Results are reported as incremental costs, quality adjusted life years (QALYs) and incremental cost per QALY. Results: Base case analysis results show that although mini-slings cost less, there was no significant difference in costs: mini-slings versus standard slings: £-6 [95% CI -228-208] or in QALYs: 0.005 [95% CI -0.068-0.073] over the 3-year follow-up. There is substantial uncertainty, with a 56% and 44% probability that mini-slings and standard slings are the most cost-effective treatment, respectively, at a £20 000 willingness-to-pay threshold value for a QALY. Conclusions: At 3 years, there is no significant difference between mini-slings and standard slings in costs and QALYs. There is still some uncertainty over the long-term complications and failure rates of the devices used in the treatment of SUI; therefore, it is important to establish the long-term clinical and cost-effectiveness of these procedures.

Evaluating Primary Treatment for People with Advanced Glaucoma: Five-Year Results of the Treatment of Advanced Glaucoma Study.

PURPOSE: To determine whether primary trabeculectomy or medical treatment produces better outcomes in terms of quality of life (QoL), clinical effectiveness, and safety in patients with advanced glaucoma. DESIGN: Multicenter randomized controlled trial. PARTICIPANTS: Between June 3, 2014, and May 31, 2017, 453 adults with newly diagnosed advanced open-angle glaucoma in at least 1 eye (Hodapp classification) were recruited from 27 secondary care glaucoma departments in the United Kingdom. Two hundred twenty-seven were allocated to trabeculectomy, and 226 were allocated medical management. METHODS: Participants were randomized on a 1:1 basis to have either mitomycin C-augmented trabeculectomy or escalating medical management with intraocular pressure (IOP)-reducing drops as the primary intervention and were followed up for 5 years. MAIN OUTCOME MEASURES: The primary outcome was vision-specific QoL measured with the 25-item Visual Function Questionnaire (VFQ-25) at 5 years. Secondary outcomes were general health status, glaucoma-related QoL, clinical effectiveness (IOP, visual field, and visual acuity), and safety. RESULTS: At 5 years, the mean ± standard deviation VFQ-25 scores in the trabeculectomy and medication arms were 83.3 ± 15.5 and 81.3 ± 17.5, respectively, and the mean difference was 1.01 (95% confidence interval [CI], -1.99 to 4.00; P = 0.51). The mean IOPs were 12.07 ± 5.18 mmHg and 14.76 ± 4.14 mmHg, respectively, and the mean difference was -2.56 (95% CI, -3.80 to -1.32; P < 0.001). Glaucoma severity measured with visual field mean deviation were -14.30 ± 7.14 dB and -16.74 ± 6.78 dB, respectively, with a mean difference of 1.87 (95% CI, 0.87-2.87 dB; P < 0.001). Safety events occurred in 115 (52.2%) of patients in the trabeculectomy arm and 124 (57.9%) of patients in the medication arm (relative risk, 0.92; 95% CI, 0.72-1.19; P = 0.54). Serious adverse events were rare. CONCLUSIONS: At 5 years, the Treatment of Advanced Glaucoma Study demonstrated that primary trabeculectomy surgery is more effective in lowering IOP and preventing disease progression than primary medical treatment in patients with advanced disease and has a similar safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Effects of socioeconomic status on baseline values and outcomes at 24 months in the Treatment of Advanced Glaucoma Study randomised controlled Trial.

BACKGROUND/AIMS: Socioeconomic status (SES) is associated with late disease presentation and poorer outcomes. We evaluate the effect of SES on treatment outcomes and report the correlation between SES and baseline characteristics of participants in the Treatment of Advanced Glaucoma Study. METHODS: Pragmatic multicentre randomised controlled trial. Four hundred and fifty-three patients presenting with advanced open-angle glaucoma in at least one eye (Hodapp-Parrish-Anderson classification). Participants were randomised to either glaucoma drops (medical arm) or trabeculectomy (surgery arm). Clinical characteristics, Quality of life measurement (QoL) and SES defined by the Index of Multiple Deprivation are reported. Subgroup analysis explored treatment effect modifications of SES at 24 months. Correlation between SES and baseline characteristics was tested with the χ2 test of association for dichotomous variables and pairwise Pearson's correlation for continuous variables. RESULTS: The mean visual field mean deviation was -17.2 (6.7)dB for the most deprived quintile of participants and -13.0 (5.5) for the least deprived quintile in the index eye. At diagnosis, there was a strong correlation between SES and ethnicity, age, extent of visual field loss and number of visits to opticians prior to diagnosis. At 24 months, there was no evidence that the treatment effect was moderated by SES. CONCLUSIONS: In patients presenting with advanced glaucoma. SES at baseline is correlated with poorer visual function, poorer Visual Function Questionnaire-25 QoL, ethnicity, age and number visits to an optician in the years preceding diagnosis. SES at baseline does not have an effect of the success of treatment at 24 months. TRIAL REGISTRATION NUMBER: ISRCTN56878850.

How surgical Trainee Research Collaboratives achieve success: a mixed methods study to develop trainee engagement strategies.

OBJECTIVES: This study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials. DESIGN: This is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees' motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses. SETTING: This study was conducted within a secondary care setting in the UK. PARTICIPANTS: The survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews. RESULTS: We observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies. CONCLUSION: Trainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities.

Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial.

OBJECTIVE: To assess the clinical and cost effectiveness of conservative management compared with laparoscopic cholecystectomy for the prevention of symptoms and complications in adults with uncomplicated symptomatic gallstone disease. DESIGN: Parallel group, pragmatic randomised, superiority trial. SETTING: 20 secondary care centres in the UK. PARTICIPANTS: 434 adults (>18 years) with uncomplicated symptomatic gallstone disease referred to secondary care, assessed for eligibility between August 2016 and November 2019, and randomly assigned (1:1) to receive conservative management or laparoscopic cholecystectomy. INTERVENTIONS: Conservative management or surgical removal of the gallbladder. MAIN OUTCOME MEASURES: The primary patient outcome was quality of life, measured by area under the curve, over 18 months using the short form 36 (SF-36) bodily pain domain, with higher scores (range 0-100) indicating better quality of life. Other outcomes included costs to the NHS, quality adjusted life years (QALYs), and incremental cost effectiveness ratio. RESULTS: Of 2667 patients assessed for eligibility, 434 were randomised: 217 to the conservative management group and 217 to the laparoscopic cholecystectomy group. By 18 months, 54 (25%) participants in the conservative management arm and 146 (67%) in the cholecystectomy arm had received surgery. The mean SF-36 norm based bodily pain score was 49.4 (standard deviation 11.7) in the conservative management arm and 50.4 (11.6) in the cholecystectomy arm. The SF-36 bodily pain area under the curve up to 18 months did not differ (mean difference 0.0, 95% confidence interval -1.7 to 1.7; P=1.00). Conservative management was less costly (mean difference -£1033, (-$1334; -€1205), 95% credible interval -£1413 to -£632) and QALYs did not differ (mean difference -0.019, 95% credible interval -0.06 to 0.02). CONCLUSIONS: In the short term (≤18 months), laparoscopic surgery is no more effective than conservative management for adults with uncomplicated symptomatic gallstone disease, and as such conservative management should be considered as an alternative to surgery. From an NHS perspective, conservative management may be cost effective for uncomplicated symptomatic gallstone disease. As costs, complications, and benefits will continue to be incurred in both groups beyond 18 months, future research should focus on longer term follow-up to establish effectiveness and lifetime cost effectiveness and to identify the cohort of patients who should be routinely offered surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN55215960.

Development of an intervention to manage benzodiazepine dependence and high-risk use in the context of escalating drug related deaths in Scotland: an application of the MRC framework.

BACKGROUND: Scotland has the highest rate of drug related deaths (DRD) in Europe. These are deaths in people who use drugs such as heroin, cocaine, benzodiazepines and gabapentinoids. It is a feature of deaths in Scotland that people use combinations of drugs which increases the chance of a DRD. Many deaths involve 'street' benzodiazepines, especially a drug called etizolam. Many of the 'street' benzodiazepines are not licensed in the UK so come from illegal sources. People who use opiates can be prescribed a safer replacement medication (e.g., methadone). While guidance on management of benzodiazepines use highlights that there is little evidence to support replacement prescribing, practice and evidence are emerging. AIM: To develop an intervention to address 'street' benzodiazepines use in people who also use opiates. METHODS: The MRC Framework for Complex Interventions was used to inform research design. Co-production of the intervention was achieved through three online workshops with clinicians, academics working in the area of substance use, and people with lived experience (PWLE). Each workshop was followed by a PWLE group meeting. Outputs from workshops were discussed and refined by the PWLE group and then further explored at the next workshop. RESULTS: After these six sessions, a finalised logic model for the intervention was successfully achieved that was acceptable to clinicians and PWLE. Key components of the intervention were: prescribing of diazepam; anxiety management, sleep, and pain; and harm reduction resources (locked box and a range of tips), personal safety conversations, as well as a virtual learning environment. CONCLUSION: A co-produced intervention was developed for next stage clinical feasibility testing.

Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta in Trauma Patients With Exsanguinating Hemorrhage: The UK-REBOA Randomized Clinical Trial.

Importance: Bleeding is the most common cause of preventable death after trauma. Objective: To determine the effectiveness of resuscitative endovascular balloon occlusion of the aorta (REBOA) when used in the emergency department along with standard care vs standard care alone on mortality in trauma patients with exsanguinating hemorrhage. Design, Setting, and Participants: Pragmatic, bayesian, randomized clinical trial conducted at 16 major trauma centers in the UK. Patients aged 16 years or older with exsanguinating hemorrhage were enrolled between October 2017 and March 2022 and followed up for 90 days. Intervention: Patients were randomly assigned (1:1 allocation) to a strategy that included REBOA and standard care (n = 46) or standard care alone (n = 44). Main Outcomes and Measures: The primary outcome was all-cause mortality at 90 days. Ten secondary outcomes included mortality at 6 months, while in the hospital, and within 24 hours, 6 hours, or 3 hours; the need for definitive hemorrhage control procedures; time to commencement of definitive hemorrhage control procedures; complications; length of stay; blood product use; and cause of death. Results: Of the 90 patients (median age, 41 years [IQR, 31-59 years]; 62 [69%] were male; and the median Injury Severity Score was 41 [IQR, 29-50]) randomized, 89 were included in the primary outcome analysis because 1 patient in the standard care alone group declined to provide consent for continued participation and data collection 4 days after enrollment. At 90 days, 25 of 46 patients (54%) had experienced all-cause mortality in the REBOA and standard care group vs 18 of 43 patients (42%) in the standard care alone group (odds ratio [OR], 1.58 [95% credible interval, 0.72-3.52]; posterior probability of an OR >1 [indicating increased odds of death with REBOA], 86.9%). Among the 10 secondary outcomes, the ORs for mortality and the posterior probabilities of an OR greater than 1 for 6-month, in-hospital, and 24-, 6-, or 3-hour mortality were all increased in the REBOA and standard care group, and the ORs were increased with earlier mortality end points. There were more deaths due to bleeding in the REBOA and standard care group (8 of 25 patients [32%]) than in standard care alone group (3 of 18 patients [17%]), and most occurred within 24 hours. Conclusions and Relevance: In trauma patients with exsanguinating hemorrhage, a strategy of REBOA and standard care in the emergency department does not reduce, and may increase, mortality compared with standard care alone. Trial Registration: isrctn.org Identifier: ISRCTN16184981.

Patient preferences for stress urinary incontinence treatments: a discrete choice experiment.

OBJECTIVES: To elicit and value patient preferences for the processes and outcomes of surgical management of stress urinary incontinence in women. DESIGN: A discrete choice experiment survey to elicit preferences for type of anaesthesia, postoperative recovery time, treatment success, adverse events, impact on daily activities and cost. An experimental design generated 40 choice tasks, and each respondent completed 1 block of 10 and 2 validity tests. Analysis was by multinomial logistical regression. SETTING: N=21 UK hospitals. PARTICIPANTS: N=325 adult women who were a subsample of those randomised to the single-incision mini-slings clinical trial. OUTCOMES: Patient preferences; valuation obtained using willingness to pay. RESULTS: N=227 of 325 (70%) returned a questionnaire, and 94% of those completed all choice tasks. Respondents preferred general anaesthesia, shorter recovery times, improved stress urinary incontinence symptoms and avoidance of adverse events. Women were willing to pay (mean (95% CI)) £76 (£33 to £119) per day of reduction in recovery time following surgery. They valued increases in Patient Global Impression of Improvement, ranging from £8173 (£5459 to £10 887) for 'improved' to £11 706 (£8267 to £15 144) for 'very much improved' symptoms, compared with no symptom improvement. This was offset by negative values attached to the avoidance of complications ranging between £-8022 (£-10 661 to £-5383) and £-10 632 (£-14 077 to £-7187) compared to no complications. Women valued treatments that reduced the need to avoid daily activities, with willingness to pay ranging from £-967 (£-2199 to £266) for rarely avoiding activities to £-5338 (£-7258 to £-3417) for frequently avoiding daily activities compared with no avoidance. CONCLUSION: This discrete choice experiment demonstrates that patients place considerable value on improvement in stress urinary incontinence symptoms and avoidance of treatment complications. Trade-offs between symptom improvement and adverse event risk should be considered within shared decision-making. The willingness to pay values from this study can be used in future cost-benefit analyses. TRIAL REGISTRATION NUMBER: ISRCTN: 93264234; Post-results.

Cost-effectiveness of cognitive behavioural and personalized exercise interventions for reducing fatigue in inflammatory rheumatic diseases.

OBJECTIVES: To estimate the cost-effectiveness of a cognitive behavioural approach (CBA) or a personalized exercise programme (PEP), alongside usual care (UC), in patients with inflammatory rheumatic diseases who report chronic, moderate to severe fatigue. METHODS: A within-trial cost-utility analysis was conducted using individual patient data collected within a multicentre, three-arm randomized controlled trial over a 56-week period. The primary economic analysis was conducted from the UK National Health Service (NHS) perspective. Uncertainty was explored using cost-effectiveness acceptability curves and sensitivity analysis. RESULTS: Complete-case analysis showed that, compared with UC, both PEP and CBA were more expensive [adjusted mean cost difference: PEP £569 (95% CI: £464, £665); CBA £845 (95% CI: £717, £993)] and, in the case of PEP, significantly more effective [adjusted mean quality-adjusted life year (QALY) difference: PEP 0.043 (95% CI: 0.019, 0.068); CBA 0.001 (95% CI: -0.022, 0.022)]. These led to an incremental cost-effectiveness ratio (ICER) of £13 159 for PEP vs UC, and £793 777 for CBA vs UC. Non-parametric bootstrapping showed that, at a threshold value of £20 000 per QALY gained, PEP had a probability of 88% of being cost-effective. In multiple imputation analysis, PEP was associated with significant incremental costs of £428 (95% CI: £324, £511) and a non-significant QALY gain of 0.016 (95% CI: -0.003, 0.035), leading to an ICER of £26 822 vs UC. The estimates from sensitivity analyses were consistent with these results. CONCLUSION: The addition of a PEP alongside UC is likely to provide a cost-effective use of health care resources.

PROSPECT: 4- and 6-year follow-up of a randomised trial of surgery for vaginal prolapse.

INTRODUCTION AND HYPOTHESIS: Our aim was to compare the mid-term results of native tissue, biological xenograft and polypropylene mesh surgery for women with vaginal wall prolapse. METHODS: A total of 1348 women undergoing primary transvaginal repair of an anterior and/or posterior prolapse were recruited between January 2010 and August 2013 from 35 UK centres. They were randomised by remote allocation to native tissue surgery, biological xenograft or polypropylene mesh. We performed both 4- and 6-year follow-up using validated patient-reported outcome measures. RESULTS: At 4 and 6 years post-operation, there was no clinically important difference in Pelvic Organ Prolapse Symptom Score for any of the treatments. Using a strict composite outcome to assess functional cure at 6 years, we found no difference in cure among the three types of surgery. Half the women were cured at 6 years but only 10.3 to 12% of women had undergone further surgery for prolapse. However, 8.4% of women in the mesh group had undergone further surgery for mesh complications. There was no difference in the incidence of chronic pain or dyspareunia between groups. CONCLUSIONS: At the mid-term outcome of 6 years, there is no benefit from augmenting primary prolapse repairs with polypropylene mesh inlays or biological xenografts. There was no evidence that polypropylene mesh inlays caused greater pain or dyspareunia than native tissue repairs.

Cost-utility analysis of shockwave lithotripsy vs ureteroscopic stone treatment in adults.

OBJECTIVES: To assess the cost-effectiveness, resource use implications, quality-adjusted life-years (QALYs) and cost per QALY of care pathways starting with either extracorporeal shockwave lithotripsy (SWL) or with ureteroscopic retrieval (ureteroscopy [URS]) for the management of ureteric stones. PATIENTS AND METHODS: Data on quality of life and resource use for 613 patients, collected prospectively in the Therapeutic Interventions for Stones of the Ureter (TISU) randomized controlled trial (ISRCTN 92289221), were used to assess the cost-effectiveness of two care pathways, SWL and URS. A health provider (UK National Health Service) perspective was adopted to estimate the costs of the interventions and subsequent resource use. Quality-of-life data were calculated using a generic instrument, the EuroQol EQ-5D-3L. Results are expressed as incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. RESULTS: The mean QALY difference (SWL vs URS) was -0.021 (95% confidence interval [CI] -0.033 to -0.010) and the mean cost difference was -£809 (95% CI -£1061 to -£551). The QALY difference translated into approximately 10 more healthy days over the 6-month period for the patients on the URS care pathway. The probabaility that SWL is cost-effective is 79% at a society's willingness to pay (WTP) threshold for 1 QALY of £30,000 and 98% at a WTP threshold of £20,000. CONCLUSION: The SWL pathway results in lower QALYs than URS but costs less. The incremental cost per QALY is £39 118 cost saving per QALY lost, with a 79% probability that SWL would be considered cost-effective at a WTP threshold for 1 QALY of £30 000 and 98% at a WTP threshold of £20 000. Decision-makers need to determine if costs saved justify the loss in QALYs.

Single-incision mini-slings versus standard synthetic mid-urethral slings for surgical treatment of stress urinary incontinence in women: The SIMS RCT.

BACKGROUND: Stress urinary incontinence is the most common type of urinary incontinence in premenopausal women. Until recently, synthetic mid-urethral slings (mesh/tape) were the standard surgical treatment, if conservative management failed. Adjustable anchored single-incision mini-slings are newer, use less mesh and may reduce perioperative morbidity, but it is unclear how their success rates and safety compare with those of standard tension-free mid-urethral slings. OBJECTIVE: The objective was to compare tension-free standard mid-urethral slings with adjustable anchored single-incision mini-slings among women with stress urinary incontinence requiring surgical intervention, in terms of patient-reported effectiveness, health-related quality of life, safety and cost-effectiveness. DESIGN: This was a pragmatic non-inferiority randomised controlled trial. Allocation was by remote web-based randomisation (1 : 1 ratio). SETTING: The trial was set in 21 UK hospitals. PARTICIPANTS: Participants were women aged ≥ 18 years with predominant stress urinary incontinence, undergoing a mid-urethral sling procedure. INTERVENTIONS: Single-incision mini-slings, compared with standard mid-urethral slings. MAIN OUTCOME MEASURES: The primary outcome was patient-reported success rates on the Patient Global Impression of Improvement scale at 15 months post randomisation (≈ 1 year post surgery), with success defined as outcomes of 'very much improved' or 'much improved'. The primary economic outcome was incremental cost per quality-adjusted life-year gained. Secondary outcomes were adverse events, impact on other urinary symptoms, quality of life and sexual function. RESULTS: A total of 600 participants were randomised. At 15 months post randomisation, adjustable anchored single-incision mini-slings were non-inferior to tension-free standard mid-urethral slings at the 10% margin for the primary outcome [single-incision mini-sling 79% (212/268) vs. standard mid-urethral sling 76% (189/250), risk difference 4.6, 95% confidence interval -2.7 to 11.8; p non-inferiority < 0.001]. Similarly, at 3 years' follow-up, patient-reported success rates in the single-incision mini-sling group were non-inferior to those of the standard mid-urethral sling group at the 10% margin [single-incision mini-sling 72% (177/246) vs. standard mid-urethral sling 67% (157/235), risk difference 5.7, 95% confidence interval -1.3 to 12.8; p non-inferiority < 0.001]. Tape/mesh exposure rates were higher for single-incision mini-sling participants, with 3.3% (9/276) [compared with 1.9% (5/261) in the standard mid-urethral sling group] reporting tape exposure over the 3 years of follow-up. The rate of groin/thigh pain was slightly higher in the single-incision mini-sling group at 15 months [single-incision mini-sling 15% (41/276) vs. standard mid-urethral sling 12% (31/261), risk difference 3.0%, 95% confidence interval -1.1% to 7.1%]; however, by 3 years, the rate of pain was slightly higher among the standard mid-urethral sling participants [single-incision mini-sling 14% (39/276) vs. standard mid-urethral sling 15% (39/261), risk difference -0.8, 95% confidence interval -4.1 to 2.5]. At the 3-year follow-up, quality of life and sexual function outcomes were similar in both groups: for the International Consultation on Incontinence Questionnaire Lower Urinary Tract Symptoms Quality of Life, the mean difference in scores was -1.1 (95% confidence interval -3.1 to 0.8; p = 0.24), and for the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, International Urogynecological Association-Revised, it was 0 (95% confidence interval -0.1, 0.1; p = 0.92). However, more women in the single-incision mini-sling group reported dyspareunia [12% (17/145), compared with 4.8% (7/145) in the standard mid-urethral sling group, risk difference 7.0%, 95% confidence interval 1.9% to 12.1%]. The base-case economics results showed no difference in costs (-£6, 95% confidence interval -£228 to £208) or quality-adjusted life-years (0.005, 95% confidence interval -0.068 to 0.073) between the groups. There is a 56% probability that single-incision mini-slings will be considered cost-effective at the £20,000 willingness-to-pay threshold value for a quality-adjusted life-year. LIMITATIONS: Follow-up data beyond 3 years post randomisation are not available to inform longer-term safety and cost-effectiveness. CONCLUSIONS: Single-incision mini-slings were non-inferior to standard mid-urethral slings in patient-reported success rates at up to 3 years' follow-up. FUTURE WORK: Success rates, adverse events, retreatment rates, symptoms, and quality-of-life scores at 10 years' follow-up will help inform long-term effectiveness. TRIAL REGISTRATION: This trial was registered as ISRCTN93264234. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 47. See the NIHR Journals Library website for further project information.

Stress urinary incontinence, the involuntary leakage of urine, is a common and distressing condition, particularly for women aged > 40 years. In the UK, it is estimated that 6 million (40%) of this age group have symptoms bothersome enough for doctors to investigate. It causes embarrassment, low self-esteem and even social isolation. Standard surgical treatment used to be a mid-urethral sling made of mesh, inserted, in most cases, under general anaesthetic. Recently, a single-incision mini-sling, using less mesh, has been available under local anaesthetic. A number of small studies have shown that mini-slings have similar success rates to those of standard slings, necessitate shorter hospital stays and are less painful immediately after surgery. However, these results were uncertain and the potential longer-term benefits and disadvantages of both types of sling treatments were unknown. We compared the two types of sling treatments in a randomised trial of 600 women to see if they were equally effective. Success was measured by asking women to report on their symptoms and experiences. We also collected information on safety, quality of life, sexual function, and costs to women and the NHS. Every participant had an equal chance of starting treatment with the standard sling or the mini-sling. Participants were followed up for 3 years. Women allocated to each treatment reported similar success rates, quality of life and sexual function at 3 years. Women who received the new mini-sling had more mesh exposure (3% for the mini-sling vs. 2% for the standard sling) and were more likely to report pain during intercourse (12% vs. 5%) than women who received the standard sling. Both treatments had similar costs. Follow-up to 10 years is under way to establish the long-term benefits and disadvantages.