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.

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.

Core outcome set for symptomatic uncomplicated gallstone disease.

BACKGROUND: Heterogeneity of outcomes is a problem for assessing intervention effectiveness when considering treatments for uncomplicated symptomatic gallstone disease. The value to all stakeholders of outcomes that have been measured and reported to date is also unclear. The aim of this study was to develop a core outcome set for symptomatic uncomplicated gallstone disease. METHODS: An in person-meeting was held with patients to prioritize potentially important outcomes from a previously developed longlist of outcomes. This was followed by an online three-round Delphi survey that was conducted with healthcare professionals. The results of each consensus process were compared and combined to produce the final core outcome set. RESULTS: A total of 82 participants enrolled in round 1 of the Delphi survey, with a final sample of 40 participants contributing to round 3. Five patients contributed to the in-person group meeting. Following the consensus processes, 11 outcomes were considered to be core by patients and healthcare professionals, and included in the core outcome set. These were: quality of life; overall health state; overall satisfaction; overall pain; common bile duct injury; biliary leak; haemorrhage; need for endoscopic retrograde cholangiopancreatography; intra-abdominal collections; admission/readmission for problems; and reoperation. CONCLUSION: A core outcome set for symptomatic uncomplicated gallstone disease has been developed with patients and healthcare professionals. Eleven outcomes across four key domains have been identified. These represent the minimum set of outcomes that should be reported in trials evaluating interventions for gallstone disease.

Seeing Picasso: an investigation into the visual system of the triggerfish Rhinecanthus aculeatus.

Vision is used by animals to find food and mates, avoid predators, defend resources and navigate through complex habitats. Behavioural experiments are essential for understanding animals' perception but are often challenging and time-consuming; therefore, using species that can be trained easily for complex tasks is advantageous. Picasso triggerfish, Rhinecanthus aculeatus, have been used in many behavioural studies investigating vision and navigation. However, little is known about the molecular and anatomical basis of their visual system. We addressed this knowledge gap here and behaviourally tested achromatic and chromatic acuity. In terms of visual opsins, R. aculeatus possessed one rod opsin gene (RH1) and at least nine cone opsins: one violet-sensitive SWS2B gene, seven duplicates of the blue-green-sensitive RH2 gene (RH2A, RH2B, RH2C1-5) and one red-sensitive LWS gene. However, only five cone opsins were expressed: SWS2B expression was consistent, while RH2A, RH2C-1 and RH2C-2 expression varied depending on whether fish were sampled from the field or aquaria. Levels of LWS expression were very low. Using fluorescence in situ hybridisation, we found SWS2B was expressed exclusively in single cones, whereas RH2A and RH2Cs were expressed in opposite double cone members. Anatomical resolution estimated from ganglion cell densities was 6.8 cycles per degree (cpd), which was significantly higher than values obtained from behavioural testing for black-and-white achromatic stimuli (3.9 cpd) and chromatic stimuli (1.7-1.8 cpd). These measures were twice as high as previously reported. This detailed information on their visual system will help inform future studies with this emerging focal species.

Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.

BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

ScotCap - A large observational cohort study.

AIM: The aim of this work was to evaluate the performance of colon capsule endoscopy (CCE) in a lower gastrointestinal diagnostic care pathway. METHOD: This large multicentre prospective clinical evaluation recruited symptomatic patients (patients requiring investigation of symptoms suggestive of colorectal pathology) and surveillance patients (patients due to undergo surveillance colonoscopy). Patients aged 18 years or over were invited to participate and undergo CCE by a secondary-care clinician if they met the referral criteria for a colonoscopy. The primary outcome was the test completion rate (visualization of the whole colon and rectum). We also measured the need for further tests after CCE. RESULTS: A total of 733 patients were invited to take part in this evaluation, with 509 patients undergoing CCE. Of these, 316 were symptomatic patients and 193 were surveillance patients. Two hundred and twenty-eight of the 316 symptomatic patients (72%) and 137 of the 193 surveillance patients (71%) had a complete test. It was found that 118/316 (37%) of symptomatic patients required no further test following CCE, while 103/316 (33%) and 81/316 (26%) required a colonoscopy and flexible sigmoidoscopy, respectively. Fifty-three of the 193 surveillance patients (28%) required no further test following CCE, while 104/193 (54%) and 30/193 (16%) required a colonoscopy and flexible sigmoidoscopy, respectively. No patient in this evaluation was diagnosed with colorectal cancer. Two patients experienced serious adverse events - one capsule retention with obstruction and one hospital admission with dehydration due to the bowel preparation. CONCLUSION: CCE is a safe, well-tolerated diagnostic test which can reduce the proportion of patients requiring colonoscopy, but the test completion rate needs to be improved to match that of lower gastrointestinal endoscopy.

Pharmaceutical policies: effects of regulating drug insurance schemes.

BACKGROUND: Drug insurance schemes are systems that provide access to medicines on a prepaid basis and could potentially improve access to essential medicines and reduce out-of-pocket payments for vulnerable populations. OBJECTIVES: To assess the effects on drug use, drug expenditure, healthcare utilisation and healthcare outcomes of alternative policies for regulating drug insurance schemes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, nine other databases, and two trials registers between November 2014 and September 2020, including a citation search for included studies on 15 September 2021 using Web of Science. We screened reference lists of all the relevant reports that we retrieved and reports from the Background section. Authors of relevant papers, relevant organisations, and discussion lists were contacted to identify additional studies, including unpublished and ongoing studies. SELECTION CRITERIA: We planned to include randomised trials, non-randomised trials, interrupted time-series studies (including controlled ITS [CITS] and repeated measures [RM] studies), and controlled before-after (CBA) studies. Two review authors independently assessed the search results and reference lists of relevant reports, retrieved the full text of potentially relevant references and independently applied the inclusion criteria to those studies. We resolved disagreements by discussion, and when necessary by including a third review author. We excluded studies of the following pharmaceutical policies covered in other Cochrane Reviews: those that determined how decisions were made about which conditions or drugs were covered; those that placed restrictions on reimbursement for drugs that were covered; and those that regulated out-of-pocket payments for drugs. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included studies and assessed risk of bias for each study, with disagreements being resolved by consensus. We used the criteria suggested by  Cochrane Effective Practice and Organisation of Care (EPOC)  to assess the risk of bias of included studies. For randomised trials, non-randomised trials and controlled before-after studies, we planned to report relative effects. For dichotomous outcomes, we reported the risk ratio (RR) when possible and adjusted for baseline differences in the outcome measures. For interrupted time series and controlled interrupted time-series studies, we computed changes along two dimensions: change in level; and change in slope. We undertook a structured synthesis following the EPOC guidance on this topic, describing the range of effects found in the studies for each category of outcomes. MAIN RESULTS: We identified 58 studies that met the inclusion criteria (25 interrupted time-series studies and 33 controlled before-after studies). Most of the studies (54) assessed a single policy implemented in the United States (US) healthcare system: Medicare Part D. The other four assessed other drug insurance schemes from Canada and the US, but only one of them provided analysable data for inclusion in the quantitative synthesis. The introduction of drug insurance schemes may increase prescription drug use (low-certainty evidence). On the other hand, Medicare Part D may decrease drug expenditure measured as both out-of-pocket spending and total drug spending (low-certainty evidence). Regarding healthcare utilisation, drug insurance policies (such as Medicare Part D) may lead to a small increase in visits to the emergency department. However, it is uncertain whether this type of policy increases or decreases hospital admissions or outpatient visits by beneficiaries of the scheme because the certainty of the evidence was very low. Likewise, it is uncertain if the policy increases or reduces health outcomes such as mortality because the certainty of the evidence was very low. AUTHORS' CONCLUSIONS: The introduction of drug insurance schemes such as Medicare Part D in the US health system may increase prescription drug use and may decrease out-of-pocket payments by the beneficiaries of the scheme and total drug expenditures. It may also lead to a small increase in visits to the emergency department by the beneficiaries of the policy. Its effects on other healthcare utilisation outcomes and on health outcomes are uncertain because of the very low certainty of the evidence. The applicability of this evidence to settings outside US healthcare is limited.

Reducing surgical site infection rates in colorectal surgery - a quality improvement approach to implementing a comprehensive bundle.

AIM: Surgical site infections (SSIs) are a preventable cause of morbidity following surgical procedures. Strategies to reduce rates of SSI must address pre-, peri- and postoperative factors and multiple interventions can be combined into 'bundles'. Adoption of these measures can reduce SSIs, but this is dependent on high levels of compliance. The aim of this work is to assess the change in rates of SSI in elective colorectal surgery after implementing a colorectal SSI bundle. METHOD: This is a single-centre prospective cohort study. All elective colorectal procedures from 2011 until 2018 (inclusive) were included. The primary outcome was inpatient SSI. A multimodal bundle was implemented using quality improvement methodology. The bundle was altered during the timeframe of the study to optimize outcomes. Data were analysed by interrupted time series analysis assessing points at which the bundle was altered. RESULTS: In the study period, 1075 elective colorectal procedures were performed. Prior to the introduction of the colorectal SSI bundle, the SSI rate was 16.4%. During the implementation period (2013-2015), the overall rate of SSI fell from 15.9% to 9.4%, with the most significant reduction being in superficial SSI, from 8.6% to 4.7%. In the postimplementation period from 2015-2018, there was a further reduction in the overall rate of SSI (5.1%). In 2018, there were 87 consecutive cases without infection. CONCLUSION: A successful reduction in the rate of SSI following elective colorectal surgery can be achieved by adopting a comprehensive perioperative bundle. This is complemented by a process of continuous measurement and evaluation. The current bundle has achieved a significant reduction in superficial SSI.

Strategies to improve retention in randomised trials.

BACKGROUND: Poor retention of participants in randomised trials can lead to missing outcome data which can introduce bias and reduce study power, affecting the generalisability, validity and reliability of results. Many strategies are used to improve retention but few have been formally evaluated. OBJECTIVES: To quantify the effect of strategies to improve retention of participants in randomised trials and to investigate if the effect varied by trial setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Scopus, PsycINFO, CINAHL, Web of Science Core Collection (SCI-expanded, SSCI, CPSI-S, CPCI-SSH and ESCI) either directly with a specified search strategy or indirectly through the ORRCA database. We also searched the SWAT repository to identify ongoing or recently completed retention trials. We did our most recent searches in January 2020. SELECTION CRITERIA: We included eligible randomised or quasi-randomised trials of evaluations of strategies to increase retention that were embedded in 'host' randomised trials from all disease areas and healthcare settings. We excluded studies aiming to increase treatment compliance. DATA COLLECTION AND ANALYSIS: We extracted data on: the retention strategy being evaluated; location of study; host trial setting; method of randomisation; numbers and proportions in each intervention and comparator group. We used a risk difference (RD) and 95% confidence interval (CI) to estimate the effectiveness of the strategies to improve retention. We assessed heterogeneity between trials. We applied GRADE to determine the certainty of the evidence within each comparison. MAIN RESULTS: We identified 70 eligible papers that reported data from 81 retention trials. We included 69 studies with more than 100,000 participants in the final meta-analyses, of which 67 studies evaluated interventions aimed at trial participants and two evaluated interventions aimed at trial staff involved in retention. All studies were in health care and most aimed to improve postal questionnaire response. Interventions were categorised into broad comparison groups: Data collection; Participants; Sites and site staff; Central study management; and Study design. These intervention groups consisted of 52 comparisons, none of which were supported by high-certainty evidence as determined by GRADE assessment. There were four comparisons presenting moderate-certainty evidence, three supporting retention (self-sampling kits, monetary reward together with reminder or prenotification and giving a pen at recruitment) and one reducing retention (inclusion of a diary with usual follow-up compared to usual follow-up alone). Of the remaining studies, 20 presented GRADE low-certainty evidence and 28 presented very low-certainty evidence. Our findings do provide a priority list for future replication studies, especially with regard to comparisons that currently rely on a single study. AUTHORS' CONCLUSIONS: Most of the interventions we identified aimed to improve retention in the form of postal questionnaire response. There were few evaluations of ways to improve participants returning to trial sites for trial follow-up. None of the comparisons are supported by high-certainty evidence. Comparisons in the review where the evidence certainty could be improved with the addition of well-done studies should be the focus for future evaluations.

The clinical and cost-effectiveness of total versus partial knee replacement in patients with medial compartment osteoarthritis (TOPKAT): 5-year outcomes of a randomised controlled trial.

BACKGROUND: Late-stage isolated medial knee osteoarthritis can be treated with total knee replacement (TKR) or partial knee replacement (PKR). There is high variation in treatment choice and little robust evidence to guide selection. The Total or Partial Knee Arthroplasty Trial (TOPKAT) therefore aims to assess the clinical effectiveness and cost-effectiveness of TKR versus PKR in patients with medial compartment osteoarthritis of the knee, and this represents an analysis of the main endpoints at 5 years. METHODS: Our multicentre, pragmatic randomised controlled trial was done at 27 UK sites. We used a combined expertise-based and equipoise-based approach, in which patients with isolated osteoarthritis of the medial compartment of the knee and who satisfied general requirements for a medial PKR were randomly assigned (1:1) to receive PKR or TKR by surgeons who were either expert in and willing to perform both surgeries or by a surgeon with particular expertise in the allocated procedure. The primary endpoint was the Oxford Knee Score (OKS) 5 years after randomisation in all patients assigned to groups. Health-care costs (in UK 2017 prices) and cost-effectiveness were also assessed. This trial is registered with ISRCTN (ISRCTN03013488) and ClinicalTrials.gov (NCT01352247). FINDINGS: Between Jan 18, 2010, and Sept 30, 2013, we assessed 962 patients for their eligibility, of whom 431 (45%) patients were excluded (121 [13%] patients did not meet the inclusion criteria and 310 [32%] patients declined to participate) and 528 (55%) patients were randomly assigned to groups. 94% of participants responded to the follow-up survey 5 years after their operation. At the 5-year follow-up, we found no difference in OKS between groups (mean difference 1·04, 95% CI -0·42 to 2·50; p=0·159). In our within-trial cost-effectiveness analysis, we found that PKR was more effective (0·240 additional quality-adjusted life-years, 95% CI 0·046 to 0·434) and less expensive (-£910, 95% CI -1503 to -317) than TKR during the 5 years of follow-up. This finding was a result of slightly better outcomes, lower costs of surgery, and lower follow-up health-care costs with PKR than TKR. INTERPRETATION: Both TKR and PKR are effective, offer similar clinical outcomes, and result in a similar incidence of re-operations and complications. Based on our clinical findings, and results regarding the lower costs and better cost-effectiveness with PKR during the 5-year study period, we suggest that PKR should be considered the first choice for patients with late-stage isolated medial compartment osteoarthritis. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Nitroglycerin for treatment of retained placenta: A randomised, placebo-controlled, multicentre, double-blind trial in the UK.

BACKGROUND: Retained placenta following vaginal delivery is a major cause of postpartum haemorrhage. Currently, the only effective treatments for a retained placenta are the surgical procedures of manual removal of placenta (MROP) and uterine curettage, which are not universally available, particularly in low- and middle-income countries. The objective of the trial was to determine whether sublingual nitroglycerin spray was clinically effective and cost-effective for medical treatment of retained placenta following vaginal delivery. METHODS AND FINDINGS: A randomised, placebo-controlled, double-blind trial was undertaken between October 2014 and July 2017 at 29 delivery units in the UK (Edinburgh, Glasgow, Manchester, Newcastle, Preston, Warrington, Chesterfield, Crewe, Durham, West Middlesex, Aylesbury, Furness, Southampton, Bolton, Sunderland, Oxford, Nottingham [2 units], Burnley, Chertsey, Stockton-on-Tees, Middlesborough, Chester, Darlington, York, Reading, Milton Keynes, Telford, Frimley). In total, 1,107 women with retained placenta following vaginal delivery were recruited. The intervention was self-administered 2 puffs of sublingual nitroglycerin (800 µg; intervention, N = 543) or placebo spray (control, N = 564). The primary clinical outcome was the need for MROP, assessed at 15 minutes following administration of the intervention. Analysis was based on the intention-to-treat principle. The primary safety outcome was measured blood loss between study drug administration and transfer to the postnatal ward or other clinical area. The primary patient-sided outcomes were satisfaction with treatment and side-effect profile, assessed by questionnaires pre-discharge and 6 weeks post-delivery. Secondary clinical outcomes were measured at 5 and 15 minutes after study drug administration and prior to hospital discharge. There was no statistically significant or clinically meaningful difference in need for MROP by 15 minutes (primary clinical outcome, 505 [93.3%] for nitroglycerin versus 518 [92.0%] for placebo, odds ratio [OR] 1.01 [95% CI 0.98-1.04], p = 0.393) or blood loss (<500 ml: nitroglycerin, 238 [44.3%], versus placebo, 249 [44.5%]; 500 ml-1,000 ml: nitroglycerin, 180 [33.5%], versus placebo, 224 [40.0%]; >1,000 ml: nitroglycerin, 119 [22.2%], versus placebo, 87 [15.5%]; ordinal OR 1.14 [95% CI 0.88-1.48], p = 0.314) or satisfaction with treatment (nitroglycerin, 288 [75.4%], versus placebo, 303 [78.1%]; OR 0.87 [95% CI 0.62-1.22], p = 0.411) or health service costs (mean difference [£] 55.3 [95% CI -199.20 to 309.79]). Palpitations following drug administration were reported more often in the nitroglycerin group (36 [9.8%] versus 15 [4.0%], OR 2.60 [95% CI 1.40-4.84], p = 0.003). There were 52 serious adverse events during the trial, with no statistically significant difference in likelihood between groups (nitroglycerin, 27 [5.0%], versus placebo, 26 [4.6%]; OR 1.13 [95% CI 0.54-2.38], p = 0.747). The main limitation of our study was the low return rate for the 6-week postnatal questionnaire. There were, however, no differences in questionnaire return rates between study groups or between women who did and did not have MROP, with the patient-reported use of outpatient and primary care services at 6 weeks accounting for only a small proportion (approximately 5%) of overall health service costs. CONCLUSIONS: In this study, we found that nitroglycerin is neither clinically effective nor cost-effective as a medical treatment for retained placenta, and has increased side effects, suggesting it should not be used. Further research is required to identify an effective medical treatment for retained placenta to reduce the morbidity caused by this condition, particularly in low- and middle-income countries where surgical management is not available. TRIAL REGISTRATION: ISRCTN.com ISRCTN88609453 ClinicalTrials.gov NCT02085213.

Methodology and reporting characteristics of studies using interrupted time series design in healthcare.

BACKGROUND: Randomised controlled trials (RCTs) are considered the gold standard when evaluating the causal effects of healthcare interventions. When RCTs cannot be used (e.g. ethically difficult), the interrupted time series (ITS) design is a possible alternative. ITS is one of the strongest quasi-experimental designs. The aim of this methodological study was to describe how ITS designs were being used, the design characteristics, and reporting in the healthcare setting. METHODS: We searched MEDLINE for reports of ITS designs published in 2015 which had a minimum of two data points collected pre-intervention and one post-intervention. There was no restriction on participants, language of study, or type of outcome. Data were summarised using appropriate summary statistics. RESULTS: One hundred and sixteen studies were included in the study. Interventions evaluated were mainly programs 41 (35%) and policies 32 (28%). Data were usually collected at monthly intervals, 74 (64%). Of the 115 studies that reported an analysis, the most common method was segmented regression (78%), 55% considered autocorrelation, and only seven reported a sample size calculation. Estimation of intervention effects were reported as change in slope (84%) and change in level (70%) and 21% reported long-term change in levels. CONCLUSIONS: This methodological study identified problems in the reporting of design features and results of ITS studies, and highlights the need for future work in the development of formal reporting guidelines and methodological work.

Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Two commonly performed surgical interventions are available for severe (grade II-IV) haemorrhoids; traditional excisional surgery and stapled haemorrhoidopexy. Uncertainty exists as to which is most effective. The eTHoS trial was designed to establish the clinical effectiveness and cost-effectiveness of stapled haemorrhoidopexy compared with traditional excisional surgery. METHODS: The eTHoS trial was a large, open-label, multicentre, parallel-group, pragmatic randomised controlled trial done in adult participants (aged 18 years or older) referred to hospital for surgical treatment for grade II-IV haemorrhoids. Participants were randomly assigned (1:1) to receive either traditional excisional surgery or stapled haemorrhoidopexy. Randomisation was minimised according to baseline EuroQol 5 dimensions 3 level score (EQ-5D-3L), haemorrhoid grade, sex, and centre with an automated system to stapled haemorrhoidopexy or traditional excisional surgery. The primary outcome was area under the quality of life curve (AUC) measured with the EQ-5D-3L descriptive system over 24 months, assessed according to the randomised groups. The primary outcome measure was analysed using linear regression with adjustment for the minimisation variables. This trial is registered with the ISRCTN registry, number ISRCTN80061723. FINDINGS: Between Jan 13, 2011, and Aug 1, 2014, 777 patients were randomised (389 to receive stapled haemorrhoidopexy and 388 to receive traditional excisional surgery). Stapled haemorrhoidopexy was less painful than traditional excisional surgery in the short term and surgical complication rates were similar between groups. The EQ-5D-3L AUC score was higher in the traditional excisional surgery group than the stapled haemorrhoidopexy group over 24 months; mean difference -0·073 (95% CI -0·140 to -0·006; p=0·0342). EQ-5D-3L was higher for stapled haemorrhoidopexy in the first 6 weeks after surgery, the traditional excisional surgery group had significantly better quality of life scores than the stapled haemorrhoidopexy group. 24 (7%) of 338 participants who received stapled haemorrhoidopexy and 33 (9%) of 352 participants who received traditional excisional surgery had serious adverse events. INTERPRETATION: As part of a tailored management plan for haemorrhoids, traditional excisional surgery should be considered over stapled haemorrhoidopexy as the surgical treatment of choice. FUNDING: National Institute for Health Research Health Technology Assessment programme.

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.

Cost-effectiveness of testosterone treatment utilising individual patient data from randomised controlled trials in men with low testosterone levels.

BACKGROUND: Testosterone is safe and highly effective in men with organic hypogonadism, but worldwide testosterone prescribing has recently shifted towards middle-aged and older men, mostly with low testosterone related to age, diabetes and obesity, for whom there is less established evidence of clinical safety and benefit. The value of testosterone treatment in middle-aged and older men with low testosterone is yet to be determined. We therefore evaluated the cost-effectiveness of testosterone treatment in such men with low testosterone compared with no treatment. METHODS: A cost-utility analysis comparing testosterone with no treatment was conducted following best practices in decision modelling. A cohort Markov model incorporating relevant care pathways for individuals with hypogonadism was developed for a 10-year-time horizon. Clinical outcomes were obtained from an individual patient meta-analysis of placebo-controlled, double-blind randomised studies. Three starting age categories were defined: 40, 60 and 75 years. Cost utility (quality-adjusted life years) accrued and costs of testosterone treatment, monitoring and cardiovascular complications were compared to estimate incremental cost-effectiveness ratios and cost-effectiveness acceptability curves for selected scenarios. RESULTS: Ten-year excess treatment costs for testosterone compared with non-treatment ranged between £2306 and £3269 per patient. Quality-adjusted life years results depended on the instruments used to measure health utilities. Using Beck depression index-derived quality-adjusted life years data, testosterone was cost-effective (incremental cost-effectiveness ratio <£20,000) for men aged <75 years, regardless of morbidity and mortality sensitivity analyses. Testosterone was not cost-effective in men aged >75 years in models assuming increased morbidity and/or mortality. CONCLUSIONS AND FUTURE RESEARCH: Our data suggest that testosterone is cost-effective in men <75 years when Beck depression index-derived quality-adjusted life years data are considered; cost-effectiveness in men >75 years is dependent on cardiovascular safety. However, more robust and longer-term cost-utility data are needed to verify our conclusion.

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.

The effect of weight loss interventions for obesity on fertility and pregnancy outcomes: A systematic review and meta-analysis.

BACKGROUND: Weight loss could improve fertility, perhaps by reducing insulin resistance. OBJECTIVES: To assess the effect of weight loss interventions on fertility in women with obesity not recruited because of known infertility. SEARCH STRATEGY: Three databases during 1966-2020, trial registry. SELECTION CRITERIA: Randomized controlled trials (RCTs) with a follow-up of 1 year or more, with a mean cohort BMI of 30 kg/m2 or above. DATA COLLECTION AND ANALYSIS: A systematic review and meta-analysis was conducted. The primary outcome was pregnancy. The secondary outcome was weight change. MAIN RESULTS: A total of 27 RCTs (5938 women) were included. Weight loss interventions showed no statistically significant increase in pregnancies compared to control interventions (24 trials, 97 women with pregnancy; risk ratio [RR] 1.43, 95% confidence interval [CI] 0.91-2.23); weight change (mean difference [MD] -2.36 kg, 21 trials, 95% CI -3.17 to -1.55). Compared with low-fat diets, very-low-carbohydrate diets showed no statistically significant effect on women with pregnancy (three trials, 14 women with pregnancy; RR 1.37, 95% CI 0.49-3.84) or weight change (MD -0.32 kg, 95% CI -3.84 to 3.21). CONCLUSIONS: Diet-based weight loss interventions for women with obesity not recruited because of infertility were effective at producing long-term weight loss. The effects on fertility were not statistically significant, but few trials provided data. Weight loss trials should routinely collect fertility outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017078819.

The RoboCOS Study: Development of an international core outcome set for the comprehensive evaluation of patient, surgeon, organisational and population level impacts of robotic assisted surgery.

BACKGROUND: The introduction of robot-assisted surgery is costly and requires whole system transformation, which makes the assessment of benefits (or drawbacks) complex. To date, there has been little agreement on which outcomes should be used in this regard. The aim of the RoboCOS study was to develop a core outcome set for the evaluation of robot-assisted surgery that would account for its impact on the whole system. METHODS: Identification of a long-list of potentially relevant outcomes through systematic review of trials and health technology assessments; interviews with individuals from a range of stakeholder groups (surgeons, service managers, policy makers and evaluators) and a focus group with patients and public; prioritisation of outcomes via a 2-round online international Delphi survey; consensus meeting. RESULTS: 721 outcomes were extracted from the systematic reviews, interviews and focus group which were conceptualised into 83 different outcome domains across four distinct levels (patient, surgeon, organisation and population) for inclusion in the international Delphi prioritisation survey (128 completed both rounds). The consensus meeting led to the agreement of a 10-item core outcome set including outcomes at: patient level (treatment effectiveness; overall quality of life; disease-specific quality of life; complications (including mortality); surgeon level (precision/accuracy; visualisation); organisation (equipment failure; standardisation of operative quality; cost-effectiveness); and population (equity of access). CONCLUSION: The RoboCOS core outcome set, which includes the outcomes of importance to all stakeholders, is recommended for use in all future evaluations of robot-assisted surgery to ensure relevant and comparable reporting of outcomes.

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.

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis.

BACKGROUND: Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. METHODS: We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. FINDINGS: 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60-72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95-7·10]; τ2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ2=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males' Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). INTERPRETATION: In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-medium-term testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme.