Transperineal biopsy devices in people with suspected prostate cancer - a systematic review and economic evaluation.

Background: People with suspected prostate cancer are usually offered either a local anaesthetic transrectal ultrasound-guided prostate biopsy or a general anaesthetic transperineal prostate biopsy. Transperineal prostate biopsy is often carried out under general anaesthetic due to pain caused by the procedure. However, recent studies suggest that performing local anaesthetic transperineal prostate biopsy may better identify cancer in particular regions of the prostate and reduce infection rates, while being carried out in an outpatient setting. Devices to assist with freehand methods of local anaesthetic transperineal prostate may also help practitioners performing prostate biopsies. Objectives: To evaluate the clinical effectiveness and cost-effectiveness of local anaesthetic transperineal prostate compared to local anaesthetic transrectal ultrasound-guided prostate and general anaesthetic transperineal prostate biopsy for people with suspected prostate cancer, and local anaesthetic transperineal prostate with specific freehand devices in comparison with local anaesthetic transrectal ultrasound-guided prostate and transperineal prostate biopsy conducted with a grid and stepping device conducted under local or general anaesthetic. Data sources and methods: We conducted a systematic review of studies comparing the diagnostic yield and clinical effectiveness of different methods for performing prostate biopsies. We used pairwise and network meta-analyses to pool evidence on cancer detection rates and structured narrative synthesis for other outcomes. For the economic evaluation, we reviewed published and submitted evidence and developed a model to assess the cost-effectiveness of the different biopsy methods. Results: We included 19 comparative studies (6 randomised controlled trials and 13 observational comparative studies) and 4 single-arm studies of freehand devices. There were no statistically significant differences in cancer detection rates for local anaesthetic transperineal prostate (any method) compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.00, 95% confidence interval 0.85 to 1.18) (n = 5 randomised controlled trials), as was the case for local anaesthetic transperineal prostate with a freehand device compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.40, 95% confidence interval 0.96 to 2.04) (n = 1 randomised controlled trial). Results of meta-analyses of observational studies were similar. The economic analysis indicated that local anaesthetic transperineal prostate is likely to be cost-effective compared with local anaesthetic transrectal ultrasound-guided prostate (incremental cost below £20,000 per quality-adjusted life-year gained) and less costly and no less effective than general anaesthetic transperineal prostate. local anaesthetic transperineal prostate with a freehand device is likely to be the most cost-effective strategy: incremental cost versus local anaesthetic transrectal ultrasound-guided prostate of £743 per quality-adjusted life-year for people with magnetic resonance imaging Likert score of 3 or more at first biopsy. Limitations: There is limited evidence for efficacy in detecting clinically significant prostate cancer. There is comparative evidence for the PrecisionPoint™ Transperineal Access System (BXTAccelyon Ltd, Burnham, UK) but limited or no evidence for the other freehand devices. Evidence for other outcomes is sparse. The cost-effectiveness results are sensitive to uncertainty over cancer detection rates, complication rates and the numbers of core samples taken with the different biopsy methods and the costs of processing them. Conclusions: Transperineal prostate biopsy under local anaesthetic is equally efficient at detecting prostate cancer as transrectal ultrasound-guided prostate biopsy under local anaesthetic but it may be better with a freehand device. local anaesthetic transperineal prostate is associated with urinary retention type complications, whereas local anaesthetic transrectal ultrasound-guided prostate has a higher infection rate. local anaesthetic transperineal prostate biopsy with a freehand device appears to meet conventional levels of costeffectiveness compared with local anaesthetic transrectal ultrasound-guided prostate. Study registration: This study is registered as PROSPERO CRD42021266443. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR134220) and is published in full in Health Technology Assessment Vol. 28, No. 60. See the NIHR Funding and Awards website for further award information.

A prostate biopsy can help determine if a person has prostate cancer. The main ways of performing a prostate biopsy involve taking small samples of the prostate out through the rectum (back passage) or through the perineum ­ the skin area between the anus and the scrotum (testicles). Both methods use ultrasound images from a probe inserted into the rectum to help the clinician see what they are doing. Taking samples through the rectum is usually carried out under local anaesthetic, whereas taking samples through the perineum is usually carried out under general anaesthetic. We wanted to find out if taking samples through the perineum under local anaesthetic (instead of general anaesthetic) would be equally effective at detecting prostate cancer as the other biopsy methods and whether there was any improvement or change in the sorts of side effects people may have. We also wanted to know if people found the biopsy painful or not. We carried out searches of computer research databases to find relevant clinical and cost-effectiveness studies and compared the effectiveness of the different biopsy methods they used. We read and summarised the results of the studies we found in our search. Our findings showed that taking biopsy samples through the perineum under local anaesthetic had rates of detecting prostate cancer similar to those of the other biopsy methods. But if the clinician also used a freehand device that helps guide the biopsy needle as part of the procedure, then this may be a better method for detecting cancer. The studies we found agreed that performing this prostate biopsy under local anaesthetic was not too painful for most people. Our economic estimates suggest that using a freehand device for local anaesthetic perineal (through the skin of the perineum) biopsy may be a cost-effective use of National Health Service resources.

Investigating the reporting of participant characteristics relating to health equity in randomised controlled trials of non-pharmacological interventions for post-stroke anxiety and/or depression: a scoping review.

PURPOSE: The review aims to identify what characteristics are reported in randomised controlled trials for the non-pharmacological management of post-stroke anxiety and/or depression and whether research has explored the correlation between participant characteristics and their outcomes. METHODS: A comprehensive systematic search was completed of five databases: CINAHL, Medline, PsychInfo, Web of Science, and The World Health Organisation. Google Scholar was also accessed. The reporting of participant characteristics was assessed by adapting the PROGRESS-Plus framework, a research framework of protected characteristics known to impact health equity (such as, age). RESULTS: 19 papers (n = 2187) were included. There was generally poor reporting of characteristics associated with an increased likelihood of post-stroke anxiety and/or depression. All studies reported the gender/sex of participants, 18 studies reported the age of participants, and 11 studies reported lesion location. None of the studies reported the sexual orientation or pre-existing disabilities of participants. CONCLUSION: There was variation in the reporting and analyses of protected characteristics. Future research should follow a health equity framework to ensure reporting of protected characteristics to support clinicians in identifying whether the proposed interventions are relevant to their stroke population and consider undergoing subgroup analyses to compare outcomes across protected characteristics.

Overall review on the reporting of protected characteristics known to impact the engagement with services and outcomes of stroke survivors.Reviewing the lack of reporting on who is taking part in stroke research and how this impacts evidence-based practice in stroke services.Identifying how demographic and social factors can impact post-stroke anxiety and depression rehabilitation.Supporting the understanding of the effectiveness of non-pharmacological interventions for post-stroke anxiety and/or depression across subgroups.Identification of which characteristics should be reported in services and in stroke rehabilitation research.Furthering the consideration of health equity in stroke rehabilitation research.

Time to STEP UP: methods and findings from the development of guidance to help researchers design inclusive clinical trials.

BACKGROUND: It is important to design clinical trials to include all those who may benefit from the intervention being tested. Several frameworks have been developed to help researchers think about the barriers to inclusion of particular under-served groups when designing a trial, but there is a lack of practical guidance on how to implement these frameworks. This paper describes the ACCESS project, the findings from each phase of the project and the guidance we developed (STEP UP) on how to design more inclusive trials. METHODS: Development of the STEP UP guidance had five phases: (1) Scoping literature review, (2) 'roundtable' discussion meetings, (3) redesign of trials, (4) interviews and (5) guidance document development, with input from public contributors and the ACCESS team. RESULTS: Over 40 experts contributed to the ACCESS project-patients and the public, clinicians, NHS research staff, trialists and other academics. The scoping review identified several strategies being used to improve inclusion, mostly around recruitment settings, but there was little evaluation of these strategies. The 'roundtable' discussions identified additional strategies being used across the UK and Ireland to improve inclusion, which were grouped into: Communication, Community engagement, Recruitment sites, Patient information, Flexibility, Recruitment settings, Consent process, Monitoring, Training for researchers and Incentives. These strategies were used to redesign three existing trials by applying one of the three INCLUDE frameworks (ethnicity, socioeconomic disadvantage, impaired capacity to consent) to one trial each, to produce the key recommendations for the guidance. Issues around implementation were explored in stakeholder interviews and key facilitators were identified: funders requesting information on inclusion, having the time and funding to implement strategies, dedicated staff, flexibility in trial protocols, and considering inclusion of under-served groups at the design stages. The STEP UP guidance is freely available at http://step-up-clinical-trials.co.uk . CONCLUSION: Researchers should consider inclusivity to shape initial trial design decisions. Trial teams and funders need to ensure that trials are given both the resources and time needed to implement the STEP UP guidance and increase the opportunities to recruit a diverse population.

Randomised clinical trials compare one or more treatments to another to see which ones work best. Trials don't always include people or groups who might benefit from the results: those excluded are sometimes called 'under- served groups'. Recent work has shone a light on this and now researchers are being asked by the public, trial funders and others to design their research so that under-served groups are more able to take part.We worked on a project to find out how to make sure everyone can be part of clinical trials. We looked at published work and held five online meetings with researchers, doctors, and patients to see what was being done already, and to think of other things that could help under-served groups take part in trials. Three groups of people, including scientists, patients, doctors and other NHS workers then  used this information to redesign three older trials using some existing inclusivity frameworks to think through the barriers for under-served groups in these trials. The three groups then talked through these trials at a 2-hour meeting, suggesting changes to the original trial plan, and discussed whether the suggestions were practical and useful. From this we came up with recommendations for how to design trials so that they have fewer barriers for under-served groups.We interviewed people to find out the best way to put these things into practice and talk through any practical issues. Using all of this information: the recommendations and what came out of the interviews, the study team created some guidance ­ 'STEP UP (Strategies for Trialists to promote Equal Participation in clinical trials for Under-served Populations)' ­ for people working in trials.

Mirabegron Versus Placebo and Other Therapeutic Modalities in the Treatment of Patients with Overactive Bladder Syndrome-A Systematic Review.

BACKGROUND AND OBJECTIVE: The prevalence of overactive bladder (OAB) increases with age. Mirabegron and other drugs are used for the management of patients with OAB. To evaluate mirabegron versus other treatments for overactive bladder syndrome (OAB). METHODS: This randomised controlled trial (RCT)-based systematic review (CRD42020200394) was conducted following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, with standards reported in the Cochrane Handbook for Systematic Reviews of Interventions. KEY FINDINGS AND LIMITATIONS: We included 28 RCTs (n = 27 481 adults), comparing the following: mirabegron 25 mg versus placebo (n = 8798; six RCTs): significant changes in urgency urinary incontinence (mean difference [MD] -0.41, 95% confidence interval [CI] -0.56 to -0.26), total incontinence (MD -0.47, 95% CI -0.63 to -0.30), and nocturia (MD -0.10, 95% CI -0.17 to -0.02), and mirabegron 50 mg versus placebo (n = 14 933; 12 RCTs): significant changes in urgency urinary incontinence (MD -0.41, 95% CI -0.52 to -0.31), urgency (MD -0.49, 95% CI -0.64 to -0.33), total incontinence (MD -0.44, 95% CI -0.55 to -0.33), favouring mirabegron 25/50 mg; mirabegron 50 mg versus tolterodine 4 mg (n = 8008; five RCTs): significant changes in micturition (MD -0.16, 95% CI -0.31 to -0.02) and overall adverse events (AEs; odds ratio [OR] 0.71, 95% CI 0.59-0.86), favouring mirabegron 50 mg; mirabegron 50 mg versus solifenacin 5 mg (n = 8911; four RCTs): significant changes in voided volume/micturition in millilitres (MD -7.77, 95% CI -12.93 to -2.61), favouring mirabegron 50 mg; and mirabegron 50 mg versus oxybutynin 73.5 mg (n = 302; one RCT): significant changes in overall AEs (OR 0.02, 95% CI 0.00-0.16), favouring mirabegron 50 mg. CONCLUSIONS AND CLINICAL IMPLICATIONS: Mirabegron is effective, safe, and well tolerated. Coadministration with anticholinergics provides an advantageous additive effect without a higher occurrence of side effects. PATIENT SUMMARY: Mirabegron is effective, safe, and well tolerated for treating overactive bladder. When used in conjunction with anticholinergic medications, it provides extra benefits without causing more side effects.

Resource use and costs of investigator-sponsored randomised clinical trials in Switzerland, Germany and the United Kingdom: a meta-research study.

BACKGROUND: Conducting high-quality randomised clinical trials (RCTs) is challenging and resource intensive. Funders and academic investigators depend on limited financial resources and, therefore, need empirical data for optimal budget planning. However, current literature lacks detailed empirical data on resource use and costs of investigator-sponsored RCTs. The aim of this study is to systematically collect cost data from investigator-sponsored RCTs from Switzerland, Germany, and the United Kingdom (UK). METHODS: Principal investigators were asked to share their RCT cost and resource use data and enter it into an online case report form. We assessed cost patterns, cost drivers, and specific cost items, examined costs by study phase (planning-, conduct-, and finalisation phase), compared planned with actual RCT costs, and explored differences in cost patterns across countries, medical fields, and intervention types. RESULTS: We included 93 RCTs which were initiated in Switzerland (n=53; including 8 conducted in low- and lower middle-income countries), Germany (n=22), and the UK (n=18). The median total trial cost in our RCT sample was $645,824 [Interquartile range (IQR), $269,846 to $1,577,924]. The median proportion of the total costs spent for planning phase was 27.5% [IQR, 20.6 to 39.7%], for conduct phase 57.3% [IQR, 44.4%-66.3%], and for finalisation phase 12.7% [IQR, 8.5% to 19.3%] with little variation across countries. The items that contributed most to the total costs were protocol writing (7.2%; IQR 3.8% to 10.6%), data management (5.0%; IQR 2.2% to 8.1%) and follow up (4.5%; IQR 2.3% to 8.4%). Of the 66 RCTs with an available original budget, 46 (69.7%) exceeded the budget by over 50%. Use of routinely collected data to assess primary outcomes was independently associated with lower per patient- and lower total trial costs. CONCLUSIONS: Over a quarter of total trial costs were incurred in the planning phase, which is typically not fully funded. Two thirds of RCTs exceeded their budget by more than 50%. Investigators and funders should consider empirical cost data to improve budgeting and funding practices.

Feasibility and acceptability of the ShareD dEciSIon making for patients with kidney failuRE to improve end-of-life care intervention: A pilot multicentre randomised controlled trial.

Background: Kidney failure is associated with a high disease burden and high mortality rates. National and international guidelines recommend health professionals involve patients with kidney failure in making decisions about end-of-life care, but implementation of these conversations within kidney services varies. We developed the DESIRE (ShareD dEciSIon-making for patients with kidney failuRE to improve end-of-life care) intervention from our studies investigating multiple decision maker needs and experiences of end-of-life care in kidney services. The DESIRE intervention's three components are a training programme for health professionals, a patient decision aid, and a kidney service consultation held to facilitate shared decision-making conversations about planning end-of-life care. Objectives: To assess the feasibility and acceptability of integrating the DESIRE intervention within kidney services. Design: A pilot study using a multicentre randomised controlled design. Setting: Four Danish nephrology departments. Participants: Patients with kidney failure who were 75 years of age or above, their relatives, and health professionals. Methods: Patients were randomised to either the intervention or usual care. Feasibility data regarding delivering the intervention, the trial design, and outcome measures were collected through questionnaires and audio recordings at four points in time: before, during, post, and 3 months after the intervention. Acceptability data were collected through semi-structured interviews with patients and relatives, as well as a focus group with health professionals post the intervention. Results: Twenty-seven patients out of the 32 planned were randomised either to the intervention (n= 14) or usual care (n= 13). In addition, four relatives and 12 health professionals participated. Follow-up was completed by 81 % (n= 22) of patient participants. We found that both feasibility and acceptability data suggested health professionals improved their decision support and shared decision-making skills via the training. Patient and relative participants experienced the intervention as supporting a shared decision-making process; from audio recordings, we showed health professionals were able to support proactively decision-making about end-of-life care within these consultations. All stakeholders perceived the intervention to be effective in promoting shared decision-making and relevant for supporting end-of-life care planning. Conclusions: Participant feedback indicated that the DESIRE intervention can be integrated into practice to support patients, relatives, and health professionals in planning end-of-life care alongside the management of worsening kidney failure. Minimising exhaustion and enhancing engagement with the intervention should be a focus for subsequent refinement of the intervention. Registration: The study has been registered at ClinicalTrials.gov with the identifier: NCT05842772. Date of first recruitment: March 20, 2023.

A survey of experts to identify methods to detect problematic studies: stage 1 of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews project.

BACKGROUND AND OBJECTIVE: Randomized controlled trials (RCTs) inform health-care decisions. Unfortunately, some published RCTs contain false data, and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesize all RCTs which have been conducted on a given topic. This means that any of these 'problematic studies' are likely to be included, but there are no agreed methods for identifying them. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is developing a tool to identify problematic RCTs in systematic reviews of health care-related interventions. The tool will guide the user through a series of 'checks' to determine a study's authenticity. The first objective in the development process is to assemble a comprehensive list of checks to consider for inclusion. METHODS: We assembled an initial list of checks for assessing the authenticity of research studies, with no restriction to RCTs, and categorized these into five domains: Inspecting results in the paper; Inspecting the research team; Inspecting conduct, governance, and transparency; Inspecting text and publication details; Inspecting the individual participant data. We implemented this list as an online survey, and invited people with expertise and experience of assessing potentially problematic studies to participate through professional networks and online forums. Participants were invited to provide feedback on the checks on the list, and were asked to describe any additional checks they knew of, which were not featured in the list. RESULTS: Extensive feedback on an initial list of 102 checks was provided by 71 participants based in 16 countries across five continents. Fourteen new checks were proposed across the five domains, and suggestions were made to reword checks on the initial list. An updated list of checks was constructed, comprising 116 checks. Many participants expressed a lack of familiarity with statistical checks, and emphasized the importance of feasibility of the tool. CONCLUSION: A comprehensive list of trustworthiness checks has been produced. The checks will be evaluated to determine which should be included in the INSPECT-SR tool. PLAIN LANGUAGE SUMMARY: Systematic reviews draw upon evidence from randomized controlled trials (RCTs) to find out whether treatments are safe and effective. The conclusions from systematic reviews are often very influential, and inform both health-care policy and individual treatment decisions. However, it is now clear that the results of many published RCTs are not genuine. In some cases, the entire study may have been fabricated. It is not usual for the veracity of RCTs to be questioned during the process of compiling a systematic review. As a consequence, these "problematic studies" go unnoticed, and are allowed to contribute to the conclusions of influential systematic reviews, thereby influencing patient care. This prompts the question of how these problematic studies could be identified. In this study, we created an extensive list of checks that could be performed to try to identify these studies. We started by assembling a list of checks identified in previous research, and conducting a survey of experts to ask whether they were aware of any additional methods, and to give feedback on the list. As a result, a list of 116 potential "trustworthiness checks" was created. In subsequent research, we will evaluate these checks to see which should be included in a tool, INveStigating ProblEmatic Clinical Trials in Systematic Reviews, which can be used to detect problematic studies.

User engagement in clinical trials of digital mental health interventions: a systematic review.

INTRODUCTION: Digital mental health interventions (DMHIs) overcome traditional barriers enabling wider access to mental health support and allowing individuals to manage their treatment. How individuals engage with DMHIs impacts the intervention effect. This review determined whether the impact of user engagement was assessed in the intervention effect in Randomised Controlled Trials (RCTs) evaluating DMHIs targeting common mental disorders (CMDs). METHODS: This systematic review was registered on Prospero (CRD42021249503). RCTs published between 01/01/2016 and 17/09/2021 were included if evaluated DMHIs were delivered by app or website; targeted patients with a CMD without non-CMD comorbidities (e.g., diabetes); and were self-guided. Databases searched: Medline; PsycInfo; Embase; and CENTRAL. All data was double extracted. A meta-analysis compared intervention effect estimates when accounting for engagement and when engagement was ignored. RESULTS: We identified 184 articles randomising 43,529 participants. Interventions were delivered predominantly via websites (145, 78.8%) and 140 (76.1%) articles reported engagement data. All primary analyses adopted treatment policy strategies, ignoring engagement levels. Only 19 (10.3%) articles provided additional intervention effect estimates accounting for user engagement: 2 (10.5%) conducted a complier-average-causal effect (CACE) analysis (principal stratum strategy) and 17 (89.5%) used a less-preferred per-protocol (PP) population excluding individuals failing to meet engagement criteria (estimand strategies unclear). Meta-analysis for PP estimates, when accounting for user engagement, changed the standardised effect to -0.18 95% CI (-0.32, -0.04) from - 0.14 95% CI (-0.24, -0.03) and sample sizes reduced by 33% decreasing precision, whereas meta-analysis for CACE estimates were - 0.19 95% CI (-0.42, 0.03) from - 0.16 95% CI (-0.38, 0.06) with no sample size decrease and less impact on precision. DISCUSSION: Many articles report user engagement metrics but few assessed the impact on the intervention effect missing opportunities to answer important patient centred questions for how well DMHIs work for engaged users. Defining engagement in this area is complex, more research is needed to obtain ways to categorise this into groups. However, the majority that considered engagement in analysis used approaches most likely to induce bias.

Pharmacogenomic Determinants of Adverse Drug Effects: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: Genomic variants can predispose individuals to adverse drug effects (ADEs), implying the potential for personalised therapy based on genetic data to prevent them. However, existing pharmacogenomic databases lack a comprehensive list of such variants due to irregular updates and incomplete literature coverage. To facilitate the assessment of the feasibility of using pharmacogenetic testing on a larger scale and identify existing gaps in the literature, this study sought to compile a comprehensive list of genomic variants associated with ADEs, with a focus on serious ADEs. PATIENTS AND METHODS: To identify relevant pharmacogenetic studies within randomised controlled trials (RCTs), post-hoc studies of RCTs and meta-analyses, two literature searches were performed across multiple databases. The compiled list of variants associated with ADEs was refined to create a set of variant-drug pairs significantly associated with serious ADEs. RESULTS: We identified 254 RCTs/post-hoc studies and 207 meta-analyses investigating variants associated with ADEs. Among the 254 RCTs/post-hoc studies identified, 24 meta-analyses were conducted. Among these, only G6PD A- showed a significant association with severe anaemia in patients receiving artemisinin-based treatment for malaria. CONCLUSION: This systematic review provides a comprehensive list of variants associated with ADEs and a set of variant-drug pairs significantly associated with serious ADEs. These resources serve as valuable references for regulatory agencies, researchers, and healthcare professionals. This study, however, underscores the need for improved indexing and standardised definitions of ADE seriousness in the literature.

Risk of bias and problematic trials: characterising the research integrity of trials submitted to Anaesthesia.

BACKGROUND: There is some evidence for systematic biases and failures of research integrity in the anaesthesia literature. However, the features of problematic trials and effect of editorial selection on these issues have not been well quantified. METHODS: We analysed 209 randomised controlled trials submitted to Anaesthesia between 8 March 2019 and 31 March 2020. We evaluated the submitted manuscript, registry data and the results of investigations into the integrity of the trial undertaken at the time of submission. Trials were labelled 'concerning' if failures of research integrity were found, and 'problematic' if identified issues would have warranted retraction if they had been found after publication. We investigated how 'problematic' trials were detected, the distribution of p values and the risk of outcome reporting bias and p-hacking. We also investigated whether there were any factors that differed in problematic trials. RESULTS: We found that false data was the most common reason for a trial to be labelled as 'concerning', which occurred in 51/62 (82%) cases. We also found that while 195/209 (93%) trials were preregistered, we found adequate registration for only 166/209 (79%) primary outcomes, 100/209 (48%) secondary outcomes and 11/209 (5%) analysis plans. We also found evidence for a step decrease in the frequency of p values > 0.05 compared with p values < 0.05. 'Problematic' trials were all single-centre and appeared to have fewer authors (incident risk ratio (95%CI) 0.8 (0.7-0.9)), but could not otherwise be distinguished reliably from other trials. CONCLUSIONS: Identification of 'problematic' trials is frequently dependent on individual patient data, which is often unavailable after publication. Additionally, there is evidence of a risk of outcome reporting bias and p-hacking in submitted trials. Implementation of alternative research and editorial practices could reduce the risk of bias and make identification of problematic trials easier.

Demographic diversity of participants in clinical trials conducted in Singapore.

Introduction: The under-representativeness of participants in clinical trials limits the generalisability of results. This review evaluates the representative-ness within pharmaceutical randomised controlled trials (RCTs) in Singapore. Method: Four bibliographic databases were searched for papers on pharmaceutical RCTs which included Singapore adults (≥18 years old), published between 2017 and 2022. The demographic characteristics of study participants were compared against the population in the 2020 Singapore census. Recruitment strategies and authors' comments on the generalisa-bility of their findings were reviewed. Results: Thirty-three publications were included (19 Singapore-only studies and 14 multiregional trials which included Singapore). Where data were available, we found that females and Indians were under-represented compared to the census (41.3% versus [vs] 51.1%, P<0.05; 7.3% vs 9.0%, P<0.05). Ethnic diversity varied between individual studies, and almost half (46.2%) of Singapore-only studies achieved census levels. However, more than one-third of the trials provided no data (31.6%) or partial data (5.3%) on ethnicity. Half of the multiregional publications stated the number of participants recruited from Singapore, but only 1 reported any detail beyond Asian participants. Recruitment strategies were mentioned in fewer than half (42.4%), and less than a quarter (24.2%) commented on sample representative-ness or the external validity of the evidence generated. Conclusion: There is room for improvement regarding the recruitment of RCT participants in Singapore, with particular attention to female gender and Indian ethnicity. Demographic data should also be presented in full. RCTs should be designed and reported such that clinicians can ascertain the generalisability to the Singapore population and the potential benefits from the studied interventions in clinical practice.

Development of the individual participant data integrity tool for assessing the integrity of randomised trials using individual participant data.

Increasing integrity concerns in medical research have prompted the development of tools to detect untrustworthy studies. Existing tools primarily assess published aggregate data (AD), though scrutiny of individual participant data (IPD) is often required to detect trustworthiness issues. Thus, we developed the IPD Integrity Tool for detecting integrity issues in randomised trials with IPD available. This manuscript describes the development of this tool. We conducted a literature review to collate and map existing integrity items. These were discussed with an expert advisory group; agreed items were included in a standardised tool and automated where possible. We piloted this tool in two IPD meta-analyses (including 116 trials) and conducted preliminary validation checks on 13 datasets with and without known integrity issues. We identified 120 integrity items: 54 could be conducted using AD, 48 required IPD, and 18 were possible with AD, but more comprehensive with IPD. An initial reduced tool was developed through consensus involving 13 advisors, featuring 11 AD items across four domains, and 12 IPD items across eight domains. The tool was iteratively refined throughout piloting and validation. All studies with known integrity issues were accurately identified during validation. The final tool includes seven AD domains with 13 items and eight IPD domains with 18 items. The quality of evidence informing healthcare relies on trustworthy data. We describe the development of a tool to enable researchers, editors, and others to detect integrity issues using IPD. Detailed instructions for its application are published as a complementary manuscript in this issue.

Fragility analysis and systematic review of patellar resurfacing versus non-patellar resurfacing in total knee arthroplasty.

Introduction: Fragility analysis is a method of further characterising the robustness of statistical outcomes. This study evaluates the statistical fragility of randomised controlled trials (RCTs) comparing patellar resurfacing versus non-patellar surfacing in total knee arthroplasty (TKA). Methods: PubMed, MEDLINE and EMBASE were searched for RCTs comparing outcomes in TKA based on patellar resurfacing. Fragility index (FI) and reverse FI (collectively, "FI") were calculated for dichotomous outcomes as the number of outcome reversals needed to change statistical significance. Fragility quotient (FQ) was calculated by dividing the FI by the sample size for that outcome. Median FI and FQ were calculated for each individual outcome and for the overall study. Subanalyses were performed to assess FI and FQ based on outcome type, statistical significance and loss to follow-up. Results: Twenty-one RCTs were included in the analysis, capturing 3910 subjects. The overall median FI was 5.0 (interquartile range, [IQR] 4.0-6.0), and the overall median FQ was 0.048 (IQR 0.022-0.065). The outcome of anterior knee pain has a median FI of 6.0 (IQR 4.0-6.0) and a median FQ of 0.057 (IQR 0.025-0.065). Only five (7%) outcomes were significant. The loss to follow-up was greater than the FI in 12 of 19 studies (63%) with available data. Conclusion: RCTs comparing patellar resurfacing in TKAs show significant statistical fragility; a few outcome reversals can alter findings. The majority of outcomes were nonsignificant, indicating that the choice to resurface the patella may not affect most clinical outcomes; however, clinical conclusions are limited by the statistical fragility of the analysed outcomes. Larger RCTs for this comparison are necessary, and we suggest adding FI and FQ to RCT reports with p values to improve the interpretability of results. Level of Evidence: Level II.

Analysis of the Current Status of Outcome Indicators of Randomised Controlled Trials of Traditional Chinese Medicine for the Treatment of Qi and Yin Deficiency in Coronary Heart Disease.

Purpose: To analyse the current status of outcome indicators in randomised controlled trials (RCTs) of traditional Chinese medicine (TCM) for the treatment of coronary heart disease (CHD) with deficiency of qi and yin, and to provide a basis for constructing a core indicator set (COS) for TCM treatment of CHD. Methods: We searched the database of China National Knowledge Infrastructure (CNKI), PubMed,etc. 8 databases in the last 5 years. RCTs of TCM for CHD included in core journals were evaluated for the risk of bias of the included studies, and the current status of the selection of outcome indicators was statistically analysed. Results: A total of 39 RCTs with a sample size of 44~398 cases were included, and 164 outcome indicators were reported, with a frequency of 383 applications. The outcome indicators were categorised into 6 indicator domains according to their functional attributes, which were, in descending order, safety indicators, physicochemical examination, effective rate, economic assessment, disease evidence score, and quality of life. The top 3 indicators in terms of frequency of application of outcome indicators were safety indicators, physical and chemical examination indicators, and efficiency, among which electrocardiogram, inflammation indicators, and clinical efficacy were the most frequently used; there were many different types of measurement tools for outcome indicators, among which total efficiency and TCM symptom points were the most frequently used; the time point of measurement was not the same. Conclusion: The RCTs of TCM for CHD in the last 5 years have many shortage in the selection of outcome indicators, and should actively promote the construction of the COS of TCM for CHD.

The Individual Participant Data Integrity Tool for assessing the integrity of randomised trials.

Increasing concerns about the trustworthiness of research have prompted calls to scrutinise studies' Individual Participant Data (IPD), but guidance on how to do this was lacking. To address this, we developed the IPD Integrity Tool to screen randomised controlled trials (RCTs) for integrity issues. Development of the tool involved a literature review, consultation with an expert advisory group, piloting on two IPD meta-analyses (including 73 trials with IPD), preliminary validation on 13 datasets with and without known integrity issues, and evaluation to inform iterative refinements. The IPD Integrity Tool comprises 31 items (13 study-level, 18 IPD-specific). IPD-specific items are automated where possible, and are grouped into eight domains, including unusual data patterns, baseline characteristics, correlations, date violations, patterns of allocation, internal and external inconsistencies, and plausibility of data. Users rate each item as having either no issues, some/minor issue(s), or many/major issue(s) according to decision rules, and justification for each rating is recorded. Overall, the tool guides decision-making by determining whether a trial has no concerns, some concerns requiring further information, or major concerns warranting exclusion from evidence synthesis or publication. In our preliminary validation checks, the tool accurately identified all five studies with known integrity issues. The IPD Integrity Tool enables users to assess the integrity of RCTs via examination of IPD. The tool may be applied by evidence synthesists, editors and others to determine whether an RCT should be considered sufficiently trustworthy to contribute to the evidence base that informs policy and practice.

Immunogenicity and seroefficacy of pneumococcal conjugate vaccines: a systematic review and network meta-analysis.

Background: Vaccination of infants with pneumococcal conjugate vaccines is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Objectives: The primary objective was to compare the immunogenicity of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. The main secondary objective was to compare the seroefficacy of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. Methods: We searched the Cochrane Library, EMBASE, Global Health, MEDLINE, ClinicalTrials.gov and trialsearch.who.int up to July 2022. Studies were eligible if they directly compared either pneumococcal conjugate vaccine-7, pneumococcal conjugate vaccine-10 or pneumococcal conjugate vaccine-13 in randomised trials of children under 2 years of age, and provided immunogenicity data for at least one time point. Individual participant data were requested and aggregate data used otherwise. Outcomes included the geometric mean ratio of serotype-specific immunoglobulin G and the relative risk of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Each trial was analysed to obtain the log of the ratio of geometric means and its standard error. The relative risk of seroinfection ('seroefficacy') was estimated by comparing the proportion of participants with seroinfection between vaccine groups. The log-geometric mean ratios, log-relative risks and their standard errors constituted the input data for evidence synthesis. For serotypes contained in all three vaccines, evidence could be synthesised using a network meta-analysis. For other serotypes, meta-analysis was used. Results from seroefficacy analyses were incorporated into a mathematical model of pneumococcal transmission dynamics to compare the differential impact of pneumococcal conjugate vaccine-10 and pneumococcal conjugate vaccine-13 introduction on invasive pneumococcal disease cases. The model estimated the impact of vaccine introduction over a 25-year time period and an economic evaluation was conducted. Results: In total, 47 studies were eligible from 38 countries. Twenty-eight and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. Geometric mean ratios comparing pneumococcal conjugate vaccine-13 versus pneumococcal conjugate vaccine-10 favoured pneumococcal conjugate vaccine-13 for serotypes 4, 9V and 23F at 1 month after primary vaccination series, with 1.14- to 1.54-fold significantly higher immunoglobulin G responses with pneumococcal conjugate vaccine-13. Risk of seroinfection prior to the time of booster dose was lower for pneumococcal conjugate vaccine-13 for serotype 4, 6B, 9V, 18C and 23F than for pneumococcal conjugate vaccine-10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Twofold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (relative risk 0.46, 95% confidence interval 0.23 to 0.96). In modelled scenarios, pneumococcal conjugate vaccine-13 or pneumococcal conjugate vaccine-10 introduction in 2006 resulted in a reduction in cases that was less rapid for pneumococcal conjugate vaccine-10 than for pneumococcal conjugate vaccine-13. The pneumococcal conjugate vaccine-13 programme was predicted to avoid an additional 2808 (95% confidence interval 2690 to 2925) cases of invasive pneumococcal disease compared with pneumococcal conjugate vaccine-10 introduction between 2006 and 2030. Limitations: Analyses used data from infant vaccine studies with blood samples taken prior to a booster dose. The impact of extrapolating pre-booster efficacy to post-booster time points is unknown. Network meta-analysis models contained significant heterogeneity which may lead to bias. Conclusions: Serotype-specific differences were found in immunogenicity and seroefficacy between pneumococcal conjugate vaccine-13 and pneumococcal conjugate vaccine-10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These methods can be used to compare the pneumococcal conjugate vaccines and optimise vaccination strategies. For future work, seroefficacy estimates can be determined for other pneumococcal vaccines, which could contribute to licensing or policy decisions for new pneumococcal vaccines. Study registration: This study is registered as PROSPERO CRD42019124580. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/03) and is published in full in Health Technology Assessment; Vol. 28, No. 34. See the NIHR Funding and Awards website for further award information.

Pneumococcal disease is a serious illness caused by a bacterial infection that can result in death. Children in the United Kingdom receive a vaccine to prevent this disease that protects against 13 different types of pneumococcal diseases. It is very effective, but other vaccines are also available, such as one that contains 10 types of pneumococcal diseases. Vaccines in the United Kingdom are bought by the government and the choice of which vaccine to provide is based on the cost of the vaccine as well as the benefits to our health. However, there is very little information comparing different vaccines and it is often assumed they are the same. We did a large analysis combining all studies of the two main licensed pneumococcal vaccines to determine which vaccine provides better protection against infection and how this affects costs. We used information from studies published in medical journals, and also data from studies done by the companies that own the vaccines. Our results showed that pneumococcal conjugate vaccine-13 vaccine provided better protection than pneumococcal conjugate vaccine-10 for 5 of the 10 serotypes that are contained in both vaccines. When we used these results to model what might have happened had either of these vaccines been introduced into the United Kingdom vaccination programme in 2006, we found that both vaccines caused a rapid decrease in the amount of disease, but that the decrease in disease was faster with pneumococcal conjugate vaccine-13 than pneumococcal conjugate vaccine-10. This resulted in 2808 cases of diseases prevented over a 25-year time frame with pneumococcal conjugate vaccine-13 compared with pneumococcal conjugate vaccine-10. Our methods can be used to compare other vaccines and we recommend this type of study be done in future when making decisions on vaccine product choice.

Effects of folic acid supplementation on cognitive function and inflammation in elderly patients with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials.

OBJECT: The aim was to assess the effect of folic acid supplementation on cognitive function and inflammatory cytokines in elderly patients with mild cognitive impairment. METHODS: From its inception until February 2024, four databases including Web of Science were searched. Two researchers independently screened the literature, assessed the quality, extracted data, and conducted a meta-analysis using RevMan. RESULTS: The systematic review included seven studies (with a total of 1102 participants, mean age 65-80 years), seven of which were appropriate for meta-analysis. Although a small number of studies found relatively large heterogeneity, the majority of studies showed significant benefit from folic acid supplementation, including the FSIQ (823 individuals, standardized mean difference [SMD] = 8.36, 95 % confidence interval [CI] = 0.79 - 1.08), Arithmetic (823 individuals, SMD = 0.17, 95 % CI = -0.03-0.31), Information, SMD = 1.73, 95 % CI 0.41-3.05), Digit Span (823 individuals, SMD = 0.17, 95 % CI = -0.03 - 0.31), Block Design (823 individuals, SMD = 0.26, 95 % CI 0.03-0.49), Picture Completion (823 individuals, SMD = 0.27, 95 % CI = -0.15 - 0.69) and Picture Arrangement (823 individuals, SMD = -0.12, 95 % CI = -0.26 - 0.01). Finally, folic acid supplementation had a significant effect on the reduction of most inflammatory cytokines, blood biomarkers of Alzheimer's disease, and Hcy. CONCLUSIONS: Folic acid supplementation seems to have a positive impact on cognitive function in older adults with mild cognitive impairment, but further evidence of its effectiveness in improving inflammatory cytokines is needed from high-quality studies.

Role of Vitamin C Supplementation in the Prevention of Premature Rupture of Membranes (PROM) and Preterm PROM: A Systematic Review and Meta-Analysis.

Vitamin C is a micronutrient assumed to have effects on the occurrence of "preterm premature rupture of membranes" (PPROM) and "premature rupture of membranes" (PROM). The objective of this review was to find the pooled incidence of PROM and/or PPROM between subgroups in relation to dose, mode of therapy (monotherapy vs. combination therapy) and history of PROM/PPROM in previous pregnancies. A search was conducted in the electronic databases (PubMed, Google Scholar, Scopus) from inception to November 2022, using the search terms "Vitamin C", "Ascorbic acid", "preterm premature rupture of membrane" and "premature rupture of membrane". The lists of references of all the selected eligible articles were also searched to find studies of interest. A total of nine randomized controlled trials (published in English) with 16,076 participants involving the supplementation of vitamin C during pregnancy were picked up for analysis. Data management was done using the Review Manager (RevMan 5.3). A statistical test for publication bias was done in jamovi, version 2.3.18. In comparison to placebo, vitamin C supplementation was not found to be significantly effective in preventing the occurrence of PPROM/PROM. However, a low dose of vitamin C and the monotherapy mode of administration significantly decreased the occurrence of PPROM/PROM. Vitamin C has significant beneficial effects in women with a history of PROM in a previous pregnancy. Hence, we conclude that vitamin C administered as monotherapy in low doses (preferably 100 mg/day) has definite benefits in preventing the occurrence of PROM/PPROM with greater advantages seen in those with a history of similar complications in a previous pregnancy.

Systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) for activities of daily living in Alzheimer's disease.

OBJECTIVE: This systematic review of randomised controlled trials (RCTs) was conducted to assess the effect of repetitive transcranial magnetic stimulation (rTMS) on activities of daily living (ADLs) in Alzheimer's disease (AD) patients. DATA SOURCES: Ten databases were retrieved for pertinent Chinese and English literatures published up until January 2024. REVIEW METHODS: All RCTs of rTMS for ADLs in AD were included in this meta-analysis. Two researchers independently selected the literatures, retrieved the data of included literatures, accessed risk-of-bias of literatures with the Cochrane Collaboration's quality criteria and then cross-checked. Meta-analysis was carried out with Cochrane's Review Manager (RevMan, version 5.4). The PRISMA guidelines were followed in this systematic review. RESULTS: The 37 literatures involving 2461 patients with AD were included in this study. Compared with the control groups received the interventions such as routine pharmacotherapy, cognitive training, ect., with/without sham-rTMS, the experiment groups received the interventions of the control groups and rTMS. The findings were as follows: ADL scale [mean difference (MD) = -3.92, 95%CI (-4.93, -2.91), P < 0.00001]; Barthel Index (BI) [MD = 9.75, 95% CI (6.66, 12.85), P < 0.00001]; Modified Barthel Index (MBI) [MD = 5.43, 95% CI (3.13, 7.73), P < 0.00001]. The differences were statistically significant for all indicators. In 29 studies, rTMS stimulation sites were located in the dorsolateral prefrontal cortex (DLPFC). CONCLUSION: The rTMS could improve the ADLs in AD patients, and the DLPFC was a frequently used stimulation site of the rTMS for AD treatment.