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.

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.

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.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

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BACKGROUND: Designing effective health interventions and evaluating their impact is crucial to improving the health of the population. To ensure interventions are of high quality and effective, evidence-based research is essential, particularly studies that use randomised controlled trials (RCTs) or systematic reviews. However, RCTs may not be feasible or ethical in certain situations, such as in intensive care units. Cluster or stepped-wedge RCTs are alternative ways to assess interventions that also address these ethical concerns.
OBJECTIVE: To explain the stepped-wedge design and its main features as well as how to use it to evaluate nursing interventions.
CONCLUSIONS: Understanding stepped-wedge designs empowers nurses to implement evidence-based interventions and improve patient outcomes. The use of stepped-wedge designs has increased in nursing research over the past two decades, indicating growing recognition of its advantages: efficient evaluation of healthcare interventions, ensuring all clusters receive treatment over time; smaller sample sizes; ethical considerations; and time control. However, challenges remain: ensuring nurse researchers\' understanding and application of it is consistent, extended duration and logistical complexities. Methodological rigour, collaboration and understanding of secular trends are crucial, and nurses\' involvement in RCTs enhances cluster selection, data collection and dissemination.
CONCLUSIONS: The stepped-wedge design offers an ethical and adaptable method for studying interventions, considering healthcare complexities and allocating resources. Its versatility assists the advancement of nursing care delivery and in promoting evidence-based practice.
CONCLUSIONS: Understanding stepped-wedge designs in nursing practice enhances evidence-based care, decision-making, collaboration and professional development, benefiting patient outcomes.

UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: This study is registered as PROSPERO CRD42019124580.
UNASSIGNED: 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.

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.
METHODS: Ten databases were retrieved for pertinent Chinese and English literatures published up until January 2024.
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).
CONCLUSIONS: The rTMS could improve the ADLs in AD patients, and the DLPFC was a frequently used stimulation site of the rTMS for AD treatment.

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.

BACKGROUND: There is a need to increase the capacity and capability of musculoskeletal researchers to design, conduct, and report high-quality clinical trials. The objective of this study was to identify and prioritise clinical trial learning needs of musculoskeletal researchers in Australia and Aotearoa New Zealand. Findings will be used to inform development of an e-learning musculoskeletal clinical trials course.
METHODS: A two-round online modified Delphi study was conducted with an inter-disciplinary panel of musculoskeletal researchers from Australia and Aotearoa New Zealand, representing various career stages and roles, including clinician researchers and consumers with lived experience of musculoskeletal conditions. Round 1 involved panellists nominating 3-10 topics about musculoskeletal trial design and conduct that they believe would be important to include in an e-learning course about musculoskeletal clinical trials. Topics were synthesised and refined. Round 2 asked panellists to rate the importance of all topics (very important, important, not important), as well as select and rank their top 10 most important topics. A rank score was calculated whereby higher scores reflect higher rankings by panellists.
RESULTS: Round 1 was completed by 121 panellists and generated 555 individual topics describing their musculoskeletal trial learning needs. These statements were grouped into 37 unique topics for Round 2, which was completed by 104 panellists. The topics ranked as most important were: (1) defining a meaningful research question (rank score 560, 74% of panellists rated topic as very important); (2) choosing the most appropriate trial design (rank score 410, 73% rated as very important); (3) involving consumers in trial design through to dissemination (rank score 302, 62% rated as very important); (4) bias in musculoskeletal trials and how to minimise it (rank score 299, 70% rated as very important); and (5) choosing the most appropriate control/comparator group (rank score 265, 65% rated as very important).
CONCLUSIONS: This modified Delphi study generated a ranked list of clinical trial learning needs of musculoskeletal researchers. Findings can inform training courses and professional development to improve researcher capabilities and enhance the quality and conduct of musculoskeletal clinical trials.