Epidemiologists frequently employ right censoring to handle missing outcome, covariate, or exposure data incurred when participants have large gaps between study visits or stop attending study visits entirely. But, if participants who are censored are more or less likely to experience outcomes of interest than those not censored, such censoring could introduce bias in estimated measures.

We examined how censoring after two consecutive missed visits may affect mortality results from the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS). MACS and WIHS provide linkages to vital statistics registries, such that mortality data were available for all participants, regardless of whether they attended study visits.

In a gold standard analysis that did not censor after two consecutive missed visits, 10-year mortality was 23% (95% CI: 22, 24) in MACS and 21% (95% CI: 20, 23) in WIHS. Estimated mortality was modestly reduced by 0%-5% across subgroups when censoring at missed visits. Applying inverse probability of censoring weights partially removed this attenuation.

While mortality was slightly elevated after two consecutive missed visits in MACS and WIHS, censoring at two consecutive missed visits did not substantially alter estimated mortality, particularly after applying inverse probability of censoring weights.

The Acute Respiratory Illness Surveillance (AcRIS) Study was a low-interventional trial that examined voice changes with respiratory illnesses. This longitudinal trial was the first of its kind, conducted in a fully decentralized manner via a Bring Your Own Device mobile application. The app enabled social-media-based recruitment, remote consent, at-home sample collection, and daily remote voice and symptom capture in real-world settings. From April 2021 to April 2022, the trial enrolled 9151 participants, followed for up to eight weeks. Despite mild symptoms experienced by reverse transcription polymerase chain reaction (RT-PCR) positive participants, two machine learning algorithms developed to screen respiratory illnesses reached the pre-specified success criteria. Algorithm testing on independent cohorts demonstrated that the algorithm's sensitivity increased as symptoms increased, while specificity remained consistent. Study findings suggest voice features can identify individuals with viral respiratory illnesses and provide valuable insights into fully decentralized clinical trials design, operation, and adoption (study registered at ClinicalTrials.gov (NCT04748445) on 5 February 2021).

This scoping review aims to collate and describe data on recruitment, retention, and strategies used to improve these, in randomised controlled trials of melanoma surveillance.

We searched MEDLINE, EMBASE, CINAHL and CENTRAL databases from inception until October 23, 2023. Two reviewers screened titles and abstracts, and full-texts, and one reviewer extracted data (convenience sample (n = 5) checked by a second). Eligibility criteria included: (i) RCT design, (ii) clinical setting, (iii) participants at increased risk of melanoma, (iv) interventions for early melanoma detection, and (v) early detection outcomes or surrogates such as improved skin self-examination. We calculated summary statistics and undertook qualitative data synthesis.

From 1746 records, 21 trials (reported in 28 papers) were included. Recruitment sources included dermatology clinics, general practice sites, and hospital databases or registries. Trials reported proportions of those screened who were eligible (mean 75 %, range 24-100 %), proportions of those eligible who were randomised (mean 63 %, range 24-95 %), numbers randomised per month (mean 25 participants, range 2-74), and proportion of those randomised who completed outcome measurements (mean 85 %, range 59-100 %) for self-report questionnaires at primary timepoints). Recruitment strategies included targeted participant identification and flexible consent processes. Retention strategies included setting narrow eligibility criteria, reminders, and financial incentives. Reporting on strategies was limited and there were no reports on effectiveness. Few studies reported recruiter facing initiatives or public and patient involvement.

More consistent and detailed reporting of recruitment and retention strategies in RCTs is needed, alongside evaluations of their effectiveness.

The first WHO Global Clinical Trials Forum was convened in November, 2023 to develop a shared vision of an effective global clinical trial infrastructure. The Paediatric Clinical Trials Working Group was formed to provide perspectives, identify challenges, and propose solutions to strengthen the paediatric clinical trials ecosystem. Participants represented paediatric disciplines, including infectious diseases, nutrition, neonatology, pharmacology, oncology, neurodevelopment, public health, and policy. Childhood diseases have profound lifelong effects on health, livelihoods, and societies. Investment in early childhood results in highly cost-effective changes to lifelong health, productivity, and human capital returns. Yet, there remain substantial gaps in knowledge on the efficacy and safety of many paediatric interventions, which represents a failure to establish shared priorities and alignment across governments, researchers, communities, and funders. Children are frequently marginalised from clinical trials, which is an issue of equity. Challenges include mismatched priorities and funding, risk adversity, poor design, power imbalances, and inadequate infrastructure. Solutions include aligning on and tracking local and global child health priorities against funding and supporting regional consortia to pool resources for larger, more consequential trials. We propose actions and responsibilities for global, regional, and national institutions for prioritisation, coordination, enabling paediatric trials consortia, funding, and tracking progress.

The aim of this study was to develop and validate a machine-learning classifier based on patient and witness questionnaires to support differential diagnosis of transient loss of consciousness (TLOC) at first presentation.

We prospectively recruited patients newly presenting with TLOC to an emergency department, an acute medical unit, and a first seizure or syncope clinic. We invited participants to complete an online questionnaire, either at home or at time of initial assessment. Two expert raters determined the cause of participants' TLOC after 6-month follow-up. We used independent development and validation samples to train a random forest classifier to predict diagnosis from participants' questionnaire responses and validate classifier performance. We compared classifier performance against penalized linear regression and referrer diagnosis.

We included 178 participants in the final analysis, of whom 46 identified a witness able to complete an additional witness questionnaire. Given low witness recruitment, we developed a classifier based on patient answers only. A classifier trained on 9 items correctly identified 63 of 78 diagnoses (80.8%) (95% CI 70.0-88.5), an increase over the accuracy of initial assessing clinicians who were only able to diagnose 70.5% correctly. Within this, 96% (87.0%-99.4%) of those expertly rated as having syncope were correctly classified by the classifier (classifier sensitivity); 40% (20%-63.6%) of those expertly rated after follow-up as having either epilepsy or functional/dissociative seizures were similarly classified as being nonsyncope (classifier specificity).

A machine-learning classifier for differential diagnosis of TLOC has comparable performance in differentiating between 3 main causes of primary TLOC as the current standard of care but is insufficiently accurate in its current form to warrant incorporation into routine care. A system including information from witnesses might improve classification performance.

Sample size estimation is a critical aspect of nutrition research methodology, yet it remains frequently overlooked, leading to underpowered studies and potentially inaccurate conclusions. This review addresses this gap by providing comprehensive guidance on how to calculate sample size in nutrition research. Emphasizing the importance of an a priori sample size calculation, the review outlines the key considerations, including the desired levels of significance and power, effect size estimation, and standard deviation assessment. Formulas for determining sample size for various comparisons, including two proportions, two means, three or more groups, and unevenly sized groups, are provided, along with strategies for addressing loss to follow-up. Hypothetical examples illustrate these formulas' application across different research scenarios, highlighting their practical value in ensuring study robustness. Additionally, the review discusses common pitfalls in sample size estimation, such as misjudging effect size or standard deviation, and emphasizes the need for transparent reporting of sample size calculations to enable accurate interpretation of study findings. This article is a resource for nutrition researchers, offering guidance on conducting appropriate sample size calculations to bolster methodological rigor and study reliability. By embracing the principles outlined herein, researchers can elevate the quality of nutrition research.

To (1) analyze trends in the publishing of statistical fragility index (FI)-based systematic reviews in the orthopaedic literature, including the prevalence of misleading or inaccurate statements related to the statistical fragility of randomized controlled trials (RCTs) and patients lost to follow-up (LTF), and (2) determine whether RCTs with relatively "low" FIs are truly as sensitive to patients LTF as previously portrayed in the literature.

All FI-based studies published in the orthopaedic literature were identified using the Cochrane Database of Systematic Reviews, Web of Science Core Collection, PubMed, and MEDLINE databases. All articles involving application of the FI or reverse FI to study the statistical fragility of studies in orthopaedics were eligible for inclusion in the study. Study characteristics, median FIs and sample sizes, and misleading or inaccurate statements related to the FI and patients LTF were recorded. Misleading or inaccurate statements-defined as those basing conclusions of trial fragility on the false assumption that adding patients LTF back to a trial has the same statistical effect as existing patients in a trial experiencing the opposite outcome-were determined by 2 authors. A theoretical RCT with a sample size of 100, P = .006, and FI of 4 was used to evaluate the difference in effect on statistical significance between flipping outcome events of patients already included in the trial (FI) and adding patients LTF back to the trial to show the true sensitivity of RCTs to patients LTF.

Of the 39 FI-based studies, 37 (95%) directly compared the FI with the number of patients LTF. Of these 37 studies, 22 (59%) included a statement regarding the FI and patients LTF that was determined to be inaccurate or misleading. In the theoretical RCT, a reversal of significance was not observed until 7 patients LTF (nearly twice the FI) were added to the trial in the distribution of maximal significance reversal.

The claim that any RCT in which the number of patients LTF exceeds the FI could potentially have its significance reversed simply by maintaining study follow-ups is commonly inaccurate and prevalent in orthopaedic studies applying the FI. Patients LTF and the FI are not equivalent. The minimum number of patients LTF required to flip the significance of a typical RCT was shown to be greater than the FI, suggesting that RCTs with relatively low FIs may not be as sensitive to patients LTF as previously portrayed in the literature; however, only a holistic approach that considers the context in which the trial was conducted, potential biases, and study results can determine the merits of any particular RCT.

Surgeons may benefit from re-examining their interpretation of prior FI reviews that have made claims of substantial RCT fragility based on comparisons between the FI and patients LTF; it is possible the results are more robust than previously believed.

Cognitive impairment is a central characteristic of schizophrenia. Executive functioning (EF) impairments are often seen in mental disorders, particularly schizophrenia, where they relate to adverse outcomes. As a heterogeneous construct, how specifically each dimension of EF to characterize the diagnostic and prognostic aspects of schizophrenia remains opaque. We used classification models with a stacking approach on systematically measured EFs to discriminate 195 patients with schizophrenia from healthy individuals. Baseline EF measurements were moreover employed to predict symptomatically remitted or non-remitted prognostic subgroups. EF feature importance was determined at the group-level and the ensuing individual importance scores were associated with four symptom dimensions. EF assessments of inhibitory control (interference and response inhibitions), followed by working memory, evidently predicted schizophrenia diagnosis (area under the curve [AUC]=0.87) and remission status (AUC=0.81). The models highlighted the importance of interference inhibition or working memory updating in accurately identifying individuals with schizophrenia or those in remission. These identified patients had high-level negative symptoms at baseline and those who remitted showed milder cognitive symptoms at follow-up, without differences in baseline EF or symptom severity compared to non-remitted patients. Our work indicates that impairments in specific EF dimensions in schizophrenia are differentially linked to individual symptom-load and prognostic outcomes. Thus, assessments and models based on EF may be a promising tool that can aid in the clinical evaluation of this disorder.

The rapid advances in genomics over the last decade have come to fruition amid intense public discussions of justice in medicine and health care. While much emphasis has been placed on increasing diversity in genomics research participation, an overly narrow focus on recruitment eschews recognition of the disparities in health care that will ultimately shape access to the benefits of genomic medicine. In this essay, we suggest that achieving a just genomics, both now and in the future, requires an explicit ELSI of translation-normative and pragmatic scholarship that embraces the interconnectedness of research and clinical care and centers the obligations of researchers, institutions, and funders to mitigate inequities throughout the translational pipeline. We propose core principles to guide an ELSI of translation and to ensure that this work balances the value of the generalizable knowledge that genomics research generates and the value of the individuals and communities who make this research possible.

The science of diabetes care has progressed to provide a better understanding of the oxidative and inflammatory lesions and pathophysiology of the neurovascular unit within the retina (and brain) that occur early in diabetes, even prediabetes. Screening for retinal structural abnormalities, has traditionally been performed by fundus examination or color fundus photography; however, these imaging techniques detect the disease only when there are sufficient lesions, predominantly hemorrhagic, that are recognized to occur late in the disease process after significant neuronal apoptosis and atrophy, as well as microvascular occlusion with alterations in vision. Thus, interventions have been primarily oriented toward the later-detected stages, and clinical trials, while demonstrating a slowing of the disease progression, demonstrate minimal visual improvement and modest reduction in the continued loss over prolonged periods. Similarly, vision measurement utilizing charts detects only problems of visual function late, as the process begins most often parafoveally with increasing number and progressive expansion, including into the fovea. While visual acuity has long been used to define endpoints of visual function for such trials, current methods reviewed herein are found to be imprecise. We review improved methods of testing visual function and newer imaging techniques with the recommendation that these must be utilized to discover and evaluate the injury earlier in the disease process, even in the prediabetic state. This would allow earlier therapy with ocular as well as systemic pharmacologic treatments that lower the and neuro-inflammatory processes within eye and brain. This also may include newer, micropulsed laser therapy that, if applied during the earlier cascade, should result in improved and often normalized retinal function without the adverse treatment effects of standard photocoagulation therapy.

Loss to follow-up of participants can compromise the statistical validity of randomised trials. Moreover, it can have financial consequences for trial teams and funders. This study explores the Occupational Therapist Intervention Study (OTIS) where, despite a withdrawal rate of less than 10%, the trial team incurred opportunity costs related to participants who were initially recruited but subsequently decided to withdraw from the trial.

To estimate the cost of participant losses to follow-up in the OTIS trial and thus introduce a costing framework to research teams on how they could estimate the opportunity costs of participant withdrawal from their randomised trials.

The participants lost to follow-up are differentiated by (1) the time point at which they were lost to follow-up; (2) the treatment group they were allocated to; (3) their response patters to follow-up questionnaires; these elements were considered to identify the relevant types of attrition. Protocol-driven costs of trial materials, including administration, print, and shipping, were gathered. We calculated unit costs for each type of attrition by multiplying protocol-driven and intervention costs with the relevant number of participants. Summing up unit costs by type of loss to follow-up yields aggregate figures, enabling the estimation of aggregate and average opportunity costs of attrition.

The average cost per participant loss to follow-up in the OTIS trial is £98.41. The aggregate cost of participant loss to follow-up is £10,234.90 from the economic perspective of the trial team. Therefore, 1.42% of the allocated funding has been misallocated because of participant loss to follow-up.

Despite the low attrition rate of the OTIS trial, loss to follow-up has still generated considerable opportunity costs. It is recommended that decision makers focus on identifying strategies which could improve participant retention in randomised trials to optimise their budget.

In drug development, the use of real-world data (RWD) has augmented our understanding of patients' health care experiences and the effects of treatments beyond clinical trials. Although electronic health record (EHR) data integration at clinical trial sites is a widely adopted practice, primarily for recruitment and data capture, a challenge to data utility is the fragmentation of health data across different sources. Linking RWD sources to each other and to trial data -- while preserving patient privacy through tokenization -- aids in filling evidence gaps with outcome data and facilitates the generalization of effects from controlled trial environments to real-world settings. This paper describes the applications of RWD linkage and how they benefit both clinical development and real-world decision-making. Trial benefits include improving interpretability and generalizability (e.g., by remediating missing data or losses to follow-up), extending follow-up beyond trial closeout, and characterizing the applicability of trial results to under-represented groups. The operational aspects of linking trial data to RWD are addressed, emphasizing the importance of using privacy-preserving record linking systems with established metrics of accuracy and precision, managing consent, and providing the necessary training and resources at trial sites to inform participants about providing access to their RWD through data linkage.

This meta-analysis aims to investigate the long-term survival rates of dental implants over a 20-year period, providing a practical guide for clinicians while identifying potential areas for future research.

Data were sourced from recent publications, focusing exclusively on screw-shaped titanium implants with a rough surface. Both retrospective and prospective studies were included to ensure an adequate sample size. A systematic electronic literature search was conducted in the databases: MEDLINE (PubMed), Cochrane, and Web of Science. The risk of bias for all studies was analyzed using a tool by Hoy et al. RESULTS: Three prospective studies (n = 237 implants) revealed a mean implant survival rate of 92% (95% CI: 82% to 97%), decreasing to 78% (95% CI: 74%-82%) after imputation (n = 422 implants). A total of five retrospective studies (n = 1440 implants) showed a survival rate of 88% (95% CI: 78%-94%). Implant failure causes were multifactorial.

This review consolidates 20-year dental implant survival data, reflecting a remarkable 4 out of 5 implants success rate. It emphasizes the need for long-term follow-up care, addressing multifactorial implant failure. Prioritizing quality standards is crucial to prevent overestimating treatment effectiveness due to potential statistical errors. While dental implantology boasts reliable therapies, there is still room for improvement, and additional high-quality studies are needed, particularly to evaluate implant success.

Never before have the implant survival over 20 years been systematically analyzed in a meta-analysis. Although a long-term survival can be expected, follow-up is essential and shouldn't end after insertion or even after 10 years.

Reporting bias, prevalent in biomedical fields, can undermine evidence credibility. Our objective was to evaluate the proportion of discrepancies between registered protocols and published manuscripts in randomized controlled trials (RCTs) on exercise interventions for patients with chronic low back pain (CLBP).

We conducted a cross-sectional meta-research study, starting from the 2021 "Exercise therapy for CLBP" Cochrane Review. We selected all RCTs reporting a protocol registration on a primary register of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) or in ClinicalTrials.gov. We extracted data from both registered protocol and published manuscript of RCTs, collecting recruitment and administrative information (eg, record dates) and details of trial characteristics (eg, outcomes, arms, statistical analysis plan details [SAPs]). Independent pairs of reviewers assessed discrepancies between registered protocol and published manuscript for the reporting of primary and secondary outcomes domains, measurement instruments, time-points, number of arms and SAPs(if attached). Outcome discrepancies were characterized as addition, omission, upgrade or downgrade.

We included 116 RCTs reporting an available protocol registration. Overall, 100 RCTs (86.2%) distinguished between primary and secondary outcomes. Of these, 39 RCTs (39.0%) reported one or more discrepancies in primary outcomes, and 78 RCTs (78.0%) reported one or more discrepancies in secondary outcomes. Focusing on discrepancies for the primary outcome, 64.5% of added, upgraded or downgraded outcomes favored statistically significant effects. Few RCTs (n = 6) reported discrepancies in the number of arms. SAPs were poorly reported in the registered protocols (n = 3) for being compared to the publications.

We found substantial outcome discrepancies comparing registered protocols and published manuscripts in RCTs assessing exercise interventions for patients with CLBP, with some impacting the statistical significance of the effects. Readers are encouraged to approach RCTs results in this field with caution.

Non-attendance with scheduled postoperative follow-up visits remains a common issue in orthopaedic clinical research. The objective of this study was to identify the risk factors associated with loss to follow-up among elderly patients with hip-fracture postoperatively.

A retrospective analysis of 1-year post-surgery was performed on patients aged over 60 years who underwent hip-fracture surgery from January 2017 to March 2019. Based on their completion of the appointed follow-up schedule, the patients were classified into 2 groups: the Loss to Follow-up (LTFU) Group and the Follow-up (FU) Group. Clinical outcomes were evaluated by Functional Recovery Score (FRS) questionnaires. Telephone interviews were conducted with patients lost to follow-up to determine the reasons for non-attendance. A comparative analysis of baseline characteristics between the 2 groups was implemented, with further exploration of statistical differences through logistic regression.

A total of 992 patients met the inclusion criteria were included in this study, of which 189 patients, accounting for 19.1%, were lost to follow-up 1 year postoperatively. The mean age of the patients in the LTFU Group was 82.0 years, significantly higher than the 76.0 years observed in the FU Group (P < 0.001). The FRS for the LTFU Group was marginally higher than that of the FU group (84.0 vs 81.0), with no significant difference (P = 0.060). Logistic regression analysis identified several significant predictors of noncompliance, including advanced age at surgery, femoral neck fracture, hip arthroplasty, long distance from residence to hospital, and the reliance on urban-rural public transportation for reaching the hospital.

Postoperative follow-up loss was prevalent among elderly patients with hip fractures. Our study indicated a constellation of risk factors contributing to noncompliance, including advanced age, transportation difficulties, long travel distance, femoral neck fracture and hip arthroplasty surgery.

The purpose of this article, part 1 of 2 on randomised controlled trials (RCTs), is to provide readers (eg, clinicians, patients, health service and policy decision-makers) of the nutrition literature structured guidance on interpreting RCTs. Evaluation of a given RCT involves several considerations, including the potential for risk of bias, the assessment of estimates of effect and their corresponding precision, and the applicability of the evidence to one's patient. Risk of bias refers to flaws in the design or conduct of a study that may lead to a deviation from measuring the underlying true effect of an intervention. Bias is assessed on a continuum from very low to very high (ie, definitely low to definitely high) risk of yielding estimates that do not represent true treatment-related effects and when appraising a study, judgement involves some degree of subjectivity. Specifically, when evaluating the risk of bias, one must first consider whether patient baseline characteristics (eg, age, smoking) are balanced between groups at randomisation, referred to as prognostic balance, and whether this balance is maintained throughout the study. While randomisation in sufficiently large trials may ensure prognostic balance between study arms at baseline; concealment of randomisation and blinding of participants, healthcare providers, data collectors, outcome adjudicators and data analysts to treatment allocation are needed to maintain prognostic balance between study arms after a trial begins. The status of each participant with respect to outcomes of interest must be known at the conclusion of a trial; when this is not the case, missing (lost) participant outcome data increases the likelihood that prognostic balance was not maintained at study completion. In addition, analysis of participants in the groups to which they were initially randomised (ie, intention-to-treat analysis) offers a reliable method to maintain prognostic balance. Finally, trials terminated early risk overestimating the treatment effect, especially when sample size is limited or stopping boundaries are not defined a priori.

Poor retention in clinical trials can impact on statistical power, reliability, validity, and generalizability of findings and is a particular challenge in smoking cessation studies. In online trials with automated follow-up mechanisms, poor response also increases the resource need for manual follow-up. This study compared two financial incentives on response rates at 6 months follow up, in an online, automated smoking cessation feasibility trial of a cessation smartphone app (Quit Sense).

A study within a trial (SWAT), embedded within a host randomized controlled trial. Host trial participants were randomized 1:1 to receive either a £10 or £20 voucher incentive, for completing the 6-month questionnaire. Stratification for randomization to the SWAT was by minimization to ensure an even split of host trial arm participants and by 6-week response rate. Outcome measures were: Questionnaire completion rate, time to completion, number of completers requiring manual follow-up, and completeness of responses.

Two hundred and four participants were randomized to the SWAT. The £20 and £10 incentives did not differ in completion rate at 6 months (79% vs. 74%; p = .362) but did reduce the proportion of participants requiring manual follow-up (46% vs. 62%; p = .018) and the median completion time (7 days vs. 15 days; p = .008). Measure response completeness rates were higher among £20 incentive participants, though differences were small for the host trial's primary smoking outcome.

Benefits to using relatively modest increases in incentive for online smoking cessation trials include more rapid completion of follow-up questionnaires and reduced manual follow-up.

A modest increase in incentive (from £10 to £20) to promote the completion of follow-up questionnaires in online smoking cessation trials may not increase overall response rates but could lead to more rapid data collection, a reduced need for manual follow-up and reduced missing data among those who initiate completing a questionnaire. Such an improvement may help to reduce bias, increase validity and generalizability, and improve statistical power in smoking cessation trials.

Host trial ISRCTN12326962, SWAT repository store ID 164.

Loss to follow-up (LTFU) distorts results of randomized controlled trials (RCTs). Understanding trial characteristics that contribute to LTFU may enable investigators to anticipate the extent of LTFU and plan retention strategies. The objective of this systematic review and meta-analysis was to investigate the extent of LTFU in surgical RCTs and evaluate associations between trial characteristics and LTFU.

MEDLINE, Embase, and PubMed Central were searched for surgical RCTs published between January 2002 and December 2021 in the 30 highest impact factor surgical journals. Two-hundred eligible RCTs were randomly selected. The pooled LTFU rate was estimated using random intercept Poisson regression. Associations between trial characteristics and LTFU were assessed using metaregression.

The 200 RCTs included 37,914 participants and 1307 LTFU events. The pooled LTFU rate was 3.10 participants per 100 patient-years (95% confidence interval [CI] 1.85-5.17). Trial characteristics associated with reduced LTFU were standard-of-care outcome assessments (rate ratio [RR] 0.17; 95% CI 0.06-0.48), surgery for transplantation (RR 0.08; 95% CI 0.01-0.43), and surgery for cancer (RR 0.10; 95% CI 0.02-0.53). Increased LTFU was associated with patient-reported outcomes (RR 14.21; 95% CI 4.82-41.91) and follow-up duration ≥ three months (odds ratio 10.09; 95% CI 4.79-21.28).

LTFU in surgical RCTs is uncommon. Participants may be at increased risk of LTFU in trials with outcomes assessed beyond the standard of care, surgical indications other than cancer or transplant, patient-reported outcomes, and longer follow-up. Investigators should consider the impact of design on LTFU and plan retention strategies accordingly.

Dichotomous outcomes are frequently reported in orthopaedic research and have substantial clinical implications. This study utilizes the fragility index (FI) and fragility quotient (FQ) metrics to determine the statistical stability of outcomes reported in total joint arthroplasty randomized controlled trials (RCTs) relating to periprosthetic joint infection (PJI).

The RCTs that reported dichotomous data related to PJI published between January 1, 2010, and December 31, 2022, were evaluated. The FI and reverse FI (RFI) were defined as the number of outcome event reversals required to reverse the significance of significant and nonsignificant outcomes, respectively. The FQ was determined by dividing the FI or RFI by the respective sample size. There were 108 RCTs screened, and 17 studies included for analysis.

A total of 58 outcome events were identified, with a median FI of 4 (interquartile range [IQR] 2 to 5) and associated FQ of 0.0417 (IQR 0.0145 to 0.0602). The 13 statistically significant outcomes had a median FI of 1 (IQR 1 to 2) and FQ of 0.00935 (IQR 0.00629 to 0.01410). The 45 nonsignificant outcomes had a median RFI of 4 (IQR 3 to 5) and FQ of 0.05 (IQR 0.0361 to 0.0723). The number of patients lost to follow-up was greater than or equal to the FI in 46.6% of outcomes.

Statistical outcomes in RCTs analyzing PJI are fragile and may lack statistical integrity. We recommend a comprehensive fragility analysis, with the reporting of FI and FQ metrics, to aid in the interpretation of outcomes in the total joint arthroplasty literature.

The objective of this meta-epidemiological study was to explore the impact of attrition rates on treatment effect estimates in randomised trials of chronic inflammatory diseases (CID) treated with biological and targeted synthetic disease-modifying drugs. We sampled trials from Cochrane reviews. Attrition rates and primary endpoint results were retrieved from trial publications; Odds ratios (ORs) were calculated from the odds of withdrawing in the experimental intervention compared to the control comparison groups (i.e., differential attrition), as well as the odds of achieving a clinical response (i.e., the trial outcome). Trials were combined using random effects restricted maximum likelihood meta-regression models and associations between estimates of treatment effects and attrition rates were analysed. From 37 meta-analyses, 179 trials were included, and 163 were analysed (301 randomised comparisons; n = 62,220 patients). Overall, the odds of withdrawal were lower in the experimental compared to control groups (random effects summary OR = 0.45, 95% CI, 0.41-0.50). The corresponding overall treatment effects were large (random effects summary OR = 4.43, 95% CI 3.92-4.99) with considerable heterogeneity across interventions and clinical specialties (I2 = 85.7%). The ORs estimating treatment effect showed larger treatment benefits when the differential attrition was more prominent with more attrition in the control group (OR = 0.73, 95% CI 0.55-0.96). Higher attrition rates from the control arm are associated with larger estimated benefits of treatments with biological or targeted synthetic disease-modifying drugs in CID trials; differential attrition may affect estimates of treatment benefit in randomised trials.

Retaining participants in randomised controlled trials (RCTs) is challenging and trial teams are often required to use strategies to ensure retention or improve it. Other than monetary incentives, there is no requirement to disclose the use of retention strategies to the participant. Additionally, not all retention strategies are developed at the planning stage, i.e. post-funding during protocol development, but some protocols include strategies for participant retention as retention is considered and planned for early in the trial planning stage. It is yet unknown if these plans are communicated in the corresponding participant information leaflets (PILs). The purpose of our study was to determine if PILs communicate plans to promote participant retention and, if so, are these outlined in the corresponding trial protocol.

Ninety-two adult PILs and their 90 corresponding protocols from Clinical Trial Units (CTUs) in the UK were analysed. Directed (deductive) content analysis was used to analyse the participant retention text from the PILs. Data were presented using a narrative summary and frequencies where appropriate.

Plans to promote participant retention were communicated in 81.5% (n = 75/92) of PILs. Fifty-seven percent (n = 43/75) of PILs communicated plans to use "combined strategies" to promote participant retention. The most common individual retention strategy was telling the participants that data collection for the trial would be scheduled during routine care visits (16%; n = 12/75 PILs). The importance of retention and the impact that missing or deleted data (deleting data collected prior to withdrawal) has on the ability to answer the research question were explained in 6.5% (n = 6/92) and 5.4% (n = 5/92) of PILs respectively. Out of the 59 PILs and 58 matching protocols that both communicated plans to use strategies to promote participant retention, 18.6% (n = 11/59) communicated the same information, the remaining 81.4% (n = 48/59) of PILs either only partially communicated (45.8%; n = 27/59) the same information or did not communicate the same information (35.6%; n = 21/59) as the protocol with regard to the retention strategy(ies).

Retention strategies are frequently communicated to potential trial participants in PILs; however, the information provided often differs from the content in the corresponding protocol. Participant retention considerations are best done at the planning stage of the trial and we encourage trial teams to be consistent in the communication of these strategies in both the protocol and PIL.

The use of routinely collected electronic healthcare records (EHR) for outcome assessment in clinical trials has been described as a 'disruptive' new technique more than a decade ago. Despite this potential, significant methodological issues and regulatory barriers have hampered the progress in this area. This article discusses the key considerations that trialists should take into account when incorporating EHR into their trials. These include considerations of the clinical relevance of the outcome, data timeliness and quality, ethical and regulatory issues, and some practical considerations for clinical trials units. In addition, this article describes the benefits of using EHR which include cost, reduced trial burden for participants and staff, follow up efficiencies, and improved health economic evaluation procedures. We also describe the major regulatory and start up costs of using EHR in clinical trials. This article focuses on the UK specific EHR landscape in clinical trials and would help researchers and trials units considering the use of this method of outcome data collection in their next trial. If the issues described are mitigated, this method will be a formidable tool for conducting pragmatic clinical trials.

Background: The American Academy of Orthopaedic Surgeons (AAOS) clinical practice guidelines (CPGs) note "strong" evidence that early and delayed mobilization protocols after small to medium arthroscopic rotator cuff repairs achieve similar rotator cuff healing rates. Purpose: We utilized the reverse fragility index (RFI) to assess the fragility of randomized controlled trials (RCTs) reporting no statistically significant difference in tendon re-tear rates after rotator cuff repair in those undergoing early versus delayed rehabilitation. Methods: Randomized controlled trials used in the most recent AAOS CPGs on the timing of postoperative mobilization after arthroscopic rotator cuff repairs were analyzed. Only RCTs with a reported P value ≥ .05 were included. The RFI at a threshold of P < .05 was calculated for each study. The reverse fragility quotient (RFQ) was calculated by dividing the RFI by the study sample size. Results: In 6 clinical trials with a total of 542 patients, the number of tendon re-tear events was 48. The median RFI at the P < .05 threshold was 4 (range: 3.25-4.75), and the median RFQ was .05 (range: 0.03-0.08). The median loss to follow-up was 6 patients. Of the 6 studies investigated, 3 reported a loss to follow-up greater than their respective RFI. Conclusion: The equivalence in rotator cuff repair healing rates associated with early and delayed mobilization protocols rests on fragile studies, as their statistical non-significance can be reversed by changing the outcome status of only a handful of patients. Consideration should be given to the routine reporting of RFI in clinical practice guidelines including RCTs with statistically non-significant results.

Biologics and small molecules have been increasingly applied in Crohn's disease (CD) and ulcerative colitis (UC). But the robustness of their trials has not been evaluated.

We initially collected all the approved biologics or small molecules for CD or UC up to December 1, 2022. Databases were then queried by keywords in chemical name and CD or UC. Randomized controlled trials (RCTs) in the two-arm, 1:1 design were included. Fragility index (FI) and fragility quotient (FQ) were subsequently calculated.

We included twenty-eight RCTs, including nine pivotal trials listed in approval labels, nineteen non-pivotal trials not included in the labels. The median sample size was 99 [IQR, 60-262] and the median number of loss-of-follow-up (LFU) was 14 [IQR, 8-43]. Pivotal trials in the labels had the median FI of 8 [IQR, 4-14, n = 6] that was marginally higher than non-pivotal trials (3 [IQR, 2-4], p = 0.08). The median FQ was 0.0330 [IQR, 0.1220-0.0466] and 0.0310 [IQR, 0.0129-0.0540] for pivotal and non-pivotal trials, respectively (p = 1.0). The sample size and FI were significantly correlated (Spearman correlation coefficient [r] = 0.56, 95 %CI 0.21-0.78, p = 0.003). The number of total events was also significantly correlated with FI (r = 0.53, 95 %CI 0.17-0.77, p = 0.006). Study p-values were significantly associated with FI (p = 0.01): trials with p-values < 0.001 had the highest median FI of 10 [IQR, 6-17]. No factor was found strongly correlated with FQ.

Results from trials assessing administration-approved biologics or small molecules for treating CD or UC were vulnerable to small changes by measuring FI or FQ. Pivotal studies contributing to regulatory approvals exhibited a relatively higher degree of resilience compared to non-pivotal trials.

Missing outcome data in clinical trials may jeopardize the validity of the trial results and inferences for clinical practice. Although sick and preterm newborns are treated as a captive patient population during their stay in the NICUs, their long-term outcomes are often ascertained after discharge. This greatly increases the risk of attrition. We surveyed recently published perinatal and neonatal randomized trials in 7 high-impact general medical and pediatric journals to review the handling of missing primary outcome data and any choice of imputation methods. Of 87 eligible trials in this survey, 77 (89%) had incomplete primary outcome data. The missing outcome data were not discussed at all in 9 reports (12%). Most study teams restricted their main analysis to participants with complete information for the primary outcome (61 trials; 79%). Only 38 of the 77 teams (49%) performed sensitivity analyses using a variety of imputation methods. We conclude that the handling of missing primary outcome data was frequently inadequate in recent randomized perinatal and neonatal trials. To improve future approaches to missing outcome data, we discuss the strengths and limitations of different imputation methods, the appropriate estimation of sample size, and how to deal with data withdrawal. However, the best strategy to reduce bias from missing outcome data in perinatal and neonatal trials remains prevention. Investigators should anticipate and preempt missing data through careful study design, and closely monitor all incoming primary outcome data for completeness during the conduct of the trial.

Retention to trials is important to ensure the results of the trial are valid and reliable. The SPIRIT guidelines (18b) require "plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols" be included in trial protocols. It is unknown how often protocols report this retention information. The purpose of our scoping review is to establish if, and how, trial teams report plans for retention during the design stage of the trial.

A scoping review with searches in key databases (PubMed, Scopus, EMBASE, CINAHL (EBSCO), and Web of Science from 2014 to 2019 inclusive) to identify randomised controlled trial protocols. We produced descriptive statistics on the characteristics of the trial protocols and also on those adhering to SPIRIT item 18b. A narrative synthesis of the retention strategies was also conducted.

Eight-hundred and twenty-four protocols met our inclusion criteria. RCTs (n = 722) and pilot and feasibility trial protocols (n = 102) reported using the SPIRIT guidelines during protocol development 35% and 34.3% of the time respectively. Of these protocols, only 9.5% and 11.4% respectively reported all aspects of SPIRIT item 18b "plans to promote participant retention and to complete follow-up, including list of any outcome data for participants who discontinue or deviate from intervention protocols". Of the RCT protocols, 36.8% included proactive "plans to promote participant retention" regardless of whether they reported using SPIRIT guidelines or not. Most protocols planned "combined strategies" (48.1%). Of these, the joint most commonly reported were "reminders and data collection location and method" and "reminders and monetary incentives". The most popular individual retention strategy was "reminders" (14.7%) followed by "monetary incentives- conditional" (10.2%). Of the pilot and feasibility protocols, 40.2% included proactive "plans to promote participant retention" with the use of "combined strategies" being most frequent (46.3%). The use of "monetary incentives - conditional" (22%) was the most popular individual reported retention strategy.

There is a lack of reporting of plans to promote participant retention in trial protocols. Proactive planning of retention strategies during the trial design stage is preferable to the reactive implementation of retention strategies. Prospective retention planning and clear communication in protocols may inform more suitable choice, costing and implementation of retention strategies and improve transparency in trial conduct.

The place of tonsillectomy in the management of sore throat in adults remains uncertain.

To establish the clinical effectiveness and cost-effectiveness of tonsillectomy, compared with conservative management, for tonsillitis in adults, and to evaluate the impact of alternative sore throat patient pathways.

This was a multicentre, randomised controlled trial comparing tonsillectomy with conservative management. The trial included a qualitative process evaluation and an economic evaluation.

The study took place at 27 NHS secondary care hospitals in Great Britain.

A total of 453 eligible participants with recurrent sore throats were recruited to the main trial.

Patients were randomised on a 1 : 1 basis between tonsil dissection and conservative management (i.e. deferred surgery) using a variable block-stratified design, stratified by (1) centre and (2) severity.

The primary outcome measure was the total number of sore throat days over 24 months following randomisation. The secondary outcome measures were the number of sore throat episodes and five characteristics from Sore Throat Alert Return, describing severity of the sore throat, use of medications, time away from usual activities and the Short Form questionnaire-12 items. Additional secondary outcomes were the Tonsil Outcome Inventory-14 total and subscales and Short Form questionnaire-12 items 6 monthly. Evaluation of the impact of alternative sore throat patient pathways by observation and statistical modelling of outcomes against baseline severity, as assessed by Tonsil Outcome Inventory-14 score at recruitment. The incremental cost per sore throat day avoided, the incremental cost per quality-adjusted life-year gained based on responses to the Short Form questionnaire-12 items and the incremental net benefit based on costs and responses to a contingent valuation exercise. A qualitative process evaluation examined acceptability of trial processes and ramdomised arms.

There was a median of 27 (interquartile range 12-52) sore throats over the 24-month follow-up. A smaller number of sore throats was reported in the tonsillectomy arm [median 23 (interquartile range 11-46)] than in the conservative management arm [median 30 (interquartile range 14-65)]. On an intention-to-treat basis, there were fewer sore throats in the tonsillectomy arm (incident rate ratio 0.53, 95% confidence interval 0.43 to 0.65). Sensitivity analyses confirmed this, as did the secondary outcomes. There were 52 episodes of post-operative haemorrhage reported in 231 participants undergoing tonsillectomy (22.5%). There were 47 re-admissions following tonsillectomy (20.3%), 35 relating to haemorrhage. On average, tonsillectomy was more costly and more effective in terms of both sore throat days avoided and quality-adjusted life-years gained. Tonsillectomy had a 100% probability of being considered cost-effective if the threshold for an additional quality-adjusted life year was £20,000. Tonsillectomy had a 69% probability of having a higher net benefit than conservative management. Trial processes were deemed to be acceptable. Patients who received surgery were unanimous in reporting to be happy to have received it.

The decliners who provided data tended to have higher Tonsillectomy Outcome Inventory-14 scores than those willing to be randomised implying that patients with a higher burden of tonsillitis symptoms may have declined entry into the trial.

The tonsillectomy arm had fewer sore throat days over 24 months than the conservative management arm, and had a high probability of being considered cost-effective over the ranges considered. Further work should focus on when tonsillectomy should be offered. National Trial of Tonsillectomy IN Adults has assessed the effectiveness of tonsillectomy when offered for the current UK threshold of disease burden. Further research is required to define the minimum disease burden at which tonsillectomy becomes clinically effective and cost-effective.

This trial is registered as ISRCTN55284102.

This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/146/06) and is published in full in Health Technology Assessment; Vol. 27, No. 31. See the NIHR Funding and Awards website for further award information.

To evaluate the reporting and rates of loss to follow-up (LTFU) in head and neck cancer (HNC) randomized controlled trials based in the United States.

Pubmed/MEDLINE, Cochrane, Scopus databases.

A systematic review of titles in Pubmed/MEDLINE, Scopus, and Cochrane Library was performed. Inclusion criteria were US-based randomized controlled trials focused on the diagnosis, treatment, or prevention of HNC. Retrospective analyses and pilot studies were excluded. The mean age, patients randomized, publication details, trial sites, funding, and LTFU data were recorded. Reporting of participants through each stage of the trial was documented. Binary logistic regression was performed to evaluate associations between study characteristics and reporting LTFU.

A total of 3255 titles were reviewed. Of these, 128 studies met the inclusion criteria for analysis. A total of 22,016 patients were randomized. The mean age of participants was 58.6 years. Overall, 35 studies (27.3%) reported LTFU, and the mean LTFU rate was 4.37%. With the exception of 2 statistical outliers, study characteristics including publication year, number of trial sites, journal discipline, funding source, and intervention type did not predict the odds of reporting LTFU. Compared to 95% of trials reporting participants at eligibility and 100% reporting randomization, only 47% and 57% reported on withdrawal and details of the analysis, respectively.

The majority of clinical trials in HNC in the United States do not report LTFU, which inhibits the evaluation of attrition bias that may impact the interpretation of significant findings. Standardized reporting is needed to evaluate the generalizability of trial results to clinical practice.

To evaluate the robustness of sports medicine and arthroscopy related randomized controlled trials (RCTs) reporting nonsignificant results by calculating the reverse fragility index (RFI) and reverse fragility quotient (RFQ).

All sports medicine and arthroscopic-related RCTs from January 1, 2010, through August 3, 2021, were identified. Randomized-controlled trials comparing dichotomous variables with a reported P value ≥ .05 were included. Study characteristics, such as publication year and sample size, as well as loss to follow-up and number of outcome events were recorded. The RFI at a threshold of P < .05 and respective RFQ were calculated for each study. Coefficients of determination were calculated to determine the relationships between RFI and the number of outcome events, sample size, and number of patients lost to follow-up. The number of RCTs in which the loss to follow-up was greater than the RFI was determined.

Fifty-four studies and 4,638 patients were included in this analysis. The mean sample size and loss to follow-up were 85.9 patients and 12.5 patients, respectively. The mean RFI was 3.7, signifying that a change of 3.7 events in one arm was needed to flip the results of the study from non-significant to significant (P < .05). Of the 54 studies investigated, 33 (61%) had a loss to follow-up greater than their calculated RFI. The mean RFQ was 0.05. A significant correlation between RFI with sample size (R2 = 0.10, P = .02) and the total number of observed events (R2 = 0.13, P < .01) was found. No significant correlation existed between RFI and loss to follow-up in the lesser arm (R2 = 0.01, P = .41).

The RFI and RFQ are statistical tools that allow the fragility of studies reporting nonsignificant results to be appraised. Using this methodology, we found that the majority of sports medicine and arthroscopy-related RCTs reporting nonsignificant results are fragile.

RFI and RFQ serve as tools that can be used to assess the validity of RCT results and provide additional context for appropriate conclusions.

Considered one of the highest levels of evidence, results of randomized controlled trials (RCTs) remain an essential building block in mental health research. They are frequently used to confirm that an intervention "works" and to guide treatment decisions. Given their importance in the field, it is concerning that the quality of many RCT evaluations in mental health research remains poor. Common errors range from inadequate missing data handling and inappropriate analyses (e.g., baseline randomization tests or analyses of within-group changes) to unduly interpretations of trial results and insufficient reporting. These deficiencies pose a threat to the robustness of mental health research and its impact on patient care. Many of these issues may be avoided in the future if mental health researchers are provided with a better understanding of what constitutes a high-quality RCT evaluation.

In this primer article, we give an introduction to core concepts and caveats of clinical trial evaluations in mental health research. We also show how to implement current best practices using open-source statistical software.

Drawing on Rubin's potential outcome framework, we describe that RCTs put us in a privileged position to study causality by ensuring that the potential outcomes of the randomized groups become exchangeable. We discuss how missing data can threaten the validity of our results if dropouts systematically differ from non-dropouts, introduce trial estimands as a way to co-align analyses with the goals of the evaluation, and explain how to set up an appropriate analysis model to test the treatment effect at one or several assessment points. A novice-friendly tutorial is provided alongside this primer. It lays out concepts in greater detail and showcases how to implement techniques using the statistical software R, based on a real-world RCT dataset.

Many problems of RCTs already arise at the design stage, and we examine some avoidable and unavoidable "weak spots" of this design in mental health research. For instance, we discuss how lack of prospective registration can give way to issues like outcome switching and selective reporting, how allegiance biases can inflate effect estimates, review recommendations and challenges in blinding patients in mental health RCTs, and describe problems arising from underpowered trials. Lastly, we discuss why not all randomized trials necessarily have a limited external validity and examine how RCTs relate to ongoing efforts to personalize mental health care.

Patients with N2-3 nasopharyngeal carcinoma have a high risk of treatment being unsuccessful despite the current practice of using a concurrent adjuvant cisplatin-fluorouracil regimen. We aimed to compare the efficacy and safety of concurrent adjuvant cisplatin-gemcitabine with cisplatin-fluorouracil in N2-3 nasopharyngeal carcinoma.

We conducted an open-label, randomised, controlled, phase 3 trial at four cancer centres in China. Eligible patients were aged 18-65 years with untreated, non-keratinising, stage T1-4 N2-3 M0 nasopharyngeal carcinoma, an Eastern Cooperative Oncology Group performance status score of 0-1, and adequate bone marrow, liver, and renal function. Eligible patients were randomly assigned (1:1) to receive concurrent cisplatin (100 mg/m2 intravenously) on days 1, 22, and 43 of intensity-modulated radiotherapy followed by either gemcitabine (1 g/m2 intravenously on days 1 and 8) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 3 weeks or fluorouracil (4 g/m2 in continuous intravenous infusion for 96 h) and cisplatin (80 mg/m2 intravenously for 4 h on day 1) once every 4 weeks, for three cycles. Randomisation was done using a computer-generated random number code with a block size of six, stratified by treatment centre and nodal category. The primary endpoint was 3-year progression-free survival in the intention-to-treat population (ie, all patients randomly assigned to treatment). Safety was assessed in all participants who received at least one dose of chemoradiotherapy. This study was registered at ClinicalTrials.gov, NCT03321539, and patients are currently under follow-up.

From Oct 30, 2017, to July 9, 2020, 240 patients (median age 44 years [IQR 36-52]; 175 [73%] male and 65 [27%] female) were randomly assigned to the cisplatin-fluorouracil group (n=120) or cisplatin-gemcitabine group (n=120). As of data cutoff (Dec 25, 2022), median follow-up was 40 months (IQR 32-48). 3-year progression-free survival was 83·9% (95% CI 75·9-89·4; 19 disease progressions and 11 deaths) in the cisplatin-gemcitabine group and 71·5% (62·5-78·7; 34 disease progressions and seven deaths) in the cisplatin-fluorouracil group (stratified hazard ratio 0·54 [95% CI 0·32-0·93]; log rank p=0·023). The most common grade 3 or worse adverse events that occurred during treatment were leukopenia (61 [52%] of 117 in the cisplatin-gemcitabine group vs 34 [29%] of 116 in the cisplatin-fluorouracil group; p=0·00039), neutropenia (37 [32%] vs 19 [16%]; p=0·010), and mucositis (27 [23%] vs 32 [28%]; p=0·43). The most common grade 3 or worse late adverse event (occurring from 3 months after completion of radiotherapy) was auditory or hearing loss (six [5%] vs ten [9%]). One (1%) patient in the cisplatin-gemcitabine group died due to treatment-related complications (septic shock caused by neutropenic infection). No patients in the cisplatin-fluorouracil group had treatment-related deaths.

Our findings suggest that concurrent adjuvant cisplatin-gemcitabine could be used as an adjuvant therapy in the treatment of patients with N2-3 nasopharyngeal carcinoma, although long-term follow-up is required to confirm the optimal therapeutic ratio.

National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Major Project of Basic and Applied Basic Research, Sci-Tech Project Foundation of Guangzhou City, Sun Yat-sen University Clinical Research 5010 Program, Innovative Research Team of High-level Local Universities in Shanghai, Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, Natural Science Foundation of Guangdong Province, Postdoctoral Innovative Talent Support Program, Pearl River S&T Nova Program of Guangzhou, Planned Science and Technology Project of Guangdong Province, Key Youth Teacher Cultivating Program of Sun Yat-sen University, the Rural Science and Technology Commissioner Program of Guangdong Province, and Fundamental Research Funds for the Central Universities.

The Australian Placental Transfusion Study (APTS) randomised 1,634 fetuses to delayed (≥60 s) versus immediate (≤10 s) clamping of the umbilical cord. Systematic reviews with meta-analyses, including this and similar trials, show that delaying clamping in preterm infants reduces mortality and need for blood transfusions. Amongst 1,531 infants in APTS followed up at two years, aiming to delay clamping for 60 s or more reduced the relative risk of the primary composite outcome of death or disability by 17% (p = 0.01). However, this result is fragile because nominal statistical significance (p < 0.05) would be abolished by only 2 patients switching from a non-event to an event, and the primary composite outcome was missing in 112 patients (7%). To achieve more robust evidence, any future trials should emulate the large, simple trials co-ordinated from Oxford which reliably identified moderate, incremental improvements in mortality in tens of thousands of participants, with <1% missing data. Those who fund, regulate, and conduct trials that aim to change practice should repay the trust of those who consent to participate by doing everything possible to minimise missing data for key outcomes.

Clinical trials are essential to evidence-based medicine. Their success relies on recruitment and retention of participants: problems with either can affect validity of results. Past research on improving trials has focused on recruitment, with less on retention, and even less considering retention at the point of recruitment, i.e., what retention-relevant information is shared during consent processes. The behaviour of trial staff communicating this information during consent is likely to contribute to retention. So, developing approaches to mitigate issues in retention at the point of consent is necessary. In this study, we describe the development of a behavioural intervention targeting the communication of information important to retention during the consent process.

We applied the Theoretical Domains Framework and Behaviour Change Wheel to develop an intervention aimed at changing the retention communication behaviours of trial staff. Building on findings from an interview study to understand the barriers/facilitators to retention communication during consent, we identified behaviour change techniques that could moderate them. These techniques were grouped into potential intervention categories and presented to a co-design group of trial staff and public partners to discuss how they might be packaged into an intervention. An intervention was presented to these same stakeholders and assessed for acceptability through a survey based on the Theoretical Framework of Acceptability.

Twenty-six behaviour change techniques were identified with potential to change communication of retention-information at consent. Six trial stakeholders in the co-design group discussed means for implementing these techniques and agreed the available techniques could be most effective within a series of meetings focussed on best practices for communicating retention at consent. The proposed intervention was deemed acceptable through survey results.

We have developed an intervention aimed at facilitating the communication of retention at informed consent through a behavioural approach. This intervention will be delivered to trial staff and will add to the available strategies for trials to improve retention.

The health effects of dietary fats are a controversial issue on which experts and authoritative organizations have often disagreed. Care providers, guideline developers, policy-makers, and researchers use systematic reviews to advise patients and members of the public on optimal dietary habits, and to formulate public health recommendations and policies. Existing reviews, however, have serious limitations that impede optimal dietary fat recommendations, such as a lack of focus on outcomes important to people, substantial risk of bias (RoB) issues, ignoring absolute estimates of effects together with comprehensive assessments of the certainty of the estimates for all outcomes.

We therefore propose a methodologically innovative systematic review using direct and indirect evidence on diet and food-based fats (i.e., reduction or replacement of saturated fat with monounsaturated or polyunsaturated fat, or carbohydrates or protein) and the risk of important health outcomes.

We will collaborate with an experienced research librarian to search MEDLINE, EMBASE, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR) for randomized clinical trials (RCTs) addressing saturated fat and our health outcomes of interest. In duplicate, we will screen, extract results from primary studies, assess their RoB, conduct de novo meta-analyses and/or network meta-analysis, assess the impact of missing outcome data on meta-analyses, present absolute effect estimates, and assess the certainty of evidence for each outcome using the GRADE contextualized approach. Our work will inform recommendations on saturated fat based on international standards for reporting systematic reviews and guidelines.

Our systematic review and meta-analysis will provide the most comprehensive and rigorous summary of the evidence addressing the relationship between saturated fat modification for people-important health outcomes. The evidence from this review will be used to inform public health nutrition guidelines.

PROSPERO Registration: CRD42023387377 .