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Linear mixed models are commonly used in analyzing stepped-wedge cluster randomized trials. A key consideration for analyzing a stepped-wedge cluster randomized trial is accounting for the potentially complex correlation structure, which can be achieved by specifying random-effects. The simplest random effects structure is random intercept but more complex structures such as random cluster-by-period, discrete-time decay, and more recently, the random intervention structure, have been proposed. Specifying appropriate random effects in practice can be challenging: assuming more complex correlation structures may be reasonable but they are vulnerable to computational challenges. To circumvent these challenges, robust variance estimators may be applied to linear mixed models to provide consistent estimators of standard errors of fixed effect parameters in the presence of random-effects misspecification. However, there has been no empirical investigation of robust variance estimators for stepped-wedge cluster randomized trials. In this article, we review six robust variance estimators (both standard and small-sample bias-corrected robust variance estimators) that are available for linear mixed models in R, and then describe a comprehensive simulation study to examine the performance of these robust variance estimators for stepped-wedge cluster randomized trials with a continuous outcome under different data generators. For each data generator, we investigate whether the use of a robust variance estimator with either the random intercept model or the random cluster-by-period model is sufficient to provide valid statistical inference for fixed effect parameters, when these working models are subject to random-effect misspecification. Our results indicate that the random intercept and random cluster-by-period models with robust variance estimators performed adequately. The CR3 robust variance estimator (approximate jackknife) estimator, coupled with the number of clusters minus two degrees of freedom correction, consistently gave the best coverage results, but could be slightly conservative when the number of clusters was below 16. We summarize the implications of our results for the linear mixed model analysis of stepped-wedge cluster randomized trials and offer some practical recommendations on the choice of the analytic model., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear., Methods: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months., Results: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively., Conclusions: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: The prevalence of gestational diabetes mellitus (GDM) has been increasing globally over recent decades; however, underlying reasons for the increase remain unclear. We analyzed trends in GDM rates and evaluated risk factors associated with the observed trends in Ontario, Canada., Methods: We conducted a retrospective population-based cohort study using the Better Outcomes Registry and Network Ontario, linked with the Canadian Institute for Health Information Discharge Abstract Database. All pregnant individuals who had a singleton hospital delivery from 1 April 2012 to 31 March 2020 were included. We calculated rates and 95% CIs for GDM by year of delivery and contrasted fiscal year 2019/20 with 2012/13. Temporal trends in GDM were quantified using crude and adjusted risk ratios by modified Poisson regression. We further quantified the temporal increase attributable to changes in maternal characteristics by decomposition analysis., Results: Among 1 044 258 pregnant individuals, 82 896 (7.9%) were diagnosed with GDM over the 8 years. GDM rate rose from 6.1 to 10.4 per 100 deliveries between fiscal years 2012/13 and 2019/20. The risk of GDM in 2019/20 was 1.53 times (95% CI 1.50-1.56) higher compared with 2012/13. 27% of the increase in GDM was due to changes in maternal age, 8 BMI, and Asian ethnicity., Conclusions: The GDM rate has been consistently increasing in Ontario, Canada. The contribution of increasing maternal age, pre-pregnancy obesity, and Asian ethnicity to the recent increase in GDM is notable. Further investigation is required to better understand the contributors to increasing GDM., (Copyright © 2024 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Background: For emergency department (ED) patients with syncope, cardiac troponin can identify acute coronary syndrome (ACS) and prognosticate for 30-day serious adverse events. However, it is unclear if serial testing improves diagnostic yield and prognostication., Methods: This was a secondary analysis of data from two prospective studies conducted to develop the Canadian Syncope Risk Score. Adults (age ≥ 16 years) with syncope were enrolled, and patient characteristics, vital signs, physician diagnostic impression, electrocardiogram and troponin results, and adjudicated 30-day serious adverse event were collected. The primary outcome was the detection of a serious adverse event within 30 days of ED disposition. The secondary outcome was comparison of ED length of stay among patients with single versus serial troponin measurements., Results: 4996 patients [mean age 64.5 (SD 18.8) years, 52.2% male] were included: 4397 (89.8%) with single troponin [232 (5.3%) with serious adverse event in the ED and 203 (4.6%) after ED disposition]; 499 (10.2%) patients with > 1 troponin measurement [39 (7.8%) with serious adverse event in ED and 60 (12.0%) after ED disposition]. Among those with serial measurements, 10 patients (2.0%) had a rise from below to above the 99th percentile threshold, of whom 4 patients (0.8%) suffered serious adverse event: two with arrhythmias diagnosed on electrocardiogram, one with ACS and one suffered respiratory failure. Nine patients (1.8%) had Canadian Syncope Risk Score risk reclassification based on serial measurement, and none suffered 30-day serious adverse event. Median ED length of stay was significantly longer for patients with serial testing (5.6 vs. 3.8 h, p < 0.001)., Conclusions: The initial troponin measurement was sufficient for serious adverse event detection and in-ED risk stratification. Serial troponin testing does not improve the diagnostic yield or prognostication and should be reserved for patients with ongoing symptoms or electrocardiogram findings suggestive of cardiac ischemia., (© 2024. The Author(s), under exclusive licence to the Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Background: Workplace mild traumatic brain injuries are frequently associated with persistent symptoms, leading to a reduction in productivity at work or even disability. People who sustain workplace injuries frequently need rehabilitation and support, and the challenges of delivering these services was heightened during the COVID-19 pandemic as injured workers had to be cared for remotely. Currently, clinicians are conducting both in-person and virtual (remote) concussion assessments; however, the measures that are being used to complete these assessments have undocumented psychometric properties., Objective: This study will document the psychometric properties of the clinical measures that are being used remotely and their ability to produce similar results to in-person assessments. Specifically, through this method-comparison study, we aim to (1) evaluate the sensitivity of the measures included in a virtual assessment toolkit when compared to an in-person assessment and (2) determine the interrater and intrarater reliabilities of the measures included in a virtual assessment toolkit., Methods: Patient participants (people living with acquired brain injuries) will attend two assessments (in person and virtual) at the Ottawa Hospital. The two assessments will be identical, consisting of the measures included in our previously developed virtual concussion assessment toolkit, which includes finger-to-nose testing, the Vestibular/Ocular Motor Screening tool, balance testing, cervical spine range of motion, saccades testing, and evaluation of effort. All virtual assessments will occur using the Microsoft Teams platform and will be audio/video-recorded. The clinician assessor and patient participant will complete a feedback form following completion of the assessments. A different clinician will also document the findings on observed videos of the virtual assessment shortly after completion of both in-person and virtual assessments and approximately 1 month later. Interrater reliability will be assessed by comparing the second clinician's observation with the first clinician's initial virtual assessment. Intrarater reliability will be evaluated by comparing the second clinician's observation with their own assessment approximately 1 month later. Sensitivity will be documented by comparing the findings (identification of abnormality) of the in-person assessment completed by the initial clinician assessor with those of the second clinician assessor on the observation of the recording of the virtual assessment., Results: As of May 2024, we have recruited 7 clinician assessors and completed study assessments with 39 patient participants. The study recruitment is expected to be completed by September 2024., Conclusions: Currently, it is unknown if completing concussion assessments virtually produces similar results to the in-person assessment. This work will serve as a first step to determining the similarity of the virtual assessment to the matching in-person assessment and will provide information on the reliability of the virtual assessment., International Registered Report Identifier (irrid): DERR1-10.2196/57663., (©Keely Barnes, Heidi Sveistrup, Mark Bayley, Michel Rathbone, Monica Taljaard, Mary Egan, Martin Bilodeau, Motahareh Karimijashni, Shawn Marshall. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.07.2024.)

Cluster-randomized trials (CRTs) often allocate intact clusters of participants to treatment or control conditions and are increasingly used to evaluate healthcare delivery interventions. While previous studies have developed sample size methods for testing confirmatory hypotheses of treatment effect heterogeneity in CRTs (i.e., targeting the difference between subgroup-specific treatment effects), sample size methods for testing the subgroup-specific treatment effects themselves have not received adequate attention-despite a rising interest in health equity considerations in CRTs. In this article, we develop formal methods for sample size and power analyses for testing subgroup-specific treatment effects in parallel-arm CRTs with a continuous outcome and a binary subgroup variable. We point out that the variances of the subgroup-specific treatment effect estimators and their covariance are given by weighted averages of the variance of the overall average treatment effect estimator and the variance of the heterogeneous treatment effect estimator. This analytical insight facilitates an explicit characterization of the requirements for both the omnibus test and the intersection-union test to achieve the desired level of power. Generalizations to allow for subgroup-specific variance structures are also discussed. We report on a simulation study to validate the proposed sample size methods and demonstrate that the empirical power corresponds well with the predicted power for both tests. The design and setting of the Umea Dementia and Exercise (UMDEX) CRT in older adults are used to illustrate our sample size methods., (© 2023. The Author(s).)

The cluster randomized crossover design has been proposed to improve efficiency over the traditional parallel-arm cluster randomized design. While statistical methods have been developed for designing cluster randomized crossover trials, they have exclusively focused on testing the overall average treatment effect, with little attention to differential treatment effects across subpopulations. Recently, interest has grown in understanding whether treatment effects may vary across pre-specified patient subpopulations, such as those defined by demographic or clinical characteristics. In this article, we consider the two-treatment two-period cluster randomized crossover design under either a cross-sectional or closed-cohort sampling scheme, where it is of interest to detect the heterogeneity of treatment effect via an interaction test. Assuming a patterned correlation structure for both the covariate and the outcome, we derive new sample size formulas for testing the heterogeneity of treatment effect with continuous outcomes based on linear mixed models. Our formulas also address unequal cluster sizes and therefore allow us to analytically assess the impact of unequal cluster sizes on the power of the interaction test in cluster randomized crossover designs. We conduct simulations to confirm the accuracy of the proposed methods, and illustrate their application in two real cluster randomized crossover trials., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To evaluate whether providing family physicians with feedback on their antibiotic prescribing compared with that of their peers reduces antibiotic prescriptions. To also identify effects on antibiotic prescribing from case-mix adjusted feedback reports and messages emphasising antibiotic associated harms., Design: Pragmatic, factorial randomised controlled trial., Setting: Primary care physicians in Ontario, Canada PARTICIPANTS: All primary care physicians were randomly assigned a group if they were eligible and actively prescribing antibiotics to patients 65 years or older. Physicians were excluded if had already volunteered to receive antibiotic prescribing feedback from another agency, or had opted out of the trial., Intervention: A letter was mailed in January 2022 to physicians with peer comparison antibiotic prescribing feedback compared with the control group who did not receive a letter (4:1 allocation). The intervention group was further randomised in a 2x2 factorial trial to evaluate case-mix adjusted versus unadjusted comparators, and emphasis, or not, on harms of antibiotics., Main Outcome Measures: Antibiotic prescribing rate per 1000 patient visits for patients 65 years or older six months after intervention. Analysis was in the modified intention-to-treat population using Poisson regression., Results: 5046 physicians were included and analysed: 1005 in control group and 4041 in intervention group (1016 case-mix adjusted data and harms messaging, 1006 with case-mix adjusted data and no harms messaging, 1006 unadjusted data and harms messaging, and 1013 unadjusted data and no harms messaging). At six months, mean antibiotic prescribing rate was 59.4 (standard deviation 42.0) in the control group and 56.0 (39.2) in the intervention group (relative rate 0.95 (95% confidence interval 0.94 to 0.96). Unnecessary antibiotic prescribing (0.89 (0.86 to 0.92)), prolonged duration prescriptions defined as more than seven days (0.85 (0.83 to 0.87)), and broad spectrum prescribing (0.94 (0.92 to 0.95)) were also significantly lower in the intervention group compared with the control group. Results were consistent at 12 months post intervention. No significant effect was seen for including emphasis on harms messaging. A small increase in antibiotic prescribing with case-mix adjusted reports was noted (1.01 (1.00 to 1.03))., Conclusions: Peer comparison audit and feedback letters significantly reduced overall antibiotic prescribing with no benefit of case-mix adjustment or harms messaging. Antibiotic prescribing audit and feedback is a scalable and effective intervention and should be a routine quality improvement initiative in primary care., Trial Registration: ClinicalTrials.gov NCT04594200., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding by the Canadian Institute for Health Research; JAL reports financial compensation for expert testimony by the Ontario Hospital Association, Ontario Ministry of the Attorney General, Seneca College and Choosing Wisely Canada. TG reports financial compensation from the Ontario Ministry of Health, Ontario College of Pharmacists, the Canadian Agency for Drugs and Technologies in Health, and Indigenous Services Canada. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

It is unclear what effect biological sex has on outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies. We searched MEDLINE and Embase for studies of intratracheal/intranasal/aerosolized lipopolysaccharide administration (the most common ALI model) that reported sex-stratified data. Screening and data extraction were conducted in duplicate. Our primary outcome was histological tissue injury and secondary outcomes included alveolar-capillary barrier alterations and inflammatory markers. We used a random-effects inverse variance meta-analysis, expressing data as standardized mean difference (SMD) with 95% confidence intervals (CIs). Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified six studies involving 132 animals across 11 independent experiments. A total of 41 outcomes were extracted, with the direction of effect suggesting greater severity in males than females in 26/41 outcomes (63%). One study reported on lung histology and found that male mice exhibited greater injury than females (SMD: 1.61, 95% CI: 0.53-2.69). Meta-analysis demonstrated significantly elevated albumin levels (SMD: 2.17, 95% CI: 0.63-3.70) and total cell counts (SMD: 0.80, 95% CI: 0.27-1.33) in bronchoalveolar lavage fluid from male mice compared with female mice. Most studies had an "unclear risk of bias." Our findings suggest sex-related differences in ALI severity. However, these conclusions are drawn from a small number of animals and studies. Further research is required to address the fundamental issue of biological sex differences in LPS-induced ALI.

Background: Acute heart failure (AHF) is a common emergency department (ED) presentation that may have poor outcomes but often does not require hospital admission. There is little evidence to guide dispositional decisions., Objectives: The authors sought to create a risk score for predicting short-term serious outcomes (SSO) in patients with AHF., Methods: We pooled data from 3 prospective cohorts: 2 published studies and 1 new cohort. The 3 cohorts prospectively enrolled patients who required treatment for AHF at 10 tertiary care hospital EDs. The primary outcome was SSO, defined as death <30 days, intubation or noninvasive ventilation (NIV), myocardial infarction, or relapse to ED <14 days. The logistic regression model evaluated 13 predictors, used an AIC-based step-down procedure, and bootstrapped internal validation., Results: Of the 2,246 patients in the 3 cohorts (N = 559; 1,100; 587), the mean age was 77.4 years, 54.5% were male, 3.1% received intravenous nitroglycerin, 5.2% received ED NIV, and 48.6% were admitted to the hospital. There were 281 (12.5%) SSOs including 70 deaths (3.1%) with many in discharged patients. The final HEARTRISK6 Scale included 6 variables: valvular heart disease, tachycardia, need for NIV, creatinine, troponin, and failed reassessment (walk test). Choosing HEARTRISK6 total-point admission thresholds of ≥1 or ≥2 would yield, respectively, sensitivities of 88.3% (95% CI: 83.9%-91.8%) and 71.5% (95% CI: 65.9%-76.7%) and specificities of 24.7% (95% CI: 22.8%-26.7%) and 50.1% (95% CI: 47.9%-52.4%) for SSO., Conclusions: Using 3 large prospectively collected datasets, we created a concise and sensitive risk scale for patients with AHF in the ED. Implementation of the HEARTRISK6 scale could lead to safer and more efficient disposition decisions., Competing Interests: This study was funded by a 10.13039/501100000024Canadian Institutes of Health Research (CIHR) Foundation grant held by IGS. The funding agency had no role in the study design, collection, analysis, or manuscript preparation. The study was sponsored by the 10.13039/100009519Ottawa Hospital Research Institute. Dr Perry is supported by a mid-career salary award from the Heart and Stroke Foundation of Ontario. Dr Rowe’s research is supported by a Scientific Director’s Grant (SOP 168483) from the CIHR (Ottawa, Ontario). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Multiple arterial grafting (MAG) and off-pump surgery are strategies proposed to improve outcomes with coronary artery bypass grafting (CABG). This study was conducted to determine the impact of off-pump surgery on outcomes after CABG with MAG in men and women., Methods: This cohort study used population-based data to identify all Ontarians undergoing isolated CABG with MAG between October 2008 and September 2019. The primary outcome was all-cause mortality. Secondary outcomes included major adverse cardiac and cerebrovascular events (MACCE; hospitalization for stroke, myocardial infarction hospitalization or heart failure, or repeat revascularization). Analysis used propensity-score overlap-weighted cause-specific Cox proportional hazard regression., Results: A total of 2989 women (1188 off-pump, 1801 on-pump) and 16,209 men (6065 off-pump, 10,144 on-pump) underwent MAG with a median follow-up of 5.0 years (interquartile range, 2.7-8.0) years. Compared to the on-pump approach, all-cause mortality was not changed with off-pump status (hazard ratio [HR] in women: 1.25 [95% CI, 0.83-1.88]; in men: 1.08 [95% CI, 0.85-1.37]). In women, the risk of MACCE was significantly higher off-pump (HR, 1.45; 95% CI, 1.04-2.03), with nonsignificantly increased risk observed for all component outcomes., Conclusions: In patients undergoing CABG with MAG, this population-based analysis found no association between pump status and survival in either men or women. However, it did suggest that off-pump MAG in women may be associated with an increased risk of MACCE., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Research teams are increasingly interested in using cluster randomized trial (CRT) designs to generate practice-guiding evidence for in-center maintenance hemodialysis. However, CRTs raise complex ethical issues. The Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials, published in 2012, provides 15 recommendations to address ethical issues arising within 7 domains: justifying the CRT design, research ethics committee review, identifying research participants, obtaining informed consent, gatekeepers, assessing benefits and harms, and protecting vulnerable participants. But applying the Ottawa Statement recommendations to CRTs in the hemodialysis setting is complicated by the unique features of the setting and population. Here, with the help of content experts and patient partners, we co-developed this implementation guidance document to provide research teams, research ethics committees, and other stakeholders with detailed guidance on how to apply the Ottawa Statement recommendations to CRTs in the hemodialysis setting, the result of a 4-year research project. Thus, our work demonstrates how the voices of patients, caregivers, and all stakeholders may be included in the development of research ethics guidance., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Recruiting participants to clinical trials is an ongoing challenge, and relatively little is known about what recruitment strategies lead to better recruitment. Recruitment interventions can be considered complex interventions, often involving multiple components, targeting a variety of groups, and tailoring to different groups. We used the Template for Intervention Description and Replication (TIDieR) reporting checklist (which comprises 12 items recommended for reporting complex interventions) to guide the assessment of how recruitment interventions are described. We aimed to (1) examine to what extent we could identify information about each TIDieR item within recruitment intervention studies, and (2) observe additional detail for each item to describe useful variation among these studies., Methods: We identified randomized, nested recruitment intervention studies providing recruitment or willingness to participate rates from two sources: a Cochrane review of trials evaluating strategies to improve recruitment to randomized trials, and the Online Resource for Research in Clinical triAls database. First, we assessed to what extent authors reported information about each TIDieR item. Second, we developed descriptive categorical variables for 7 TIDieR items and extracting relevant quotes for the other 5 items., Results: We assessed 122 recruitment intervention studies. We were able to extract information relevant to most TIDieR items (e.g., brief rationale, materials, procedure) with the exception of a few items that were only rarely reported (e.g., tailoring, modifications, planned/actual fidelity). The descriptive variables provided a useful overview of study characteristics, with most studies using various forms of informational interventions (55%) delivered at a single time point (90%), often by a member of the research team (59%) in a clinical care setting (41%)., Conclusions: Our TIDieR-based variables provide a useful description of the core elements of complex trial recruitment interventions. Recruitment intervention studies report core elements of complex interventions variably; some process elements (e.g., mode of delivery, location) are almost always described, while others (e.g., duration, fidelity) are reported infrequently, with little indication of a reason for their absence. Future research should explore whether these TIDieR-based variables can form the basis of an approach to better reporting of elements of successful recruitment interventions., (© 2024. The Author(s).)

Background/aims: The stepped-wedge cluster randomized trial (SW-CRT), in which clusters are randomized to a time at which they will transition to the intervention condition - rather than a trial arm - is a relatively new design. SW-CRTs have additional design and analytical considerations compared to conventional parallel arm trials. To inform future methodological development, including guidance for trialists and the selection of parameters for statistical simulation studies, we conducted a review of recently published SW-CRTs. Specific objectives were to describe (1) the types of designs used in practice, (2) adherence to key requirements for statistical analysis, and (3) practices around covariate adjustment. We also examined changes in adherence over time and by journal impact factor., Methods: We used electronic searches to identify primary reports of SW-CRTs published 2016-2022. Two reviewers extracted information from each trial report and its protocol, if available, and resolved disagreements through discussion., Results: We identified 160 eligible trials, randomizing a median (Q1-Q3) of 11 (8-18) clusters to 5 (4-7) sequences. The majority (122, 76%) were cross-sectional (almost all with continuous recruitment), 23 (14%) were closed cohorts and 15 (9%) open cohorts. Many trials had complex design features such as multiple or multivariate primary outcomes (50, 31%) or time-dependent repeated measures (27, 22%). The most common type of primary outcome was binary (51%); continuous outcomes were less common (26%). The most frequently used method of analysis was a generalized linear mixed model (112, 70%); generalized estimating equations were used less frequently (12, 8%). Among 142 trials with fewer than 40 clusters, only 9 (6%) reported using methods appropriate for a small number of clusters. Statistical analyses clearly adjusted for time effects in 119 (74%), for within-cluster correlations in 132 (83%), and for distinct between-period correlations in 13 (8%). Covariates were included in the primary analysis of the primary outcome in 82 (51%) and were most often individual-level covariates; however, clear and complete pre-specification of covariates was uncommon. Adherence to some key methodological requirements (adjusting for time effects, accounting for within-period correlation) was higher among trials published in higher versus lower impact factor journals. Substantial improvements over time were not observed although a slight improvement was observed in the proportion accounting for a distinct between-period correlation., Conclusions: Future methods development should prioritize methods for SW-CRTs with binary or time-to-event outcomes, small numbers of clusters, continuous recruitment designs, multivariate outcomes, or time-dependent repeated measures. Trialists, journal editors, and peer reviewers should be aware that SW-CRTs have additional methodological requirements over parallel arm designs including the need to account for period effects as well as complex intracluster correlations., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: Patients undergoing emergency general surgery are at high risk of complications and death. Our objectives were to estimate the incidence of emergency general surgery in a Swiss University Hospital, to describe the characteristics and outcomes of patients undergoing such procedures, and to study the impact of age on clinical outcomes., Methods: This was a retrospective cohort study of adult patients who visited the emergency department (ED) of Geneva University Hospitals between January 2015 and December 2019. Routinely collected data were extracted from electronic medical records. The primary outcome was the incidence of emergency general surgery among patients visiting the emergency department, defined as general surgery within three days of emergency department admission. We also assessed demographic characteristics, mortality, intensive care unit admission and patient disposition. Multivariable log-binomial regression was used to study the associations of age with intensive care unit (ICU) admission, one-year mortality and dependence at discharge. Age was modelled as a continuous variable using restricted cubic splines and we compared older patients (75th percentile) with younger patients (25th percentile)., Results: Between January 2015 and December 2019, a total of 310,914 emergency department visits met our inclusion criteria. Among them, 3592 patients underwent emergency general surgery within 3 days of emergency department admission, yielding an annual incidence of 116 events per 10,000 emergency department visits (95% CI: 112-119), with a higher incidence in females and young patients. Overall, 5.3% of patients were admitted to ICU, 7.8% were dependent on rehabilitation or assisted living at discharge and 4.8% were dead after one year. Older patients had a higher risk of ICU admission (adjusted risk ratio (aRR) 2.9 [1.5-5.4]), dependence at discharge (aRR 15.3 [5.5-42.4]) and one-year mortality (aRR 5.4 [2.2-13.4])., Conclusion: Emergency department visits resulting in emergency general surgery are frequent, but their incidence decreases with patient age. Mortality, ICU admission and dependence at discharge following emergency general surgery are more frequent in older patients. Taking into account the increased risk for older patients, a shared process is appropriate for making more informed decisions about their options for care.

Pakistan has among the highest rates of maternal, perinatal, and neonatal mortality globally. Many of these deaths are potentially preventable with low-cost, scalable interventions delivered through community-based health worker programs to the most remote communities. We conducted a cross-sectional survey of 10,264 households during the baseline phase of a cluster randomized controlled trial (cRCT) in Gilgit-Baltistan, Pakistan from June-August 2021. The survey was conducted through a stratified, two-stage sampling design with the objective of estimating the neonatal mortality rate (NMR) within the study catchment area, and informing implementation of the cRCT. Study outcomes were self-reported and included neonatal death, stillbirth, health facility delivery, maternal death, postpartum hemorrhage (PPH), and Lady Health Worker (LHW) coverage. Summary statistics (proportions and rates) were weighted according to the sampling design, and mixed-effects Poisson regression was conducted to explore the relationship between LHW coverage and maternal/newborn outcomes. We identified 7,600 women who gave birth in the past five years, among whom 13% reported experiencing PPH. The maternal mortality ratio was 225 maternal deaths per 100,000 live births (95% confidence interval [CI] 137-369). Among 12,376 total births, the stillbirth rate was 41.4 per 1,000 births (95% CI 36.8-46.7) and the perinatal mortality rate was 53.0 per 1,000 births (95% CI 47.6-59.0). Among 11,863 live births, NMR was 16.2 per 1,000 live births (95% CI 13.6-19.3) and 65% were delivered at a health facility. LHW home visits were associated with declines in PPH (risk ratio [RR] 0.89 per each additional visit, 95% CI 0.83-0.96) and late neonatal mortality (RR 0.80, 95% CI 0.67-0.97). Intracluster correlation coefficients were also estimated to inform the planning of future trials. The high rates of maternal, perinatal, and neonatal death in Gilgit-Baltistan continue to fall behind targets of the 2030 Sustainable Development Goals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Farrar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Childhood cancer treatment while often curative, leads to elevated risks of morbidity and mortality. Survivors require lifelong periodic surveillance for late effects of treatment, yet adherence to guideline-recommended tests is suboptimal. We created ONLOOP to provide adult survivors of childhood cancer with detailed health information, including summaries of their childhood cancer treatment and recommended surveillance tests for early detection of cardiomyopathy, breast cancer, and/or colorectal cancer, with personalized reminders over time., Methods: This is an individually randomized, registry-based pragmatic trial with an embedded process and economic evaluation to understand ONLOOP's impact and whether it can be readily implemented at scale. All adult survivors of childhood cancer in Ontario overdue for guideline-recommended tests will be randomly assigned to one of two arms: (1) intervention or (2) delayed intervention. A letter of information and invitation will detail the ONLOOP program. Those who sign up will receive a personalized toolkit and a screening reminder 6 months later. With the participants' consent, ONLOOP will also send their primary care clinician a letter detailing the recommended tests and a reminder 6 months later. The primary outcome will be the proportion of survivors who complete one or more of the guideline-recommended cardiac, breast, or colon surveillance tests during the 12 months after randomization. Data will be obtained from administrative databases. The intent-to-treat principle will be followed. Based on our analyses of administrative data, we anticipate allocating at least 862 individuals to each trial arm, providing 90% power to detect an absolute increase of 6% in targeted surveillance tests completed. We will interview childhood cancer survivors and family physicians in an embedded process evaluation to examine why and how ONLOOP achieved success or failed. A cost-effectiveness evaluation will be performed., Discussion: The results of this study will determine if ONLOOP is effective at helping adult survivors of childhood cancer complete their recommended surveillance tests. This study will also inform ongoing provincial programs for this high-risk population., Trial Registration: ClinicalTrials.gov NCT05832138., (© 2024. The Author(s).)

Background: The Interrupted Time Series (ITS) is a robust design for evaluating public health and policy interventions or exposures when randomisation may be infeasible. Several statistical methods are available for the analysis and meta-analysis of ITS studies. We sought to empirically compare available methods when applied to real-world ITS data., Methods: We sourced ITS data from published meta-analyses to create an online data repository. Each dataset was re-analysed using two ITS estimation methods. The level- and slope-change effect estimates (and standard errors) were calculated and combined using fixed-effect and four random-effects meta-analysis methods. We examined differences in meta-analytic level- and slope-change estimates, their 95% confidence intervals, p-values, and estimates of heterogeneity across the statistical methods., Results: Of 40 eligible meta-analyses, data from 17 meta-analyses including 282 ITS studies were obtained (predominantly investigating the effects of public health interruptions (88%)) and analysed. We found that on average, the meta-analytic effect estimates, their standard errors and between-study variances were not sensitive to meta-analysis method choice, irrespective of the ITS analysis method. However, across ITS analysis methods, for any given meta-analysis, there could be small to moderate differences in meta-analytic effect estimates, and important differences in the meta-analytic standard errors. Furthermore, the confidence interval widths and p-values for the meta-analytic effect estimates varied depending on the choice of confidence interval method and ITS analysis method., Conclusions: Our empirical study showed that meta-analysis effect estimates, their standard errors, confidence interval widths and p-values can be affected by statistical method choice. These differences may importantly impact interpretations and conclusions of a meta-analysis and suggest that the statistical methods are not interchangeable in practice., (© 2024. The Author(s).)

Cluster randomized trials are an essential design in public health and medical research, when individual randomization is infeasible or undesirable for scientific or logistical reasons. However, the correlation among observations within clusters leads to a decrease in statistical power compared to an individually randomised trial with the same total sample size. This correlation - often quantified using the intra-cluster correlation coefficient - must be accounted for in the sample size calculation to ensure that the trial is adequately powered. In this paper, we first describe the principles of sample size calculation for parallel-arm CRTs, and explain how these calculations can be extended to CRTs with cross-over designs, with a baseline measurement and stepped-wedge designs. We introduce tools to guide researchers with their sample size calculation and discuss methods to inform the choice of the a priori estimate of the intra-cluster correlation coefficient for the calculation. We also include additional considerations with respect to anticipated attrition, a small number of clusters, and use of covariates in the randomisation process and in the analysis., Competing Interests: Declaration of Competing Interest None of the authors have conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

A cluster randomized trial is defined as a randomized trial in which intact social units of individuals are randomized rather than individuals themselves. Outcomes are observed on individual participants within clusters (such as patients). Such a design allows assessing interventions targeting cluster-level participants (such as physicians), individual participants or both. Indeed, many interventions assessed in cluster randomized trials are actually complex ones, with distinct components targeting different levels. For a cluster-level intervention, cluster randomization is an obvious choice: the intervention is not divisible at the individual-level. For individual-level interventions, cluster randomization may nevertheless be suitable to prevent group contamination, for logistical reasons, to enhance participants' adherence, or when objectives pertain to the cluster level. An unacceptable reason for cluster randomization would be to avoid obtaining individual consent. Indeed, participants in cluster randomized trials have to be protected as in any type of trial design. Participants may be people from whom data are collected, but they may also be people who are intervened upon, and this includes both patients and physicians (for example, physicians receiving training interventions). Consent should be sought as soon as possible, although there may exist situations where participants may consent only for data collection, not for being exposed to the intervention (because, for instance, they cannot opt-out). There may even be situations where participants are not able to consent at all. In this latter situation a waiver of consent must be granted by a research ethics committee., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions., Methods: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care., Results: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30)., Conclusion: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population., Patient or Public Contribution: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination., (© 2023 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits., Methods: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death., Results: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated., Conclusions: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented., (© 2024. The Author(s).)

Background: New classes of long-lasting insecticidal nets (LLINs) containing two active ingredients have been recently recommended by WHO in areas where malaria vectors are resistant to pyrethroids. This policy was based on evidence generated by the first 2 years of our recently published trial in Tanzania. In this Article, we report the final third-year trial findings, which are necessary for assessing the long-term effectiveness of new classes of LLIN in the community and the replacement intervals required., Methods: A third year of follow-up of a four-arm, single-blind, cluster-randomised controlled trial of dual active ingredient LLINs was conducted between July 14, 2021, and Feb 10, 2022, in Misungwi, Tanzania. Restricted randomisation was used to assign 84 clusters to the four LLIN groups (1:1:1:1) to receive either standard pyrethroid (PY) LLINs (reference), chlorfenapyr-PY LLINs, pyriproxyfen-PY LLINs, or piperonyl butoxide (PBO)-PY LLINs. All households received one LLIN for every two people. Data collection was done in consenting households in the cluster core area with at least one child between 6 months and 15 years of age who permanently resided in the selected household. Exclusion criteria were householders absent during the visit, living in the cluster buffer area, no adult caregiver capable of giving informed consent, or eligible children who were severely ill. Field staff and study participants were masked to allocation, and those analysing data were not. The primary 24-month endpoint was reported previously; here, we present the secondary outcome, malaria infection prevalence in children at 36 months post LLIN distribution, reported in the intention-to-treat analysis. The trial was registered with ClinicalTrials.gov (NCT03554616) and is now complete., Findings: Overall usage of study nets was 1023 (22·3%) of 4587 people at 36 months post distribution. In the standard PY LLIN group, malaria infection was prevalent in 407 (37·4%) of 1088 participants, compared with 261 (22·8%) of 1145 in the chlorfenapyr-PY LLIN group (odds ratio 0·57, 95% CI 0·38-0·86; p=0·0069), 338 (32·2%) of 1048 in the PBO-PY LLIN group (0·95, 0·64-1·42; p=0·80), and 302 (28·8%) of 1050 in the pyriproxyfen-PY LLIN group (0·82, 0·55-1·23; p=0·34). None of the participants or caregivers reported side-effects., Interpretation: Despite low coverage, the protective efficacy against malaria offered by chlorfenapyr-PY LLINs was superior to that provided by standard PY LLINs over a 3-year LLIN lifespan. Appropriate LLIN replacement strategies to maintain adequate usage of nets will be necessary to maximise the full potential of these nets., Funding: Department for International Development, UK Medical Research Council, Wellcome Trust, Department of Health and Social Care, and Bill & Melinda Gates Foundation via the Innovative Vector Control Consortium., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Ongoing high neonatal mortality rates (NMRs) represent a global challenge. In 2021, of the 5 million deaths reported worldwide for children under five years of age, 47% were newborns. Pakistan has one of the five highest national NMRs in the world, with an estimated 39 neonatal deaths per 1,000 live births. Reducing newborn deaths requires sustainable, evidence-based, and cost-effective interventions that can be integrated within existing community healthcare infrastructure across regions with high NMR., Methods: This pragmatic, community-based, parallel-arm, open-label, cluster randomized controlled trial aims to estimate the effect of Lady Health Workers (LHWs) providing an integrated newborn care kit (iNCK) with educational instructions to pregnant women in their third trimester, compared to the local standard of care in Gilgit-Baltistan, Pakistan, on neonatal mortality and other newborn and maternal health outcomes. The iNCK contains a clean birth kit, 4% chlorhexidine topical gel, sunflower oil emollient, a ThermoSpot™ temperature monitoring sticker, a fleece blanket, a click-to-heat reusable warmer, three 200 μg misoprostol tablets, and a pictorial instruction guide and diary. LHWs are also provided with a handheld scale to weigh the newborn. The primary study outcome is neonatal mortality, defined as a newborn death in the first 28 days of life., Discussion: This study will generate policy-relevant knowledge on the effectiveness of integrating evidence-based maternal and newborn interventions and delivering them directly to pregnant women via existing community health infrastructure, for reducing neonatal mortality and morbidity, in a remote, mountainous area with a high NMR., Trial Registration: NCT04798833, March 15, 2021., (© 2023. The Author(s).)

Objective: To investigate whether a Bayesian interpretation might help prevent misinterpretation of statistical findings and support authors to differentiate evidence of no effect from statistical uncertainty., Design: A Bayesian re-analysis to determine posterior probabilities of clinically important effects (e.g., a large effect is set at a 4 percentage point difference and a trivial effect to be within a 0.5 percentage point difference). Posterior probabilities greater than 95% are considered as strong statistical evidence, and less than 95% as inconclusive., Sample: 150 major women's health trials with binary outcomes., Main Outcome Measures: Posterior probabilities of large, moderate, small and trivial effects., Results: Under frequentist methods, 48 (32%) were statistically significant (p-value ≤ 0.05) and 102 (68%) statistically non-significant. The frequentist and Bayesian point estimates and confidence intervals showed strong concordance. Of the statistically non-significant trials (n = 102), the Bayesian approach classified the majority (94, 92%) as inconclusive, neither able to confirm or refute effectiveness. A small number of statistically non-significant findings (8, 8%) were classified as having strong statistical evidence of an effect., Conclusions: Whilst almost all trials report confidence intervals, in practice most statistical findings are interpreted on the basis of statistical significance, mostly concluding evidence of no effect. Findings here suggest the majority are likely uncertain. A Bayesian approach could help differentiate evidence of no effect from statistical uncertainty., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objectives: Children and families are increasingly involved as equal partners in child health research, however, considerations around authorship have received little attention and there is limited guidance on the topic. Our objective was to determine the frequency and nature of patient partner authorship and/or acknowledgment among articles focused on patient engagement in child health research., Study Design and Setting: In this umbrella review, we searched MEDLINE, Embase, APA PsycINFO, Cochrane Database of Systematic Reviews, CINAHL, and Web of Science for systematic/scoping reviews on patient engagement in child health research. Individual articles included in eligible reviews comprised the sample of articles for analysis and were examined to identify patient partner authorship. Descriptive statistics were used to quantify patient partner authorship and/or acknowledgment and to summarize article characteristics., Results: Twelve systematic/scoping reviews met eligibility criteria, from which 230 individual articles were examined. In 16/230 (7%) articles, there was at least one patient partner author, and in 6/230 (3%) articles, patient partners were included as group authors. Within article Acknowledgments sections, patient partners were acknowledged by name in 41/230 (18%) articles, and anonymously or as a group in 98/230 (43%) articles. Patient partner authorship and/or acknowledgment was more frequent among articles published more recently (after 2015) and among articles where patient engagement was explicitly reported in the article., Conclusion: Patient partners were more likely to be acknowledged than listed as an author on articles on patient engagement in child health research. Understanding patient partner preferences about authorship and acknowledgment, examination of the unique aspects of child and youth authorship and developing supports to empower patient partner authorship are needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: We offered a practice facilitation intervention to family physicians in Ontario, Canada, known to have large numbers of patients not yet vaccinated against coronavirus disease 2019 (COVID-19)., Methods: We conducted a multimethod process evaluation embedded within a randomized controlled trial (clinical trial #NCT05099497). We collected descriptive statistics regarding engagement and qualitative interview data from family physicians and practice facilitators, as well as data from facilitator field notes. We analyzed and triangulated the data using thematic analysis and mapped barriers to and enablers for implementation to structural, organizational, physician, and patient factors., Results: Of the 300 approached, 90 family physicians (30%) accepted facilitation. Of these, 57% received technical support to identify unvaccinated patients, 29% used trained medical student volunteers to contact patients on their behalf, and 30% used automated calling to reach patients. Key factors affecting engagement with the intervention were staff shortages owing to COVID-19 (structural), clinic characteristics such as technical issues and gatekeeping by staff, which prevented facilitators from talking with physicians (organizational), burnout (physician), and specialized populations that required targeted resources (patient). The facilitator's ability to address technical issues and connect family physicians with medical students helped with engagement., Conclusions: Strategies to help underresourced family physicians serving high-needs populations for issues of public health importance, such as vaccine promotion, must acknowledge the scarcity of physicians' time and provide new resources. To successfully engage family physicians, practice facilitators should seek to build trust and relationships over time, including with front-office staff., (© 2023 Annals of Family Medicine, Inc.)

Background: Older trauma patients have a higher mortality yet are more likely to be under-triaged compared to younger patients. Studies have suggested that current trauma team activation criteria are suboptimal for older patients., Objectives: The objective was to describe trauma care delivered, patient outcomes, and to identify variables independently associated with mortality., Methods: We performed a health records review from 2014 to 2020 of older (age ≥ 65 years) trauma patients presenting to a level one trauma centre with any of the following: injury severity score (ISS) > 12, and all trauma team activations or admission to the trauma ward. The primary outcome was 30-day all-cause mortality. Secondary outcomes included injury mechanism and trauma care delivered. Multivariable logistic regression was used to identify factors independently associated with 30-day all-cause mortality. Multiple imputation was used to deal with missing data., Results: We enrolled 1,380 patients (mean age 80 years, mean ISS 18); 26.8% had multimorbidity (≥ 2 chronic conditions) and 65.9% met criteria for polypharmacy (≥ 5 medications). The most common mechanism was fall from standing height (61.1%). Thirty-day all-cause mortality occurred in 239 (17.3%) patients. A Glasgow coma scale (GCS) < 15 (odds ratio [OR] = 5.55; 95% CI 3.73-8.24), ISS > 15 (OR = 3.75, 95% CI 2.35-6.01), age ≥ 85 years (OR = 2.04, 95% CI 1.29-3.22), anticoagulation with a direct oral anticoagulant (DOAC) or warfarin (OR = 1.59, 95% CI 1.08-2.35) and multimorbidity (OR = 1.53, 95% CI 1.06-2.22) were significantly associated with increased risk 30-day mortality (C-statistic = 0.82, 95% CI 0.79-0.85). Dementia (OR = 0.61, 95% CI 0.40-0.95) and time to CT scan > 60 min (OR = 0.50, 95% CI 0.34-0.74) were associated with decreased mortality risk., Conclusion: We identified five factors associated with increased 30-day mortality in older trauma patients: GCS < 15, ISS > 15, age ≥ 85 years, anticoagulation, and multimorbidity. These factors should be considered when developing modified trauma team activation criteria for older adults., (© 2023. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

A frequently applied assumption in the analysis of data from cluster randomised trials is that the outcomes from all participants within a cluster are equally correlated. That is, the intracluster correlation, which describes the degree of dependence between outcomes from participants in the same cluster, is the same for each pair of participants in a cluster. However, recent work has discussed the importance of allowing for this correlation to decay as the time between the measurement of participants in a cluster increases. Incorrect omission of such a decay can lead to under-powered studies, and confidence intervals for estimated treatment effects can be too narrow or too wide, depending on the characteristics of the design. When planning studies, researchers often rely on previously reported analyses of trials to inform their choice of intracluster correlation. However, most reported analyses of clustered data do not incorporate a correlation decay. Thus, often all that is available are estimates of intracluster correlations obtained under the potentially incorrect assumption of no decay. In this article, we show that it is possible to use intracluster correlation values obtained from models that incorrectly omit a decay to inform plausible choices of decaying correlations. Our focus is on intracluster correlation estimates for continuous outcomes obtained by fitting linear mixed models with exchangeable or block-exchangeable correlation structures. We describe how plausible values for decaying correlations may be obtained given these estimated intracluster correlations. An online app is presented that allows users to obtain plausible values of the decay, which can be used at the trial planning stage to assess the sensitivity of sample size and power calculations to decaying correlation structures., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Interrupted time series (ITS) are often meta-analysed to inform public health and policy decisions but examination of the statistical methods for ITS analysis and meta-analysis in this context is limited. We simulated meta-analyses of ITS studies with continuous outcome data, analysed the studies using segmented linear regression with two estimation methods [ordinary least squares (OLS) and restricted maximum likelihood (REML)], and meta-analysed the immediate level- and slope-change effect estimates using fixed-effect and (multiple) random-effects meta-analysis methods. Simulation design parameters included varying series length; magnitude of lag-1 autocorrelation; magnitude of level- and slope-changes; number of included studies; and, effect size heterogeneity. All meta-analysis methods yielded unbiased estimates of the interruption effects. All random effects meta-analysis methods yielded coverage close to the nominal level, irrespective of the ITS analysis method used and other design parameters. However, heterogeneity was frequently overestimated in scenarios where the ITS study standard errors were underestimated, which occurred for short series or when the ITS analysis method did not appropriately account for autocorrelation. The performance of meta-analysis methods depends on the design and analysis of the included ITS studies. Although all random effects methods performed well in terms of coverage, irrespective of the ITS analysis method, we recommend the use of effect estimates calculated from ITS methods that adjust for autocorrelation when possible. Doing so will likely to lead to more accurate estimates of the heterogeneity variance., (© 2023 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.)

Background: Normal saline (NS) and Ringer's lactate (RL) are the most common crystalloids given to hospitalized patients. Despite concern about possible harm associated with NS (eg, hyperchloremic metabolic acidosis, impaired kidney function, and death), few large multicenter randomized trials focused on critically ill patients have compared these fluids. Uncertainty exists about the effects of these fluids on clinically important outcomes across all hospitalized patients., Objective: The FLUID trial is a pragmatic, multicenter, 2×2 cluster crossover comparative effectiveness randomized trial that aims to evaluate the effectiveness of a hospital-wide policy that stocks either NS or RL as the main crystalloid fluid in 16 hospitals across Ontario, Canada., Methods: All hospitalized adult and pediatric patients (anticipated sample size 144,000 patients) with an incident admission to the hospital over the course of each study period will be included. Either NS or RL will be preferentially stocked throughout the hospital for 12 weeks before crossing to the alternate fluid for the subsequent 12 weeks. The primary outcome is a composite of death and hospital readmission within 90 days of hospitalization. Secondary outcomes include death, hospital readmission, dialysis, reoperation, postoperative reintubation, length of hospital stay, emergency department visits, and discharge to a facility other than home. All outcomes will be obtained from health administrative data, eliminating the need for individual case reports. The primary analysis will use cluster-level summaries to estimate cluster-average treatment effects., Results: The statistical analysis plan has been prepared "a priori" in advance of receipt of the trial data set from ICES and any analyses., Conclusions: We describe the protocol and statistical analysis plan for the evaluation of primary and secondary outcomes for the FLUID trial., Trial Registration: ClinicalTrials.gov NCT04512950; https://classic.clinicaltrials.gov/ct2/show/NCT04512950., International Registered Report Identifier (irrid): DERR1-10.2196/51783., (©Julia F Shaw, Yongdong Ouyang, Dean A Fergusson, Tracy McArdle, Claudio Martin, Deborah Cook, Ian D Graham, Steven Hawken, Colin J L McCartney, Kusum Menon, Raphael Saginur, Andrew Seely, Ian Stiell, Alison Fox-Robichaud, Shane English, John Marshall, Kednapa Thavorn, Monica Taljaard, Lauralyn A McIntyre, Canadian Critical Care Trials Group. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 06.10.2023.)

It is well-known that designing a cluster randomized trial (CRT) requires an advance estimate of the intra-cluster correlation coefficient (ICC). In the case of longitudinal CRTs, where outcomes are assessed repeatedly in each cluster over time, estimates for more complex correlation structures are required. Three common types of correlation structures for longitudinal CRTs are exchangeable, nested/block exchangeable and exponential decay correlations-the latter two allow the strength of the correlation to weaken over time. Determining sample sizes under these latter two structures requires advance specification of the within-period ICC and cluster autocorrelation coefficient as well as the intra-individual autocorrelation coefficient in the case of a cohort design. How to estimate these coefficients is a common challenge for investigators. When appropriate estimates from previously published longitudinal CRTs are not available, one possibility is to re-analyse data from an available trial dataset or to access observational data to estimate these parameters in advance of a trial. In this tutorial, we demonstrate how to estimate correlation parameters under these correlation structures for continuous and binary outcomes. We first introduce the correlation structures and their underlying model assumptions under a mixed-effects regression framework. With practical advice for implementation, we then demonstrate how the correlation parameters can be estimated using examples and we provide programming code in R, SAS, and Stata. An Rshiny app is available that allows investigators to upload an existing dataset and obtain the estimated correlation parameters. We conclude by identifying some gaps in the literature., (© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Not only do cluster randomized trials require a larger sample size than individually randomized trials, they also face many additional complexities. The potential for contamination is the most commonly used justification for using cluster randomization, but the risk of contamination should be carefully weighed against the more serious problem of questionable scientific validity in settings with post-randomization identification or recruitment of participants unblinded to the treatment allocation. In this paper we provide some simple guidelines to help researchers conduct cluster trials in a way that minimizes potential biases and maximizes statistical efficiency. The overarching theme of this guidance is that methods that apply to individually randomized trials rarely apply to cluster randomized trials. We recommend that cluster randomization be only used when necessary-balancing the benefits of cluster randomization with its increased risks of bias and increased sample size. Researchers should also randomize at the lowest possible level-balancing the risks of contamination with ensuring an adequate number of randomization units-as well as exploring other options for statistically efficient designs. Clustering should always be allowed for in the sample size calculation; and the use of restricted randomization (and adjustment in the analysis for covariates used in the randomization) should be considered. Where possible, participants should be recruited before randomizing clusters and, when recruiting (or identifying) participants post-randomization, recruiters should be masked to the allocation. In the analysis, the target of inference should align with the research question, and adjustment for clustering and small sample corrections should be used when the trial includes less than about 40 clusters., (© The Author(s) 2023. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: We developed the Canadian Syncope Pathway (CSP) based on the Canadian Syncope Risk Score (CSRS) to aid emergency department (ED) syncope management. This pilot implementation study assessed patient inclusion, length of transition period, as well as process measures (engagement, reach, adoption, and fidelity) to prepare for multicenter implementation., Methods: A non-randomized stepped wedge trial at two hospitals was conducted over a 7-month period. After 2-3 months in the control condition, the hospitals crossed over in a stepwise fashion to the intervention condition. Study participants were ED and non-ED physicians, or their delegates, and patients (aged ≥ 18 years) with syncope. We aimed to analyze patient characteristics, ED management including disposition decision, and CSRS recommendations application for all eligible patients during the intervention period. Our targets were 95% inclusion rate, 70% adoption (proportion of physicians who applied the pathway), 60% reach (intervention applied to eligible patients) and 70% fidelity (appropriate recommendations application) for all eligible patients. Clinical Trials registration NCT04790058., Results: 1002 eligible patients (mean age 56.6 years; 51.0% males) were included: 349 patients during the control and 653 patients during the intervention period. Physician engagement varied from 39.7% to 97.1% for presentation at meetings. Process measures for the first month and the end of the intervention were: adoption 70.7% (58/82) and 84.4% (103/122), reach 67.5% (108/160) and 55.0% (359/653), fidelity among patients with physician data form completion 86.3% (88/102) and 88.3% (294/333), versus fidelity among all eligible patients 83.8% (134/160) and 83.3% (544/653) respectively with no significant differences in fidelity at one month and the end of the intervention period., Conclusion: In this pilot study, we achieved all prespecified benchmarks for proceeding to the multicenter CSP implementation except reach. Our results indicate a 1-month transition period will be adequate though regular reminders will be needed during full-scale implementation., (© 2023. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Background: There are few data on patient and public involvement (PPI) in pragmatic trials. We aimed to describe the prevalence and nature of PPI within pragmatic trials, describe variation in prevalence of PPI by trial characteristics and compare prevalence of PPI reported by trial authors to that reported in trial publications., Methods: We applied a search filter to identify pragmatic trials published from 2014 to 2019 in MEDLINE. We invited the corresponding authors of pragmatic trials to participate in an online survey about their specific trial., Results: Of 3163 authors invited, 2585 invitations were delivered, 710 (27.5%) reported on 710 unique trials and completed the survey; 334 (47.0%) conducted PPI. Among those who conducted PPI, for many the aim was to increase the research relevance (86.3%) or quality (76.5%). Most PPI partners were engaged at protocol development stages (79.1%) and contributed to the co-design of interventions (70.9%) or recruitment or retention strategies (60.5%). Patient and public involvement was more common among trials involving children, trials conducted in the United Kingdom, cluster randomized trials, those explicitly labelled as "pragmatic" in the study manuscript, and more recent trials. Less than one-quarter of trials (22.8%) that reported PPI in the survey also reported PPI in the trial manuscript., Interpretation: Nearly half of trialists in this survey reported conducting PPI and listed several benefits of doing so, but researchers who did not conduct PPI often cited a lack of requirement for it. Patient and public involvement appears to be significantly underreported in trial publications. Consistent and standardized reporting is needed to promote transparency about PPI methods, outcomes, challenges and benefits., Competing Interests: Competing interests: Charles Weijer reports receiving consulting fees from Cardialen and Eli Lilly & Company. Shelley Vanderhout reports receiving a Postdoctoral Fellowship Award and a System Impact Fellowship Award from the Canadian Institutes of Health Research (in support of the current manuscript). Anne Spinewine reports receiving a Mobility Grant from Fondation Mont-Godinne. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

An important consideration in the design and analysis of randomized trials is the need to account for outcome observations being positively correlated within groups or clusters. Two notable types of designs with this consideration are individually randomized group treatment trials and cluster randomized trials. While sample size methods for testing the average treatment effect are available for both types of designs, methods for detecting treatment effect modification are relatively limited. In this article, we present new sample size formulas for testing treatment effect modification based on either a univariate or multivariate effect modifier in both individually randomized group treatment and cluster randomized trials with a continuous outcome but any types of effect modifier, while accounting for differences across study arms in the outcome variance, outcome intracluster correlation coefficient (ICC) and the cluster size. We consider cases where the effect modifier can be measured at either the individual level or cluster level, and with a univariate effect modifier, our closed-form sample size expressions provide insights into the optimal allocation of groups or clusters to maximize design efficiency. Overall, our results show that the required sample size for testing treatment effect heterogeneity with an individual-level effect modifier can be affected by unequal ICCs and variances between arms, and accounting for such between-arm heterogeneity can lead to more accurate sample size determination. We use simulations to validate our sample size formulas and illustrate their application in the context of two real trials: an individually randomized group treatment trial (the AWARE study) and a cluster randomized trial (the K-DPP study)., (© 2023 John Wiley & Sons Ltd.)

Background: Uncontrolled bleeding is a common cause of preventable mortality in trauma. While it is intuitive that delays to hemostasis may lead to worse outcomes, the impacts of these delays remain incompletely explored. This systematic review aimed to characterize the extant definitions of delayed hemostatic intervention and to quantify the impacts of delays on clinical outcomes., Methods: We searched EMBASE, MEDLINE, and Web of Science from inception to August 2022. Studies defining "delayed intervention" and those comparing times to intervention among adults presenting to hospital with blunt or penetrating injuries who required major hemostatic intervention were eligible. The coprimary outcomes were mortality and the definition of delay to hemostasis used. Secondary outcomes included units of packed red blood cells received, length of stay in hospital, and length of stay in intensive care., Results: We identified 2,050 studies, with 24 studies including 10,168 patients meeting the inclusion criteria. The majority of studies were retrospective observational cohort studies, and most were at high risk of bias. A variety of injury patterns and hemostatic interventions were considered, with 69.6% of studies reporting a statistically significant impact of increased time to intervention on mortality. Definitions of delayed intervention ranged from 10 minutes to 4 hours. Conflicting data were reported for impact of time on receipt of blood products, while one study found a significant impact on intensive care length of stay. No studies assessed length of stay in hospital., Conclusion: The extant literature is heterogeneous with respect to injuries included, methods of hemostasis employed, and durations of delay examined. While the majority of the included studies demonstrated a statistically significant relationship between time to intervention and mortality, an evidence-informed definition of delayed intervention for bleeding trauma patients at large has not been solidified. In addition, standardized research is needed to establish targets, which could reduce morbidity and mortality., Level of Evidence: Systematic Review; Level IV., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Health behaviors such as physical inactivity, unhealthy eating, smoking tobacco, and alcohol use are each leading risk factors for non-communicable chronic disease. Better understanding which behaviors tend to co-occur (i.e., cluster together) and co-vary (i.e., are correlated) may provide novel opportunities to develop more comprehensive interventions to promote multiple health behavior change. However, whether co-occurrence or co-variation-based approaches are better suited for this task remains relatively unknown., Purpose: To compare the utility of co-occurrence vs. co-variation-based approaches for understanding the interconnectedness between multiple health-impacting behaviors., Methods: Using baseline and follow-up data (N = 40,268) from the Canadian Longitudinal Study of Aging, we examined the co-occurrence and co-variation of health behaviors. We used cluster analysis to group individuals based on their behavioral tendencies across multiple behaviors and to examine how these clusters are associated with demographic characteristics and health indicators. We compared outputs from cluster analysis to behavioral correlations and compared regression analyses of clusters and individual behaviors predicting future health outcomes., Results: Seven clusters were identified, with clusters differentiated by six of the seven health behaviors included in the analysis. Sociodemographic characteristics varied across several clusters. Correlations between behaviors were generally small. In regression analyses individual behaviors accounted for more variance in health outcomes than clusters., Conclusions: Co-occurrence-based approaches may be more suitable for identifying sub-groups for intervention targeting while co-variation approaches are more suitable for building an understanding of the relationships between health behaviors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Behavioral Medicine.)

Background: Induction at 38-40 weeks of gestation has been broadly suggested for women with gestational diabetes mellitus (GDM), yet its benefits and risks remain unclear. This study aimed to systematically review and meta-analyze existing evidence on the effect of induction at term gestation among women with GDM., Methods: We searched MEDLINE, EMBASE, Cochrane Libraries, and Web of Science from inception to June 2021. We included randomized controlled trials (RCTs) and observational studies comparing induction with expectant management among GDM term pregnancies. Primary outcomes included caesarean section (CS) and macrosomia. All screening and extraction were conducted independently and in duplicates. Meta-analyses with random-effects models were conducted to generate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) using the Mantel-Haenszel method. Methodological quality was assessed independently by two reviewers using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale for observational studies., Results: Of the 4,791 citations, 11 studies were included (3 RCTs and 8 observational studies). Compared to expectant management, GDM women with induction had a significantly lower odds for macrosomia (RCTs 0.49 [0.30-0.81]); observational studies 0.64 [0.54-0.77]), but not for CS (RCTs 0.95 [0.64-1.43]); observational studies 1.03 [0.79-1.34]). Induction was associated with a lower odds of severe perineal lacerations in observational studies (0.59 [0.39-0.88]). No significant difference was observed for other maternal or neonatal morbidities, or perinatal mortality between groups., Conclusions: For GDM women, induction may reduce the risk of macrosomia and severe perineal lacerations compared to expectant management. Further rigorous studies with large sample sizes are warranted to better inform clinical implications., (© 2023. The Author(s).)

Background: While simple Audit & Feedback (A&F) has shown modest effectiveness in reducing low-value care, there is a knowledge gap on the effectiveness of multifaceted interventions to support de-implementation efforts. Given the need to make rapid decisions in a context of multiple diagnostic and therapeutic options, trauma is a high-risk setting for low-value care. Furthermore, trauma systems are a favorable setting for de-implementation interventions as they have quality improvement teams with medical leadership, routinely collected clinical data, and performance-linked to accreditation. We aim to evaluate the effectiveness of a multifaceted intervention for reducing low-value clinical practices in acute adult trauma care., Methods: We will conduct a pragmatic cluster randomized controlled trial (cRCT) embedded in a Canadian provincial quality assurance program. Level I-III trauma centers (n = 30) will be randomized (1:1) to receive simple A&F (control) or a multifaceted intervention (intervention). The intervention, developed using extensive background work and UK Medical Research Council guidelines, includes an A&F report, educational meetings, and facilitation visits. The primary outcome will be the use of low-value initial diagnostic imaging, assessed at the patient level using routinely collected trauma registry data. Secondary outcomes will be low-value specialist consultation, low-value repeat imaging after a patient transfer, unintended consequences, determinants for successful implementation, and incremental cost-effectiveness ratios., Discussion: On completion of the cRCT, if the intervention is effective and cost-effective, the multifaceted intervention will be integrated into trauma systems across Canada. Medium and long-term benefits may include a reduction in adverse events for patients and an increase in resource availability. The proposed intervention targets a problem identified by stakeholders, is based on extensive background work, was developed using a partnership approach, is low-cost, and is linked to accreditation. There will be no attrition, identification, or recruitment bias as the intervention is mandatory in line with trauma center designation requirements, and all outcomes will be assessed with routinely collected data. However, investigators cannot be blinded to group allocation and there is a possibility of contamination bias that will be minimized by conducting intervention refinement only with participants in the intervention arm., Trial Registration: This protocol has been registered on ClinicalTrials.gov (February 24, 2023, # NCT05744154 )., (© 2023. The Author(s).)

Background: Stroke is a common and serious disorder. With optimal care, 90-day recurrent stroke risk can be reduced from 10% to about 1%. Stroke prevention clinics (SPCs) can improve patient outcomes and resource allocation but lack standardization in patient management. The extent of variation in patient management among SPCs is unknown. Our aims were to assess baseline practice variation between Canadian SPCs and the impact of COVID-19 on SPC patient care., Methods: We conducted an electronic survey of 80 SPCs across Canada from May to November 2021. SPC leads were contacted by email with up to five reminders., Results: Of 80 SPCs contacted, 76 were eligible from which 38 (50.0%) responded. The majority (65.8%) of SPCs are open 5 or more days a week. Tests are more likely to be completed before the SPC visit if referrals were from clinic's own emergency department compared to other referring sources. COVID-19 had a negative impact on routine patient care including longer wait times (increased for 36.4% clinics) and higher number of patients without completed bloodwork prior to arriving for appointments (increased for 27.3% clinics). During COVID-19 pandemic, 87.9% of SPCs provided virtual care while 72.7% plan to continue with virtual care post-COVID-19 pandemic., Conclusion: Despite the time-sensitive nature of transient ischemic attack patient management, some SPCs in Canada are not able to see patients quickly. SPCs should endeavor to implement strategies so that they can see high-risk patients within the highest risk timeline and implement strategies to complete some tests while waiting for SPC appointment.

Objectives: Registry-based randomized controlled trials (RRCTs) have potential to address limitations of traditional clinical trials. To describe their current use, information on planned and published RRCTs was identified and synthesized., Study Design and Setting: A scoping review of published RRCT protocols and reports was conducted. Articles published between 2010 and 2021 identified from electronic database searching, a recent review of RRCTs, and targeted searching for recent RRCT protocols (2018-2021) were screened. Data on trial data sources, types of primary outcomes, and how these primary outcomes were described, selected, and reported were extracted., Results: Ninety RRCT articles (77 reports; 13 protocols) were included. Forty nine (54%) used or planned to rely on registry data for their trial, 26 (29%) used both registry and additional data, and 15 (17%) used the registry solely for recruitment. Primary outcomes were routinely collected from the registry for 66 articles (73%). Only 28 articles (31%) described any methods to promote outcome data quality during or after data collection. Core outcome sets were not used in any of the trials., Conclusion: With improvements in registry design, outcome selection, measurement, and reporting, future RRCTs may deliver on promises of efficient, high-quality trials that address clinically relevant questions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite known analgesic effects of breastfeeding (BF), skin-to-skin care (SSC), and sweet solutions (sucrose) for newborns, these interventions remain underutilized. Our team produced a five-minute parent-targeted video (BSweet2Babies) demonstrating BF, SSC, and sucrose during newborn blood sampling. We conducted a sequential exploratory mixed-methods study with eight maternal-newborn units across Ontario, Canada to identify barriers and facilitators to implementing the video and the three pain management strategies.Over a 6-month period, data collection included 15 telephone interviews, two email communications, and three community of practice teleconferences with the participating sites ( n = 8). We used the Theoretical Domains Framework as the coding matrix. Participants discussed integrating the video in prenatal education and the importance of involving leadership when planning for practice change. Key barriers included lack of comfort with parental presence, perception of high complexity of the strategies, short postpartum stays, competing priorities, and interprofessional challenges. Key facilitators included alignment with the Baby-Friendly Hospital Initiative, modeling by Lactation Consultants, and frequent reminders.

Background: Older adults with frailty are at an increased risk of adverse outcomes after surgery. Exercise before surgery (exercise prehabilitation) may reduce adverse events and improve recovery after surgery. However, adherence with exercise therapy is often low, especially in older populations. The purpose of this study was to qualitatively assess the barriers and facilitators to participating in exercise prehabilitation from the perspective of older people with frailty participating in the intervention arm of a randomized trial., Methods: This was a research ethics approved, nested descriptive qualitative study within a randomized controlled trial of home-based exercise prehabilitation vs. standard care with older patients (≥ 60 years) having elective cancer surgery, and who were living with frailty (Clinical Frailty Scale ≥ 4). The intervention was a home-based prehabilitation program for at least 3 weeks before surgery that involved aerobic activity, strength and stretching, and nutritional advice. After completing the prehabilitation program, participants were asked to partake in a semi-structured interview informed by the Theoretical Domains Framework (TDF). Qualitative analysis was guided by the TDF., Results: Fifteen qualitative interviews were completed. Facilitators included: 1) the program being manageable and suitable to older adults with frailty, 2) adequate resources to support engagement, 3) support from others, 4) a sense of control, intrinsic value, noticing progress and improving health outcomes and 5) the program was enjoyable and facilitated by previous experience. Barriers included: 1) pre-existing conditions, fatigue and baseline fitness, 2) weather, and 3) guilt and frustration when unable to exercise. A need for individualization and variety was offered as a suggestion by participants and was therefore described as both a barrier and facilitator., Conclusions: Home-based exercise prehabilitation is feasible and acceptable to older people with frailty preparing for cancer surgery. Participants identified that a home-based program was manageable, easy to follow with helpful resources, included valuable support from the research team, and they reported self-perceived health benefits and a sense of control over their health. Future studies and implementation should consider increased personalization based on health and fitness, psychosocial support and modifications to aerobic exercises in response to adverse weather conditions., (© 2023. The Author(s).)

Pragmatic trials evaluating health care interventions often adopt cluster randomization due to scientific or logistical considerations. Systematic reviews have shown that coprimary endpoints are not uncommon in pragmatic trials but are seldom recognized in sample size or power calculations. While methods for power analysis based on K ( K ≥ 2 $K\ge 2$ ) binary coprimary endpoints are available for cluster randomized trials (CRTs), to our knowledge, methods for continuous coprimary endpoints are not yet available. Assuming a multivariate linear mixed model (MLMM) that accounts for multiple types of intraclass correlation coefficients among the observations in each cluster, we derive the closed-form joint distribution of K treatment effect estimators to facilitate sample size and power determination with different types of null hypotheses under equal cluster sizes. We characterize the relationship between the power of each test and different types of correlation parameters. We further relax the equal cluster size assumption and approximate the joint distribution of the K treatment effect estimators through the mean and coefficient of variation of cluster sizes. Our simulation studies with a finite number of clusters indicate that the predicted power by our method agrees well with the empirical power, when the parameters in the MLMM are estimated via the expectation-maximization algorithm. An application to a real CRT is presented to illustrate the proposed method., (© 2022 The Authors. Biometrics published by Wiley Periodicals LLC on behalf of International Biometric Society.)

Background: While audit & feedback (A&F) is an effective implementation intervention, the design elements which maximize effectiveness are unclear. Partnering with a healthcare quality advisory organization already delivering feedback, we conducted a pragmatic, 2 × 2 factorial, cluster-randomized trial to test the impact of variations in two factors: (A) the benchmark used for comparison and (B) information framing. An embedded process evaluation explored hypothesized mechanisms of effect., Methods: Eligible physicians worked in nursing homes in Ontario, Canada, and had voluntarily signed up to receive the report. Groups of nursing homes sharing physicians were randomized to (A) physicians' individual prescribing rates compared to top-performing peers (the top quartile) or the provincial median and (B) risk-framed information (reporting the number of patients prescribed high-risk medication) or benefit-framed information (reporting the number of patients not prescribed). We hypothesized that the top quartile comparator and risk-framing would lead to greater practice improvements. The primary outcome was the mean number of central nervous system-active medications per resident per month. Primary analyses compared the four arms at 6 months post-intervention. Factorial analyses were secondary. The process evaluation comprised a follow-up questionnaire and semi-structured interviews., Results: Two hundred sixty-seven physicians (152 clusters) were randomized: 67 to arm 1 (median benchmark, benefit framing), 65 to arm 2 (top quartile benchmark, benefit framing), 75 to arm 3 (median benchmark, risk framing), and 60 to arm 4 (top quartile benchmark, risk framing). There were no significant differences in the primary outcome across arms or for each factor. However, engagement was low (27-31% of physicians across arms downloaded the report). The process evaluation indicated that both factors minimally impacted the proposed mechanisms. However, risk-framed feedback was perceived as more actionable and more compatible with current workflows, whilst a higher target might encourage behaviour change when physicians identified with the comparator., Conclusions: Risk framing and a top quartile comparator have the potential to achieve change. Further work to establish the strategies most likely to enhance A&F engagement, particularly with physicians who may be most likely to benefit from feedback, is required to support meaningfully addressing intricate research questions concerning the design of A&F., Trial Registration: ClinicalTrials.gov, NCT02979964 . Registered 29 November 2016., (© 2023. The Author(s).)

Objectives: In stepped-wedge cluster randomized trials (SW-CRTs), clusters are randomized not to treatment and control arms but to sequences dictating the times of crossing from control to intervention conditions. Randomization is an essential feature of this design but application of standard methods to promote and report on balance at baseline is not straightforward. We aimed to describe current methods of randomization and reporting of balance at baseline in SW-CRTs., Study Design and Setting: We used electronic searches to identify primary reports of SW-CRTs published between 2016 and 2022., Results: Across 160 identified trials, the median number of clusters randomized was 11 (Q1-Q3: 8-18). Sixty-three (39%) used restricted randomization-most often stratification based on a single cluster-level covariate; 12 (19%) of these adjusted for the covariate(s) in the primary analysis. Overall, 50 (31%) and 134 (84%) reported on balance at baseline on cluster- and individual-level characteristics, respectively. Balance on individual-level characteristics was most often reported by condition in cross-sectional designs and by sequence in cohort designs. Authors reported baseline imbalances in 72 (45%) trials., Conclusion: SW-CRTs often randomize a small number of clusters using unrestricted allocation. Investigators need guidance on appropriate methods of randomization and assessment and reporting of balance at baseline., (Copyright © 2023 Elsevier Inc. All rights reserved.)