Utility of serial troponin testing for emergency department patients with syncope.

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.

ABSTRAIT: CONTEXTE: Pour les patients du service des urgences (DE) atteints de syncope, la troponine cardiaque peut identifier le syndrome coronarien aigu (SCA) et le pronostic pour les événements indésirables graves de 30 jours. Cependant, il n'est pas clair si les tests en série améliorent le rendement diagnostique et le pronostic. MéTHODES: Il s'agissait d'une analyse secondaire des données de deux études prospectives menées pour élaborer le Canadian Syncope Risk Score. Des adultes (âgés de 16 ans) atteints de syncope ont été recrutés, et les caractéristiques du patient, les signes vitaux, l'empreinte diagnostique du médecin, les résultats de l'électrocardiogramme et de la troponine, ainsi que les événements indésirables graves évalués à 30 jours ont été recueillis. Le critère de jugement principal était la détection d'un événement indésirable grave dans les 30 jours suivant la décision de l'urgence. Le critère de jugement secondaire était la comparaison de la durée de séjour à l'urgence chez les patients ayant une seule mesure de troponine par rapport à la mesure en série. RéSULTATS: 4 996 patients [âge moyen 64,5 (ET 18,8) ans, 52,2 % d'hommes] ont été inclus : 4 397 (89,8 %) avec une seule troponine [232 (5,3 %) avec un événement indésirable grave à l'urgence et 203 (4,6 %) après l'urgence]; 499 (10,2 %) patients avec > 1 mesure de la troponine [39 (7,8 %) avec événement indésirable grave à l'urgence et 60 (12,0 %) après la décision à l'urgence]. Parmi les patients ayant fait l'objet de mesures en série, 10 (2,0 %) présentaient une augmentation du seuil inférieur à supérieur au seuil du 99e percentile, dont 4 (0,8 %) ont subi un événement indésirable grave : deux avec arythmies diagnostiquées par électrocardiogramme, un avec SCA et un avec insuffisance respiratoire. Neuf patients (1,8 %) ont présenté une reclassification du risque selon le score canadien de risque de syncope en fonction de la mesure en série, et aucun n'a subi d'événement indésirable grave de 30 jours. La durée médiane de séjour aux urgences était significativement plus longue pour les patients ayant subi des tests en série (5,6 vs. 3,8 heures, p < 0,001). CONCLUSIONS: La mesure initiale de la troponine était suffisante pour la détection des effets indésirables graves et la stratification des risques aux urgences. Les tests de troponine en série n'améliorent pas le rendement diagnostique ou le pronostic et doivent être réservés aux patients présentant des symptômes continus ou des résultats d'électrocardiogramme suggérant une ischémie cardiaque.

Reliability and Sensitivity of a Virtual Assessment Developed for Workplace Concussions: Protocol for a Method-Comparison Study.

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.

Mailed feedback to primary care physicians on antibiotic prescribing for patients aged 65 years and older: pragmatic, factorial randomised controlled trial.

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.

Temporal Trends in Gestational Diabetes Mellitus and Associated Risk Factors in Ontario, Canada, 2012-2020: A Population-Based Cohort Study.

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.

A Population-Based Matched Cohort Study of Digestive System Cancer Incidence and Mortality in Individuals With and Without Inflammatory Bowel Disease.

INTRODUCTION: To study digestive system cancer risks in individuals with inflammatory bowel diseases (IBDs) in the biologic era. METHODS: We used population-level administrative and cancer registry data from Ontario, Canada, (1994-2020) to compare people with IBD to matched controls (1:10 by sex and birth year) on trends in age-sex standardized cancer incidence and risk ratios of incident cancers and cancer-related deaths. RESULTS: Among 110,919 people with IBD and 1,109,190 controls, colorectal cancer incidence (per 100,000 person-years) declined similarly in people with ulcerative colitis (average annual percentage change [AAPC] -1.81; 95% confidence interval [CI] -2.48 to -1.156) and controls (AAPC -2.79; 95% CI -3.44 to -2.14), while small bowel cancer incidence rose faster in those with Crohn's disease (AAPC 9.68; 95% CI 2.51-17.3) than controls (AAPC 3.64; 95% CI 1.52-5.80). Extraintestinal digestive cancer incidence rose faster in people with IBD (AAPC 3.27; 95% CI 1.83-4.73) than controls (AAPC -1.87; 95% CI -2.33 to -1.42), particularly for liver (IBD AAPC 8.48; 95% CI 4.11-13.1) and bile duct (IBD AAPC 7.22; 95% CI 3.74-10.8) cancers. Beyond 2010, the incidences (and respective mortality rates) of colorectal (1.60; 95% CI 1.46-1.75), small bowel (4.10; 95% CI 3.37-4.99), bile duct (2.33; 95% CI 1.96-2.77), and pancreatic (1.19; 95% CI 1.00-1.40) cancers were higher in people with IBD. DISCUSSION: Cancer incidence is declining for colorectal cancer and rising for other digestive cancers in people with IBD. Incidence and mortality remain higher in people with IBD than controls for colorectal, small bowel, bile duct, and pancreatic cancers.

Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

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.).

Maintaining the validity of inference from linear mixed models in stepped-wedge cluster randomized trials under misspecified random-effects structures.

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.

Sample size and power calculation for testing treatment effect heterogeneity in cluster randomized crossover designs.

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.

The association between alcohol retail access and health care visits attributable to alcohol for individuals with and without a history of alcohol-related health-care use.

BACKGROUND AND AIMS: Alcohol retail access is associated with alcohol use and related harms. This study measured whether this association differs for people with and without heavy and disordered patterns of alcohol use. DESIGN: The study used a repeated cross-sectional analysis of health administrative databases. SETTING, PARTICIPANTS/CASES: All residents of Ontario, Canada aged 10-105 years with universal health coverage (n = 10 677 604 in 2013) were included in the analysis. MEASUREMENTS: Quarterly rates of emergency department (ED) and outpatient visits attributable to alcohol in 464 geographic regions between 2013 and 2019 were measured. Quarterly off-premises alcohol retail access scores were calculated (average drive to the closest seven stores) for each geographic region. Mixed-effect linear regression models adjusted for area-level socio-demographic covariates were used to examine associations between deciles of alcohol retail access and health-care visits attributable to alcohol. Stratified analyses were run for individuals with and without prior alcohol-attributable health-care use in the past 2 years. FINDINGS: We included 437 707 ED visits and 505 271 outpatient visits attributable to alcohol. After adjustment, rates of ED visits were 39% higher [rate ratio (RR) = 1.39, 95% confidence interval (CI) = 1.20-1.61] and rates of outpatient visits were 49% higher (RR = 1.49, 95% CI = 1.26-1.75) in the highest versus lowest decile of alcohol access. There was a positive association between alcohol access and outpatient visits attributable to alcohol for individuals without prior health-care attributable to alcohol (RR = 1.65, 95% CI = 1.39-1.95 for the highest to lowest decile of alcohol access) but not for individuals with prior health-care attributable to alcohol (RR = 1.08, 95% CI = 0.90-1.30). There was a positive association between alcohol access and ED visits attributable to alcohol for individuals with and without prior health-care for alcohol for ED visits. CONCLUSION: In Ontario, Canada, greater alcohol retail access appears to be associated with higher rates of emergency department (ED) and outpatient health-care visits attributable to alcohol. Individuals without prior health-care for alcohol may be more susceptible to greater alcohol retail access for outpatient but not ED visits attributable to alcohol.

The Ottawa Statement implementation guidance document for cluster randomized trials in the hemodialysis setting.

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.

Incidence and outcomes of emergency department patients requiring emergency general surgery: a 5-year retrospective cohort study.

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.

Describing the content of trial recruitment interventions using the TIDieR reporting checklist: a systematic methodology review.

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.

Why and when should we cluster randomize?

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.

Practical considerations for sample size calculation for cluster randomized trials.

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.

RAFF-5 Study to Improve the Quality and Safety of Care for Patients Seen in the Emergency Department With Acute Atrial Fibrillation and Flutter.

BACKGROUND: We sought to improve the immediate and subsequent care of emergency department (ED) patients with acute atrial fibrillation (AF) and flutter (AFL) by implementing the principles of the Canadian Association of Emergency Physicians AF/AFL Best Practices Checklist. METHODS: This cohort study included 3 periods: before (7 months), intervention introduction (1 month), and after (7 months), and was conducted at a major academic centre. We included patients who presented with an episode of acute AF or AFL and used multiple strategies to support ED adoption of the Canadian Association of Emergency Physicians checklist. We developed new cardiology rapid-access follow-up processes. The main outcomes were unsafe and suboptimal treatments in the ED. RESULTS: We included 1108 patient visits, with 559 in the before and 549 in the after period. In a comparison of the periods, there was an increase in use of chemical cardioversion (20.6% vs 25.0%; absolute difference [AD], 4.4%) and in electrical cardioversion (39.2% vs 51.2%; AD, 12.0%). More patients were discharged with sinus rhythm restored (66.9% vs 75.0%; AD, 8.1%). The proportion seen in a follow-up cardiology clinic increased from 24.2% to 39.9% (AD, 15.7%) and the mean time until seen decreased substantially (103.3 vs 49.0 days; AD, -54.3 days). There were very few unsafe cases (0.4% vs 0.7%) and, although there was an increase in suboptimal care (19.5% vs 23.1%), overall patient outcomes were excellent. CONCLUSIONS: We successfully improved the care for ED patients with acute AF/AFL and achieved more frequent and more rapid cardiology follow-up. Although cases of unsafe management were uncommon and patient outcomes were excellent, there are opportunities for physicians to improve their care of acute AF/AFL patients. GOV IDENTIFIER: NCT05468281.

Protocol for the ONLOOP trial: pragmatic randomized trial evaluating a province-wide system of personalized reminders for evidence-based surveillance tests in adult survivors of childhood cancer in Ontario.

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.

Comparison of statistical methods used to meta-analyse results from interrupted time series studies: an empirical study.

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.

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

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.