BACKGROUND:Health-related quality of life is a key secondary end point in stroke trials. Differential item functioning (DIF) occurs when individuals with the same underlying health-related quality of life interpret and respond differently to questionnaire items, potentially biasing treatment comparisons. This study evaluates DIF in the patient-reported 5-level EuroQOL questionnaire among patients with acute ischemic stroke across age, sex, and treatment groups. METHODS:Data were from the AcT trial (Alteplase Compared to Tenecteplase), a registry-based randomized comparison of alteplase and tenecteplase conducted at 22 stroke centers across Canada (December 2019-January 2022). Patients with acute ischemic stroke presenting within 4.5 hours of symptom onset and eligible for thrombolysis completed the 5-level EuroQOL questionnaire at 90 days poststroke. DIF was assessed using multigroup graded response models with the Wald-based sweep procedure, which accounts for between-group differences in latent trait distributions. We quantified effect sizes using signed weighted area between curves (sWABC); |sWABC| <0.10=negligible. RESULTS:Of 1577 patients enrolled in the trial, 1264 survived to 90 days with complete 5-level EuroQOL questionnaire data (51.2% tenecteplase; 46.5% female; 30.1% aged ≥80). Omnibus testing revealed significant DIF only for age (χ2=86.9, P<0.001); neither sex (χ2=31.7, P=0.063) nor treatment (χ2=22.4, P=0.379) showed evidence of DIF. Four items flagged for age-related DIF: self-care, usual activities, pain/discomfort, and anxiety/depression. However, only self-care (sWABC=-0.46) and usual activities (sWABC=-0.34) showed moderate effects, while pain/discomfort (sWABC=-0.002) and anxiety/depression (sWABC=0.09) were negligible. Importantly, factor scores from models with and without DIF adjustment correlated (correlation coefficient=0.98). CONCLUSIONS:The 5-level EuroQOL questionnaire appears to function equivalently across sex and treatment groups in this stroke population. Age-related DIF, though statistically detectable in physical functioning items, had little practical consequence for individual scores, supporting the instrument's use for health-related quality of life comparisons in stroke trials. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

BACKGROUND:Cerebral amyloid angiopathy (CAA) is thought to increase the risk of postthrombolytic intracranial bleeding, yet CAA neuroimaging markers and magnetic resonance imaging criteria have not been systematically evaluated in large acute stroke trials. We, therefore, examined the association of radiological Boston CAA criteria and their constituent markers with hemorrhagic risks and functional outcomes after intravenous thrombolysis in the AcT trial (Alteplase Compared to Tenecteplase). METHODS:Blinded raters recorded lobar cerebral microbleeds, cortical superficial siderosis, white matter hyperintensity multispot sign, and centrum semiovale enlarged perivascular spaces, and classified possible and probable CAA according to radiological Boston criteria iterations, versions 1.0, 1.5, and 2.0. Multivariable logistic or ordinal regressions, adjusted for age, sex, baseline stroke severity, diabetes, hypertension, onset-to-needle time, thrombolytic agent, and endovascular therapy, assessed associations of these features/criteria with safety end points: symptomatic intracerebral hemorrhage (ICH), any ICH, Heidelberg hemorrhage grade, 90-day mortality, and functional outcomes (modified Rankin Scale score of 0-1 and ordinal modified Rankin Scale score shift). RESULTS:Among 1600 patients in the trial, 482 had suitable magnetic resonance imaging (mean age, 71 years; 47.1% female). Cortical superficial siderosis burden emerged as the dominant harmful marker: each increment was associated with increased risk of symptomatic ICH (adjusted odds ratio [aOR] per additional affected sulcus, 3.88 [95% CI, 2.87-5.26]), any ICH (aOR, 1.91 [95% CI, 1.22-2.98]), hemorrhage severity, 90-day mortality (aOR, 1.42 [95% CI, 1.18-1.71]), worse modified Rankin Scale scores (adjusted common odds ratio, 1.74 [95% CI, 1.58-1.91]), and lower odds of excellent functional recovery (aOR, 0.70 [95% CI, 0.64-0.77]). Fulfilling probable radiological Boston criteria, versions 1.0 and 1.5, increased odds of any ICH (aOR, 2.57 and 2.39 [95% CI, 2.05-3.23]; aOR, 2.39 [95% CI, 1.71-3.34], respectively), whereas fulfilling possible Boston criteria, version 1.5, was associated with worse modified Rankin Scale scores (adjusted common odds ratio, 2.34 [95% CI, 1.30-4.22]). Boston criteria, version 2.0, were not significantly associated with any hemorrhagic outcomes. CONCLUSIONS:In thrombolyzed patients with acute ischemic stroke, cortical superficial siderosis burden is strongly and consistently associated with higher risk of severe hemorrhage, disability, and death, making it a particularly relevant CAA marker when weighing thrombolytic risk versus benefit. Meeting radiological Boston criteria, versions 1.0 or 1.5, increases hemorrhagic risk, but meeting the latest 2.0 criteria does not.

BACKGROUND:To determine whether computed tomography (CT) thrombus characteristics modify the effect of intravenous (IV) thrombolysis type (tenecteplase vs alteplase) on outcomes. METHODS:This is a secondary analysis of the Alteplase compared to Tenecteplase (AcT) trial. Patients with visible intracranial occlusions on thin-slice baseline imaging were included. Key thrombus characteristics assessed by CT imaging were hyperdense artery sign, thrombus length, residual flow, clot burden score, and occlusion site. Multivariable analyses were performed to test for interactions between thrombolysis type and thrombus characteristics on clinical and angiographic outcomes. RESULTS:Of 1577 patients, 939 met inclusion criteria; 479 (51.0%) received tenecteplase and 460 (49.0%) alteplase. Among the 498 patients (53.0%) treated with endovascular thrombectomy (EVT), angiographic outcomes were comparable between treatment groups. A significant interaction was observed between thrombolysis type and thrombus length; longer thrombi were associated with reduced likelihood of modified Rankin Scale (mRS) 0-1 with alteplase (adjusted odds ratio (aOR) per 1 mm increase, 0.97 (95% confidence interval (CI): 0.95-1.00)), but not with tenecteplase (aOR: 1.00 (95% CI: 0.98-1.02); interaction p = 0.04). Similarly, the presence of residual flow within the thrombus was associated with higher odds of mRS 0-2 in the alteplase group (aOR: 2.00 (95% CI: 1.25-3.20)), but had no significant effect in the tenecteplase group (aOR: 0.93 (95% CI: 0.62-1.41); interaction p = 0.01). No other significant interactions between thrombus characteristics and thrombolysis type were identified. CONCLUSION:In the AcT trial, alteplase appeared less effective with longer thrombi and those lacking residual flow, whereas IV tenecteplase showed more consistent effectiveness across thrombus characteristics. These findings require confirmation in future prospective studies.

This study used latent Markov modelling (LMM) to identify distinct HRQOL states and predictors of transitions in a large CAD cohort. Data were from 6,030 patients in the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) registry who underwent coronary angiography between 2004 and 2014. HRQOL was assessed using the 7-item Seattle Angina Questionnaire (SAQ-7) at 2 weeks, 1 year, and 3 years post-angiography. LLM identified distinct subgroups and transition probabilities between states. Covariates were incorporated via multinomial logistic regressions for state membership and transitions. The mean age was 65.5 years (SD 10.6); 79.3

Background Patients with chronic kidney disease are at high risk of adverse outcomes after acute coronary syndrome (ACS) and need optimized treatment decisions. We derived and validated a series of risk models for predicting 1‐year mortality, readmission for myocardial infarction, and progression to kidney failure following ACS. Methods The development cohort included adults with chronic kidney disease who had an admission for non‐ST‐segment–elevation ACS, in Alberta, Canada between April 1, 2004 and March 31, 2017. Cox proportional hazard and Fine and Gray competing risk models were externally validated and updated in a temporally distinct cohort of patients in Alberta and a geographically distinct cohort of patients with chronic kidney disease and ACS in British Columbia, Canada. Results The derivation cohort included 11 980 patients, the temporal validation cohort 4204, and the geographic validation cohort 1787. All models showed comparable discrimination and calibration in the temporal validation cohort; comparable model performance was achieved in the geographic validation cohort after updating. In the temporal and geographic validation cohorts, respectively, discrimination was very good for kidney failure (C‐indexes, 0.93 [95% CI, 0.89–0.97] and 0.80 [95% CI, 0.78–0.82]), and modest for mortality (0.77 [95% CI, 0.75–0.78] and 0.71 [95% CI, 0.69–0.73]), and readmission for myocardial infarction (0.65 [95% CI, 0.62–0.67] and 0.57 [95% CI, 0.53–0.62]). All models were well calibrated after updating. Conclusions We have developed, validated, and updated risk models for cardiac and renal outcomes in patients with chronic kidney disease and ACS, which can help facilitate shared decision‐making surrounding diagnostic testing, treatment, and monitoring of these patients.

BACKGROUND:With the increasing use of tenecteplase, it is important to understand its safety compared with alteplase. We aimed to determine the incidence, predictors, and functional impact of serious adverse events (SAEs) in patients treated with alteplase versus tenecteplase. METHODS:This is a post hoc analysis of the AcT (Alteplase Compared to Tenecteplase) trial, a phase 3 multicenter randomized controlled trial that randomized 1577 ischemic patients with stroke (2019-2022) into tenecteplase versus alteplase presenting <4.5 hours of onset. SAEs were recorded within 24 hours of treatment and classified by organ system using the Medical Dictionary for Regulatory Activities. Mixed-effects logistic regression evaluated predictors of SAEs and their impact on 90-day modified Rankin Scale. RESULTS:Of the 1577 enrolled, 219 (13.9%) patients had SAEs. Patients with SAEs had higher National Institutes of Health Stroke Scale (median, 11 versus 9; P=0.002) and higher endovascular treatment rates (50.2% versus 29.2%; P<0.001) than those without SAEs. Nervous system disorders were the most common SAE (58.2%), including stroke worsening (26.7%) and intracranial hemorrhage (25%). No significant differences were observed in SAE distribution by thrombolytic. Patients with SAEs had higher 90-day modified Rankin Scale scores (median, 4 versus 2; odds ratio [OR], 3.93 [95% CI, 2.78-5.56]). Independent predictors of SAEs included baseline National Institutes of Health Stroke Scale (per SD increase: OR, 1.2 [95% CI, 1.0-1.5]), large-vessel occlusion (OR, 1.6 [95% CI, 1.1-2.5]), Alberta Stroke Program Early Computed Tomography Score (per point increase: OR, 0.9 [95% CI, 0.8-1.0]), and cerebral atrophy (per point increase: OR, 1.5 [95% CI, 1.1-1.9]). CONCLUSIONS:Our study found no difference between rate or type of SAEs by thrombolytic type, supporting the safety of tenecteplase. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03889249.

BACKGROUND:Preservation of treatment allocation randomness, achievement of treatment group size balance, and balance on prognostic baseline covariates are desirable properties of optimal randomization schemes. Previous studies have demonstrated the accuracy of covariate-adaptive randomizations, such as minimal sufficient balance (MSB) randomization, for achieving covariate balance in acute stroke trials at the end of the trial. This study evaluates the performance of covariate-adaptive randomization techniques against simple and block randomization in minimizing site-specific treatment group imbalance in multicenter acute stroke trials. METHODS:Monte Carlo simulations were used to evaluate the performance of stratified and unstratified versions of MSB, common scale MSB, and common scale group-size MSB (CSSize-MSB), against permuted block and simple randomization designs, for achieving balance across baseline covariates and sites. Simulation conditions investigated include the number of sites (3, 6, or 20 sites), enrollment per site (equal or unequal enrollment across sites), number and distribution of baseline covariates (sex, age, National Institutes of Health Stroke Scale score, large vessel occlusion status), and sample size (N=250, 600, 1000, 3000). The probability of observing statistically significant imbalance on any baseline covariate, proportion of biased allocations, and overall and site-specific group allocation ratio at interims and end of enrollment were used to evaluate the performance of the randomization schemes. RESULTS:The average probability of observing imbalance on any of the baseline covariates for the simple randomization, permuted block, common scale MSB, common scale group-size MSB, and MSB were 21%, 21%, 0%, 2%, and 2%, respectively, at N=600 with 20 study sites. Although site-specific treatment allocation imbalance was improved under MSB algorithms, imbalance at low-enrolling sites persisted, regardless of the randomization scheme. Treatment allocation randomness and treatment-control group balance were preserved in high-volume sites under MSB. CONCLUSIONS:Although site-specific treatment group imbalance persisted in low-enrolling sites, regardless of the randomization technique adopted, the overall randomness of treatment allocation and balance of covariates were preserved with MSB algorithms. Logistical considerations and oversight to minimize low enrollment across sites are recommended before onboarding sites in multicenter acute stroke trials.

PURPOSE:Longitudinal assessments of patient-reported outcome measures may be threatened by response shift (RS), a change in individual interpretation of a construct over time. This study tested for RS in parent-reported disability in children with chronic physical illness. MATERIALS AND METHODS:Data come from Multimorbidity in Children and Youth across the Life course (MY LIFE). Parent-reported disability was assessed using the 12-item World Health Organization Disability Assessment Schedule (WHODAS) 2.0, which was completed at baseline, 6, 12, 24, and 48-month follow-up. RS in longitudinal changes in WHODAS 2.0 domains (between baseline and 24 months was assessed using Oort's structural equation model. RESULTS:Parents reported on 263 children (9.5 ± 4.2 years; 47.5% female). RS was detected in mobility (reprioritization, uniform and non-uniform recalibration; RS effect size = -0.21) and household activities (uniform recalibration; RS effect size = 0.12). Cognition, society/participation, self-care, and social/getting along exhibited non-uniform recalibration, which affected measurement variance but not bias mean-level change estimates. CONCLUSION:The impact of RS on the overall assessment of change was small to moderate across domains. Though parents may change their evaluation of disability in their children over time, clinicians can rely on observed scores to assess changes in this population.

The Seattle Angina Questionnaire (SAQ) is widely used to measure disease-specific health status in coronary artery disease, but its psychometric properties have not been evaluated using multidimensional item response theory (MIRT). We evaluated the SAQ's dimensional structure, measurement precision, differential item functioning (DIF), and short form performance in a population-based cohort. SAQ responses collected within two weeks of coronary angiography from 6,665 patients in the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) registry were analyzed using a confirmatory five-factor multidimensional graded response model. Item fit, local dependence, and conditional standard errors were evaluated. DIF by sex and age was examined using a two-step anchored multigroup approach. Short forms were derived based on discrimination, test information, and DIF magnitude. The confirmatory five-factor model demonstrated good global fit (RMSEA = 0.031, CFI = 0.987, TLI = 0.982), supporting three distinct Physical Limitation dimensions: Basic, Moderate, and Strenuous. Empirical reliability ranged from 0.748 (Basic Physical Limitation) to 0.900 (Moderate Physical Limitation), with precision sufficient for individual-level interpretation in Moderate and Strenuous Physical Limitation. Moderate sex-related DIF was noted on Basic and Moderate Physical Limitation items, with females scoring lower than males. Age-related DIF was negligible to small. The 14-item short form preserved all five factors with theta correlations of 0.964 with the 18-item version. MIRT revealed three distinct Physical Limitation dimensions, enabling targeted functional monitoring. Precision gradients and sex-related DIF inform interpretation, and the 14-item short form is supported as the preferred version. The Seattle Angina Questionnaire (SAQ) is one of the most widely used tools for measuring how coronary artery disease affects patients' daily life, symptoms, and quality of life. Despite decades of widespread use, its measurement properties have never been examined using modern statistical methods. This study used a statistical approach, multidimensional item response theory, to examine how well the SAQ measures what it purports to capture. We analyzed responses from over 6,600 Canadian patients who had recently undergone a heart procedure. We found that physical functioning in heart disease patients is better understood as three separate dimensions: basic, moderate, and strenuous activities, rather than one combined score, though one of these (moderate activities) overlapped considerably with the others statistically. We also found that the questionnaire measures some health areas more precisely than others, and that women tend to score lower than men on physical activity items, even when their actual health is the same, which could lead to underestimating how heart disease affects women. Finally, we showed that a shorter 14-question version of the SAQ captures all five health areas with very little loss of information, making it practical for both routine clinical use and large research studies, and supporting more accurate and equitable use of the SAQ across different patient groups.

BACKGROUND:With the increasing use of tenecteplase for acute ischemic stroke, it is important to determine its safety in young adults. We aimed to characterize the clinical characteristics and imaging findings of young adults (≤45 years) in the AcT trial (Intravenous Tenecteplase Compared With Alteplase for Acute Ischaemic Stroke in Canada) and to compare their safety and efficacy outcomes. METHODS:This is a secondary analysis of the AcT trial, a phase 3 pragmatic multicenter registry-linked randomized controlled trial. We describe clinical and imaging characteristics of young adults with acute ischemic stroke. Logistic regression adjusted for sex and stroke severity was performed to assess safety and efficacy outcomes between the tenecteplase and alteplase arms. RESULTS:Of the 1577 enrolled patients, 68 (4.31%) were ≤45 years. Of 53 patients with available comorbidity data, 33 (62.26%) had no comorbidities. Hypertension was the most common comorbidity (n=8, 15%), whereas cardiac pathologies were observed in a smaller proportion (n=4, 7.5%). Intracranial atherosclerosis was identified in 7 patients (10%) and carotid or vertebral artery dissection in 6 patients (9%). Safety outcomes, including mortality, intracranial hemorrhage, and serious adverse events, were similar between the tenecteplase and alteplase arms. Excellent functional outcome (modified Rankin Scale score 0-1) at 90 days was better in the tenecteplase arm (84.72% versus 45%; adjusted odds ratio, 6.55 [95% CI, 1.89-22.71]). CONCLUSIONS:The majority of young adults presenting with acute ischemic stroke did not have any traditional risk factors for stroke at presentation. Safety outcomes were similar between the tenecteplase and alteplase arms. Although functional outcomes were observed to be better in the tenecteplase arm, these findings are exploratory and should be interpreted cautiously, given the study's limited sample size and lack of adjustment for key confounders. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

INTRODUCTION:Fast delivery of intravenous thrombolysis (IVT) and transportation to a comprehensive stroke center (CSC) are paramount for primary stroke centers (PSCs). We investigated outcomes and workflow times of patients treated with IVT at PSCs. METHODOLOGY:This is a secondary analysis of the AcT trial, a multicenter, phase-3, randomized, controlled, noninferiority trial comparing tenecteplase with alteplase in patients with acute ischemic stroke within 4.5 hours of onset. We compared baseline characteristics, imaging and clinical outcomes at 90 days, and workflow times between PSCs and CSCs. RESULTS:Of 1577 patients enrolled in the trial, 99 (6.27%) were treated at PSCs and 1,478 (93.72%) at CSCs. Both groups had similar age, proportion of females, baseline NIHSS and presence of LVO. The proportion of patients achieving excellent functional outcome at 90 days was higher in PSCs compared to CSCs (mRS 0-1: 48.48% versus 35.01%, adjusted IRR, 1.42 [CI 95%, 1.04-1.95]). Patients at PSCs had longer door-to-needle times (median, 56.5 [42-70] versus 35 [27-47] minutes, p < 0.001). In the 24 patients transferred to CSCs, the needle-to-puncture time was more favorable for tenecteplase compared to alteplase (median, 35.5 [21-58] versus 52 [18-74] minutes, p < 0.001). CONCLUSIONS:Our findings suggest that patients treated at PSCs may achieve outcomes comparable to those treated at CSCs, despite differences in workflow efficiency. These results should be interpreted cautiously, as this is a hypothesis-generating analysis, and observed differences may reflect multiple factors, including site-level practices, referral patterns and workflow characteristics.

Importance:Collaborative statisticians and methodologists are essential members of multidisciplinary teams, yet little is known about how their diverse responsibilities, including technical analysis, project leadership, and domain-specific consultation across multiple concurrent projects, affect their work-life balance and professional well-being. Objective:To assess perceptions of work-life balance and identify individual, job-related, and organizational factors associated with work-life balance among collaborative statisticians and methodologists working in multidisciplinary settings. Design, Setting, and Participants:This cross-sectional survey study collected data from November 2022 to May 2024, with analysis conducted in December 2024. Anonymous electronic surveys were distributed through international professional statistical societies, including organizations in North America, Europe, Africa, South America, and Asia. Participants were recruited via a convenience sample through society email listservs and newsletters. Eligible respondents were statisticians, data scientists, or methodologists working in multidisciplinary collaborative settings who had been continuously employed full-time during the previous year. Main Outcomes and Measures:Work-life balance was assessed using the 15-item Work-Life Balance Self-Assessment Scale, which consists of 3 subscales: Work Interference With Personal Life, Personal Life Interference With Work, and Work/Personal Life Enhancement. Regression analyses were used to identify the demographic, organizational, and discipline-specific factors associated with respondents' perception of work-life balance. Results:Of 627 individuals who accessed the survey, 450 (71.8%) met eligibility criteria and completed the survey. Of the 450 respondents who completed the survey, the mean (SD) age was x (y) years, 240 (53.7%) were female, and 270 (60.0%) worked in academia; 143 (31.8%) reported dissatisfaction with their work-life balance, and an additional 47 (10.4%) reported neutral satisfaction. Factors associated with higher work interference scores included unmanageable workload (mean difference, 0.70; 95% CI, 0.48 to 0.92), work-related health issues (mean difference, 0.58; 95% CI, 0.33 to 0.83), inability to complete work during regular hours (mean difference, 0.56; 95% CI, 0.34 to 0.78), and lack of organizational support for work-life balance (mean difference, 0.48; 95% CI, 0.24 to 0.73). Organizational flexibility to attend to personal matters (mean difference, -0.33; 95% CI, -0.64 to -0.01) and adequate compensation (mean difference, -0.29; 95% CI, -0.49 to -0.09) were associated with lower interference scores. Conclusions and Relevance:These findings suggest that targeted educational initiatives, effective mentorship, and wellness-focused organizational policies can foster sustainable work-life balance among statisticians and methodologists in multidisciplinary settings.

Patients with chest pain and symptoms of acute coronary syndromes account for > 600,000 emergency department (ED) visits annually in Canada. Of these patients, 85% do not have acute coronary syndromes, and most are discharged from the ED after a thorough evaluation. However, a large proportion of these patients are referred for outpatient cardiac testing after ED discharge, even though their short-term risk of major adverse cardiac events (MACE), including death, new myocardial infarction, and need for revascularization, is very small. These referrals contribute to substantial low-value healthcare utilization, and limit access for those patients who are more likely to benefit from objective testing.Existing risk-prediction tools-developed prior to the advent of new high-sensitivity cardiac troponin assays-were derived in nonrepresentative populations, and when applied to ED patients with low cardiac troponin concentrations, systematically overestimate the short-term risk of MACE.This multicentre prospective cohort study will enroll ED patients with chest pain to derive and validate a novel risk prediction tool that distinguishes patients at low risk of MACE who do not require further cardiac testing from those who may benefit from additional cardiac testing. We will enroll 6500 patients in 13 Canadian EDs and prospectively follow them to ascertain a primary outcome of MACE within 30 days after their index ED encounter. The risk-prediction tool developed in this project will guide the safe, efficient, and appropriate referral of ED patients with chest pain. Clinical Trial Registration:NCT06743672.

BACKGROUND:Randomized controlled trials (RCTs) have traditionally been designed with an explanatory approach, in contrast to incorporating real-world, pragmatic considerations. AIMS:This methodological review assesses the uptake of pragmatic designs in Phase III acute stroke RCTs. METHODS:We conducted a comprehensive literature search of the MEDLINE, Embase, and Cochrane Library databases from inception to 1 July 2024. Eligible articles included English-language published Phase III RCTs of acute ischemic stroke and intracerebral hemorrhage interventions. Using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) tool, each trial was rated on nine key domains, and relevant study characteristics were extracted. Trials with an average rating of 3 or higher, or a total score (sum of ratings) of 27 or higher (given that all domains were assessed), were considered to adopt an overall pragmatic approach to their design. Risk of bias was evaluated using the Cochrane risk of bias tool. RESULTS:Of the 5663 unique articles obtained after deduplication, 136 trials were included, and 71 (52%) trials were classified as pragmatic using the PRECIS-2 tool. A majority had a low risk of bias (63.2%). Pragmatic trials were more likely to be large sample, multicenter, multinational trials with broad inclusion criteria that cover multiple types of strokes. CONCLUSION:There has been an increased uptake of pragmatic designs in acute stroke over the last decade, reflecting improvements in acute stroke care and a greater consideration of real-world applicability by trialists.

BACKGROUND:The 9-item Patient Health Questionnaire (PHQ-9) is a valid and widely used self-reported tool for assessing depressive symptoms. Although previous studies have demonstrated its sensitivity to change at the summary score level, there is limited investigation of the sensitivity of individual PHQ-9 items to change over time. This study aims to evaluate the sensitivity of PHQ-9 items to change using data from three separate samples. METHODS:Secondary analyses were conducted using longitudinal datasets from three randomized controlled trials in individuals with depression. Constrained and unconstrained longitudinal factor models of change were used to assess the sensitivity of PHQ-9 items. Multiple goodness-of-fit indices were used to assess the fit of the measurement models to each dataset. RESULTS:The PHQ-9 items were generally sensitive to detecting change over time across the three datasets. In the first dataset, the magnitude of the factor loadings associated with change over time ranged between 0.54 and 0.93; item 2 (depressive mood) was the most sensitive to change. In the other two datasets, the magnitude of the factor loadings associated with change over time ranged between 0.18 and 0.87; item 1 (anhedonia) was most sensitive to change, with item 2 (depressive mood) being a close second. Item 9 (suicidality) was the least sensitive to change across the three datasets. CONCLUSION:The PHQ-2 items are sensitive to detecting within-person change in depressive symptoms over time across all three trials and are thus appropriate for assessing changes in depressive symptoms in research and clinical practice.

Background and Objectives: Emerging literature suggests that non-stenotic carotid disease (<50% stenosis), especially in the presence of high-risk plaque features, can be a possible etiology for ischemic stroke. We aimed to evaluate the odds of concordant stroke among individuals with non-stenotic carotid arteries with various plaque features. Methods: This is a secondary analysis from the Alteplase compared to Tenecteplase (AcT) trial. We evaluated carotid arteries on baseline CT Angiogram (CTA) to assess the degree of stenosis, plaque features such as ulceration, thickness, irregularity, hypodensity and presence of intraluminal thrombi, carotid web and dissection. 24hour follow-up imaging was used to evaluate stroke location. At a carotid level, we performed mixed effects logistic regression analysis adjusted for age and sex, with patient ID as a random effects variable, to determine the association between each high-risk plaque feature and the presence of concordant stroke (ipsilateral acute stroke in the territory of the carotid artery). Results: Of 1577 patients in the trial, 1407 (89.2%) had interpretable baseline imaging. Of these, 329 (23.4%) had no carotid disease, 869 (61.8%) had non-stenotic (<50%) carotid disease and 209 (14.9%) had stenotic (>50%) carotid disease. At a carotid level, 2519 (89.5%) had non-stenotic carotid disease. Of these, 689 (27.4%) had concordant stroke. Intraluminal thrombi and carotid webs were significantly associated with concordant stroke (aOR 8.11, 95% CI 1.6 – 41.08 and aOR 3.58, 95% CI 1.53 – 8.35, respectively). None of the other plaque features were significantly associated with concordant stroke. Conclusions: Among patients with non-stenotic carotid disease, only the presence of intraluminal thrombi and carotid webs were found to be associated with increased odds of concordant stroke. Further CTA-based studies on larger populations are required to identify plaque features associated with concordant ischemic stroke.