Sex-Based Analysis of Workflow and Outcomes in Acute Ischemic Stroke Patients Treated With Alteplase Versus Tenecteplase.

BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Intravenous tenecteplase compared with alteplase for minor ischaemic stroke: a secondary analysis of the AcT randomised clinical trial.

BACKGROUND: In ischaemic stroke, minor deficits (National Institutes of Health Stroke Scale (NIHSS) ≤5) at presentation are common but often progress, leaving patients with significant disability. We compared the efficacy and safety of intravenous thrombolysis with tenecteplase versus alteplase in patients who had a minor stroke enrolled in the Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke (AcT) trial. METHODS: The AcT trial included individuals with ischaemic stroke, aged >18 years, who were eligible for standard-of-care intravenous thrombolysis. Participants were randomly assigned 1:1 to intravenous tenecteplase (0.25 mg/kg) or alteplase (0.9 mg/kg). Patients with minor deficits pre-thrombolysis were included in this post-hoc exploratory analysis. The primary efficacy outcome was the proportion of patients with a modified Rankin Score (mRS) of 0-1 at 90-120 days. Safety outcomes included mortality and symptomatic intracranial haemorrhage (sICH). RESULTS: Of the 378 patients enrolled in AcT with an NIHSS of ≤5, the median age was 71 years, 39.7% were women; 194 (51.3%) received tenecteplase and 184 (48.7%) alteplase. The primary outcome (mRS score 0-1) occurred in 100 participants (51.8%) in the tenecteplase group and 86 (47.5 %) in the alteplase group (adjusted risk ratio (RR) 1.14 (95% CI 0.92 to 1.40)). There were no significant differences in the rates of sICH (2.9% in tenecteplase vs 3.3% in alteplase group, unadjusted RR 0.79 (0.24 to 2.54)) and death within 90 days (5.5% in tenecteplase vs 11% in alteplase group, adjusted HR 0.99 (95% CI 0.96 to 1.02)). CONCLUSION: In this post-hoc analysis of patients with minor stroke enrolled in the AcT trial, safety and efficacy outcomes with tenecteplase 0.25 mg/kg were not different from alteplase 0.9 mg/kg.

Quality of Life After Intravenous Thrombolysis for Acute Ischemic Stroke: Results From the AcT Randomized Controlled Trial.

BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Response shift results of quantitative research using patient-reported outcome measures: a descriptive systematic review.

PURPOSE: The objective of this systematic review was to describe the prevalence and magnitude of response shift effects, for different response shift methods, populations, study designs, and patient-reported outcome measures (PROM)s. METHODS: A literature search was performed in MEDLINE, PSYCINFO, CINAHL, EMBASE, Social Science Citation Index, and Dissertations & Theses Global to identify longitudinal quantitative studies that examined response shift using PROMs, published before 2021. The magnitude of each response shift effect (effect sizes, R-squared or percentage of respondents with response shift) was ascertained based on reported statistical information or as stated in the manuscript. Prevalence and magnitudes of response shift effects were summarized at two levels of analysis (study and effect levels), for recalibration and reprioritization/reconceptualization separately, and for different response shift methods, and population, study design, and PROM characteristics. Analyses were conducted twice: (a) including all studies and samples, and (b) including only unrelated studies and independent samples. RESULTS: Of the 150 included studies, 130 (86.7%) detected response shift effects. Of the 4868 effects investigated, 793 (16.3%) revealed response shift. Effect sizes could be determined for 105 (70.0%) of the studies for a total of 1130 effects, of which 537 (47.5%) resulted in detection of response shift. Whereas effect sizes varied widely, most median recalibration effect sizes (Cohen's d) were between 0.20 and 0.30 and median reprioritization/reconceptualization effect sizes rarely exceeded 0.15, across the characteristics. Similar results were obtained from unrelated studies. CONCLUSION: The results draw attention to the need to focus on understanding variability in response shift results: Who experience response shifts, to what extent, and under which circumstances?

Safety and efficacy of tenecteplase versus alteplase in stroke patients with carotid tandem lesions: Results from the AcT trial.

BACKGROUND: Carotid tandem lesions ((TL) ⩾70% stenosis or occlusion) account for 15-20% of acute stroke with large vessel occlusion. AIMS: We investigated the safety and efficacy of intravenous tenecteplase (0.25 mg/kg) versus intravenous alteplase (0.9 mg/kg) in patients with carotid TL. METHODS: This is a substudy of the alteplase compared with the tenecteplase trial. Patients with ⩾70% stenosis of the extracranial internal carotid artery (ICA) and concomitant occlusion of the intracranial ICA, M1 or M2 segments of the middle cerebral artery on baseline computed tomography angiography (CTA) were included. Primary outcome was 90-day-modified Rankin Scale (mRS) 0-1. Secondary outcomes were mRS 0-2, mortality, and symptomatic ICH (sICH). Angiographic outcomes were successful recanalization (revised Arterial Occlusive Lesion (rAOL) 2b-3) on first and successful reperfusion (eTICI 2b-3) on final angiographic acquisitions. Multivariable mixed-effects logistic regression was performed. RESULTS: Among 1577 alteplase versus tenecteplase randomized controlled trial (AcT) patients, 128 (18.8%) had carotid TL. Of these, 93 (72.7%) underwent intravenous thrombolysis plus endovascular thrombectomy (IVT + EVT), while 35 (27.3%) were treated with IVT alone. In the IVT + EVT group, tenecteplase was associated with higher odds of 90-day-mRS 0-1 (46.0% vs. 32.6%, adjusted OR (aOR) 3.21; 95% CI = 1.06-9.71) compared with alteplase. No statistically significant differences in rates of mRS 0-2 (aOR 1.53; 95% CI = 0.51-4.55), initial rAOL 2b-3 (16.3% vs. 28.6%), final eTICI 2b-3 (83.7% vs. 85.7%), and mortality (18.0% vs. 16.3%) were found. SICH only occurred in one patient. There were no differences in outcomes between thrombolytic agents in the IVT-only group. CONCLUSION: In patients with carotid TL treated with EVT, intravenous tenecteplase may be associated with similar or better clinical outcomes, similar angiographic reperfusion rates, and safety outcomes as compared with alteplase.

Unsupervised item response theory models for assessing sample heterogeneity in patient-reported outcomes measures.

PURPOSE: Unsupervised item-response theory (IRT) models such as polytomous IRT based on recursive partitioning (IRTrees) and mixture IRT (MixIRT) models can be used to assess differential item functioning (DIF) in patient-reported outcome measures (PROMs) when the covariates associated with DIF are unknown a priori. This study examines the consistency of results for IRTrees and MixIRT models. METHODS: Data were from 4478 individuals in the Alberta Provincial Project on Outcome Assessment in Coronary Heart Disease registry who received cardiac angiography in Alberta, Canada, and completed the Hospital Anxiety and Depression Scale (HADS) depression subscale items. The partial credit model (PCM) based on recursive partitioning (PCTree) and mixture PCM (MixPCM) were used to identify covariates associated with differential response patterns to HADS depression subscale items. Model covariates included demographic and clinical characteristics. RESULTS: The median (interquartile range) age was 64.5(15.7) years, and 3522(78.5%) patients were male. The PCTree identified 4 terminal nodes (subgroups) defined by smoking status, age, and body mass index. A 3-class PCM fits the data well. The MixPCM latent classes were defined by age, disease indication, smoking status, comorbid diabetes, congestive heart failure, and chronic obstructive pulmonary disease. CONCLUSION: PCTree and MixPCM were not consistent in detecting covariates associated with differential interpretations of PROM items. Future research will use computer simulations to assess these models' Type I error and statistical power for identifying covariates associated with DIF.

Response shift in coronary artery disease.

PURPOSE: Patients with coronary artery disease (CAD) experience significant angina symptoms and lifestyle changes. Revascularization procedures can result in better patient-reported outcomes (PROs) than optimal medical therapy (OMT) alone. This study evaluates the impact of response shift (RS) on changes in PROs of patients with CAD across treatment strategies. METHODS: Data were from patients with CAD in the Alberta Provincial Project on Outcome Assessment in Coronary Heart Disease (APPROACH) registry who completed the 16-item Canadian version of the Seattle Angina Questionnaire at 2 weeks and 1 year following a coronary angiogram. Multi-group confirmatory factor analysis (MG-CFA) was used to assess measurement invariance across treatment groups at week 2. Longitudinal MG-CFA was used to test for RS according to receipt of coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or optimal medical therapy (OMT) alone. RESULTS: Of the 3116 patients included in the analysis, 443 (14.2%) received CABG, 2049(65.8%) PCI, and the remainder OMT alone. The MG-CFA revealed a partial-strong invariance across the treatment groups at 2 weeks (CFI = 0.98, RMSEA [90% CI] = 0.05 [0.03, 0.06]). Recalibration RS was detected on the Angina Symptoms and Burden subscale and its magnitude in the OMT, PCI, and CABG groups were 0.32, 0.28, and 0.53, respectively. After adjusting for RS effects, the estimated target changes were largest in the CABG group and negligible in the OMT group. CONCLUSION: Adjusting for RS is recommended in studies that use SAQ-CAN to assess changes in patients with CAD who have received revascularization versus OMT alone.

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack.

Background: Stroke, even when minor, increases the risk of dementia. We aimed to determine whether patients with transient ischaemic attack (TIA) exhibit higher rates of cerebral and regional atrophy 1-year after first stroke symptoms and evaluate the relationship with small vessel disease and cognitive performance. Methods: TIA patients and controls without cognitive symptoms underwent high-resolution T1-weighted MRI and cognitive testing at baseline and 1-year. Percent brain volume change (PBVC) was measured, and the location of regional atrophy and small vessel disease (CSVD) burden was evaluated. Neuropsychological testing assessed memory, processing speed, and executive function. Results: A total of 76 TIA patients and 53 controls of mean age 67 (SD = 8) and 68 years (SD = 8) were recruited. TIA patients demonstrated greater improvement of visual memory and executive function at 1-year. TIA patients had greater median PBVC/year compared to controls (-0.79% [(-1.22)-(-0.38)] vs. -0.41% [(-0.62)-0.19]; p < 0.001), and higher rates of volume loss (ml/year) in subcortical gray (-0.53 [(-1.09)-(-0.06)] vs. -0.13 [(-0.61)-0.31]; p < 0.05) and white matter (-2.21 [-5.47, 0.40] vs. -0.93 [(-3.43)-2.10]; p < 0.05). Linear regression showed that TIA, age, and systolic blood pressure (SBP) were associated with greater cerebral volume loss over 1-year. There was no significant relationship between PBVC and 1-year cognition. Conclusion: A near two-fold increase in rate of cerebral atrophy 1-year after TIA is associated with higher SBP emphasizing the need for improved treatment of SBP. Cerebral and regional atrophy rates may be used to select patients for vascular risk reduction trials or novel therapeutics in future dementia prevention trials.

Crowd-sourcing and automation facilitated the identification and classification of randomized controlled trials in a living review.

OBJECTIVES: To evaluate an approach using automation and crowdsourcing to identify and classify randomized controlled trials (RCTs) for rheumatoid arthritis (RA) in a living systematic review (LSR). METHODS: Records from a database search for RCTs in RA were screened first by machine learning and Cochrane Crowd to exclude non-RCTs, then by trainee reviewers using a Population, Intervention, Comparison, and Outcome (PICO) annotator platform to assess eligibility and classify the trial to the appropriate review. Disagreements were resolved by experts using a custom online tool. We evaluated the efficiency gains, sensitivity, accuracy, and interrater agreement (kappa scores) between reviewers. RESULTS: From 42,452 records, machine learning and Cochrane Crowd excluded 28,777 (68%), trainee reviewers excluded 4,529 (11%), and experts excluded 7,200 (17%). The 1,946 records eligible for our LSR represented 220 RCTs and included 148/149 (99.3%) of known eligible trials from prior reviews. Although excluded from our LSRs, 6,420 records were classified as other RCTs in RA to inform future reviews. False negative rates among trainees were highest for the RCT domain (12%), although only 1.1% of these were for the primary record. Kappa scores for two reviewers ranged from moderate to substantial agreement (0.40-0.69). CONCLUSION: A screening approach combining machine learning, crowdsourcing, and trainee participation substantially reduced the screening burden for expert reviewers and was highly sensitive.

Effect of Time to Thrombolysis on Clinical Outcomes in Patients With Acute Ischemic Stroke Treated With Tenecteplase Compared to Alteplase: Analysis From the AcT Randomized Controlled Trial.

BACKGROUND: The AcT (Alteplase Compared to Tenecteplase) randomized controlled trial showed that tenecteplase is noninferior to alteplase in treating patients with acute ischemic stroke within 4.5 hours of symptom onset. The effect of time to treatment on clinical outcomes with alteplase is well known; however, the nature of this relationship is yet to be described with tenecteplase. We assessed whether the association of time to thrombolysis treatment with clinical outcomes in patients with acute ischemic stroke differs by whether they receive intravenous tenecteplase versus alteplase. METHODS: Patients included were from AcT, a pragmatic, registry-linked, phase 3 randomized controlled trial comparing intravenous tenecteplase to alteplase in patients with acute ischemic stroke. Eligible patients were >18 years old, with disabling neurological deficits, presenting within 4.5 hours of symptom onset, and eligible for thrombolysis. Primary outcome was modified Rankin Scale score 0 to 1 at 90 days. Safety outcomes included 24-hour symptomatic intracerebral hemorrhage and 90-day mortality rates. Mixed-effects logistic regression was used to assess the following: (a) the association of stroke symptom onset to needle time; (b) door (hospital arrival) to needle time with outcomes; and (c) if these associations were modified by type of thrombolytic administered (tenecteplase versus alteplase), after adjusting for age, sex, baseline stroke severity, and site of intracranial occlusion. RESULTS: Of the 1538 patients included in this analysis, 1146 (74.5%; 591 tenecteplase and 555 alteplase) presented within 3 hours versus 392 (25.5%; 196: TNK and 196 alteplase) who presented within 3 to 4.5 hours of symptom onset. Baseline patient characteristics in the 0 to 3 hours versus 3- to 4.5-hour time window were similar, except patients in the 3- to 4.5-hour window had lower median baseline National Institutes of Health Stroke Severity Scale (10 versus 7, respectively) and lower proportion of patients with large vessel occlusion on baseline CT angiography (26.9% versus 18.7%, respectively). Type of thrombolytic agent (tenecteplase versus alteplase) did not modify the association between continuous onset to needle time (Pinteraction=0.161) or door-to-needle time (Pinteraction=0.972) and primary clinical outcome. Irrespective of the thrombolytic agent used, each 30-minute reduction in onset to needle time was associated with a 1.8% increase while every 10 minutes reduction in door-to-needle time was associated with a 0.2% increase in the probability of achieving 90-day modified Rankin Scale score 0 to 1, respectively. CONCLUSIONS: The effect of time to tenecteplase administration on clinical outcomes is like that of alteplase, with faster administration resulting in better clinical outcomes. REGISTRATION: URL: https://classic. CLINICALTRIALS: gov; Unique identifier: NCT03889249.

The British Columbia Farmers' Market Nutrition Coupon Program Reduces Short-Term Household Food Insecurity Among Adults With Low Incomes: A Pragmatic Randomized Controlled Trial.

BACKGROUND: The British Columbia Farmers' Market Nutrition Coupon Program (BC FMNCP) provides households with low incomes with coupons to purchase healthy foods from farmers' markets. OBJECTIVE: To examine the impact of the BC FMNCP on the short-term household food insecurity, malnutrition risk, mental well-being, sense of community (secondary outcomes), and subjective social status (exploratory outcome) of adults with low incomes post-intervention and 16 weeks post-intervention. DESIGN: Secondary analyses from a pragmatic randomized controlled trial conducted in 2019 that collected data at baseline, post-intervention, and 16 weeks post-intervention. PARTICIPANTS/SETTING: Adults ≥18 years with low incomes were randomized to an FMNCP group (n = 143) or a no-intervention control group (n = 142). INTERVENTION: Participants in the FMNCP group received 16 coupon sheets valued at $21 Canadian dollars (CAD)/sheet over 10 to 15 weeks to purchase healthy foods from farmers' markets and were eligible to participate in nutrition skill-building activities. MAIN OUTCOME MEASURES: Outcomes included short-term household food insecurity (modified version of Health Canada's 18-item Household Food Security Survey Module), malnutrition risk (Malnutrition Universal Screening Tool), mental well-being (Warwick-Edinburgh Mental Well-Being Scale), sense of community (Brief Sense of Community Scale), and subjective social status (MacArthur Scale of Subjective Social Status community scale). STATISTICAL ANALYSIS: Mixed-effects linear regression and multinomial logistic regression examined between-group differences in outcomes post-intervention and 16 weeks post-intervention. RESULTS: The risk of marginal and severe short-term household food insecurity was lower among those in the FMNCP group compared with those in the control group (relative risk ratio [RRR] 0.15, P = 0.01 and RRR 0.16, P = 0.02) post-intervention, with sustained reductions in severe household food insecurity 16 weeks post-intervention (RRR 0.11, P = 0.01). No statistically significant differences were observed in malnutrition risk, mental well-being, sense of community, or subjective social status post-intervention or 16 weeks post-intervention. CONCLUSIONS: The BC FMNCP reduced short-term household food insecurity but was not found to improve malnutrition risk or psychosocial well-being among adults with low incomes compared with a no-intervention control group.

Association of comorbid-socioeconomic clusters with mortality in late onset epilepsy derived through unsupervised machine learning.

BACKGROUND AND OBJECTIVES: Late-onset epilepsy is a heterogenous entity associated with specific aetiologies and an elevated risk of premature mortality. Specific multimorbid-socioeconomic profiles and their unique prognostic trajectories have not been described. We sought to determine if specific clusters of late onset epilepsy exist, and whether they have unique hazards of premature mortality. METHODS: We performed a retrospective observational cohort study linking primary and hospital-based UK electronic health records with vital statistics data (covering years 1998-2019) to identify all cases of incident late onset epilepsy (from people aged ≥65) and 1:10 age, sex, and GP practice-matched controls. We applied hierarchical agglomerative clustering using common aetiologies identified at baseline to define multimorbid-socioeconomic profiles, compare hazards of early mortality, and tabulating causes of death stratified by cluster. RESULTS: From 1,032,129 people aged ≥65, we identified 1048 cases of late onset epilepsy who were matched to 10,259 controls. Median age at epilepsy diagnosis was 68 (interquartile range: 66-72) and 474 (45%) were female. The hazard of premature mortality related to late-onset epilepsy was higher than matched controls (hazard ratio [HR] 1.73; 95% confidence interval [95%CI] 1.51-1.99). Ten unique phenotypic clusters were identified, defined by 'healthy' males and females, ischaemic stroke, intracerebral haemorrhage (ICH), ICH and alcohol misuse, dementia and anxiety, anxiety, depression in males and females, and brain tumours. Cluster-specific hazards were often similar to that derived for late-onset epilepsy as a whole. Clusters that differed significantly from the base late-onset epilepsy hazard were 'dementia and anxiety' (HR 5.36; 95%CI 3.31-8.68), 'brain tumour' (HR 4.97; 95%CI 2.89-8.56), 'ICH and alcohol misuse' (HR 2.91; 95%CI 1.76-4.81), and 'ischaemic stroke' (HR 2.83; 95%CI 1.83-4.04). These cluster-specific risks were also elevated compared to those derived for tumours, dementia, ischaemic stroke, and ICH in the whole population. Seizure-related cause of death was uncommon and restricted to the ICH, ICH and alcohol misuse, and healthy female clusters. SIGNIFICANCE: Late-onset epilepsy is an amalgam of unique phenotypic clusters that can be quantitatively defined. Late-onset epilepsy and cluster-specific comorbid profiles have complex effects on premature mortality above and beyond the base rates attributed to epilepsy and cluster-defining comorbidities alone.

Machine learning using multimodal clinical, electroencephalographic, and magnetic resonance imaging data can predict incident depression in adults with epilepsy: A pilot study.

OBJECTIVE: This study was undertaken to develop a multimodal machine learning (ML) approach for predicting incident depression in adults with epilepsy. METHODS: We randomly selected 200 patients from the Calgary Comprehensive Epilepsy Program registry and linked their registry-based clinical data to their first-available clinical electroencephalogram (EEG) and magnetic resonance imaging (MRI) study. We excluded patients with a clinical or Neurological Disorders Depression Inventory for Epilepsy (NDDI-E)-based diagnosis of major depression at baseline. The NDDI-E was used to detect incident depression over a median of 2.4 years of follow-up (interquartile range [IQR] = 1.5-3.3 years). A ReliefF algorithm was applied to clinical as well as quantitative EEG and MRI parameters for feature selection. Six ML algorithms were trained and tested using stratified threefold cross-validation. Multiple metrics were used to assess model performances. RESULTS: Of 200 patients, 150 had EEG and MRI data of sufficient quality for ML, of whom 59 were excluded due to prevalent depression. Therefore, 91 patients (41 women) were included, with a median age of 29 (IQR = 22-44) years. A total of 42 features were selected by ReliefF, none of which was a quantitative MRI or EEG variable. All models had a sensitivity > 80%, and five of six had an F1 score ≥ .72. A multilayer perceptron model had the highest F1 score (median = .74, IQR = .71-.78) and sensitivity (84.3%). Median area under the receiver operating characteristic curve and normalized Matthews correlation coefficient were .70 (IQR = .64-.78) and .57 (IQR = .50-.65), respectively. SIGNIFICANCE: Multimodal ML using baseline features can predict incident depression in this population. Our pilot models demonstrated high accuracy for depression prediction. However, overall performance and calibration can be improved. This model has promise for identifying those at risk for incident depression during follow-up, although efforts to refine it in larger populations along with external validation are required.

Safety and Efficacy of Tenecteplase Compared With Alteplase in Patients With Large Vessel Occlusion Stroke: A Prespecified Secondary Analysis of the ACT Randomized Clinical Trial.

Importance: It is unknown whether intravenous thrombolysis using tenecteplase is noninferior or preferable compared with alteplase for patients with acute ischemic stroke. Objective: To examine the safety and efficacy of tenecteplase compared to alteplase among patients with large vessel occlusion (LVO) stroke. Design, Setting, and Participants: This was a prespecified analysis of the Intravenous Tenecteplase Compared With Alteplase for Acute Ischaemic Stroke in Canada (ACT) randomized clinical trial that enrolled patients from 22 primary and comprehensive stroke centers across Canada between December 10, 2019, and January 25, 2022. Patients 18 years and older with a disabling ischemic stroke within 4.5 hours of symptom onset were randomly assigned (1:1) to either intravenous tenecteplase or alteplase and were monitored for up to 120 days. Patients with baseline intracranial internal carotid artery (ICA), M1-middle cerebral artery (MCA), M2-MCA, and basilar occlusions were included in this analysis. A total of 1600 patients were enrolled, and 23 withdrew consent. Exposures: Intravenous tenecteplase (0.25 mg/kg) vs intravenous alteplase (0.9 mg/kg). Main Outcomes and Measures: The primary outcome was the proportion of modified Rankin scale (mRS) score 0-1 at 90 days. Secondary outcomes were an mRS score from 0 to 2, mortality, and symptomatic intracerebral hemorrhage. Angiographic outcomes were successful reperfusion (extended Thrombolysis in Cerebral Infarction scale score 2b-3) on first and final angiographic acquisitions. Multivariable analyses (adjusting for age, sex, National Institute of Health Stroke Scale score, onset-to-needle time, and occlusion location) were carried out. Results: Among 1577 patients, 520 (33.0%) had LVO (median [IQR] age, 74 [64-83] years; 283 [54.4%] women): 135 (26.0%) with ICA occlusion, 237 (45.6%) with M1-MCA, 117 (22.5%) with M2-MCA, and 31 (6.0%) with basilar occlusions. The primary outcome (mRS score 0-1) was achieved in 86 participants (32.7%) in the tenecteplase group vs 76 (29.6%) in the alteplase group. Rates of mRS 0-2 (129 [49.0%] vs 131 [51.0%]), symptomatic intracerebral hemorrhage (16 [6.1%] vs 11 [4.3%]), and mortality (19.9% vs 18.1%) were similar in the tenecteplase and alteplase groups, respectively. No difference was noted in successful reperfusion rates in the first (19 [9.2%] vs 21 [10.5%]) and final angiogram (174 [84.5%] vs 177 [88.9%]) among 405 patients who underwent thrombectomy. Conclusions and Relevance: The findings in this study indicate that intravenous tenecteplase conferred similar reperfusion, safety, and functional outcomes compared to alteplase among patients with LVO.

Independent Associations of Incident Epilepsy and Enzyme-Inducing and Non-Enzyme-Inducing Antiseizure Medications With the Development of Osteoporosis.

Importance: Both epilepsy and enzyme-inducing antiseizure medications (eiASMs) having varying reports of an association with increased risks for osteoporosis. Objective: To quantify and model the independent hazards for osteoporosis associated with incident epilepsy and eiASMS and non-eiASMs. Design, Setting, and Participants: This open cohort study covered the years 1998 to 2019, with a median (IQR) follow-up of 5 (1.7-11.1) years. Data were collected for 6275 patients enrolled in the Clinical Practice Research Datalink and from hospital electronic health records. No patients who met inclusion criteria (Clinical Practice Research Datalink-acceptable data, aged 18 years or older, follow-up after the Hospital Episode Statistics patient care linkage date of 1998, and free of osteoporosis at baseline) were excluded or declined. Exposure: Incident adult-onset epilepsy using a 5-year washout and receipt of 4 consecutive ASMs. Main Outcomes and Measures: The outcome was incident osteoporosis as determined through Cox proportional hazards or accelerated failure time models where appropriate. Incident epilepsy was treated as a time-varying covariate. Analyses controlled for age, sex, socioeconomic status, cancer, 1 or more years of corticosteroid use, body mass index, bariatric surgery, eating disorders, hyperthyroidism, inflammatory bowel disease, rheumatoid arthritis, smoking status, falls, fragility fractures, and osteoporosis screening tests. Subsequent analyses (1) excluded body mass index, which was missing in 30% of patients; (2) applied propensity score matching for receipt of an eiASM; (3) restricted analyses to only those with incident onset epilepsy; and (4) restricted analyses to patients who developed epilepsy at age 65 years or older. Analyses were performed between July 1 and October 31, 2022, and in February 2023 for revisions. Results: Of 8 095 441 adults identified, 6275 had incident adult-onset epilepsy (3220 female [51%] and 3055 male [49%]; incidence rate, 62 per 100 000 person-years) with a median (IQR) age of 56 (38-73) years. When controlling for osteoporosis risk factors, incident epilepsy was independently associated with a 41% faster time to incident osteoporosis (time ratio [TR], 0.59; 95% CI, 0.52-0.67; P < .001). Both eiASMs (TR, 0.91; 95% CI, 0.87-0.95; P < .001) and non-eiASMs (TR, 0.77; 95% CI, 0.76-0.78; P < .001) were also associated with significant increased risks independent of epilepsy, accounting for 9% and 23% faster times to development of osteoporosis, respectively. The independent associations among epilepsy, eiASMs, and non-eiASMs remained consistent in propensity score-matched analyses, cohorts restricted to adult-onset epilepsy, and cohorts restricted to late-onset epilepsy. Conclusions and Relevance: These findings suggest that epilepsy is independently associated with a clinically meaningful increase in the risk for osteoporosis, as are both eiASMs and non-eiASMs. Routine screening and prophylaxis should be considered in all people with epilepsy.

Response shift in parent-reported psychopathology in children with chronic physical illness.

PURPOSE: Because physical-mental comorbidity in children is relatively common, this study tested for response shift (RS) in children with chronic physical illness using a parent-reported measure of child psychopathology. METHODS: Data come from Multimorbidity in Children and Youth across Life-course (MY LIFE), a prospective study of n = 263 children aged 2-16 years with physical illness in Canada. Parents provided information on child psychopathology using the Ontario Child Health Study Emotional Behavioral Scales (OCHS-EBS) at baseline and 24 months. Oort's structural equation modeling was used to test for different forms of RS in parent-reported assessments between baseline and 24 months. Model fit was evaluated using root mean square error of approximation (RMSEA), comparative fit index (CFI), and standardized root mean residual (SRMR). RESULTS: There were n = 215 (81.7%) children with complete data and were included in this analysis. Of these, n = 105 (48.8%) were female and the mean (SD) age was 9.4 (4.2) years. A two-factor measurement model provided good fit to the data [RMSEA (90% CI) = 0.05 (0.01, 0.10); CFI = 0.99; SRMR = 0.03]. Non-uniform recalibration RS was detected on the conduct disorder subscale of the OCHS-EBS. This RS effect had negligible impact on the longitudinal change in externalizing and internalizing disorders construct over time. CONCLUSIONS: Response shift detected on the conduct disorder subscale of the OCHS-EBS, indicated that parents of children with physical illness may recalibrate their responses on child psychopathology over 24 months. Researchers and health professionals should be aware of RS when using the OCHS-EBS to assess child psychopathology over time.

Arterial spin labelling reveals multi-regional cerebral hypoperfusion in patients with transient ischemic attack that are unrelated to ischemia location: A proof-of-concept study.

Background and Aims: Patients with transient ischemic attack (TIA) have a substantially increased risk of early dementia. In this exploratory study, we aim to determine whether patients with TIA have 1) measurable regional cerebral hypoperfusion unrelated to the location of ischemia, and 2) determine the relationship of regional cerebral blood flow (rCBF) with their cognitive profiles. Methods: Patients with TIA (N = 49) and seventy-nine (N = 79) age and sex matched controls underwent formal neuropsychological testing and MRI. Quantitative arterial spin labelling rCBF maps (mL/min/100 g) were registered to the corresponding high resolution T1-weighted image. Linear regression was used to determine the association between demographic, clinical and cognitive variables and rCBF. Results: Patients with TIA had significantly (p < 0.05) lower cognitive scores in the MMSE, MOCA, ACE-R, WAIS-IV DS Coding and Trail Making Tests A and B compared to controls. TIA patients had significantly lower rCBF in the left entorhinal cortex (p = 0.03), right posterior cingulate (p = 0.04), and right precuneus (p = 0.05), after adjusting for age and sex, that were unrelated to the regional anatomical volume and DWI positivity. Regional hypoperfusion in the right posterior cingulate and right precuneus was associated with impaired visual memory (BVMT total, p = 0.05 for both regions) and slower processing speed (TMT A, p = 0.04 and p = 0.01), respectively after adjusting for age and sex. Conclusions: TIA patients have patterns of regional hypoperfusion in multiple cortical regions unrelated to the parcellated regional anatomical volume or the presence of a DWI lesion. Regional hypoperfusion in patients with TIA may be an early marker conferring risk of future cognitive decline that needs to be confirmed by future studies.

Unplanned Extubations Requiring Reintubation in Pediatric Critical Care: An Epidemiological Study.

OBJECTIVES: Unplanned extubations are an infrequent but life-threatening adverse event in pediatric critical care. Due to the rarity of these events, previous studies have been small, limiting the generalizability of findings and the ability to detect associations. Our objectives were to describe unplanned extubations and explore predictors of unplanned extubation requiring reintubation in PICUs. DESIGN: Retrospective observational study and multilevel regression model. SETTING: PICUs participating in Virtual Pediatric Systems (LLC). PATIENTS: Patients (≤ 18 yr) who had an unplanned extubation in PICU (2012-2020). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We developed and trained a multilevel least absolute shrinkage and selection operator (LASSO) logistic regression model in the 2012-2016 sample that accounted for between-PICU variations as a random effect to predict reintubation after unplanned extubation. The remaining sample (2017-2020) was used to externally validate the model. Predictors included age, weight, sex, primary diagnosis, admission type, and readmission status. Model calibration and discriminatory performance were evaluated using Hosmer-Lemeshow goodness-of-fit (HL-GOF) and area under the receiver operating characteristic curve (AUROC), respectively. Of the 5,703 patients included, 1,661 (29.1%) required reintubation. Variables associated with increased risk of reintubation were age (< 2 yr; odds ratio [OR], 1.5; 95% CI, 1.1-1.9) and diagnosis (respiratory; OR, 1.3; 95% CI, 1.1-1.6). Scheduled admission was associated with decreased risk of reintubation (OR, 0.7; 95% CI, 0.6-0.9). With LASSO (lambda = 0.011), remaining variables were age, weight, diagnosis, and scheduled admission. The predictors resulted in AUROC of 0.59 (95% CI, 0.57-0.61); HL-GOF showed the model was well calibrated (p = 0.88). The model performed similarly in external validation (AUROC, 0.58; 95% CI, 0.56-0.61). CONCLUSIONS: Predictors associated with increased risk of reintubation included age and respiratory primary diagnosis. Including clinical factors (e.g., oxygen and ventilatory requirements at the time of unplanned extubation) in the model may increase predictive ability.

The contribution of modifiable risk factors to socioeconomic inequities in cardiovascular disease morbidity and mortality: A nationally representative population-based cohort study.

This study examined the individual and joint effects of modifiable risk factors mediating the associations between socioeconomic position (SEP) and morbidity and mortality from cardiovascular diseases (CVD) in a nationally representative sample of adults in Canada. Participants in the Canadian Community Health Survey (n = 289,800) were followed longitudinally for CVD morbidity and mortality using administrative health and mortality data. SEP was measured as a latent variable consisting of household income and individual educational attainment. Mediators included smoking, physical inactivity, obesity, diabetes and hypertension. The primary outcome was CVD morbidity and mortality, defined as the first fatal/nonfatal CVD event during follow-up (median 6.2 years). Generalized structural equation modeling tested the mediating effects of modifiable risk factors in associations between SEP and CVD in the total population and stratified by sex. Lower SEP was associated with 2.5 times increased odds of CVD morbidity and mortality (OR: 2.52, 95% CI: 2.28, 2.76). Modifiable risk factors mediated 74% of associations between SEP and CVD morbidity and mortality in the total population and were more important mediators of associations in females (83%) than males (62%). Smoking mediated these associations independently and jointly with other mediators. The mediating effects of physical inactivity were through joint mediating effects with obesity, diabetes or hypertension. There were additional joint mediating effects of obesity through diabetes or hypertension in females. Findings point to modifiable risk factors as important targets for interventions along with interventions that target structural determinants of health to reduce socioeconomic inequities in CVD.