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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.

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.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.

IMPORTANCE: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. OBJECTIVE: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. DESIGN, SETTING, AND PARTICIPANTS: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. EXPOSURES: Receipt of 4 consecutive eiASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age ≥18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. MAIN OUTCOMES AND MEASURES: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. RESULTS: Of 10 916 166 adults, 50 888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31 479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from amedian (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years’ follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. CONCLUSIONS AND RELEVANCE: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

IMPORTANCE: Patients with epilepsy are at an elevated risk of premature mortality. Interventions to reduce this risk are crucial. OBJECTIVE: To determine if the level of care (non-neurologist, neurologist, or comprehensive epilepsy program) is negatively associated with the risk of premature mortality. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective open cohort study, all adult patients 18 years or older who met the administrative case definition for incident epilepsy in linked databases (Alberta Health Services administrative health data and the Comprehensive Calgary Epilepsy Programme Registry [CEP]) inclusive of the years 2002 to 2016 were followed up until death or loss to follow-up. The final analyses were performed on May 1, 2019. EXPOSURES: Evaluation by a non-neurologist, neurologist, or epileptologist. MAIN OUTCOMES AND MEASURES: The outcome was all-cause mortality. We used extended Cox models treating exposure to a neurologist or the CEP as time-varying covariates. Age, sex, socioeconomic deprivation, disease severity, and comorbid burden at index date were modeled as fixed-time coefficients. RESULTS: A total 23 653 incident cases were identified (annual incidence of 89 per 100 000); the mean age (SD) at index date was 50.8 (19.1) years and 12 158 (50.3%) were women. A total of 14 099 (60%) were not exposed to specialist neurological care, 9554 (40%) received care by a neurologist, and 2054 (9%) received care in the CEP. In total, 4098 deaths (71%) occurred in the nonspecialist setting, 1481 (26%) for those seen by a neurologist, and 176 (3%) for those receiving CEP care. The standardized mortality rate was 7.2% for the entire cohort, 9.4% for those receiving nonspecialist care, 5.6% for those seen by a neurologist, and 2.8% for those seen in the CEP. The hazard ratio (HR) of mortality was lower in those receiving neurologist (HR, 0.85; 95% CI, 0.77-0.93) and CEP (HR, 0.49; 95% CI, 0.38-0.62) care. In multivariable modeling, specialist care, the age at index, and disease severity were retained in the final model of the association between specialist care and mortality. CONCLUSIONS AND RELEVANCE: Exposure to specialist care is associated with incremental reductions in the hazard of premature mortality. Those referred to a comprehensive epilepsy program received the greatest benefit.

Contrast-induced acute kidney injury (CI-AKI) is a common and serious complication of invasive cardiac procedures. Quality improvement programs have been associated with a lower incidence of CI-AKI over time, but there is a lack of high-quality evidence on clinical decision support for prevention of CI-AKI and its impact on processes of care and clinical outcomes.

IMPORTANCE: Levetiracetam is a commonly used antiepileptic drug, yet psychiatric adverse effects are common and may lead to treatment discontinuation. OBJECTIVE: To derive prediction models to estimate the risk of psychiatric adverse effects from levetiracetam use. DESIGN, SETTING, AND PARTICIPANTS: Retrospective open cohort study. All patients meeting the case definition for epilepsy after the Acceptable Mortality Reporting date in The Health Improvement Network (THIN) database based in the United Kingdom (inclusive January 1, 2000, to May 31, 2012) who received a first-ever prescription for levetiracetam were included. Of 11 194 182 patients registered in THIN, this study identified 7400 presumed incident cases (66.1 cases per 100 000 persons) over a maximum of 12 years’ follow-up. The index date was when patients received their first prescription code for levetiracetam, and follow-up lasted 2 years or until an event, loss to follow-up, or censoring. The analyses were performed on April 22, 2018. EXPOSURE: A presumed first-ever prescription for levetiracetam. MAIN OUTCOMES AND MEASURES: The outcome of interest was a Read code for any psychiatric sign, symptom, or disorder as reached through consensus by 2 authors. This study used regression techniques to derive 2 prediction models, one for the overall population and one for those without a history of a psychiatric sign, symptom, or disorder during the study period. RESULTS: Among 1173 patients with epilepsy receiving levetiracetam, the overall median age was 39 (interquartile range, 25-56) years, and 590 (50.3%) were female. A total of 14.1% (165 of 1173) experienced a psychiatric symptom or disorder within 2 years of index prescription. The odds of reporting a psychiatric symptom were significantly elevated for women (odds ratio [OR], 1.41; 95% CI, 0.99-2.01; P = .05) and those with a preexposure history of higher social deprivation (OR, 1.15; 95% CI, 1.01-1.31; P = .03), depression (OR, 2.20; 95% CI, 1.49-3.24; P < .001), anxiety (OR, 1.74; 95% CI, 1.11-2.72; P = .02), or recreational drug use (OR, 2.02; 95% CI, 1.20-3.37; P = .008). The model performed well after stratified k = 5-fold cross-validation (area under the curve [AUC], 0.68; 95% CI, 0.58-0.79). There was a gradient in risk, with probabilities increasing from 8% for 0 risk factors to 11% to 17% for 1, 17% to 31% for 2, 30% to 42% for 3, and 49% when all risk factors were present. For those free of a preexposure psychiatric code, a second model performed comparably well after k = 5-fold cross-validation (AUC, 0.72; 95% CI, 0.54-0.90). Specificity was maximized using threshold cutoffs of 0.10 (full model) and 0.14 (second model); a score below these thresholds indicates safety of prescription. CONCLUSIONS AND RELEVANCE: This study derived 2 simple models that predict the risk of a psychiatric adverse effect from levetiracetam. These algorithms can be used to guide prescription in clinical practice.

Aims. Patient satisfaction with therapeutic interventions is an important outcome of care. Although generic measures of patient satisfaction exist, there is no validated scale for measuring patient satisfaction with epilepsy surgery. We aimed to systematically obtain patient‐identified factors related to satisfaction with epilepsy surgery as a means of informing clinicians about the ways that patients evaluate outcomes of their treatment and as a conceptual basis for the future development of epilepsy surgery patient satisfaction scales. Methods. Focus group discussions with epilepsy surgery patients (n=9) were conducted to identify themes relevant to patient satisfaction with epilepsy surgery and to draft initial items of importance. Consensus methodology (Delphi technique) was used to obtain expert opinion (n=13) to refine the items. Member‐checking with focus group participants was performed to ensure the identified items were relevant, clear, and inclusive. Results. A list of 31 items embodied 12 themes related to patient‐reported satisfaction with epilepsy surgery. These included adverse effects, medical care or rehabilitation, seizure control, post‐operative recovery, anti‐seizure medication, independence, seizure worry, ability to drive, social relationships, self‐confidence, improved cognitive function, and improved physical health. Conclusions. This study used a systematic approach to identify factors that are important to patients when assessing satisfaction with epilepsy surgery. This knowledge can assist clinicians caring for these patients and is also a critical step towards the validation of a formal scale to assess satisfaction with epilepsy surgery.

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IMPORTANCE: A bidirectional relationship exists between epilepsy and depression. However, any putative biological gradient between depression severity and the risk of epilepsy, and the degree to which depression mediates the influence of independent risk factors for epilepsy, has yet to be examined. OBJECTIVE: To determine the effect of depression on the risk of epilepsy and seizure outcomes. DESIGN, SETTING, AND PARTICIPANTS: An observational study of a population-based primary care cohort (all patients free of prevalent depression and epilepsy at 18-90 years of age who were active after the Acceptable Mortality Reporting date in The Health Improvement Network database) and a prospectively collected tertiary care cohort (all patients whose data were prospectively collected from the Calgary Comprehensive Epilepsy Programme). The analyses were performed on March 16, 2016. MAIN OUTCOME AND MEASURES: The hazard of developing epilepsy after incident depression and vice versa was calculated. In addition, a mediation analysis of the effect of depression on risk factors for epilepsy and the odds of seizure freedom stratified by the presence of depression were performed. RESULTS: We identified 10 595 709 patients in The Health Improvement Network of whom 229 164 (2.2%) developed depression and 97 177 (0.9%) developed epilepsy. The median age was 44 years (interquartile range, 32-58 years) for those with depression and 56 years (interquartile range, 43-71 years) for those with epilepsy. Significantly more patients with depression (144 373 [63%] were women, and 84 791 [37%] were men; P < .001) or epilepsy (54 419 [56%] were women, and 42 758 [44%] were men; P < .001) were female. Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04 [95% CI, 1.97-2.09]; P < .001), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55 [95% CI, 2.49-2.60]; P < .001) There was an incremental hazard according to depression treatment type with lowest risk for those receiving counselling alone (HR, 1.84 [95% CI, 1.30-2.59]; P < .001), an intermediate risk for those receiving antidepressants alone (HR, 3.43 [95% CI, 3.37-3.47]; P < .001), and the highest risk for those receiving both (HR, 9.85 [95% CI, 5.74-16.90]; P < .001). Furthermore, depression mediated the relationship between sex, social deprivation, and Charlson Comorbidity Index with incident epilepsy, accounting for 4.6%, 7.1%, and 20.6% of the total effects of these explanatory variables, respectively. In the Comprehensive Epilepsy Programme, the odds of failing to achieve 1-year seizure freedom were significantly higher for those with depression or treated depression. CONCLUSIONS AND RELEVANCE: Common underlying pathophysiological mechanisms may explain the risk of developing epilepsy following incident depression. Treated depression is associated with worse epilepsy outcomes, suggesting that this may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy.

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Ordinal outcomes, such as modified Rankin Scale (mRS), are the standard primary end points in acute stroke trials. Regression models for assessing treatment efficacy after adjusting for baseline covariates have been developed for continuous, binary, or ordinal end points. There has been no consensus on the best choice of method for analyzing these data.

Abstract: Discriminant analysis (DA) procedures based on parsimonious mean and/or covariance structures have recently been proposed for repeated measures data. However, these procedures rest on the assumption of a multivariate normal distribution. This study examines repeated measures DA (RMDA) procedures based on maximum likelihood (ML) and coordinatewise trimming (CT) estimation methods and investigates bias and root mean square error (RMSE) in discriminant function coefficients (DFCs) using Monte Carlo techniques. Study parameters include population distribution, covariance structure, sample size, mean configuration, and number of repeated measurements. The results show that for ML estimation, bias in DFC estimates was usually largest when the data were normally distributed, but there was no consistent trend in RMSE. For non-normal distributions, the average bias of CT estimates for procedures that assume unstructured group means and structured covariances was at least 40% smaller than the values for corresponding procedures based on ML estimators. The average RMSE for the former procedures was at least 10% smaller than the average RMSE for the latter procedures, but only when the data were sampled from extremely skewed or heavy-tailed distributions. This finding was observed even when the covariance and mean structures of the RMDA procedure were mis-specified. The proposed robust procedures can be used to identify measurement occasions that make the largest contribution to group separation when the data are sampled from multivariate skewed or heavy-tailed distributions. [Copyright &y& Elsevier]

IMPORTANCE: Several real-world oncology studies have produced findings that contradict those from randomized clinical trials. Such disparities may be associated with methodological shortcomings. OBJECTIVE: To examine the association between a shortened duration of adjuvant chemotherapy among individuals with stage III colon cancer using real-world data. DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness study included individuals diagnosed with stage III colon cancer between January 2004 and December 2015 who initiated adjuvant chemotherapy at oncology clinics within the province of Alberta, Canada. Patients were identified through record linkage of various administrative databases and were followed up until September 2017. Eligibility criteria were modeled after those used in the International Duration Evaluation of Adjuvant (IDEA) trial. A target trial emulation and naive observational analysis were conducted. Results from both cohorts were benchmarked against findings from the IDEA trial. Data analysis was conducted from March to December 2020. EXPOSURE: A shortened duration of adjuvant 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX) chemotherapy, defined as 3 to 5 months of treatment vs 6 months. MAIN OUTCOMES AND MEASURES: Overall survival assessed via vital statistics. The per-protocol hazard ratio (HR) was estimated using a weighted pooled logistic regression model. Subgroup analyses were conducted by treatment regimen (ie, FOLFOX vs CAPOX) and cancer stage (ie, T1-3 and N1 vs T4 or N2). RESULTS: From an initial cohort of 3086 patients, 485 (16%) were eligible for inclusion in the target trial analysis. The median age was 59 years (range, 19-81 years), and 230 (47%) were women. The maximum follow-up was 11.6 years. Median overall survival was not reached. A total of 90 patients (19%) died. The 5-year Kaplan Meier overall survival estimate was 0.79 (95% CI, 0.75-0.84). Estimates from the trial emulation were similar to those from the IDEA trial. For example, a shortened duration of adjuvant chemotherapy was not associated with overall survival among patients prescribed CAPOX in the IDEA trial (HR, 0.96; 95% CI, 0.85-1.08) or in the trial emulation (HR, 0.96; 95% CI, 0.43-2.14). In contrast, the naive observational analysis suggested that a shortened duration of CAPOX was significantly associated with worse survival (HR, 3.33; 95% CI, 1.04-10.65). CONCLUSIONS AND RELEVANCE: In this study, the explicit emulation of a target trial better approximated results from an analogous well-conducted randomized clinical trial.

Transient ischemic attack (TIA) and minor ischemic stroke (IS) is associated with a increased risk of late life dementia. In this study we aim to study the extent to which the rates of hippocampal atrophy in TIA/IS differ from healthy controls, and how they are correlated to neuropsychological measurements.

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