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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. [ABSTRACT FROM AUTHOR]

Objective: We aimed to assess the reliability and validity of single‐item global ratings (GR) of satisfaction with epilepsy surgery. Methods: We recruited 240 patients from four centers in Canada and Sweden who underwent epilepsy surgery ≥1 year earlier. Participants completed a validated questionnaire on satisfaction with epilepsy surgery (the ESSQ‐19), plus a single‐item GR of satisfaction with epilepsy surgery twice, 4–6 weeks apart. They also completed validated questionnaires on quality of life, depression, health state utilities, epilepsy severity and disability, medical treatment satisfaction and social desirability. Test‐retest reliability of the GR was assessed with the intra‐class correlation coefficient (ICC). Construct and criterion validity were examined with polyserial correlations between the GR measure of satisfaction and validated questionnaires and with the ESSQ‐19 summary score. Non‐parametric rank tests evaluated levels of satisfaction, and ROC analysis assessed the ability of GRs to distinguish among clinically different patient groups. Results: Median age and time since surgery were 42 years (IQR 32–54) and 5 years (IQR 2–8), respectively. The GR demonstrated good to excellent test‐retest reliability (ICC = 0.76; 95% CI 0.67–0.84) and criterion validity (0.85; 95% CI 0.81–0.89), and moderate correlations in the expected direction with instruments assessing quality of life (0.59; 95% CI 0.51–0.63), health utilities (0.55; 95% CI 0.45–0.65), disability (−0.51; 95% CI −0.41, −0.61), depression (−0.48; 95% CI −0.38, −0.58), and epilepsy severity (−0.48; 95% CI −0.38, −0.58). As expected, correlations were lower for social desirability (0.40; 95% CI 0.28–0.52) and medical treatment satisfaction (0.33; 95% CI 0.21–0.45). The GR distinguished participants who were seizure‐free (AUC 0.75; 95% CI 0.67–0.82), depressed (AUC 0.75; 95% CI 0.67–0.83), and self‐rated as having more severe epilepsy (AUC 0.78; 95% CI 0.71–0.85) and being more disabled (AUC 0.82; 95% CI 0.74–0.90). Significance: The GR of epilepsy surgery satisfaction showed good measurement properties, distinguished among clinically different patient groups, and appears well‐suited for use in clinical practice and research. [ABSTRACT FROM AUTHOR]

Purpose: The Seattle Angina Questionnaire (SAQ) is a widely used patient-reported measure of health status in patients with coronary artery disease. Comparisons of SAQ scores amongst population groups and over time rely on the assumption that its factorial structure is invariant. This study evaluates the measurement invariance of the SAQ across different demographic and clinical groups and over time. Methods: Data were obtained from the Alberta Provincial Project on Outcome Assessment in Coronary Heart Disease registry, a registry of patients who received coronary angiogram in Alberta, Canada. The study cohort consists of adult patients who completed the paper-based version of the 16-item Canadian version of the SAQ (SAQ-CAN) 2 weeks and 1-year post-coronary angiogram between 2009 and 2016. Multi-group confirmatory factor analysis was used to assess configural, weak, strong, and strict measurement invariance across age groups, sex, angina type, treatment, and over time. Model fit was assessed using the comparative fit index and root mean square error of approximation. Results: Of the 8101 patients included in these analysis, 1300 (16.1%) were at least 75 years old, while 1755 (21.7%) were female, 5154 (63.6%) were diagnosed with acute coronary syndrome, 1177 (14.5%) received coronary artery bypass graft treatment, and 3279 had complete data on the SAQ-CAN at both occasions. There was evidence of strict invariance across age, sex, and angina type, and treatment groups, but partial strict invariance was established over time. Conclusion: SAQ-CAN can be used to compare the health status of coronary artery disease patients across population groups and over time. [ABSTRACT FROM AUTHOR]

Objective: The relationship between antiseizure medications (ASMs), which improve health outcomes by controlling seizures, and health‐related quality of life (HRQOL) is poorly understood and may involve intermediate variables. We evaluated the potential mediators of the association between ASMs and HRQOL. Methods: Data are from an outpatient registry of adult patients with epilepsy seen at the Foothills Medical Center, Calgary, Alberta, Canada. Quality of life was measured using the 10‐item Quality of Life in Epilepsy, and depression was measured using the Neurological Disorders Depression Inventory for Epilepsy. Propensity score matching was used to adjust for covariate imbalance between patients who received a single ASM (monotherapy) and those who received two or more ASMs (polytherapy) due to confounding. Mediation analysis was used to estimate the mediating effects of depression and ASM side effects on the association between patients' ASM polytherapy and HRQOL. Results: Of 778 patients included in this analysis, 274 (35.2%) were on two or more ASMs. Patient‐reported depression and ASM side effects jointly mediated the association between ASMs and HRQOL; these mediators accounted for 42% of the total average effect of ASM polytherapy (β = −13.6, 95% confidence interval = −18.2 to −8.6) on HRQOL. Significance: These findings highlight the importance of managing depression and ASM side effects for improving health outcomes of patients requiring treatment with ASMs. Intervention programs aimed at improving HRQOL of patients with epilepsy need to target these potential mediators. [ABSTRACT FROM AUTHOR]

Background: Compared with those with a higher socio-economic position (SEP), individuals with a lower SEP have higher cancer morbidity and mortality. However, the contribution of modifiable risk factors to these inequities is not known. This study aimed to quantify the mediating effects of modifiable risk factors to associations between SEP and cancer morbidity and mortality.Methods: This study used a prospective observational cohort design. We combined eight cycles of the Canadian Community Health Survey (2000/2001-2011) as baseline data to identify a cohort of adults (≥35 years) without cancer at the time of survey administration (n = 309 800). The cohort was linked to the Discharge Abstract Database and the Canadian Mortality Database for cancer morbidity and mortality ascertainment. Individuals were followed from the date they completed the Canadian Community Health Survey until 31 March 2013. Dates of individual first hospitalizations for cancer and deaths due to cancer were captured during this time period. SEP was operationalized using a latent variable combining measures of education and household income. Self-reported modifiable risk factors, including smoking, excess alcohol consumption, low fruit-and-vegetable intake, physical inactivity and obesity, were considered as potential mediators. Generalized structural equation modelling was used to estimate the mediating effects of modifiable risk factors in associations between low SEP and cancer morbidity and mortality in the total population and stratified by sex.Results: Modifiable risk factors together explained 45.6% of associations between low SEP and overall cancer morbidity and mortality. Smoking was the most important mediator in the total population and for males, accounting for 15.5% and 40.2% of the total effect, respectively. For females, obesity was the most important mediator.Conclusions: Modifiable risk factors are important mediators of socio-economic inequities in cancer morbidity and mortality. Nevertheless, more than half of the variance in these associations remained unexplained. Midstream interventions that target modifiable risk factors may help to alleviate inequities in cancer risk in the short term. However, ultimately, upstream interventions that target structural determinants of health are needed to reduce overall socio-economic inequities in cancer morbidity and mortality. [ABSTRACT FROM AUTHOR]

Objective: The 19‐item Epilepsy Surgery Satisfaction Questionnaire (ESSQ‐19) is a validated and reliable post hoc means of assessing patient satisfaction with epilepsy surgery. Prediction models building on these data can be used to counsel patients. Methods: The ESSQ‐19 was derived and validated on 229 patients recruited from Canada and Sweden. We isolated 201 (88%) patients with complete clinical data for this analysis. These patients were adults (≥18 years old) who underwent epilepsy surgery 1 year or more prior to answering the questionnaire. We extracted each patient's ESSQ‐19 score (scale is 0–100; 100 represents complete satisfaction) and relevant clinical variables that were standardized prior to the analysis. We used machine learning (linear kernel support vector regression [SVR]) to predict satisfaction and assessed performance using the R2 calculated following threefold cross‐validation. Model parameters were ranked to infer the importance of each clinical variable to overall satisfaction with epilepsy surgery. Results: Median age was 41 years (interquartile range [IQR] = 32–53), and 116 (57%) were female. Median ESSQ‐19 global score was 68 (IQR = 59–75), and median time from surgery was 5.4 years (IQR = 2.0–8.9). Linear kernel SVR performed well following threefold cross‐validation, with an R2 of.44 (95% confidence interval =.36–.52). Increasing satisfaction was associated with postoperative self‐perceived quality of life, seizure freedom, and reductions in antiseizure medications. Self‐perceived epilepsy disability, age, and increasing frequency of seizures that impair awareness were associated with reduced satisfaction. Significance: Machine learning applied postoperatively to the ESSQ‐19 can be used to predict surgical satisfaction. This algorithm, once externally validated, can be used in clinical settings by fixing immutable clinical characteristics and adjusting hypothesized postoperative variables, to counsel patients at an individual level on how satisfied they will be with differing surgical outcomes. [ABSTRACT FROM AUTHOR]

Objective: No validated tools exist to assess satisfaction with epilepsy surgery. We aimed to develop and validate a new measure of patient satisfaction with epilepsy surgery, the 19‐item Epilepsy Surgery Satisfaction Questionnaire (ESSQ‐19). Methods: An initial 31‐item measure was developed based on literature review, patient focus groups, thematic analysis, and Delphi panels. The questionnaire was administered twice, 4‐6 weeks apart, to 229 adults (≥18 years old) who underwent epilepsy surgery ≥1 year earlier, at three centers in Canada and one in Sweden. Participants also completed seven validated questionnaires to assess construct validity. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) assessed the factorial structure of the questionnaire. Cronbach alpha and intraclass correlation coefficients (ICCs) assessed the internal consistency and test‐retest reliability of the ESSQ‐19. Spearman and polyserial correlations assessed construct validity. Results: Median age of participants and time since surgery were 42 years (interquartile range [IQR] = 32‐54) and 5 years (IQR = 2‐8.75), respectively. EFA and CFA yielded 18 items that segregated into four domains (mean score [SD]), namely, seizure control (76.4 [25]), psychosocial functioning (67.3 [26]), surgical complications (84 [22]), and recovery from surgery (73 [24]), one global satisfaction item, and a summary global score (74 [21]). The domain and summary scores demonstrated good to excellent internal reliability (Cronbach ⍺ range =.84‐.95) and test‐retest reliability (ICC range = 0.71‐0.85). Construct validity was supported by predicted correlations with other instruments. Significance: The ESSQ‐19 is a new, valid, and reliable measure of patient satisfaction with epilepsy surgery that can be used in clinical and research settings. [ABSTRACT FROM AUTHOR]

Background: Comparisons of population health status using self-report measures such as the SF-36 rest on the assumption that the measured items have a common interpretation across sub-groups. However, self-report measures may be sensitive to differential item functioning (DIF), which occurs when sub-groups with the same underlying health status have a different probability of item response. This study tested for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scales in population-based data using latent variable mixture models (LVMMs).Methods: Data were from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective national cohort study. LVMMs were applied to the ten PF and five MH SF-36 items. A standard two-parameter graded response model with one latent class was compared to multi-class LVMMs. Multivariable logistic regression models with pseudo-class random draws characterized the latent classes on demographic and health variables.Results: The CaMos cohort consisted of 9423 respondents. A three-class LVMM fit the PF sub-scale, with class proportions of 0.59, 0.24, and 0.17. For the MH sub-scale, a two-class model fit the data, with class proportions of 0.69 and 0.31. For PF items, the probabilities of reporting greater limitations were consistently higher in classes 2 and 3 than class 1. For MH items, respondents in class 2 reported more health problems than in class 1. Differences in item thresholds and factor loadings between one-class and multi-class models were observed for both sub-scales. Demographic and health variables were associated with class membership.Conclusions: This study revealed DIF in population-based SF-36 data; the results suggest that PF and MH sub-scale scores may not be comparable across sub-groups defined by demographic and health status variables, although effects were frequently small to moderate in size. Evaluation of DIF should be a routine step when analysing population-based self-report data to ensure valid comparisons amongst sub-groups. [ABSTRACT FROM AUTHOR]

Background: Clinical trials and meta-analyses provide some evidence for effectiveness of forgiveness therapy delivered individually or in groups. To date, however, forgiveness therapy has not been evaluated with mentally disordered offenders. Given the high prevalence of experienced and perpetrated trauma among such people, this population may particularly benefit from such an intervention.Aim: The aim of this study is to test the feasibility and impact of a 'learn to forgive' group programme among mentally disordered offenders on a specialist secure hospital setting.Methods: We conducted a non-randomised trial with 36 offenders with mental disorders and 29 comparison patients. The intervention group engaged in a six-week manual-based 'learn to forgive' treatment programme, while the comparison group watched a 90-minute video on forgiveness. Both groups completed measures of anger, depression, stress, forgiveness and satisfaction with life at baseline and then 6 and 18 weeks later. A repeated measures mixed-effects model was used to investigate the association between affective outcomes and type of intervention received, after adjusting for baseline characteristics.Results: The group completion rate was over 90%. The treatment and comparison groups were similar on baseline demographic and criminological measures, but the treatment group had higher baseline anger and depression scores. While both groups showed improved capacity to forgive and reduced negative affect over time, those in the 'learn to forgive' programme showed significantly more improvement in forgiveness and on anger measures.Conclusions and Implications For Practice: Forgiveness training can be delivered effectively to offenders with mental disorders in clinical settings. Its range of benefits, including reduction I in anger as well as improved capacity to forgive, suggest that it may have longer term implications for personal safety and reintegration into mainstream societal settings. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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. • Lower socioeconomic position was associated with 2.5 times increased odds of CVD morbidity and mortality. • Modifiable risk factors mediated 74% of associations between socioeconomic position and CVD morbidity and mortality. • Modifiable risk factors suggest targets for interventions to reduce socioeconomic inequities in CVD. [ABSTRACT FROM AUTHOR]

Background: Outcome data from smoking cessation trials indicate that improvement in mental health occurs after smoking cessation. This suggests that smoking cessation should be a priority for mental health services. However, participants in such trials may not be representative of the general population. This study investigates changes in mental health following smoking cessation in a set of general population samples.Methods: Data from a library of cross-sectional surveys conducted by Statistics Canada between 2001 and 2013 were included in this analysis. Survey estimates were pooled in order to increase precision. Associations between smoking (and smoking cessation), major depressive episodes (MDE) and non-specific distress (assessed using the K-6 scale) were evaluated using meta-analysis and meta-regression techniques.Results: The annual prevalence of major depression was higher in daily (11.0%) than in never smokers (4.4%). The prevalence in former daily smokers was 5.1%. The prevalence of MDE and distress was elevated in those recently quitting but returned to baseline levels within one year.Conclusions: After smoking cessation, indicators of mental health improve over time, especially in the first year. The findings support the idea that smoking cessation should be a part of the management of common mood and anxiety disorders. However, due to its observational nature this study in itself cannot confirm causality, sustained abstinence may be an effect of improved mental health rather than its cause.Limitations: The cross-sectional nature of the constituent surveys does not allow causal inference. No biological measures (e.g. cotinine) were available. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder is a relatively common diagnosis with onset across the lifespan. There is a recent belief that major depressive episodes (MDE) are increasing in adolescence; however, it is not clear if this is truly an increase in prevalence or reflective of other causes such as change in diagnostic patterns. This study aimed to determine whether evidence supports an epidemic of MDE in Canadian adolescents.Methods: Past year MDE prevalence estimates were derived from a series of nationally representative surveys. Random effects meta-regression and graphical analyses were used to evaluate trends. A post hoc analysis compared trends in MDE prevalence to trends in self-reported mood disorder diagnosis (made by a health professional). The sample was split into 9 birth cohorts to examine whether MDE prevalence increased in more recent cohorts.Results: Prevalence of MDE did not significantly change between 2000 and 2014 (β=0.001; p=0.532), and there was no modification of trends by sex or age. However, prevalence of self-reported mood disorder diagnosis by a health professional increased from 2003 to 2014 (β=0.001; p=0.024). There was no indication that MDE prevalence differed by birth cohort.Limitations: Limitations include reduced precision in subgroup analyses, lack of clinical judgement in the structured diagnostic interview, and inability to differentiate mild, moderate and severe episodes of depression.Conclusion: These findings do not support an epidemic of MDE in adolescents, however as more individuals report diagnoses by a health professional, future policy may need to incorporate an increase in need of mental health services. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Disclosures Dr Menon reports stock in Circle NVI and patents for systems of triage in acute stroke. Dr Sajobi reports consulting fees received from Circle NVI and employment at the University of Calgary. Dr Almekhlafi reports to be on the medical advisory board of Palmera Medical, Inc. Dr Deschaintre reports being part of the Association des neurologues du Québec, the Société des Sciences Vasculaires du Québec, and the Université de Montréal. Dr Coutts reports that Boehringer Ingelheim provided a study drug (tenecteplase) for the TEMPO-2 trial. Dr Catanese reports employment with Hamilton Health Sciences and McMaster University, consulting fees from Hoffmann-La Roche Ltd, and a grant/contract from Servier Pharmaceuticals LLC. Dr Field reports consulting fees from AstraZeneca Canada, Bayer, HLS Therapeutics, and Roche; stock and being a fiduciary officer (board member) in Destine Health; grants/contracts from Boehringer Ingelheim and Bayer; and being an expert witness for the Canadian Medical Protective Association. Dr Siddiqui reports a grant/contract from Allergan and other interests from Bayer and Boehringer Ingelheim. Dr Demchuk reports stock in Circle NVI and patents for stroke imaging software; consulting fees from Servier Pharmaceuticals LLC, NovaSignal, Boehringer Ingelheim, HLS Therapeutics, Inc, Hoffmann-La Roche Ltd, and Medtronic; data and safety monitoring with Philips; and other interests from AstraZeneca Canada, Novo Nordisk AS, and Pfizer Canada, Inc. Dr Hill reports employment with the University of Calgary; consulting fees from Brainsgate Ltd; grants/contracts from Biogen, Inc, Boehringer Ingelheim, the Canadian Institutes of Health Research, Medtronic, MicroVention, Inc, and NoNO, Inc; being part of the end point review committee at Merck; stock in Circle NVI; and patents for systems of triage in acute stroke. Dr Poppe reports grant funding from the Fondation Brain Canada and the Heart and Stroke Foundation of Canada and research funding from Stryker. Dr Swartz reports stock in FollowMD, Inc, and grants/contracts from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the National Institutes of Health, the Ontario Brain Institute, and the Sunnybrook Research Institute. The other authors report no conflicts.

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., Competing Interests: Disclosures Dr Field reports compensation from AstraZeneca, Bayer, BMS-Pfizer, HLS Therapeutics, and Roche for consultant services, the Canadian Medical Protective Association as an expert witness, a grant from Bayer, and is on the board of DESTINE Health. Dr Menon reports stock options in Circle CVI and has consulted for Hoffman-Laroche and Boehringer Ingelheim. Dr Coutts is a principal investigator for the TEMPO-2 trial (A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) with the study drug (tenecteplase) provided by Boehringer Ingelheim. Dr Hill reports compensation from BrainsGate for consultant services, grants from Boehringer Ingelheim, the Canadian Institutes of Health Research, Medtronic, MicroVention, Inc, and NoNo, Inc, end point review committee work for Merck, and employment as a professor with the University of Calgary. Dr Poppe reports grants from Stryker, Fondation Brain Canada, and the Heart and Stroke Foundation of Canada. Dr Demchuk reports compensation from Boehringer Ingelheim, HLS Therapeutics, Hoffman-Laroche, Medtronic, NovaSignal, and Servier for consultant services, others from AstraZeneca, Novo Nordisk, and Pfizer, data safety monitoring board participation with Philips, and stock and patent for stroke imaging software with Circle NVI. Dr Catanese reports compensation from Hoffman-Laroche for consultant fees and a grant from Servier. Dr Yu reports grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. Dr Deschaintre reports other compensation from the Association des neurologues du Québec, the Société des Sciences Vasculaires du Québec, and the Université du Montréal. Dr Siddiqui reports a grant from Allergan and other compensation from Bayer and Boehringer Ingelheim. Dr Swartz reports grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the National Institutes of Health, and the Sunnybrook Research Institute and stock in FollowMD, Inc. The other authors report no conflicts.

Background and Objective: Frailty is an important aspect of biological aging, referring to the increased vulnerability of individuals with frailty to physical and psychological stressors. While older adults with epilepsy are an important and distinct clinical group, there are no data on frailty in this population. We hypothesize that frailty will correlate with the seizure frequency and especially the tolerability of antiseizure medications (ASMs) in older adults with epilepsy., Methods: We recruited individuals aged 60 years or older with active epilepsy from 4 Canadian hospital centers. We reported the seizure frequency in the 3 months preceding the interview, while ASM tolerability was quantified using the Liverpool Adverse Events Profile (LAEP). We applied 3 measures of frailty: grip strength as a measure of physical frailty, 1 self-reported score (Edmonton frail score [EFS]), and 1 scale completed by a healthcare professional (clinical frailty scale [CFS]). We also administered standardized questionnaires measuring levels of anxiety, depression, functional disability, and quality of life and obtained relevant clinical and demographic data., Results: Forty-three women and 43 men aged 60-93 years were recruited, 87% of whom had focal epilepsy, with an average frequency of 3.4 seizures per month. Multiple linear regression and zero-inflated negative binomial regression models showed that EFS and CFS scores were associated with decreased ASM tolerability, each point increase leading to 1.83 (95% CI: 0.67-4.30) and 2.49 (95% CI: 1.27-2.39) point increases on the LAEP scale, respectively. Neither the EFS and CFS scores nor grip strength were significantly associated with seizure frequency. The EFS was moderately correlated with depression, anxiety, quality of life, and functional disability, demonstrating the best construct validity among the 3 tested measures of frailty., Discussion: The EFS was significantly, both statistically and clinically, associated with ASM tolerability. It also showed multiple advantages in performance while assessing for frailty in older adults with epilepsy, when compared with the 2 other measures of frailty that we tested. Future studies must focus on what role the EFS during epilepsy diagnosis may play in ASM selection among older adults with epilepsy., (© 2022 American Academy of Neurology.)

Background: 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., Methods: In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual., Findings: Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis., Funding: Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit., Competing Interests: Declaration of interests BKM has stock options in Circle NVI and has consulted for Biogen and Boehringer Ingelheim. SBC is principal investigator of the TEMPO-2 trial, for which Boehringer Ingelheim provides the study drug (tenecteplase). LC has received payments by Servier and consulting fees from Ischaemavie RAPID, Circle NV, and Canadian Medical Protective Association. JS has a grant from Medtronic to the University of Manitoba. AMD has received consulting fees from Medtronic and honoraria from Boehringer Ingelheim. LCG is on advisory boards for AstraZeneca and Servier and has stock options in AstraZenca. ASh has received consulting fees from Bayer, Servier Canada, Daiichi Sanyko Compan, AstraZeneca, VarmX, and Takeda; honoraria from Bayer and Daiichi Sankyo; is on an advisory board for Bayer; and has stock options in Ensho. MDH has received consulting fees from Sun Pharma and Brainsgate and has stock options in Circle NVI. DJG has received consulting fees from HSL Therapeutics. APo has received a project research grant from Stryker and honoraria from BMS-Pfizer. TTS has received consulting fees from Circle NVI. RHS has stock options in FollowMD and receives salary support for research from the Heart & Stroke Foundation of Canada, Sandra Black Centre for Brain Resilience & Recovery, and Ontario Brain Institute. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To assess the use of ketotifen fumarate (KF) to reduce posttraumatic contractures after elbow fractures and/or dislocations., Design: Randomized clinical trial., Setting: Three hospitals in Calgary, Canada, including one Level 1 trauma center., Participants: Adults (n = 151) sustaining operative or nonoperatively managed isolated distal humerus or proximal radius ± ulna fractures or elbow dislocations within 7 days of injury., Interventions: KF 5 mg (n = 74) or lactose placebo (PL, n = 77) orally twice daily for 6 weeks., Main Outcomes: Primary outcome elbow flexion-extension arc range of motion (ROM) at 12 weeks postrandomization. Safety measures including serious adverse events and radiographic fracture line disappearance from 2 to 52 weeks postrandomization., Results: The elbow ROM (mean, confidence interval) was not significantly different between KF (122 degrees, 118-127 degrees) and PL (124 degrees, 119-130 degrees) groups (P = 0.56). There was a significant difference in elbow ROM at 12 weeks postrandomization comparing operative (117 degrees, 112-122 degrees) versus nonoperative groups (128 degrees, 124-133 degrees) irrespective of intervention (P = 0.0011). There were 11 serious adverse events (KF = 6, PL = 5) that were those expected in an elbow fracture population potentially taking KF. There was no statistically significant difference in the rates of these events between the groups. The disappearance of fracture lines over the course of time was similar between groups. There was one nonunion in each group., Conclusions: In a population of operative and nonoperatively managed elbow fractures and/or dislocations KF did not reduce posttraumatic contractures. The administration of KF in this population was not found to result in a significantly higher number of major adverse events when compared with placebo., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Joint replacement, an increasingly common procedure amongst older adults, can substantially improve health-related quality of life (HRQoL). However, differential item functioning (DIF) may affect the accurate interpretation of differences in HRQoL amongst patients with different demographic and health status characteristics but the same underlying (i.e., latent) level of the investigated construct. This study tested for DIF in pre-operative SF-12 physical health (PH) and mental health (MH) sub-scale items amongst patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA)., Methods: Data were from a population-based joint replacement registry from the Canadian province of Manitoba. TKA and THA patients who had surgery between 2009 and 2015 and completed a pre-operative assessment were included. DIF was tested using the multiple indicators multiple causes (MIMIC) method with sex, age group, body weight status, and presence of multiple comorbid conditions (i.e., multimorbidity) as covariates. Analyses were stratified by joint type., Results: The study cohort included 8820 patients; 42.1% underwent THA, 57.3% were female, 32.7% were 70+ years, and 52.8% were obese. For each sub-scale, four of the six items exhibited DIF in both THA and TKA groups. Differences in the covariate effect estimates for DIF and No-DIF models on the MH latent variable were largest for age and body weight status for the THA group, and for sex and multimorbidity for the TKA group. All of the differences were small for PH. Multimorbidity had the strongest association with PH and age and sex had the strongest association with MH in the DIF models., Conclusions: Demographic and health status characteristics influenced SF-12 PH and MH item responses in joint replacement populations, although the size of the effects were not large for PH. We recommend testing and adjusting for DIF effects to ensure comparability of HRQoL measures in joint replacement populations.

Background: Late-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer's vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline., Methods: A total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer's pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid β 1-42 ) and by MR measurements of iron accumulation, a marker for Alzheimer's-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer's disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively., Discussion: The PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high-level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging.

Background: Comparisons of population health status using self-report measures such as the SF-36 rest on the assumption that the measured items have a common interpretation across sub-groups. However, self-report measures may be sensitive to differential item functioning (DIF), which occurs when sub-groups with the same underlying health status have a different probability of item response. This study tested for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scales in population-based data using latent variable mixture models (LVMMs)., Methods: Data were from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective national cohort study. LVMMs were applied to the ten PF and five MH SF-36 items. A standard two-parameter graded response model with one latent class was compared to multi-class LVMMs. Multivariable logistic regression models with pseudo-class random draws characterized the latent classes on demographic and health variables., Results: The CaMos cohort consisted of 9423 respondents. A three-class LVMM fit the PF sub-scale, with class proportions of 0.59, 0.24, and 0.17. For the MH sub-scale, a two-class model fit the data, with class proportions of 0.69 and 0.31. For PF items, the probabilities of reporting greater limitations were consistently higher in classes 2 and 3 than class 1. For MH items, respondents in class 2 reported more health problems than in class 1. Differences in item thresholds and factor loadings between one-class and multi-class models were observed for both sub-scales. Demographic and health variables were associated with class membership., Conclusions: This study revealed DIF in population-based SF-36 data; the results suggest that PF and MH sub-scale scores may not be comparable across sub-groups defined by demographic and health status variables, although effects were frequently small to moderate in size. Evaluation of DIF should be a routine step when analysing population-based self-report data to ensure valid comparisons amongst sub-groups.

Background: Self-reported health status measures, like the Short Form 36-item Health Survey (SF-36), can provide rich information about the overall health of a population and its components, such as physical, mental, and social health. However, differential item functioning (DIF), which arises when population sub-groups with the same underlying (i.e., latent) level of health have different measured item response probabilities, may compromise the comparability of these measures. The purpose of this study was to test for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scale items in a Canadian population-based sample., Methods: Study data were from the prospective Canadian Multicentre Osteoporosis Study (CaMos), which collected baseline data in 1996-1997. DIF was tested using a multiple indicators multiple causes (MIMIC) method. Confirmatory factor analysis defined the latent variable measurement model for the item responses and latent variable regression with demographic and health status covariates (i.e., sex, age group, body weight, self-perceived general health) produced estimates of the magnitude of DIF effects., Results: The CaMos cohort consisted of 9423 respondents; 69.4% were female and 51.7% were less than 65 years. Eight of 10 items on the PF sub-scale and four of five items on the MH sub-scale exhibited DIF. Large DIF effects were observed on PF sub-scale items about vigorous and moderate activities, lifting and carrying groceries, walking one block, and bathing or dressing. On the MH sub-scale items, all DIF effects were small or moderate in size., Conclusions: SF-36 PF and MH sub-scale scores were not comparable across population sub-groups defined by demographic and health status variables due to the effects of DIF, although the magnitude of this bias was not large for most items. We recommend testing and adjusting for DIF to ensure comparability of the SF-36 in population-based investigations.

Purpose: In health-related quality of life (HRQOL) studies, data are often collected on multiple domains for two or more groups of study participants. Quantitative measures of relative importance, which are used to rank order the domains based on their ability to discriminate between groups, are an alternative to multiple tests of significance on the group differences. This study describes relative importance measures based on logistic regression (LR) and multivariate analysis of variance (MANOVA) models., Methods: Relative importance measures are illustrated using data from the Manitoba Inflammatory Bowel Disease (IBD) Cohort Study. Study participants with self-reported active (n = 244) and inactive (n = 105) disease were compared on 12 HRQOL domains from the Inflammatory Bowel Disease Questionnaire (IBDQ) and Medical Outcomes Study 36-item Short-Form (SF-36) Questionnaire., Results: All but two relative importance measures ranked the IBDQ bowel symptoms and emotional health domains as most important., Conclusions: MANOVA-based importance measures are recommended for multivariate normal data and when group covariances are equal, while LR measures are recommended for non-normal data and when the correlations among the domains are small. Relative importance measures can be used in exploratory studies to identify a small set of domains for further research.