Timing of sodium-glucose cotransporter 2 inhibitor initiation and post-discharge outcomes in acute heart failure with diabetes: A population-based cohort study.

AIMS: Results from randomized trials suggest benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation in clinically stable acute heart failure. We aim to examine the real-world effectiveness of early versus delayed post-discharge SGLT2 inhibitor initiation in people with acute heart failure and type 2 diabetes. METHODS AND RESULTS: Using linkable administrative databases in Ontario, Canada, individuals aged 66 years or older with type 2 diabetes who were discharged to the community from acute care hospitals for heart failure between 1 July 2016 and 31 March 2020 were included in this retrospective, population-based cohort study. The primary outcome was hospitalization for heart failure (HHF) or cardiovascular mortality as a composite. Follow-up started from discharge for maximum 1 year. We compared outcomes between post-discharge SGLT2 inhibitor initiation within 3 days, 4-90 days, or 91-180 days, versus delayed initiation for at least 180 days. The 'clone-censor-weight' approach with a target trial emulation framework was used to address time-related biases. There were 9641 eligible individuals. After cloning and artificial censoring, there were 38 564 clones, 12 439 person-years, and 7584 events. Compared to delayed initiation for at least 180 days, initiation within 3 days post-discharge was associated with a lower 1-year risk of HHF or cardiovascular mortality (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.45-0.83), while initiation 4-90 days (RR 0.83, 95% CI 0.72-0.93) or 91-180 days (RR 0.89, 95% CI 0.79-0.97) showed smaller risk reduction. CONCLUSION: Real-world evidence supports early SGLT2 inhibitor initiation to reduce HHF or cardiovascular mortality in acute heart failure and type 2 diabetes.

Cardiovascular phenotypes in type 2 diabetes: Latent class analysis of the CANVAS Program and CREDENCE trial.

AIM: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis. METHODS: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes. RESULTS: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05). CONCLUSION: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability.

A Bayesian model calibration framework for stochastic compartmental models with both time-varying and time-invariant parameters.

We consider state and parameter estimation for compartmental models having both time-varying and time-invariant parameters. In this manuscript, we first detail a general Bayesian computational framework as a continuation of our previous work. Subsequently, this framework is specifically tailored to the susceptible-infectious-removed (SIR) model which describes a basic mechanism for the spread of infectious diseases through a system of coupled nonlinear differential equations. The SIR model consists of three states, namely, the susceptible, infectious, and removed compartments. The coupling among these states is controlled by two parameters, the infection rate and the recovery rate. The simplicity of the SIR model and similar compartmental models make them applicable to many classes of infectious diseases. However, the combined assumption of a deterministic model and time-invariance among the model parameters are two significant impediments which critically limit their use for long-term predictions. The tendency of certain model parameters to vary in time due to seasonal trends, non-pharmaceutical interventions, and other random effects necessitates a model that structurally permits the incorporation of such time-varying effects. Complementary to this, is the need for a robust mechanism for the estimation of the parameters of the resulting model from data. To this end, we consider an augmented state vector, which appends the time-varying parameters to the original system states whereby the time evolution of the time-varying parameters are driven by an artificial noise process in a standard manner. Distinguishing between time-varying and time-invariant parameters in this fashion limits the introduction of artificial dynamics into the system, and provides a robust, fully Bayesian approach for estimating the time-invariant system parameters as well as the elements of the process noise covariance matrix. This computational framework is implemented by leveraging the robustness of the Markov chain Monte Carlo algorithm permits the estimation of time-invariant parameters while nested nonlinear filters concurrently perform the joint estimation of the system states and time-varying parameters. We demonstrate performance of the framework by first considering a series of examples using synthetic data, followed by an exposition on public health data collected in the province of Ontario.

Latent profiles of modifiable dementia risk factors in later midlife: relationships with incident dementia, cognition, and neuroimaging outcomes.

In 2020, the Lancet Commission identified 12 modifiable factors that increase population-level dementia risk. It is unclear if these risk factors co-occur among individuals in a clinically meaningful way. Using latent class analysis, we identified profiles of modifiable dementia risk factors in dementia-free adults aged 60-64 years from the UK Biobank. We then estimated associations between these profiles with incident dementia, cognition, and neuroimaging outcomes, and explored the differences across profiles in the effects of a polygenic risk score for Alzheimer's disease on outcomes. In 55,333 males and 63,063 females, three sex-specific latent profiles were identified: cardiometabolic risk, substance use-related risk, and low risk. The cardiometabolic risk profile in both males and females was associated with greater incidence of all-cause dementia (male: OR [95% CI] = 2.33 [2.03, 2.66]; female: OR [95% CI] = 1.44 [1.24, 1.68]), poorer cognitive performance, greater brain atrophy, and greater white matter hyperintensity volume compared to the low risk profile. The substance use-related risk profile in males was associated with poorer cognitive performance and greater white matter hyperintensities compared to the low risk profile, but no difference in all-cause dementia incidence was observed (OR [95% CI] = 1.00 [0.95, 1.06]). In females, the substance use-related risk profile demonstrated increased dementia incidence (OR [95% CI] = 1.58 [1.57, 1.58]) and greater brain atrophy but smaller white matter hyperintensity volume compared to the low risk profile. The polygenic risk score had larger effects among females, and differentially influenced outcomes across profiles; for instance, there were larger effects of the polygenic risk score on atrophy in the cardiometabolic profile vs. the low risk profile among males, and larger effects of the polygenic risk score on loss of white matter integrity in the cardiometabolic profile vs. the low risk profile among females. These results reveal three modifiable dementia risk profiles, their unique cognitive/neuroimaging outcomes, and their interactions with genetic risk for Alzheimer's disease. These differences highlight the need to consider population heterogeneity in risk prediction tools and in planning personalized prevention strategies.

Longitudinal relationships between depressive symptoms, functional impairment, and physical activity in later late life.

The purpose of this study was to investigate relationships between depressive symptoms, functional disability, and physical activity over time in community-dwelling older adults. The Religious Order Study and Rush Memory and Aging Project are longitudinal cohort studies based in the United States which began recruitment in 1994 and 1997, respectively. This analysis included 1611 participants (27.4% male, 92.9% White, 74.7% cognitively normal) who were included at age 80 and followed until age 90. Depressive symptoms were assessed using the modified Center for Epidemiologic Studies Depression scale. Functional disability was assessed using the Instrumental Activities of Daily Living (IADL) scale. Physical activity was self-reported hours of weekly exercise. Reciprocal temporal relationships between these variables were investigated using a random intercept cross-lagged panel model, which decomposes observed variables into stable between-person ('trait') and variable within-person ('state') components to estimate the directional effects between variables over time. Traits for depressive symptoms, IADL disability, and physical activity were correlated. IADL disability showed autoregressive effects; disability starting at age 82 strongly predicted subsequent disability. Consistent autoregressive effects were not observed for depressive symptoms nor physical activity. Several small cross-lagged effects between states were observed for IADL disability and physical activity, as well as for IADL disability and depressive symptoms. There were no direct effects between depressive symptoms and physical activity, but several paths through IADL disability were observed between ages 82 and 88. Functional disability played an important role in octogenarians, highlighting the importance of maintaining functional independence later in life.

Assessing cardiovascular disease risk in women with a history of hypertensive disorders of pregnancy: A guidance paper for studies using administrative data.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity and mortality, and their association with increased cardiovascular disease (CVD) risk represents a major public health concern. However, assessing CVD risk in women with a history of these conditions presents unique challenges, especially when studies are carried out using routinely collected data. OBJECTIVES: To summarise and describe key challenges related to the design and conduct of administrative studies assessing CVD risk in women with a history of HDP and provide concrete recommendations for addressing them in future research. METHODS: This is a methodological guidance paper. RESULTS: Several conceptual and methodological factors related to the data-generating mechanism and study conceptualisation, design/data management and analysis, as well as the interpretation and reporting of study findings should be considered and addressed when designing and carrying out administrative studies on this topic. Researchers should develop an a priori conceptual framework within which the research question is articulated, important study variables are identified and their interrelationships are carefully considered. CONCLUSIONS: To advance our understanding of CVD risk in women with a history of HDP, future studies should carefully consider and address the conceptual and methodological considerations outlined in this guidance paper. In highlighting these challenges, and providing specific recommendations for how to address them, our goal is to improve the quality of research carried out on this topic.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable.

BACKGROUND AND AIMS: The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations to address outstanding barriers for the translation of preclinical and clinical research using the non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) and provide a roadmap for the integration of these techniques into clinical practice. METHODS: International NIBS and stroke recovery experts (N = 18) contributed to the consensus process. Using a nominal group technique, recommendations were reached via a five-stage process, involving a thematic survey, two priority ranking surveys, a literature review and an in-person meeting. RESULTS AND CONCLUSIONS: Results of our consensus process yielded five key evidence-based and feasibility barriers for the translation of preclinical and clinical NIBS research, which were formulated into five core consensus recommendations. Recommendations highlight an urgent need for (1) increased understanding of NIBS mechanisms, (2) improved methodological rigor in both preclinical and clinical NIBS studies, (3) standardization of outcome measures, (4) increased clinical relevance in preclinical animal models, and (5) greater optimization and individualization of NIBS protocols. To facilitate the implementation of these recommendations, the expert panel developed a new SRRR3 Unified NIBS Research Checklist. These recommendations represent a translational pathway for the use of NIBS in stroke rehabilitation research and practice.

Scalable computational algorithms for geospatial COVID-19 spread using high performance computing.

A nonlinear partial differential equation (PDE) based compartmental model of COVID-19 provides a continuous trace of infection over space and time. Finer resolutions in the spatial discretization, the inclusion of additional model compartments and model stratifications based on clinically relevant categories contribute to an increase in the number of unknowns to the order of millions. We adopt a parallel scalable solver that permits faster solutions for these high fidelity models. The solver combines domain decomposition and algebraic multigrid preconditioners at multiple levels to achieve the desired strong and weak scalabilities. As a numerical illustration of this general methodology, a five-compartment susceptible-exposed-infected-recovered-deceased (SEIRD) model of COVID-19 is used to demonstrate the scalability and effectiveness of the proposed solver for a large geographical domain (Southern Ontario). It is possible to predict the infections for a period of three months for a system size of 186 million (using 3200 processes) within 12 hours saving months of computational effort needed for the conventional solvers.

Systematic review of validated case definitions to identify hypertensive disorders of pregnancy in administrative healthcare databases.

BACKGROUND: Administrative data are frequently used to study cardiovascular disease (CVD) risk in women with hypertensive disorders of pregnancy (HDP). Little is known about the validity of case-finding definitions (CFDs, eg, disease classification codes/algorithms) designed to identify HDP in administrative databases. METHODS: A systematic review of the literature. We searched MEDLINE, Embase, CINAHL, Web of Science and grey literature sources for eligible studies. Two independent reviewers screened articles for eligibility and extracted data. Quality of reporting was assessed using checklists; risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, adapted for administrative studies. Findings were summarised descriptively. RESULTS: Twenty-six studies were included; most (62%) validated CFDs for a variety of maternal and/or neonatal outcomes. Six studies (24%) reported reference standard definitions for all HDP definitions validated; seven reported all 2×2 table values for ≥1 CFD or they were calculable. Most CFDs (n=83; 58%) identified HDP with high specificity (ie, ≥98%); however, sensitivity varied widely (3%-100%). CFDs validated for any maternal hypertensive disorder had the highest median sensitivity (91%, range: 15%-97%). Quality of reporting was generally poor, and all studies were at unclear or high risk of bias on ≥1 QUADAS-2 domain. CONCLUSIONS: Even validated CFDs are subject to bias. Researchers should choose the CFD(s) that best align with their research objective, while considering the relative importance of high sensitivity, specificity, negative predictive value and/or positive predictive value, and important characteristics of the validation studies from which they were derived (eg, study prevalence of HDP, spectrum of disease studied, methodological rigour, quality of reporting and risk of bias). Higher quality validation studies on this topic are urgently needed. PROSPERO REGISTRATION NUMBER: CRD42021239113.

Association of sulfonylureas with the risk of dementia: A population-based cohort study.

BACKGROUND: Sulfonylureas are oral glucose-lowering medications positioned as a second-line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase-4 (DPP4) inhibitor use. METHODS: Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population-based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention-to-treat exposure definition. A separate propensity-score weighted analysis was conducted to explore within-class differences in dementia risk among sulfonylurea new users selected from the primary cohort. RESULTS: Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person-years; aHR [95% CI] = 1.09 [1.04-1.15]) over a mean follow-up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03-1.32]). CONCLUSION: New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes.

Maternal Health Outcomes After Pregnancy-Associated Stroke: A Population-Based Study With 19 Years of Follow-Up.

BACKGROUND: Pregnancy-associated stroke carries high short-term morbidity and mortality, but data on subsequent maternal outcomes are limited. We evaluated long-term maternal health outcomes after pregnancy-associated stroke. METHODS: In this retrospective cohort study, we used administrative data to identify pregnant adults aged ≤49 years with stroke between 2002-2020 in Ontario, Canada and 2 comparison groups: (1) non-pregnant female patients with stroke and (2) pregnant patients without stroke. Patients who survived the index admission were followed until 2021. After propensity score matching, we used Cox regression with a robust variance estimator to compare pregnant patients with stroke and the 2 comparison groups for the composite outcome of death and all-cause non-pregnancy readmission. Where proportional hazard assumption was not met, we reported time-varying hazard ratios (HR) with 95% CIs by modeling the log-hazard ratio as a function of time using restricted cubic splines. RESULTS: We identified 217 pregnant patients with stroke, 7604 non-pregnant patients with stroke, and 1 496 256 pregnant patients without stroke. Of the 202 pregnant patients with stroke who survived the index stroke admission, 41.6% (6.8 per 100 person-years) subsequently died or were readmitted during follow-up. Median follow-up times were 5 years (pregnancy-associated stroke), 3 years (non-pregnant stroke), and 8 years (pregnant without stroke). Pregnant patients with stroke had a lower hazard of death and all-cause readmission compared with non-pregnant patients with stroke at 1-year follow-up (HR, 0.64 [95% CI, 0.44-0.94]), but this association did not persist during longer-term follow-up. Conversely, pregnant patients with stroke had higher hazard of death and readmission compared with pregnant patients without stroke at 1-year follow-up (HR, 5.70 [95% CI, 3.04-10.66]), and this association persisted for a decade. CONCLUSIONS: Stroke during pregnancy is associated with long-term health consequences. It is essential to transition care postpartum to primary or specialty care to optimize vascular health.

Sex Differences in Intensity of Care and Outcomes After Acute Ischemic Stroke Across the Age Continuum.

BACKGROUND AND OBJECTIVES: Sex differences in stroke care and outcomes have been previously reported, but it is not known whether these associations vary across the age continuum. We evaluated whether the magnitude of female-male differences in care and outcomes varied with age. METHODS: In a population-based cohort study, we identified patients hospitalized with ischemic stroke between 2012 and 2019 and followed through 2020 in Ontario, Canada, using administrative data. We evaluated sex differences in receiving intensive care unit services, mechanical ventilation, gastrostomy tube insertion, comprehensive stroke center care, stroke unit care, thrombolysis, and endovascular thrombectomy using logistic regression and reported odds ratios (ORs) and 95% CIs. We used Cox proportional hazard models and reported the hazard ratios (HRs) and 95% CI of death within 90 or 365 days. Models were adjusted for covariates and included an interaction between age and sex. We used restricted cubic splines to model the relationship between age and care and outcomes. Where the p-value for interaction was statistically significant (p < 0.05), we reported age-specific OR or HR. RESULTS: Among 67,442 patients with ischemic stroke, 45.9% were female and the median age was 74 years (64-83). Care was similar between both sexes, except female patients had higher odds of receiving endovascular thrombectomy (OR 1.35, 95% CI [1.19-1.54] comparing female with male), and these associations were not modified by age. There was no overall sex difference in hazard of death (HR 95% CI 0.99 [0.95-1.04] for death within 90 days; 0.99 [0.96-1.03] for death within 365 days), but these associations were modified by age with the hazard of death being higher in female than male patients between the ages of 50-70 years (most extreme difference around age 57, HR 95% CI 1.25 [1.10-1.40] at 90 days, p-interaction 0.002; 1.15 [1.10-1.20] at 365 days, p-interaction 0.002). DISCUSSION: The hazard of death after stroke was higher in female than male patients aged 50-70 years. Examining overall sex differences in outcomes without accounting for the effect modification by age may miss important findings in specific age groups.

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study.

OBJECTIVE: Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. RESEARCH DESIGN AND METHODS: Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. RESULTS: Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis. CONCLUSIONS: SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.

Dynamic relationships between depressive symptoms and insulin resistance over 20 years of adulthood.

BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.

Predicting Individual Treatment Response to rTMS for Motor Recovery After Stroke: A Review and the CanStim Perspective.

Background: Rehabilitation is critical for reducing stroke-related disability and improving quality-of-life post-stroke. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique used as stand-alone or adjunct treatment to physiotherapy, may be of benefit for motor recovery in subgroups of stroke patients. The Canadian Platform for Trials in Non-Invasive Brain Stimulation (CanStim) seeks to advance the use of these techniques to improve post-stroke recovery through clinical trials and pre-clinical studies using standardized research protocols. Here, we review existing clinical trials for demographic, clinical, and neurobiological factors which may predict treatment response to identify knowledge gaps which need to be addressed before implementing these parameters for patient stratification in clinical trial protocols. Objective: To provide a review of clinical rTMS trials of stroke recovery identifying factors associated with rTMS response in stroke patients with motor deficits and develop research perspectives for pre-clinical and clinical studies. Methods: A literature search was performed in PubMed, using the Boolean search terms stroke AND repetitive transcranial magnetic stimulation OR rTMS AND motor for studies investigating the use of rTMS for motor recovery in stroke patients at any recovery phase. A total of 1,676 articles were screened by two blinded raters, with 26 papers identified for inclusion in this review. Results: Multiple possible factors associated with rTMS response were identified, including stroke location, cortical thickness, brain-derived neurotrophic factor (BDNF) genotype, initial stroke severity, and several imaging and clinical factors associated with a relatively preserved functional motor network of the ipsilesional hemisphere. Age, sex, and time post-stroke were generally not related to rTMS response. Factors associated with greater response were identified in studies of both excitatory ipsilesional and inhibitory contralesional rTMS. Heterogeneous study designs and contradictory data exemplify the need for greater protocol standardization and high-quality controlled trials. Conclusion: Clinical, brain structural and neurobiological factors have been identified as potential predictors for rTMS response in stroke patients with motor impairment. These factors can inform the design of future clinical trials, before being considered for optimization of individual rehabilitation therapy for stroke patients. Pre-clinical models for stroke recovery, specifically developed in a clinical context, may accelerate this process.

The Canadian Women's Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women - Chapter 5: Sex- and Gender-Unique Manifestations of Cardiovascular Disease.

This Atlas chapter summarizes sex- and some gender-associated, and unique aspects and manifestations of cardiovascular disease (CVD) in women. CVD is the primary cause of premature death in women in Canada and numerous sex-specific differences related to symptoms and pathophysiology exist. A review of the literature was done to identify sex-specific differences in symptoms, pathophysiology, and unique manifestations of CVD in women. Although women with ischemic heart disease might present with chest pain, the description of symptoms, delay between symptom onset and seeking medical attention, and prodromal symptoms are often different in women, compared with men. Nonatherosclerotic causes of angina and myocardial infarction, such as spontaneous coronary artery dissection are predominantly identified in women. Obstructive and nonobstructive coronary artery disease, aortic aneurysmal disease, and peripheral artery disease have worse outcomes in women compared with men. Sex differences exist in valvular heart disease and cardiomyopathies. Heart failure with preserved ejection fraction is more often diagnosed in women, who experience better survival after a heart failure diagnosis. Stroke might occur across the lifespan in women, who are at higher risk of stroke-related disability and age-specific mortality. Sex- and gender-unique differences exist in symptoms and pathophysiology of CVD in women. These differences must be considered when evaluating CVD manifestations, because they affect management and prognosis of cardiovascular conditions in women.

Dans le présent chapitre d'Atlas sont récapitulés les aspects et les manifestations uniques, associés au sexe et certains associés au genre, des maladies cardiovasculaires (MCV) chez les femmes. Les MCV sont la cause principale de décès prématurés chez les femmes au Canada. De nombreuses différences quant aux symptômes et à la physiopathologie existent entre les sexes. Nous avons réalisé une revue de la littérature pour déterminer les différences entre les sexes dans les symptômes et la physiopathologie, et les manifestations uniques des MCV chez les femmes. Bien que les femmes atteintes d'une cardiopathie ischémique puissent éprouver des douleurs thoraciques, la description des symptômes, le délai entre l'apparition des symptômes et l'obtention de soins médicaux, et les symptômes prodromiques sont souvent différents de ceux des hommes. Les causes de l'angine et de l'infarctus du myocarde non liées à l'athérosclérose telles que la dissection spontanée de l'artère coronaire sont principalement observées chez les femmes. La coronaropathie obstructive et non obstructive, l'anévrisme aortique et la maladie artérielle périphérique montrent de plus mauvaises issues chez les femmes que chez les hommes. Des différences entre les sexes sont observées dans la cardiopathie valvulaire et les cardiomyopathies. Le diagnostic d'insuffisance cardiaque avec fraction d'éjection préservée est plus souvent posé chez les femmes qui présentent un meilleur taux de survie après un diagnostic d'insuffisance cardiaque. L'accident vasculaire cérébral (AVC) pourrait survenir tout au long de la vie des femmes, qui sont exposées à un risque plus élevé d'incapacités liées à l'AVC et de mortalité par âge. Il existe des différences uniques entre les sexes et les genres pour ce qui est des symptômes et de la physiopathologie des MCV chez les femmes. Lors de l'évaluation des manifestations des MCV, il faut tenir compte de ces différences puisqu'elles influencent la prise en charge et le pronostic des maladies cardiovasculaires chez les femmes.

Comprehensive compartmental model and calibration algorithm for the study of clinical implications of the population-level spread of COVID-19: a study protocol.

INTRODUCTION: The complex dynamics of the coronavirus disease 2019 (COVID-19) pandemic has made obtaining reliable long-term forecasts of the disease progression difficult. Simple mechanistic models with deterministic parameters are useful for short-term predictions but have ultimately been unsuccessful in extrapolating the trajectory of the pandemic because of unmodelled dynamics and the unrealistic level of certainty that is assumed in the predictions. METHODS AND ANALYSIS: We propose a 22-compartment epidemiological model that includes compartments not previously considered concurrently, to account for the effects of vaccination, asymptomatic individuals, inadequate access to hospital care, post-acute COVID-19 and recovery with long-term health complications. Additionally, new connections between compartments introduce new dynamics to the system and provide a framework to study the sensitivity of model outputs to several concurrent effects, including temporary immunity, vaccination rate and vaccine effectiveness. Subject to data availability for a given region, we discuss a means by which population demographics (age, comorbidity, socioeconomic status, sex and geographical location) and clinically relevant information (different variants, different vaccines) can be incorporated within the 22-compartment framework. Considering a probabilistic interpretation of the parameters allows the model's predictions to reflect the current state of uncertainty about the model parameters and model states. We propose the use of a sparse Bayesian learning algorithm for parameter calibration and model selection. This methodology considers a combination of prescribed parameter prior distributions for parameters that are known to be essential to the modelled dynamics and automatic relevance determination priors for parameters whose relevance is questionable. This is useful as it helps prevent overfitting the available epidemiological data when calibrating the parameters of the proposed model. Population-level administrative health data will serve as partial observations of the model states. ETHICS AND DISSEMINATION: Approved by Carleton University's Research Ethics Board-B (clearance ID: 114596). Results will be made available through future publication.

Gastric acid suppressants and cognitive decline in people with or without cognitive impairment.

INTRODUCTION: Studies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine-2 receptor antagonists (H2RAs) nor baseline cognitive status. METHODS: Participants (National Alzheimer's Coordinating Center Database; 2005-2021) using a PPI or H2RA were compared. Covariate-adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity-score-matched subsample of mild-moderate Alzheimer's disease (AD), mixed-effects negative binomial regression was used to estimate decline in delayed recall memory. RESULTS: Compared to PPI, H2RA use was associated with earlier progression from MCI to dementia (HR = 1.40 [1.09-1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio = 0.76 [0.64-0.92]; n = 628), but not with progression from normal cognition to MCI (HR = 0.94 [0.71-1.24]; n = 2784). DISCUSSION: Compared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre-existing cognitive impairment.