Tea and Coffee Consumption and Risk of Acute Stroke: the INTERSTROKE Study.

BACKGROUND: Stroke is a leading global cause of death and disability. Daily tea/coffee intake is consumed by >50% of populations and may represent an important population-level exposure. Therefore, it is first essential that we better understand the associations between the tea/coffee intake and stroke. AIMS: This research aims to generate hypotheses about the global associations between tea and coffee intake and stroke. These insights will identify interventions for stroke prevention that can be further explored using alternative study designs. METHODS: INTERSTROKE is a large international matched case-control study of first stroke from 32 countries. Participants were asked "how many cups do you drink each day?" of coffee, green tea, black tea and other tea. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between intake and stroke. RESULTS: We included 13,462 cases and 13,488 controls from INTERSTROKE; mean age was 61.7 (13.4) years and 59.6% (n=16,010) were male. Overall, 19.4% (n=5,239) did not consume tea/coffee, 47.0% (n=12,666) consumed tea only, 14.9% (n=4,024) consumed coffee alone and 18.6% (n=5,021) consumed both, with significant regional variations. After multivariable adjustment, there was no association between low/moderate coffee intake and stroke, but high consumption (>4/day) was associated with higher odds of all stroke (OR 1.37 (95%CI 1.06-1.77)) or ischaemic stroke (OR 1.32 (95% CI 1.00-1.74)). Tea consumption was associated with lower odds of all (OR 0.81 (95% CI 0.69-0.94) for highest intake) or ischaemic stroke (OR 0.81 (95% CI 0.68-0.98) for highest intake). CONCLUSIONS: High coffee consumption was associated with higher odds of all or ischaemic stroke; low-moderate coffee had no association with stroke. In contrast, tea consumption was associated with lower odds of stroke. These associations suggest that individuals consider avoiding high coffee consumption (>=5cups/day) to impact future stroke risk. DATA ACCESS STATEMENT: The design and rationale of INTERSTROKE was published previously. Individual participant data, or other documents are not available.

Blood pressure variability in acute stroke: Risk factors and association with functional outcomes at 1 month.

BACKGROUND AND PURPOSE: Blood pressure variability, in acute stroke, may be an important modifiable determinant of functional outcome after stroke. In a large international cohort of participants with acute stroke, it was sought to determine the association of blood pressure variability (in the early period of admission) and functional outcomes, and to explore risk factors for increased blood pressure variability. PATIENTS AND METHODS: INTERSTROKE is an international case-control study of risk factors for first acute stroke. Blood pressure was recorded at the time of admission, the morning after admission and the time of interview in cases (median time from admission 36.7 h). Multivariable ordinal regression analysis was employed to determine the association of blood pressure variability (standard deviation [SD] and coefficient of variance) with modified Rankin score at 1-month follow-up, and logistic regression was used to identify risk factors for blood pressure variability. RESULTS: Amongst 13,206 participants, the mean age was 62.19 ± 13.58 years. When measured by SD, both systolic blood pressure variability (odds ratio 1.13; 95% confidence interval 1.03-1.24 for SD ≥20 mmHg) and diastolic blood pressure variability (odds ratio 1.15; 95% confidence interval 1.04-1.26 for SD ≥10 mmHg) were associated with a significant increase in the odds of poor functional outcome. The highest coefficient of variance category was not associated with a significant increase in risk of higher modified Rankin score at 1 month. Increasing age, female sex, high body mass index, history of hypertension, alcohol use, and high urinary potassium and low urinary sodium excretion were associated with increased blood pressure variability. CONCLUSION: Increased blood pressure variability in acute stroke, measured by SD, is associated with an increased risk of poor functional outcome at 1 month. Potentially modifiable risk factors for increased blood pressure variability include low urinary sodium excretion.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case­control study

BACKGROUND Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. METHODS The INTERSTROKE study is a case­control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). FINDINGS Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46­1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61­2.11) than ICH (OR 1.19 95% CI 1.00­1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24­4.10) and PAR (18.6%, 15.1­22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63­2.87) and undetermined cause (OR 1.97, 95% CI 1.55­2.50). Both filtered (OR 1.73, 95% CI 1.50­1.99) and non-filtered (OR 2.59, 95% CI 1.79­3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69­2.27), ischemic stroke (OR 1.89, 95% CI 1.59­2.24) and ICH (OR 2.00, 95% CI 1.60­2.50). INTERPRETATION There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. FUNDING The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Tobacco use and risk of acute stroke in 32 countries in the INTERSTROKE study: a case-control study.

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels. Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined). Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50). Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke. Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke.

Variations in the prevalence of atrial fibrillation, and in the strength of its association with ischemic stroke, in countries with different income levels: INTERSTROKE case-control study

BACKGROUND: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level. AIMS: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level. METHODS: In the INTERSTROKE case­control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups­UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke. RESULTS: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29­0.41) and LMIC (aOR 0.50, 95% CI 0.41­0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7­17.8) in HIC, 14.6% (95% CI 12.3­17.1) in UMIC-1, 5.7% (95% CI 4.9­6.7) in UMIC-2, and 6.3% (95% CI 5.3­7.3) in LMIC. CONCLUSION: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio.

Variations in the prevalence of atrial fibrillation, and in the strength of its association with ischemic stroke, in countries with different income levels: INTERSTROKE case-control study.

BACKGROUND: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level. AIMS: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level. METHODS: In the INTERSTROKE case-control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups-UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke. RESULTS: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29-0.41) and LMIC (aOR 0.50, 95% CI 0.41-0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7-17.8) in HIC, 14.6% (95% CI 12.3-17.1) in UMIC-1, 5.7% (95% CI 4.9-6.7) in UMIC-2, and 6.3% (95% CI 5.3-7.3) in LMIC. CONCLUSION: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio.

Pleocytosis in cerebrospinal fluid attributed to ischemic stroke: A review of the literature.

INTRODUCTION: Lumbar puncture is generally performed in stroke settings when infectious or inflammatory diseases are suspected to be the etiology. This review aimed to assess the prevalence of pleocytosis in the cerebrospinal fluid following ischemic stroke without inflammatory or infectious etiology. METHODS: We searched PubMed for studies with mentions of "[ischemic stroke] AND [cerebrospinal fluid]". We included only studies written in English, including patients with a primary diagnosis of either ischemic stroke or transient ischemic attack (TIA), and where white blood cell count in the spinal fluid was presented. Studies investigating common etiologies for pleocytosis, was excluded. Study and patient characteristics, white blood cell count and time to lumbar puncture were presented in tables, and the prevalence of pleocytosis were reported and plotted graphically. RESULTS: We included 15 studies with 1607 patients, 1522 with ischemic stroke and 85 with TIA. The prevalence of pleocytosis was between 0% to 28,6% and a mean of 11.8%. The highest white blood cell count found with common etiologies for pleocytosis ruled out was 56 cells/mm3. A mean white blood cell count of 4.0 was based on the three studies where this was available. DISCUSSION: The included studies were methodologically heterogenous and few had pleocytosis as primary outcome. Pleocytosis following ischemic stroke is uncommon and should prompt further investigations.

Processes of Care and Associated Factors in Patients With Stroke by Immigration Status.

BACKGROUND: Receiving evidence-based stroke care processes is associated with good clinical outcome. However, data on early stroke care among immigrants are scarce. OBJECTIVE: We investigated whether guideline-recommended acute stroke care and associated factors differ between immigrants and Danish-born residents. DESIGN: Patients admitted with ischemic and hemorrhagic stroke diagnoses (n=129,724) between 2005 and 2018 were identified from the Danish Stroke Registry. RESULTS: We included 123,928 Danish-born residents and 5796 immigrants with stroke. Compared with Danish-born residents, immigrants were less likely to be admitted to a stroke unit within 24 hours after stroke onset (81.5% vs. 83.9%, P <0.001) and had lower odds of early stroke care including dysphagia screening, physiotherapy, occupational therapy, and nutritional assessment. After adjustment for age, sex, clinical, and sociodemographic factors, immigrants had lower odds of early stroke unit admission (odds ratio [OR]: 0.97; 95% CI, 0.94-0.99), early dysphagia screening (OR: 0.96; 95% CI, 0.93-0.98), early physiotherapy (OR: 0.96; 95% CI, 0.94-0.99), and early occupational therapy (OR: 0.96; 95% CI, 0.93-0.98) than Danish-born residents. Small absolute differences in overall quality of stroke care were found when comparing immigrants and Danish-born residents. Significant factors associated with greater likelihood of stroke care included high income, high education, and cohabitation. CONCLUSIONS: Immigrants had lower chances of early stroke unit admission and received fewer individual early stroke care processes such as dysphagia screening, physiotherapy and occupational therapy than Danish-born residents. However, the absolute disparities were in general minor and largely influenced by socioeconomic status and cohabitation.

High-intensity training in patients with lacunar stroke: A one-year follow-up.

OBJECTIVES: Physical inactivity is a major risk factor for stroke. It is a challenge for patients to initiate and adhere to regular exercise post-stroke. Early initiation of home-based high-intensity interval training (HIIT) may engage patients in physical activity, improve cardiorespiratory fitness, and reduce risk of recurrent stroke. MATERIALS AND METHODS: Post-intervention follow-up of patients with lacunar stroke, randomized to three-months HIIT including weekly motivational calls, or usual care. At follow-up (six- and 12-months post-stroke), we investigated changes in cardiorespiratory fitness, physical activity, fatigue, depression, mental well-being, stress, cognition, cardiovascular function, and recurrent stroke. RESULTS: We included 71 patients of whom 59 patients (mean age: 63.9 ± 8.8 years) completed six- and 12-month follow-up. No change was detected in cardiorespiratory fitness between groups from baseline to 12-months follow-up. At six months, vigorous-intensity activity (median hours/week [interquartile range]) was maintained in the intervention group (baseline, 0[0;2]; post-intervention, 2[0;3]; six-month, 2[0;4]) and increased in the usual care group (baseline, 0[0;1]; post-intervention, 1[0;2]; six-month, 1[0;3]), with no difference between groups. Vigorous-intensity activity declined to baseline levels at 12-months in both groups. Secondary outcomes improved from baseline to 12-months with no significant differences between groups. Similar rate of recurrent stroke (n=3) occurred in each group with a three-month delay in the intervention group. CONCLUSIONS: Early initiated HIIT did not increase long-term cardiorespiratory fitness, but increased time spent doing vigorous-intensity activities post-stroke. Decline to baseline activity level at 12 months warrants identification of motivators to initiate and sustain physical activity post-stroke.

Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD: A Simulation Study From DA VINCI.

PURPOSE: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated. METHODS: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated. RESULTS: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81-115) mg/dl and 32% (25-43%), respectively. Median LDL-C reductions of 24 (12-46) and 39 (27-91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7-25%) and 22% (15-32%), respectively, and ARRs of 4% (2-7%) and 6% (4-9%), respectively. CONCLUSION: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach.

Capillary transit time heterogeneity inhibits cerebral oxygen metabolism in patients with reduced cerebrovascular reserve capacity from steno-occlusive disease.

The healthy cerebral perfusion demonstrates a homogenous distribution of capillary transit times. A disruption of this homogeneity may inhibit the extraction of oxygen. A high degree of capillary transit time heterogeneity (CTH) describes that some capillaries have very low blood flows, while others have excessively high blood flows and consequently short transit times. Very short transit times could hinder the oxygen extraction due to insufficient time for diffusion of oxygen into the tissue. CTH could be a consequence of cerebral vessel disease. We examined whether patients with cerebral steno-occlusive vessel disease demonstrate high CTH and if elevation of cerebral blood flow (CBF) by administration of acetazolamide (ACZ) increases the cerebral metabolic rate of oxygen (CMRO2), or if some patients demonstrate reduced CMRO2 related to detrimental CTH. Thirty-four patients and thirty-one healthy controls participated. Global CBF and CMRO2 were acquired using phase-contrast MRI. Regional brain maps of CTH were acquired using dynamic contrast-enhanced MRI. Patients with impaired cerebrovascular reserve capacity demonstrated elevated CTH and a significant reduction of CMRO2 after administration of ACZ, which could be related to high CTH. Impaired oxygen extraction from CTH could be a contributing part of the declining brain health observed in patients with cerebral vessel disease.

Association of Psychosocial Stress With Risk of Acute Stroke.

Importance: Psychosocial stress is considered a modifiable risk factor for stroke. Given the prevalence of chronic and acute exposure to stress, it represents a potentially attractive target for population-health interventions. Objectives: To determine the association of psychosocial stress with the risk of acute stroke and explore factors that might modify the association of stress with risk of acute stroke in a large international population. Design, Setting, and Participants: INTERSTROKE is an international retrospective case-control study of risk factors for first acute stroke in 32 countries in Asia, North and South America, Europe, Australia, the Middle East, and Africa. A total of 13 462 patients with stroke and 13 488 matched controls were recruited between January 11, 2007, and August 8, 2015. The present analyses were performed from June 1 to 30, 2021, and included 13 350 cases and 13 462 controls with available data on psychosocial stress. Exposures: Psychosocial stress and occurrence of stressful life events within the preceding year were measured using a standardized questionnaire of self-reported stress at home and work. Main Outcomes and Measures: The association of stress with acute stroke and its subtypes was examined using multivariable conditional logistic regression and factors that might modify the association, particularly self-reported locus of control. Results: Among 26 812 participants included in the analysis, the mean (SD) age of cases was 62.2 (13.6) years; that of controls, 61.3 (13.3) years; 7960 cases (59.6%) and 8017 controls (59.6%) were men. Several periods of stress and permanent stress were reported for 2745 cases (20.5%) and 1933 controls (14.4%), with marked regional variation in prevalence, with the lowest in China (201 of 3981 [5.0%] among controls and 364 of 3980 [9.1%] among cases) and highest in South East Asia (233 of 855 [26.1%] among controls and 241 of 782 [30.8%] among cases). Increased stress at home (odds ratio [OR], 1.95 [95% CI, 1.77-2.15]) and at work (OR, 2.70 [95% CI, 2.25-3.23]) and recent stressful life events (OR, 1.31 [95% CI, 1.19-1.43]) were associated with an increased risk of acute stroke on multivariable analyses (vs no self-reported stress). Higher locus of control at home was associated with a reduced odds of all stroke (OR, 0.73 [95% CI, 0.68-0.79]), and higher locus of control both at work and at home were associated with a lower odds of acute stroke and significantly diminished the association with stress at work (OR, 2.20 [95% CI, 1.88-2.58]; P = .008 for interaction) and home (OR, 1.69 [95% CI, 1.44-1.98]; P < .001 for interaction) for acute stroke. Conclusions and Relevance: Psychosocial stress is a common risk factor for acute stroke. The findings of this case-control study suggest that higher locus of control is associated with lower risk of stroke and may be an important effect modifier of the risk associated with psychosocial stress.

Immigration status and utilization of secondary preventive treatment after ischemic stroke.

Introduction: The objective of the study was to assess use and persistence of secondary preventive treatment after ischemic stroke comparing immigrants and Danish-born residents. Patients and methods: A cohort of patients discharged with ischemic stroke (IS) diagnosis (n = 106,224) by immigration status was identified from the Danish Stroke Registry between 2005 and 2018. We investigated use (claiming at least one prescription in 180 days post-discharge according to information from the Register of Medicinal Products Statistics) and persistence of treatment within 180 days thereafter using multivariable logistic regression and Fine and Gray models. Results: Overall, 82,078 Danish-born residents (80.6%) and 3589 (80.7%) immigrants with IS used at least one of the recommended preventive medications post-discharge. Immigrants had lower odds of use of anticoagulants and angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB) (odds ratio (OR), 0.66; 95% confidence interval (CI), 0.53-0.82 and OR, 0.87; 95% CI, 0.75-0.98, respectively) but had higher odds of use of beta-blockers (OR, 1.25; 95% CI, 1.02-1.53) than Danish-born residents after adjustment for age at stroke, sex, sociodemographic factors, duration of residence, stroke severity, and comorbidities. The odds were most evident among immigrants originating from non-Western countries. Persistence of medication use did not differ between immigrants and Danish-born residents after adjustment for sociodemographic factors and comorbidities. Conclusion: Modest disparities in use of standard guideline recommended secondary preventive medications were observed when comparing immigrants and Danish-born residents with ischemic stroke. Furthermore, no differences in persistence of medication therapy were observed.

Corrigendum: Sex-differences in oral anticoagulant-related intracerebral hemorrhage.

[This corrects the article DOI: 10.3389/fneur.2022.832903.].

Role of Proxy Respondents in International Stroke Research: Experience of the INTERSTROKE Study.

INTRODUCTION: Measuring patient-reported information in stroke research is challenging. To overcome this, use of proxy respondents is often a necessary strategy. In this study, we report on use and effect of proxy respondents on patient case-mix in a large international epidemiologic stroke study (INTERSTROKE). METHODS: This was a cross-sectional study of 13,458 cases of acute first stroke in 32 countries. A standardized study questionnaire recording behavioural cardiovascular risk factors was administered to the patient, and if unable to communicate adequately, a valid proxy, or both. We used logistic regression to evaluate the association of age, sex, education, occupation, stroke severity, and region with need for proxy respondent, and report odds ratio (OR) with 95% confidence interval (CI). RESULTS: Among 13,458 participants with acute stroke, questionnaires were completed by patients alone in 41.4% (n = 5,573), combination of patient and proxy together in 21.7% (n = 2,918), and proxy alone in 36.9% (n = 4,967). Use of proxy alone was greater in participants with severe stroke (4.7% with modified-Rankin score of 0 vs. 80.5% in those with score 5; OR 187.13; 95% CI: 119.61-308.22), older persons (43.8% of those aged 80 years and over vs. 33.2% of those aged less than 40 years; age per decade OR 1.09; 95% CI: 1.06-1.12), women (40.7% vs. 34.3% of men; OR 1.32 95% CI: 1.22-1.43), and those less educated (58.9% of those never educated vs. 25.7% of those who attended third level education; OR 7.84; 95% CI: 6.78-9.08). CONCLUSION: Use of proxy respondents enhances the generalizability of international research studies of stroke, by increasing representation of women, patients with severe stroke, older age, and lower education.

Association of Lipids, Lipoproteins, and Apolipoproteins with Stroke Subtypes in an International Case Control Study (INTERSTROKE).

BACKGROUND AND PURPOSE: The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes. METHODS: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH). RESULTS: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001). CONCLUSIONS: The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Sex-Differences in Oral Anticoagulant-Related Intracerebral Hemorrhage.

Introduction and Aim: Data remain limited on sex-differences in patients with oral anticoagulant (OAC)-related intracerebral hemorrhage (ICH). We aim to explore similarities and differences in risk factors, acute presentation, treatments, and outcome in men and women admitted with OAC-related ICH. Method: This study was a retrospective observational study based on 401 consecutive patients with OAC-related ICH admitted within 24 h of symptom onset. The study was registered on osf.io. We performed logarithmic regression and cox-regression adjusting for age, hematoma volume, Charlson Comorbidity Index (CCI), and pre-stroke modified Ranking Scale (mRS). Gender and age were excluded from CHA2DS2-VASc and CCI was not adjusted for age. Results: A total of 226 men and 175 women were identified. More men were pre-treated with vitamin K-antagonists (73.5% men vs. 60.6% women) and more women with non-vitamin K-antagonist oral anticoagulants (26.5% men vs. 39.4% women), p = 0.009. Women were older (mean age 81.9 vs. 76.9 years, p < 0.001). CHA2DS2-VASc and CCI were similar in men and women.Hematoma volumes (22.1 ml in men and 19.1 ml in women) and National Institute of Health Stroke Scale (NIHSS) scores (13 vs. 13) were not statistically different, while median Glasgow Coma Scale (GCS) was lower in women, (14 [8;15] vs. 14 [10;15] p = 0.003).Women's probability of receiving reversal agents was significantly lower (adjusted odds ratio [aOR] = 0.52, p = 0.007) but not for surgical clot removal (aOR = 0.56, p = 0.25). Women had higher odds of receiving do-not-resuscitate (DNR) orders within a week (aOR = 1.67, p = 0.04). There were no sex-differences in neurological deterioration (aOR = 1.48, p = 0.10), ability to walk at 3 months (aOR = 0.69, p = 0.21) or 1-year mortality (adjusted hazard ratio = 1.18, p = 0.27). Conclusion: Significant sex-differences were observed in age, risk factors, access to treatment, and DNRs while no significant differences were observed in comorbidity burden, stroke severity, or hematoma volume. Outcomes, such as adjusted mortality, ability to walk, and neurological deterioration, were comparable. This study supports the presence of sex-differences in risk factors and care but not in presentation and outcomes.

Is the TOAST Classification Suitable for Use in Personalized Medicine in Ischemic Stroke?

Pathophysiologic classification of ischemic stroke is essential to a personalized approach to stroke treatment. The Trial of Org 101072 in Acute Stroke Treatment (TOAST) classification is the most frequently used tool to classify index ischemic strokes. We aimed to assess presence of small and large vessel disease markers across the TOAST groups. In an observational study, 99 ischemic stroke patients were consecutively included and classified according to TOAST. The assessment was supplemented with cerebral small vessel disease (SVD) score, based on Magnetic Resonance Imaging (MRI), and tests for carotid atherosclerosis, ankle−brachial index (ABI), estimated glomerular filtration rate (eGFR), and peripheral reactive hyperemia index (RHI). Markers of small and large vessel disease were present in all TOAST groups. Carotid stenosis and atrial fibrillation were associated with their respective TOAST groups (p = 0.023 and p < 0.001, respectively). We found no association between the SVD score and the small vessel occlusion TOAST group (p = 0.59), and carotid atherosclerosis (p = 0.35), RHI (p = 0.39), ABI (p = 0.20), and eGFR (p = 0.79) were not associated with TOAST groups. The TOAST classification does not provide differential information on the pathophysiologies of the ischemic stroke. An operational classification that contains quantification of each vascular pathophysiology in the individual patient is pivotal for future research and development of personalized medicine.

Use of reperfusion therapy and time delay in patients with ischaemic stroke by immigration status: A register-based cohort study in Denmark.

BACKGROUND AND PURPOSE: Reperfusion therapy is the mainstay of treatment for acute ischaemic stroke (AIS); however, little is known about the use of reperfusion therapy and time delay amongst immigrants. METHODS: This is a Danish nationwide register-based cohort study of patients with AIS aged ≥18 years (n = 49,817) recruited from 2009 to 2018. Use of reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy) and time delay between immigrants and Danish-born residents were compared using multivariable logistics and quantile regression. RESULTS: Overall, 10,649 (39.8%) Danish-born residents and 452 (39.0%) immigrants with AIS were treated with reperfusion therapy in patients arriving <4.5 h following stroke onset. Compared with Danish-born residents, immigrants had lower odds of receiving reperfusion therapy after adjustment for prehospital delay, age, sex, stroke severity, sociodemographic factors and comorbidities (adjusted odds ratio 0.67; 95% confidence interval 0.49-0.92, p = 0.01). The lowest odds were observed amongst immigrants originating from Poland and non-Western countries. Similarly, immigrants had a longer prehospital delay than Danish-born residents in the fully adjusted model in patients arriving <4.5 h after stroke onset (15 min; 95% confidence interval 4-26 min, p = 0.03). No evidence was found that system delay and clinical outcome differed between immigrants and Danish-born residents in patients eligible for reperfusion therapy after adjustment for sociodemographic factors and comorbidities. CONCLUSION: Immigration status was significantly associated with lower chances of receiving reperfusion therapy and there may be differences in patient delay between immigrants and Danish-born residents in patients arriving to a stroke unit <4.5 h after stroke onset.

Melatonin profile in healthy, elderly subjects - A systematic literature review.

Melatonin plays an important role in regulation and maintaining of the circadian rhythm. In the elderly population, an array of disturbances of circadian rhythm and sleep can be observed; however the current knowledge within the group of healthy, elderly is scarce. This systematic literature review of studies on the melatonin profile measured in the blood of healthy, elderly individuals included 519 studies, found in the primary search on PubMed. After reviewing the title and abstract, 47 studies were found eligible for full text review. The inclusion criteria were defined as follows: healthy, elderly individuals, with a mean or average age over 65 years and analysis done in blood or plasma. In addition to the primary search, three studies were directly identified by the reference lists of already included studies. A final total of 23 studies were included in the systematic literature review. In reviewing the literature, a clear circadian melatonin profile with a nocturnal peak at 3 am and lower daytime levels was observed in the healthy, elderly population. In elderly over 75 years of age, the nocturnal level of melatonin may be lower; however, the circadian rhythmicity is maintained. In the comparison of elderly, independently living individuals and individuals living in care facilities, the latter group had lower levels of nocturnal melatonin peak as well as higher daytime levels; however one can wonder if elderly in care facilities are healthy. The 23 included studies in the systematic literature review had varying primary objectives and generally the term "healthy" within this population group proves difficult to clearly define. As a result of this, an obvious interstudy variability existed, which is a limitation of this systematic literature review. However, the graphs depicted represent the best possible estimation of the melatonin profile in a healthy, elderly population. Future research in the melatonin profile within this population should focus on clearly defined healthy elderly to ensure a valid normal material in this age group.