Age-dependent seasonality in the incidence of stroke: A 21-year population-based study.

INTRODUCTION: Seasonality in the incidence of stroke has been examined in numerous studies, yet data on whether it differs with age are limited. To fill this gap, we utilized a largescale dataset from Israel. PATIENTS AND METHODS: We retrieved data of all hospitalizations for ischemic stroke (IS), transient ischemic attack (TIA) and intra cerebral hemorrhage (ICH) from 2000 to 2020. We maintained separate datasets for IS/TIA and ICH, divided into five age groups: 18-49, 50-59, 60-69, 70-79, and 80+. We modeled the monthly incidence using a generalized additive model. The seasonal effect was defined by the rate ratio (RR) of each month compared to the annual mean. RESULTS: The analysis included 317,586 and 23,789 events of IS/TIA and ICH respectively. We found an interaction between age and seasonality, accounting for a phase shift with age in the seasonal pattern of IS/TIA incidence. For cases under 70 years, the peak was during summertime and the RRs increased with decreasing age, reaching 1.11 (95% CI 1.09-1.13) at the youngest age group. In contrast, among the elderly, a winter peak was observed and the RRs increased with age to 1.07 (95% CI 1.06-1.08) at the oldest age group. For ICH, a winter/autumn peak was identified and the RRs increased with age to 1.20 (95% CI 1.16-1.24). CONCLUSIONS: Our finding of age-dependent seasonal patterns in the occurrence of stroke, suggests closer monitoring of cardiovascular risk factors during wintertime among elderly individuals. The mechanism governing the seasonal phase shift with age in IS/TIA incidence, requires further investigation.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

An Increased Risk for Ischemic Stroke in the Short-Term Period following COVID-19 Infection: A Nationwide Population-Based Study.

INTRODUCTION: The association disclosed between coronavirus disease 2019 (COVID-19) infection and ischemic stroke (IS) raises concern. The exact risk periods, which were not consistent between studies, require further investigation. METHODS: We linked two national databases: the COVID-19 database and the Israeli National Stroke Registry. The self-controlled case series method was used to estimate the association between COVID-19 infection and a first IS. The study population included all Israeli residents who had both a first IS event and a first COVID-19 diagnosis during 2020. The date of the PCR test served to define the day of exposure, and the 28 days following it were categorized into three risk periods: days 1-7, 8-14, and 15-28. A relative incidence (RI) with a 95% confidence interval (95% CI) was calculated based on the incidence rate of events in a post-exposure period, compared to the incidence rate in a control period. RESULTS: From January 1, 2020, to December 31, 2020, 308,015 Israelis aged 18+ were diagnosed with COVID-19 and 9,535 were diagnosed with a first IS. Linking the two databases, 555 persons had both diagnoses during 2020. The mean age of the study population was 71.5 ± 13.7, 55.1% were males, 77.8% had hypertension, 73.7% had hyperlipidemia, 51.9% had diabetes, and 28.5% had ischemic heart disease. Comparing the risk period and the control period, we found a very similar distribution of the cardiovascular risk factors. The risk for an acute IS was 3.3-fold higher in the first week following COVID-19 diagnosis, compared with a control period (RI = 3.3; 95% CI: 2.3-4.6). The RI among males (RI = 4.5; 95% CI: 2.9-6.8) was 2.2-fold higher compared to females. The increased risk did not last beyond the first week following exposure. CONCLUSION: Physicians should be aware of the elevated risk for IS among patients experiencing COVID-19, particularly among men with high burden of cardiovascular risk factors.

Adolescent Hypertension Is Associated With Stroke in Young Adulthood: A Nationwide Cohort of 1.9 Million Adolescents.

BACKGROUND: Adult hypertension is a well-established risk factor for stroke in young adults (aged <55 years), and the effects are even more deleterious than at an older age. However, data are limited regarding the association between adolescent hypertension and the risk of stroke in young adulthood. METHODS: A nationwide, retrospective cohort study of adolescents (aged 16-19 years) who were medically evaluated before compulsory military service in Israel during 1985 to 2013. For each candidate for service, hypertension was designated after constructed screening, and the diagnosis was confirmed through a comprehensive workup process. The primary outcome was ischemic and hemorrhagic stroke incidence as registered at the national stroke registry. Cox proportional-hazards models were used. We conducted sensitivity analyses by excluding people with a diabetes diagnosis at adolescence or a new diabetes diagnosis during the follow-up period, analysis of adolescents with overweight, and adolescents with baseline unimpaired health status. RESULTS: The final sample included 1 900 384 adolescents (58% men; median age, 17.3 years). In total, 1474 (0.08%) incidences of stroke (1236 [84%] ischemic) were recorded, at a median age of 43 (interquartile range, 38-47) years. Of these, 18 (0.35%) occurred among the 5221 people with a history of adolescent hypertension. The latter population had a hazard ratio of 2.4 (95% CI, 1.5-3.9) for incident stroke after adjustment for body mass index and baseline sociodemographic factors. Further adjustment for diabetes status yielded a hazard ratio of 2.1 (1.3-3.5). We found similar results when the outcome was ischemic stroke with a hazard ratio of 2.0 (1.2-3.5). Sensitivity analyses for overall stroke, and ischemic stroke only, yielded consistent findings. CONCLUSIONS: Adolescent hypertension is associated with an increased risk of stroke, particularly ischemic stroke, in young adulthood.

Peripheral sensory nerve function, type 2 diabetes and frailty among men with cardiovascular disease.

OBJECTIVE: To investigated the cross-sectional association between peripheral sensory nerve function and frailty among community-dwelling men, and examine whether type 2 diabetes (T2D) modifies this association. METHODS: A sample of 349 men [mean age = 77.1 ± 6.4 years; 37 % with T2D] who previously (1990-1998) participated in the Bezafibrate Infarction Prevention (BIP) trial, underwent assessment of frailty and legs vibratory thresholds (LVT), a measure of peripheral sensory nerve function, as part of the BIP Neurocognitive study during 2011-2013. LVT was assessed using a graduated tuning fork and frailty was assessed using the Fried criteria. An ordered logistic regression model was used to assess the link between LVT and degrees of frailty and to test for effect modification by T2D. RESULTS: Overall, 117 (33.5 %) of patients were non-frail, 134 (38.4 %) pre-frail, and 98 (28.1 %) frail. A significant interaction between LVT and T2D with regard to frailty was found. Among men with T2D, estimated OR (95%CI) for increasing frailty at the 1st, 2nd, and 3rd as compared to the top LVT quartile were 13.5 (3.4-54.3), 5.9 (1.5-23.5), and 4.4 (1.20-16.0), respectively. Among men without T2D, the estimated ORs for increasing frailty in patients at the 1st, 2nd, and 3rd quartiles compared to the top LVT quartile were 2.8 (1.1-7.4), 1.6 (0.6-4.1), and 2.5 (1.0-6.5), respectively. CONCLUSION: Frailty is significantly associated with worsening peripheral sensory nerve function, particularly among men with T2D.

The contribution of potentially modifiable risk factors to acute ischemic stroke burden - Comparing young and older adults.

Stroke is a leading cause of death and disability. In order to estimate the contribution of five modifiable risk factors to acute ischemic stroke (AIS) incidence in Israel, we conducted a case-control study based on first AIS cases aged 21-90 reported to the Israeli National Stroke Registry during 2014-2015, and controls from a national health survey conducted between 2013 and 2015. We calculated the population attributable risk (PAR) of each risk factor and the combined PAR for all risk factors (hypertension, diabetes, current smoking, obesity and hyperlipidemia), in all study population and by subgroups of young adults (age < 55) and older adults (age ≥ 55). The final analysis included 571, 577 and 500 matched pairs for all study population, young adults and older adults, respectively. Among young adults, current smoking and hypertension were the two most contributing risk factors for AIS, accounting for 33.6% (95% CI 27.3-39.9) and 28.9% (95% CI 22.1-35.7) of AIS cases, respectively. Among older adults, hypertension was the single most contributing risk factor for AIS and diabetes was the second most contributing risk factor for AIS, accounting for 64.9% (95% CI 57.3-72.5) and 25.7% (95% CI 17.5-33.9) of AIS cases, respectively. The combined PAR was significantly lower among young adults (PAR = 67.9%), compared with older adults (PAR = 80.7%). The combined PAR for all study population was 80.1% (95% CI 74.0-86.2), indicating that five common and modifiable risk factors explain ~80% of AIS incidence in Israel. Primary prevention strategies targeting these risk factors have the potential to drastically reduce stroke related morbidity and mortality.

Adherence to Mediterranean diet and subsequent cognitive decline in men with cardiovascular disease.

Backgrounds and aims: Evidence from recent years highlighted the importance of the Mediterranean diet for brain health. We investigated the association between adherence to Mediterranean diet and change in cognitive functions two decades later in patients with cardiovascular disease (CVD).Methods: Participants were men with a history of CVD, who previously participated in the Bezafibrate Infarction Prevention (BIP) trial between 1990 and 1997, had a food diary record, and underwent cognitive evaluations 14.6 ± 1.9 years (T1) and 19.9 ± 1.0 years after baseline (T2) as part of the BIP Neurocognitive study (n = 200, mean age at 57.3 ± 6.3 years). Adherence to the Mediterranean diet was determined from the self-administered 4-day food diary record, with patients categorized into high, middle and poor levels of adherence if they received >5, 4-5 and <4 points, respectively. Cognitive function was assessed using the NeuroTrax computerized battery. Linear mixed models were applied.Results: Among the 200 patients, 52 (26%) had poor adherence, 98 (49%) had middle adherence and 50 (25%) had high levels of adherence to the Mediterranean diet. Those categorized to the poor adherence level had poorer cognitive function at T1 compared to the other groups. Additionally, poor vs. high level of adherence was associated with a greater decline in overall cognitive performance [z-score = -0.23 and 95% confidence interval (CI), -0.43;-0.04; p = 0.021] and in visual spatial functions (-0.46 95% CI, -0.86;-0.06; p = 0.023).Conclusion: This study stresses the possible role of the Mediterranean diet in men with a high vascular burden and may set the ground for future intervention to reduce their risk for cognitive decline.

Brain Network Integrity Changes in Subjective Cognitive Decline: A Possible Physiological Biomarker of Dementia.

Objective: The current study seeks to illustrate potential early and objective neurophysiological biomarkers of neurodegenerative cognitive decline by evaluating features of brain network physiological performance and structure utilizing different modalities. Methods: This study included 17 clinically healthy individuals with self-reported cognitive decline (Subjective Cognitive Decline group, SCD, no objective finding of cognitive decline), 12 individuals diagnosed with amnestic Mild Cognitive Impairment (aMCI), 11 individuals diagnosed with Dementia, and 15 healthy subjects. All subjects underwent computerized cognitive performance testing, MRI scans including T1 for gray matter (GM) volume quantification, DTI for quantification of white matter (WM) microstructure fractional anisotropy (FA) and mean diffusivity (MD), and brain network function evaluation using DELPHI (TMS-EEG) measures of connectivity, excitability, and plasticity. Results: Both DELPHI analysis of network function and DTI analysis detected a significant decrease in connectivity, excitability, and WM integrity in the SCD group compared to healthy control (HC) subjects; a significant decrease was also noted for aMCI and Dementia groups compared to HC. In contrast, no significant decrease was observed in GM volume in the SCD group compared to healthy norms, a significant GM volume decrease was observed only in objectively cognitively impaired aMCI subjects and in dementia subjects. Conclusions: This study results suggest that objective direct measures of brain network physiology and WM integrity may provide early-stage biomarkers of neurodegenerative-related changes in subjects that have not yet displayed any other objective measurable cognitive or GM volume deficits which may facilitate early preventive care for neurodegenerative decline and dementia.

Including Distal Motor Function within the NIHSS: Correlation with Motor Arm Function and IV rt-PA Treatment Response.

OBJECTIVES: The Distal Motor Function (DMF) sub-score of the NIH Stroke Scale (NIHSS) was measured in the NINDS rt-PA Stroke Trials but is currently not included in the NIHSS. The correlation of DMF with the NIHSS Motor Arm Function (MAF) sub-score, the effect of IV tPA treatment on DMF, and whether adding DMF changes the utility of the NIHSS have not been analyzed. MATERIALS AND METHODS: MAF and DMF sub-scores were retrieved from the original NINDS rt-PA Stroke Trials for both sides of the body at baseline, 2 hours, 24 hours, 7-10 days, and 3 months after IV tPA treatment. MAF and DMF scores were correlated using Spearman correlation. Clustering of DMF and MAF scores was determined using a Bentler Comparative Fit Index (CFI) to estimate variation in NIHSS when adding DMF. The effect of IV tPA on DMF and MAF was assessed using a linear model comparing changes in scores from baseline to 3 months. RESULTS: MAF and DMF were highly correlated (p < 0.0001) across all time points for both dichotomous and continuous data on both sides. Intravenous tPA accounted for 21% of the change in DMF (p < 0.014, R2 = 0.0157, N = 423) and 39% of the change in MAF (p < 0.093, R2 = 0.0125, N = 547) from 0 to 3 months. On adding DMF to NIHSS, CFI decreased from 0.98 to 0.80 and DMF clustered with MAF, indicating that addition of DMF is unlikely to produce any discrepancy to NIHSS. CONCLUSIONS: Including DMF to the NIHSS does not appear to be of additional value. After IV tPA treatment, proximal and distal motor function in upper extremity strongly correlate over time but greater improvement in MAF is noted. Further research is needed on the role of IV tPA on minor strokes with deficits of DMF.

Diabetes associated risk for mortality increases with time among first stroke survivors - Findings from the Israeli National Stroke Registry.

BACKGROUND: Diabetes is a major risk factor for ischemic stroke and may affect post-stroke survival. Previous large scale studies of long-term post-stroke survival are limited and most of them excluded older patients from the study population. OBJECTIVES: To compare the risk factors and sociodemographic characteristics between first ischemic stroke cases with and without diabetes and to assess the mortality risk associated with diabetes. METHODS: Using population-based National Stroke Registry in Israel, all patients hospitalized for a first event of ischemic stroke between the years 2014-2018 were followed for all-cause mortality. Chi-square analysis was used to compare the differences in risk factors, sociodemographic profile and cumulative mortality between patients with and without diabetes. Cox proportional hazards models were used to estimate the hazard ratio for mortality in selected timeframes. RESULTS: Among 41,639 patients with a first event of ischemic stroke, 44.5% were previously diagnosed with diabetes. Diabetic patients were more likely to be males, members of the Arab ethnic group, with lower socioeconomic status and a higher prevalence of cardiovascular comorbidities, anemia, leukocytosis and abnormal kidney function. Diabetes was associated with a higher mortality risk in the first year and long term, but not in the first month following stroke. Diabetes-associated mortality risk interacted with time and age, was higher in younger age and increased with time. CONCLUSIONS: Our findings suggest that diabetes is associated with a higher prevalence of comorbidities among patients with first ischemic stroke and with a higher risk for mortality in the mid and long term, which is more profound in younger age.

Admission Hydration Status and Ischemic Stroke Outcome-Experience from a National Registry of Hospitalized Stroke Patients.

Reduced intravascular volume upon ischemic stroke (IS) admission has been associated with in-hospital complications, disability, and reduced survival. We aimed to evaluate the association of the urea-to-creatinine ratio (UCR) with disability or death at discharge, length of stay, in-hospital complications, and mortality during the first year. Using a national registry, we identified hospitalized IS patients without renal failure. Disability or death at discharge, length of stay, in-hospital complications, and mortality during the first year were studied by UCR, and associations between UCR levels and each outcome were assessed adjusting for age, sex, stroke severity, comorbidities, use of statins, and use of diuretics. In total, 2212 patients were included. Levels (median (25-75%)) for the main study variables were: urea 5.16 (3.66-6.83) mmol/L; creatinine 80 (64-92) µmol/L; and UCR 65 (58-74). Levels of UCR were significantly higher in patients with disability or death at discharge (p < 0.0001), those with complications during hospitalization (p = 0.03), those with infection during hospitalization (p = 0.0003), and those dead at 1 year (p < 0.0001). Analysis by UCR quartile showed that rates of disability or death at discharge, infections, complications overall, and death at 1 year in patients with UCR in the 4th quartile were significantly higher than in others. Risk-factor-adjusted analysis by UCR quartiles demonstrated an inconsistent independent association between UCR and disability or death after ischemic stroke. A high 1-year mortality rate was observed in IS patients with elevated UCR, yet this finding was not statistically significant after controlling for risk factors. Our study shows inconsistent associations between hydration status and poor functional status at discharge, and no association with length of stay, in-hospital complications (infectious and overall), and 1-year mortality.

Colchicine for prevention of vascular inflammation in Non-CardioEmbolic stroke (CONVINCE) - study protocol for a randomised controlled trial.

BACKGROUND: Inflammation contributes to unstable atherosclerotic plaque and stroke. In randomised trials in patients with coronary disease, canukinumab (an interleukin-1B antagonist) and colchicine (a tubulin inhibitor with pleiotropic anti-inflammatory effects) reduced recurrent vascular events.Hypothesis: Anti-inflammatory therapy with low-dose colchicine plus usual care will reduce recurrent vascular events in patients with non-severe, non-cardioembolic stroke and TIA compared with usual care alone. DESIGN: CONVINCE is a multi-centre international (in 17 countries) Prospective, Randomised Open-label, Blinded-Endpoint assessment (PROBE) controlled Phase 3 clinical trial in 3154 participants. The intervention is colchicine 0.5 mg/day and usual care versus usual care alone (antiplatelet, lipid-lowering, antihypertensive treatment, lifestyle advice). Included patients are at least 40 years, with non-severe ischaemic stroke (modified Rankin score ≤3) or high-risk TIA (ABCD2 > 3, or positive DWI, or cranio-cervical artery stenosis) within 72 hours-28 days of randomisation, with qualifying stroke/TIA most likely caused by large artery stenosis, lacunar disease, or cryptogenic embolism. Exclusions are stroke/TIA caused by cardio-embolism or other defined cause (e.g. dissection), contra-indication to colchicine (including potential drug interactions), or incapacity for participation in a clinical trial. The anticipated median follow-up will be 36 months. The primary analysis will be by intention-to-treat. OUTCOME: The primary outcome is time to first recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation with unstable angina (non-fatal or fatal). SUMMARY: CONVINCE will provide high-quality randomised data on the efficacy and safety of anti-inflammatory therapy with colchicine for secondary prevention after stroke. SCHEDULE: First-patient first-visit was December 2016. Recruitment to complete in 2021, follow-up to complete in 2023.

Reduction in Acute Stroke Admissions during the COVID-19 Pandemic: Data from a National Stroke Registry.

INTRODUCTION: The COVID-19 pandemic overwhelmed health-care systems worldwide, and medical care for other acute diseases was negatively impacted. We aimed to investigate the effect of the COVID-19 outbreak on admission rates and in-hospital care for acute stroke and transient ischemic attack (TIA) in Israel, shortly after the start of the pandemic. METHODS: We conducted a retrospective observational study, based on data reported to the Israeli National Stroke Registry from 7 tertiary hospitals. All hospital admissions for acute stroke or TIA that occurred between January 1 and April 30, 2020 were included. Data were stratified into 2 periods according to the timing of COVID-19 restrictions as follows: (1) "pre-pandemic" - January 1 to March 7, 2020 and (2) "pandemic" - March 8 to April 30, 2020. We compared the weekly counts of hospitalizations between the 2 periods. We further investigated changes in demographic characteristics and in some key parameters of stroke care, including the percentage of reperfusion therapies performed, time from hospital arrival to brain imaging and to thrombolysis, length of hospital stay, and in-hospital mortality. RESULTS: 2,260 cases were included: 1,469 in the pre-COVID-19 period and 791 in the COVID-19 period. Hospital admissions significantly declined between the 2 periods, by 48% for TIA (rate ratio [RR] = 0.52; 95% CI 0.43-0.64) and by 29% for stroke (RR = 0.71; 95% CI 0.64-0.78). No significant changes were detected in demographic characteristics and in most parameters of stroke management. While the percentage of reperfusion therapies performed remained unchanged, the absolute number of patients treated with reperfusion therapies seemed to decrease. Higher in-hospital mortality was observed only for hemorrhagic stroke. CONCLUSION: The marked decrease in admissions for acute stroke and TIA, occurring at a time of a relatively low burden of COVID-19, is of great concern. Public awareness campaigns are needed as patients reluctant to seek urgent stroke care are deprived of lifesaving procedures and secondary prevention treatments.

Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.

Background and Purpose: There is a continuous rise in the prevalence of adolescent obesity and incidence of stroke among young adults in many Western countries, but the association between them is unclear. Methods: A nationwide population-based study of 1 900 384 Israeli adolescents (58% men; mean age, 17.3 years) who were evaluated before mandatory military service during 1985 and 2013. Body mass index was classified according to the US Center for Disease Control and Prevention percentiles. Primary outcome was a first stroke event as recorded by the Israeli National Stroke Registry between 2014 and 2018. Cox proportional hazard models were applied. Results: There were 1088 first stroke events (921 ischemic and 167 hemorrhagic; mean diagnosis age, 41.0 years). Adolescent body mass index was significantly associated with a graded increase in the risk for any stroke, ischemic stroke, but less so with hemorrhagic stroke. The hazard ratios for the first ischemic stroke event were 1.4 (95% CI, 1.2­1.6), 2.0 (95% CI, 1.6­2.4), and 3.4 (95% CI, 2.7­4.3) for the 50th to 84th percentile, overweight and obese groups, respectively, after adjustment for sex, age, and sociodemographic confounders with the 5th to 49th body mass index percentile group as the reference. The respective hazard ratios after further adjustment for diabetes status were 1.3 (1.1­1.5), 1.6 (1.3­2.0), and 2.4 (1.9­3.1). Results persisted when the cohort was divided by diabetes status and when ischemic stroke before age 30 was the outcome. Conclusions: High adolescent body mass index was associated with ischemic stroke in young adults with or without diabetes. The rising prevalence of adolescent obesity may increase the future burden of stroke in young adults.

Are there disparities in acute stroke treatment between the Jewish and Arab populations in Israel? Results from the National Acute Stroke Israeli registry.

BACKGROUND: According to the latest reported data from the National Acute Stroke Israeli Survey (NASIS), around 18,000 strokes occur annually in Israel. Data regarding disparities in stroke care between the Jewish and the Arab populations in Israel are lacking. AIMS: We wished to compare demographics, comorbidities, stroke characteristics and outcomes between Jewish and Arab stroke patients in Israel that were acutely treated with intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT), in order to test if there are disparities or any ethnic-specific parameters. METHODS: The National Acute Stroke Israeli registry of patients undergoing revascularization (NASIS-REVASC) prospectively enrolled patients in six comprehensive stroke centers between 1/2014 and 3/2016. In this observational research, we compared demographics, comorbidities, time metrics, stroke characteristics and outcomes between Jewish and Arab patients enrolled. RESULTS: NASIS-REVASC included 1432 patients out of which 143 (10%) were of Arab ethnicity and 1289 (90%) of Jewish ethnicity. Arab patients were significantly younger (66 ± 14 vs. 73 ± 29, p = 0·004), exhibited higher rates of smoking and diabetes (31% vs. 18% and 57% vs. 34%, p < 0·001 for both), and were less often treated with systemic thrombolysis (48% vs. 59%, p = 0·012). However, the rates of any interventional treatment with either intravenous thrombolysis or endovascular thrombectomy as well as the rates of favorable outcomes and mortality were comparable between groups. CONCLUSIONS: Despite several baseline differences between Arab and Jewish Israeli stroke patients, treatment allocations, survival and functional outcomes were similar indicating lack of disparity in stroke care among patients treated acutely with IVT and/or EVT in Israel. DATA ACCESS STATEMENT: Full data is available following a formal request to the NASIS-REVASC registry at the Israeli Health Ministry.

[UPDATED ISRAELI GUIDELINES FOR THE TREATMENT OF DYSLIPIDEMIA 2020].

INTRODUCTION: Despite the impressive decline in mortality from atherosclerotic cardiovascular diseases (ASCVD), these diseases still account for a large proportion of the overall morbidity and mortality worldwide. A vast amount of research has demonstrated the key role played by circulating lipoproteins, and especially low-density lipoprotein (LDL), in the etiology of atherosclerosis, and numerous studies have proven the efficacy of interventions that lower the atherogenic lipoproteins in reducing morbidity and mortality from ASCVD. While previous guidelines placed an emphasis on the use HMG-CoA reductase inhibitors (statins) for the treatment of dyslipidemia, recent studies have shown that other LDL cholesterol lowering drugs, including ezetimibe and the PCSK9 inhibitors, can provide additional benefit when used in combination with (and in certain cases instead of) statins. These studies have also shown that blood LDL cholesterol levels lower than previously recommended targets provide additional benefit, without evidence of a threshold beyond which the benefit ceases and without excess adverse effects. The updated guidelines were formulated by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, the Israel Society of Internal Medicine, the Israeli Heart Association, the Israeli Neurology Association and the Israel Association of Family Medicine. They provide recommendations for revised risk stratification of patients, novel target goals, and the use of evidence-based treatment and follow-up strategies with reference to specific patient sub-groups.

Widespread cortical dyslamination in epilepsy patients with malformations of cortical development.

PURPOSE: Recent research in epilepsy patients confirms our understanding of epilepsy as a network disorder with widespread cortical compromise. Here, we aimed to investigate the neocortical laminar architecture in patients with focal cortical dysplasia (FCD) and periventricular nodular heterotopia (PNH) using clinically feasible 3 T MRI. METHODS: Eighteen epilepsy patients (FCD and PNH groups; n = 9 each) and age-matched healthy controls (n = 9) underwent T1 relaxation 3 T MRI, from which component probability T1 maps were utilized to extract sub-voxel composition of 6 T1 cortical layers. Seventy-eight cortical areas of the automated anatomical labeling atlas were divided into 1000 equal-volume sub-areas for better detection of cortical abnormalities, and logistic regressions were performed to compare FCD/PNH patients with healthy controls with the T1 layers composing each sub-area as regressors. Statistical significance (p < 0.05) was determined by a likelihood-ratio test with correction for false discovery rate using Benjamini-Hochberg method. RESULTS: Widespread cortical abnormalities were observed in the patient groups. Out of 1000 sub-areas, 291 and 256 bilateral hemispheric cortical sub-areas were found to predict FCD and PNH, respectively. For each of these sub-areas, we were able to identify the T1 layer, which contributed the most to the prediction. CONCLUSION: Our results reveal widespread cortical abnormalities in epilepsy patients with FCD and PNH, which may have a role in epileptogenesis, and likely related to recent studies showing widespread structural (e.g., cortical thinning) and diffusion abnormalities in various human epilepsy populations. Our study provides quantitative information of cortical laminar architecture in epilepsy patients that can be further targeted for study in functional and neuropathological studies.

Holocaust exposure and late-life cognitive performance in men with coronary heart disease.

BACKGROUND: Holocaust victims experienced extreme physical and mental stress that could lead to prolonged deficits in psychological and physiological well-being. We aimed to examine whether exposure to Holocaust conditions is associated with cognitive function and decline in a sample of old male adults with coronary heart disease (CHD). METHODS: The sample included 346 individuals with CHD who participated in a clinical trial in 1990-1997 (mean age 56.7 ± 6.5 y). During 2004-2008 (mean age 71.8 ± 6.5 y) and 2011-2013 (mean age 77.1 ± 6.4 y) participants underwent computerized cognitive assessments. Exposure to Holocaust conditions was based on self-report at the second assessment. Linear regression and mixed-effect models were conducted to evaluate the associations between Holocaust survivorship and subsequent cognitive performance and rate of cognitive decline. RESULTS: Forty-Three participants (12%) survived concentration camps/ghettos, 69 (20%) were Holocaust survivors who escaped concentration camps/ghettos, and 234 (68%) were not Holocaust survivors. After adjustment for potential confounders, concentration camp/ghetto survivors had poorer global cognitive performance and poorer attention (ß = -3.90; 95%CI: 7.11;-0.68 and ß = -4.11; 95%CI: 7.83;-0.38, respectively) compared to individuals who were not exposed to Holocaust conditions. Additionally, participants who reported being at concentration camps/ghettoes had increased cognitive decline in global performance and executive function (ß = -0.19; 95%CI: 0.37;-0.008 and ß = -0.29; 95%CI: 0.53;-0.06, respectively) compared to participants who were not Holocaust survivors. Lastly, those who were Holocaust survivors but not in concentration camps/ghettos had greater decline in attention (ß = -0.11; 95%CI: 0.21;-0.01). DISCUSSION: Exposure to Holocaust conditions in early-life may be linked with poorer cognitive function and greater cognitive decline decades later in old-adults with CHD.

Overweight, Obesity, and Late-Life Sarcopenia Among Men With Cardiovascular Disease, Israel.

INTRODUCTION: Little is known about the association between obesity and sarcopenia - age-related loss of muscle mass and function - among patients with cardiovascular disease. We investigated the association between overweight, obesity, and sarcopenia among community-dwelling men in Israel with cardiovascular disease. METHODS: A subset of 337 men (mean age at baseline 56.7 [SD, 6.5]) who previously (1990-1997) participated in the Bezafibrate Infarction Prevention trial underwent a neurovascular evaluation as part of the Bezafibrate Infarction Prevention Neurocognitive Study 15.0 (SD, 3.0) years after baseline and a sarcopenia evaluation 19.9 (SD, 1.0) years after baseline. We applied a multinomial logistic model to estimate odds ratios and 95% CIs for 3 categories of sarcopenia: no evidence of sarcopenia (ie, robust), probable sarcopenia, and sarcopenia. RESULTS: We found sarcopenia among 54.3% of participants with obesity (body mass index [BMI, in kg/m2] ≥30.0), 37.0% of participants who were overweight (25.0 ≤ BMI ≤29.9), and 24.8% of participants with normal weight (BMI 18.5 to 24.9). In a comparison of BMI ≥25.0 and BMI <25.0, adjusting for covariates, the odds ratio of having probable sarcopenia was 3.27 (95% CI, 1.68-6.36) and having sarcopenia was 5.31 (95% CI, 2.50-11.27). CONCLUSION: We found a positive association between obesity and late-life sarcopenia and suggest that obesity might be an important modifiable risk factor related to sarcopenia among men with cardiovascular disease.

Long-term trajectories of BMI predict carotid stiffness and plaque volume in type 2 diabetes older adults: a cohort study.

BACKGROUND: High body mass index (BMI) is a risk factor for type 2 diabetes and cardiovascular disease. However, its relationships with indices of carotid stiffness and plaque volume are unclear. We investigated associations of long-term measurements of BMI with indices of carotid stiffness and atherosclerosis among non-demented diabetes patients from the Israel Diabetes and Cognitive Decline (IDCD) study. METHODS: Carotid ultrasound indices [carotid intima media thickness (cIMT), distensibility, elastography and plaque volume] were assessed in N = 471 participants. Mean BMI across all MHS diabetes registry measurements and trajectories of BMI were calculated. BMI was categorized into three trajectory groups representing: a relatively stable normal weight (n = 185, 44%), overweight trajectory (n = 188, 44.8%) and a trajectory of obesity (n = 47, 11.2%). Linear and logistic regressions estimated associations of carotid indices with mean BMI and BMI trajectories. RESULTS: Compared to the normal weight trajectory, an obesity trajectory was associated with carotid distensibility (ß = - 3.078, p = 0.037), cIMT (ß = 0.095, p = 0.004), and carotid elastography (ß = 0.181, p = 0.004) but not with plaque volume (ß = 0.066, p = 0.858). Compared with the normal weight trajectory, an obesity trajectory was associated with increased odds for impaired carotid distensibility (OR = 2.790, p = 0.033), impaired cIMT (OR = 5.277, p = 0.001) and large carotid plaque volume (OR = 8.456, p = 0.013) but not with carotid elastography (OR = 1.956, p = 0.140). Mean BMI was linearly associated with Distensibility (ß = - 0.275, p = 0.005) and cIMT (ß = 0.005, p = 0.026). CONCLUSIONS: Long-term measurements of adiposity are associated with indices of carotid stiffness and plaque volume among older type 2 diabetes adults.