Stroke Risk After COVID-19 Bivalent Vaccination Among US Older Adults.

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.

Chronic Hepatitis B Virus Infection and Risk of Stroke Types: A Prospective Cohort Study of 500†000 Chinese Adults.

BACKGROUND: Stroke is a leading cause of mortality and permanent disability in China, with large and unexplained geographic variations in rates of different stroke types. Chronic hepatitis B virus infection is prevalent among Chinese adults and may play a role in stroke cause. METHODS: The prospective China Kadoorie Biobank included >500 000 adults aged 30 to 79 years who were recruited from 10 (5 urban and 5 rural) geographically diverse areas of China from 2004 to 2008, with determination of hepatitis B surface antigen (HBsAg) positivity at baseline. During 11 years of follow-up, a total of 59 117 incident stroke cases occurred, including 11 318 intracerebral hemorrhage (ICH), 49 971 ischemic stroke, 995 subarachnoid hemorrhage, and 3036 other/unspecified stroke. Cox regression models were used to estimate adjusted hazard ratios (HRs) for risk of stroke types associated with HBsAg positivity. In a subset of 17 833 participants, liver enzymes and lipids levels were measured and compared by HBsAg status. RESULTS: Overall, 3.0% of participants were positive for HBsAg. HBsAg positivity was associated with an increased risk of ICH (adjusted HR, 1.29 [95% CI, 1.16-1.44]), similarly for fatal (n=5982; adjusted HR, 1.36 [95% CI, 1.16-1.59]) and nonfatal (n=5336; adjusted HR, 1.23 [95% CI, 1.06-1.44]) ICH. There were no significant associations of HBsAg positivity with risks of ischemic stroke (adjusted HR, 0.97 [95% CI, 0.92-1.03]), subarachnoid hemorrhage (adjusted HR, 0.87 [95% CI, 0.57-1.33]), or other/unspecified stroke (adjusted HR, 1.12 [95% CI, 0.89-1.42]). Compared with HBsAg-negative counterparts, HBsAg-positive individuals had lower lipid and albumin levels and higher liver enzyme levels. After adjustment for liver enzymes and albumin, the association with ICH from HBsAg positivity attenuated to 1.15 (0.90-1.48), suggesting possible mediation by abnormal liver function. CONCLUSIONS: Among Chinese adults, chronic hepatitis B virus infection is associated with an increased risk of ICH but not other stroke types, which may be mediated through liver dysfunction and altered lipid metabolism.

Epidemiology of ischemic stroke and hemorrhagic stroke in venoarterial extracorporeal membrane oxygenation.

BACKGROUND: While venoarterial extracorporeal membrane oxygenation (V-A ECMO) provides lifesaving support for cardiopulmonary failure, complications may increase mortality, with few studies focusing on ischemic/hemorrhagic stroke. We aimed to determine the trends and associations of stroke incidence and mortality, and their risk factors, including the effects of annual case volumes of ECMO centers. METHODS: Retrospective analysis was performed on the Extracorporeal Life Support Organization (ELSO) registry, including adult V-A ECMO patients from 534 international centers between 2012 and 2021, excluding extracorporeal cardiopulmonary resuscitation. Temporal trend analyses were performed for stroke incidence and mortality. Univariate testing, multivariable regression, and survival analysis were used to evaluate the associations of stroke, 90-day mortality, and impact of annual center volume. RESULTS: Of 33,041 patients, 20,297 had mortality data, and 12,327 were included in the logistic regression. Between 2012 and 2021, ischemic stroke incidence increased (p < 0.0001), hemorrhagic stroke incidence remained stable, and overall 90-day mortality declined (p < 0.0001). Higher 24-h PaO2 and greater decrease between pre-ECMO PaCO2 and post-cannulation 24-h PaCO2 were associated with greater ischemic stroke incidence, while annual case volume was not. Ischemic/hemorrhagic strokes were associated with increased 90-day mortality (both p < 0.0001), while higher annual case volume was associated with lower 90-day mortality (p = 0.001). Hazard of death was highest in the first several days of V-A ECMO. CONCLUSION: In V-A ECMO patients between 2012 and 2021, 90-day mortality decreased, while ischemic stroke incidence increased. ELSO centers with higher annual case volumes had lower mortality, but were not associated with ischemic/hemorrhagic stroke incidence. Both ischemic/hemorrhagic strokes were associated with increased mortality.

Dialysis Modality and Incident Stroke Among Patients With End-Stage Kidney Disease: A Registry-Based Cohort Study.

BACKGROUND: Patients with end-stage kidney disease undergoing dialysis are at significant risk of stroke. Whether dialysis modality is associated with cerebrovascular disease is unclear. This study compared the risk of incident stroke in patients undergoing peritoneal dialysis or hemodialysis. METHODS: Thirty-nine thousand five hundred forty-two patients without a history of stroke who initiated dialysis between January 1, 2010, and December 31, 2014 were retrospectively studied using Taiwan's National Health Insurance Research Database. We matched 3809 patients undergoing peritoneal dialysis (mean age 59±13 years; 46.5% women) and 11 427 patients undergoing hemodialysis (mean age 59±13 years; 47.3% women) by propensity score in a 1:3 ratio with follow-up through December 31, 2015. The primary outcome was incident acute ischemic stroke. Secondary outcomes included hemorrhagic stroke, acute coronary syndrome, and all-cause mortality. Cox proportional hazard models were conducted to determine hazard ratios of clinical outcomes according to the dialysis modality. RESULTS: During a median follow-up of 2.59 (interquartile range 1.50-3.93) years, acute ischemic stroke, hemorrhagic stroke, and acute coronary syndrome occurred in 783 (5.1%), 376 (2.5%), and 1350 (8.9%) patients, respectively. In a multivariable Cox model that accounted for the competing risk of death, acute ischemic stroke occurred more frequently in the peritoneal dialysis group than in the hemodialysis group (subdistribution hazard ratio, 1.32 [95% CI, 1.13-1.54]; P=0.0005). There were no significant treatment-related differences in the risk of hemorrhagic stroke (subdistribution hazard ratio, 0.89 [95% CI, 0.70-1.14]; P=0.3571) and acute coronary syndrome (subdistribution hazard ratio, 0.99 [95% CI, 0.88-1.12]; P=0.9080). Patients undergoing peritoneal dialysis were more likely to die from any cause than patients undergoing hemodialysis (adjusted hazard ratio, 1.24 [95% CI, 1.15-1.33]; P<0.0001). CONCLUSIONS: Peritoneal dialysis was associated with a significantly increased risk of acute ischemic stroke compared with hemodialysis. Further studies are needed to clarify whether more aggressive cerebrovascular preventive strategies might mitigate the excess risk for ischemic stroke among patients receiving peritoneal dialysis.

Scoping Review of Racial, Ethnic, and Sex Disparities in the Diagnosis and Management of Hemorrhagic Stroke.

BACKGROUND AND OBJECTIVES: In the United States, Black, Hispanic, and Asian Americans experience excessively high incidence rates of hemorrhagic stroke compared with White Americans. Women experience higher rates of subarachnoid hemorrhage than men. Previous reviews detailing racial, ethnic, and sex disparities in stroke have focused on ischemic stroke. We performed a scoping review of disparities in the diagnosis and management of hemorrhagic stroke in the United States to identify areas of disparities, research gaps, and evidence to inform efforts aimed at health equity. METHODS: We included studies published after 2010 that assessed racial and ethnic or sex disparities in the diagnosis or management of patients aged 18 years or older in the United States with a primary diagnosis of spontaneous intracerebral hemorrhage or aneurysmal subarachnoid hemorrhage. We did not include studies assessing disparities in incidence, risks, or mortality and functional outcomes of hemorrhagic stroke. RESULTS: After reviewing 6,161 abstracts and 441 full texts, 59 studies met our inclusion criteria. Four themes emerged. First, few data address disparities in acute hemorrhagic stroke. Second, racial and ethnic disparities in blood pressure control after intracerebral hemorrhage exist and likely contribute to disparities in recurrence rates. Third, racial and ethnic differences in end-of-life care exist, but further work is required to understand whether these differences represent true disparities in care. Fourth, very few studies specifically address sex disparities in hemorrhagic stroke care. DISCUSSION: Further efforts are necessary to delineate and correct racial, ethnic, and sex disparities in the diagnosis and management of hemorrhagic stroke.

Behavioral trigger factors for hemorrhagic stroke: a case-crossover study.

BACKGROUND: The role and extent of the effects of short-term behavioral factors on the risk of hemorrhagic stroke (HS) are unclear. This study aimed to assess and quantify behavioral trigger factors (BTFs) for HS and identify the differences in BTFs between Chinese and other populations. METHODS: A case-crossover study was performed from March 2021 to February 2022. New-onset HS patients were recruited from two university hospitals in China. The patients were interviewed to evaluate their exposure to 20 potential BTFs during the predefined risk and control periods and to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). A comprehensive literature review was conducted to synthesize the evidence. RESULTS: A total of 284 patients with HS were included (150 with intracerebral hemorrhage and 134 with subarachnoid hemorrhage). Multivariate regression analysis showed that straining for defecation (OR: 3.06; 95% CI: 1.01-8.40), weightlifting (OR: 4.82; 95% CI: 1.02-22.83), overeating (OR: 4.33; 95% CI: 1.24-15.21), heavy physical exertion (OR: 3.02; 95% CI: 1.18-7.78), and chess/cards/mahjong games (OR: 2.51; 95% CI: 1.05-6.01) were associated with an increased risk within 2 hours before HS onset, and critical life events (OR: 3.81; 95% CI: 1.06-13.74) were associated with an increased risk 7 days before the onset of HS. Exposure to anger (OR: 3.17; 95% CI: 1.73-5.81) and heavy physical exertion (OR: 2.12; 95% CI: 1.65, 2.74) showed an increased risk of HS events after the pooled analysis. CONCLUSIONS: Several behavioral activities and mood modifications are associated with the onset of HS. In addition to the common BTFs, Chinese patients have specific BTFs due to their habits and customs distinct from those of different populations in other regions. Key messages What is already known on this topic It is known that several behavioral trigger factors (BTFs) are associated with the onset of hemorrhagic stroke (HS), such as vigorous physical exercise and anger. Evidence for other potential trigger factors was of less robustness. Which BTFs contribute to HS among the Chinese population is poorly understood, since individuals in different countries and regions have their own habits of life and customs. What this study adds Our study identified that two special behaviors, chess/card/mahjong games and critical life events, were associated with the onset of HS in Chinese populations, besides heavy physical exertion, weightlifting, overeating, and straining for defecation, which were previously reported in other populations. Heavy physical exertion and anger could potentially increase the risk of HS based on a comprehensive aggregation and evidence synthesis. How this study might affect research, practice, or policy Patients in different populations or regions may possess specific BTFs owing to their distinct habits and customs. Avoidance of these behaviors and regulation of emotions to maintain a steady mentality would help minimize exposure and prevent the disease for high-risk populations in China.

Stroke Complications in Patients Requiring Durable Mechanical Circulatory Support Systems After Extracorporeal Life Support.

Stroke is one of the leading complications following durable mechanical circulatory support (MCS) implantation. The aim of this multicenter study was to investigate stroke complications in patients requiring durable MCS following extracorporeal life support (ECLS). Data of 11 high volume MCS centers were collected and evaluated to identify patients who underwent durable MCS implantation after ECLS support between January 2010 and August 2018. The primary outcome was stroke following durable MCS implantation. Univariate and multivariate logistic regression analyses were performed to determine predictors of stroke. Overall, 531 patients met the inclusion criteria. Only patients who were supported with continuous flow pumps were included in this study accounting for 495 patients (median age 54 years old [interquartile range 47-60]). A total of 136 patients (27%) developed postoperative stroke on device during the follow-up (48% ischemic and 52% hemorrhagic) after a median durable MCS support of 320 [32-1,000] days, accounting for 0.17 events per patient-year. Of 133 patients with known date of stroke, a total of 47 (10%) developed stroke during the first 30 days (64% ischemic and 36% hemorrhagic), and 86 patients developed stroke after 30 days (38% ischemic and 62% hemorrhagic) of durable MCS support (late stroke). Survival rate was significantly lower in patients with hemorrhagic stroke ( p = 0.00091). Stroke appears to be a common complication in patients transitioned to durable MCS support after ECLS. Hemorrhagic stroke is a more common type of late stroke and is associated with inferior outcomes.

Comparison of Arterial Ischemic and Hemorrhagic Pediatric Stroke in Etiology, Risk Factors, Clinical Manifestations, and Prognosis.

BACKGROUND: Stroke is relatively rare in children but has a significant impact on long-term morbidity and mortality. There are limited data regarding the etiology, clinical manifestation, and prognosis of arterial ischemic stroke (AIS) and hemorrhagic stroke (HS) in children. OBJECTIVE: The aim of this study is to identify and compare etiology, risk factors, clinical manifestations, and prognostic outcomes between arterial ischemic and hemorrhagic pediatric stroke. METHODS: We retrospectively reviewed all hospital medical records and pediatric neurology database of 83 children who were first diagnosed with AIS and HS at the Pediatric Department, Chiang Mai University Hospital, Chiang Mai, Thailand between January 1, 2009, and December 31, 2018. All children were from 1 month to 18 years old. RESULTS: Fifty-one AIS (56%) and 32 (35.2%) HS were identified. The median age of onset was 6.9 years for AIS and 5.3 years for HS. Moyamoya disease/syndrome was the most common cause in AIS (21.6%). Rupture of cerebral arteriovenous malformation was the most common cause in HS (21.9%). More than one-third (39%) of children had multiple risk factors associated with stroke. Iron deficiency anemia was commonly found in children with AIS (39.2%). The majority of clinical presentations were hemiparesis (80.4%) for AIS and alteration of consciousness (68.8%) for HS. The median time to diagnosis exceeded 6 hours in both AIS and HS. The overall mortality rate of acute stroke was 5.1 per 100 person-years (95% confidence interval [CI], 2.9-9). The mortality rate was higher in HS compared with that in AIS with statistical significance (16.6; 95% CI, 8.9-30.8 vs 1.1%; 95% CI, 0.3-4.6 per 100 person-years). Thirty children (36.1%) developed epilepsy during the follow-up (median duration, 26 months). Recurrent stroke occurred in 1 child with AIS and 1 child with HS. CONCLUSIONS: Moyamoya disease/syndrome and arteriovenous malformation rapture are the most common cause of AIS and HS, respectively. Iron deficiency anemia was commonly found in childhood AIS. The time to diagnosis in both AIS and HS was delayed. The mortality rate in HS was higher than in AIS. Neurological deficits are seen in 70% of childhood AIS during the follow-up. One-third of the children in our study developed epilepsy, which generally responds to a single antiseizure medication. The recurrence rate of childhood stroke was low compared with adult stroke.

High incidence of stroke and mortality in pediatric critical care patients with COVID-19 in Peru.

INTRODUCTION: Pediatric critical care patients with COVID-19 treated in Peru have higher mortality than those previously reported from other countries. Pediatric providers have reported a high number of patients without comorbidities presenting with hemorrhagic strokes associated with COVID-19. We present a study analyzing the factors associated with mortality in this setting. METHODS: Prospective case-control study that included patients <17 years old admitted to a pediatric critical care unit with a positive test confirming COVID-19. The primary outcome was mortality. Fisher's exact test and the Mann-Whitney U test were used for the analysis. RESULTS: Forty-seven patients were admitted to critical care. The mortality of our study is 21.3%. The mortality of patients with neurological presentation was 45.5%, which was significantly higher than the mortality of acute COVID-19 (26.7%) and MIS-C (4.8%), p 0.18. Other risk factors for mortality in our cohort were strokes and comorbidities. Only one patient presenting with hemorrhagic stroke had an undiagnosed comorbidity. CONCLUSION: Cerebrovascular events associated with COVID-19 in pediatric patients, including infants, must be recognized as one of the more severe presentations of this infection in pediatric patients. IMPACT: Pediatric patients with COVID-19 can present with hemorrhagic and ischemic strokes on presentation. Neurological presentation in pediatric patients with COVID-19 has high mortality. Mortality of pediatric patients with COVID-19 is associated with comorbidities. Pediatric presentation and outcomes of COVID-19 in different regions can be novel to previously described.

Perioperative neurologic outcomes of right versus left upper extremity access for fenestrated-branched endovascular aortic aneurysm repair.

OBJECTIVE: Upper extremity (UE) access is frequently used for fenestrated-branched endovascular aortic aneurysm repair (F-BEVAR), particularly for complex repairs. Traditionally, left-side UE access has been used to avoid crossing the arch and the origin of the supra-aortic vessels, which could potentially result in cerebral embolization and an increased risk of perioperative cerebrovascular events. More recently, right UE has been more frequently used as it is more convenient and ergonomic. The purpose of this study was to assess the outcomes and cerebrovascular events after F-BEVAR with the use of right- vs left-side UE access. METHODS: During an 8-year period, 453 patients (71% male) underwent F-BEVAR at a single institution. UE access was used in more complex repairs. Left UE access was favored in the past, whereas right UE access is currently the preferred UE access side. Brachial artery cutdown was used in all patients for the placement of a 12F sheath. Outcomes were compared between patients undergoing right vs left UE access. End points included cerebrovascular events, perioperative mortality, technical success, and local access-related complications. RESULTS: UE access was used in 361 (80%) patients. The right side was used in 232 (64%) and the left side in 129 (36%) patients for the treatment of 88 (25%) juxtarenal, 135 (38%) suprarenal, and 137 (38%) thoracoabdominal aortic aneurysms. Most procedures were elective (94%). Technical success was achieved in 354 patients (98%). In-patient or 30-day mortality was 3.3%. Five (1%) perioperative strokes occurred in patients undergoing right UE access, of which three were ischemic and two were hemorrhagic. No transient ischemic attacks occurred perioperatively. Two hemorrhagic strokes were associated with permissive hypertension to prevent spinal cord ischemia. No perioperative strokes occurred in patients undergoing left UE access (P = .16). Overall, perioperative strokes occurred with similar frequency in patients undergoing UE (5, 1%) and femoral access only (1, 1%) (P = .99). Arm access-related complications occurred in 15 (5%) patients, 11 (4.8%) on the right side and 4 (6%) on the left side (P = .74). CONCLUSIONS: Right UE access can be used for F-BEVAR with low morbidity and minimal risk of perioperative ischemic stroke or transient ischemic attacks. In general, UE access is not associated with an increased risk of perioperative stroke compared with femoral access only. Tight blood pressure control is, however, critical to avoid intracranial bleeding related to uncontrolled hypertension.

Hemorrhagic stroke associated to COVID-19 infection in Mexico General Hospital.

INTRODUCCIÓN: en la actual pandemia de COVID-19, existe evidencia creciente que ha identificado el neurotropismo del virus SARS-CoV-2 y sus complicaciones neurológicas, incluida la enfermedad cerebrovascular isquémica y escasamente hemorragia cerebral (HC). OBJETIVO: describir las características clínicas, radiológicas, de laboratorio y pronósticas de los pacientes con HC asociada al SARS-CoV-2. MÉTODOS: se incluyeron pacientes consecutivos con prueba de PCR confirmatoria para infección por SARS-CoV-2 y HC. RESULTADOS: en un período de 90 días, en un centro de referencia COVID-19 en México, de 1108 pacientes con infección por SARS-CoV-2, se encontraron 4 pacientes (0.36%) con HC. Tenían una edad de 71(±12.2) años, 2 eran mujeres. Se encontró que dos tenían factores de riesgo cardiovascular previos. En dos casos se encontró el origen en el núcleo dentado mientras que los otros dos correspondieron al tálamo. Tres de los cuatro pacientes murieron. Postulamos que el descontrol hipertensivo, coagulopatía, trombocitopenia y la respuesta inmune inducida por el virus SARS-CoV-2 podrían desencadenar HC en un paciente con riesgo previo. CONCLUSIONES: la HC se asocia a la infección por SARS-CoV-2 con mal pronóstico cuando se presenta. Los equipos de neurocirugía deben estar preparados para el tratamiento oportuno de estos pacientes. INTRODUCTION: In the current COVID-19 pandemic, there is a growing body of evidence that has identified the neurotropism of the SARS-CoV-2 virus and its neurological complications, including cerebrovascular disease, focusing mainly in ischemic and scarcely about hemorrhagic stroke (HS). OBJECTIVE: The objective of the study was to describe clinical, radiological, laboratory tests, and prognostic characteristics of patients with SARS-CoV-2 associated HS. METHODS: Consecutive patients with a confirmatory PCR test for SARS-CoV-2 infection and a HS demonstrated by head CT were included in the study. RESULTS: Over a period of 90 days, in a COVID-19 reference center in Mexico, out of a total of 1108 patients with SARS-CoV-2 infection, it found 4 patients (0.36%) who meet criteria. They had an age of 71 (±12.2) years, 2 were women. It was found that two had prior cardiovascular risk factors. Two of the HS originated in the dentate nucleus while the other two corresponded to the thalamus. Three of the four patients died. We suggest that catastrophic uncontrolled blood pressure, coagulopathy, thrombocytopenia, and immune response induced by SARS-CoV-2 could in a specific patient trigger HS. CONCLUSIONS: HS is associated to SARS-CoV-2 infection with poor prognosis when it presented. Neurosurgery teams should prepare for the timely and appropriate treatment of this patients.

Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study.

Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.

Association of Body Mass Index with Ischemic and Hemorrhagic Stroke.

Data on the association between body mass index (BMI) and stroke are scarce. We aimed to examine the association between BMI and incident stroke (ischemic or hemorrhagic) and to clarify the relationship between underweight, overweight, and obesity and stroke risk stratified by sex. We analyzed the JMDC Claims Database between January 2005 and April 2020 including 2,740,778 healthy individuals (Median (interquartile) age, 45 (38-53) years; 56.2% men; median (interquartile) BMI, 22.3 (20.2-24.8) kg/m2). None of the participants had a history of cardiovascular disease. Each participant was categorized as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), or obese (BMI ≥ 30 kg/m2). We investigated the association of BMI with incidence stroke in men and women using the Cox regression model. We used restricted cubic spline (RCS) functions to identify the association of BMI as a continuous parameter with incident stroke. The incidence (95% confidence interval) of total stroke, ischemic stroke, and hemorrhagic stroke was 32.5 (32.0-32.9), 28.1 (27.6-28.5), and 5.5 (5.3-5.7) per 10,000 person-years in men, whereas 25.7 (25.1-26.2), 22.5 (22.0-23.0), and 4.0 (3.8-4.2) per 10,000 person-years in women, respectively. Multivariable Cox regression analysis showed that overweight and obesity were associated with a higher incidence of total and ischemic stroke in both men and women. Underweight, overweight, and obesity were associated with a higher hemorrhagic stroke incidence in men, but not in women. Restricted cubic spline showed that the risk of ischemic stroke increased in a BMI dose-dependent manner in both men and women, whereas there was a U-shaped relationship between BMI and the hemorrhagic stroke risk in men. In conclusion, overweight and obesity were associated with a greater incidence of stroke and ischemic stroke in both men and women. Furthermore, underweight, overweight, and obesity were associated with a higher hemorrhagic stroke risk in men. Our results would help in the risk stratification of future stroke based on BMI.

Stroke Mechanism in COVID-19 Infection: A Prospective Case-Control Study.

BACKGROUND: The characteristics and pathophysiological mechanisms involved in acute ischemic stroke in patients with COVID-19 infection have not been fully clarified. We prospectively studied the phenotypic and etiological features of acute stroke occurring in COVID-19 infection. PATIENTS & METHODS: Within nine months starting from April-2020, the presence of COVID-19 infection was determined by thoracic CT and SARS-CoV-2 PCR in all acute stroke cases managed in a single tertiary center. Consecutive and prospective data on vascular risk factors/comorbidities, in-hospital quality metrics, discharge outcomes, etiological subclassification and blood markers of thrombosis / inflammation were compared in 44 COVID-19 positive cases (37 acute ischemic stroke, 5 TIA, 2 intracerebral hematoma) and 509 COVID-19 negative patients (355 ischemic, 105 TIA, 44 hematoma and 5 stroke mimic). RESULTS: COVID-19 positive patients had more severe strokes, delayed hospital admission, longer hospital stay, higher mortality rates, but had similar vascular risk factors/comorbidities frequency, thrombolysis/thrombectomy utilization rates, metrics, and stroke etiological subtype. They had significantly higher CRP, fibrinogen, ferritin, leukocyte count and lower lymphocyte count. No difference was detected in aPTT, INR, D-dimer, platelet, hemoglobin, homocysteine levels and ANA, anti-dsDNA antibody and ENA panel positivity rates. Anti-phospholipid antibodies have been studied in 70% of COVID-19 positive and all cryptogenic patients, but were never found positive. Tests for coagulation factor levels and hereditary thrombophilia did not show major thrombophilia in any of the stroke patients with COVID-19. CONCLUSION: We documented that there is no significant difference in etiological spectrum in acute stroke patients with COVID-19 infection. In addition, cryptogenic stroke and antiphospholipid antibody positivity rates did not increase.

Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors.

Background and Purpose: Statins were shown to increase hemorrhagic stroke (HS) in patients with a first cerebrovascular event in 2006 (SPARCL), likely due to off-target antithrombotic effects, but continued to sometimes be used in patients with elevated HS risk due to absence of alternative medications. Recently, the PCSK9Is (proprotein convertase subtilisin kexin 9 inhibitors) have become available as a potent lipid-lowering class with potentially less hemorrhagic propensity. Methods: We performed a systematic comparative meta-analysis assessing HS rates across all completed statin and PCSK9I randomized clinical trials with treatment >3 months, following PRISMA guidelines. In addition to HS rates across all trials, causal relation was probed by evaluating for dose-response relationships by medication (low versus high medication dose/potency) and by presence and type of preceding brain vascular events at inception (none versus ischemic stroke/transient ischemic attack versus HS). Results: The systematic review identified 36 statin randomized clinical trials (204 918 patients) and 5 PCSK9I randomized clinical trials (76 140 patients). Across all patient types and all medication doses/potencies, statins were associated with increased HS: relative risk 1.15, P=0.04; PCSK9Is were not (P=0.77). In the medication dose/potency analysis, higher dose/potency statins (7 trials, 62 204 patients) were associated with magnified HS risk: relative risk, 1.53; P=0.002; higher dose/potency PCSK9Is (1 trial, 27 564 patients) were not (P=0.99). In the type of index brain vascular injury analysis for statins (5 trials, 9772 patients), prior ischemic stroke/transient ischemic attack was associated with a magnified risk of HS: relative risk, 1.43; P=0.04; and index intracerebral hemorrhage was associated with an extremely high effect estimate of risk of recurrent HS: hazard ratio, 4.06. For PCSK9Is, prior ischemic stroke/transient ischemic attack (1 trial, 5337 patients) was not associated with increased HS risk (P=0.97). Conclusions: Statins increase the risk of HS in a medication dose- and type of index brain vascular injury-dependent manner; PCSK9Is do not increase HS risk. PCSK9Is may be a preferred lipid-lowering medication class in patients with elevated HS risk, including patients with prior HS.

L-3-n-butylphthalide promotes restoration after an experimental animal model of intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating type of stroke with high morbidity and mortality, and the effective therapies for ICH remain to be explored. L-3-n-butylphthalide (NBP) is widely used in the treatment of ischemic stroke. However, few studies evaluated the therapeutic effects of NBP on ICH. Therefore, the present study aims to evaluate the effects of NBP on ICH and its potential mechanism. The rats were randomly divided into sham-operated group, saline-treated (ICH + saline) group, and NBP-treated (ICH + NBP) group. The ICH model of SD rats induced by IV collagenase was established. The modified Garcia JH score was used to detect the neurological deficit in rats. Western Blot and immunohistochemistry analysis was applied to test the levels of UBIAD1 and caspase-3 expressions in the perihematomal region. The rates of apoptotic cells were detected by TUNEL staining. The results showed that NBP up-regulated the expression of UBIAD1, reduced the apoptotic cells in the perihematomal region, and improved the neurological deficit. Taken together, our study added some new evidence to the application of NBP in ICH treatment.

Association between Angiotensin Converting Enzyme Insertion/Deletion gene polymorphism with the risk of Hemorrhagic Stroke: A systematic review and Meta-Analysis of 53 studies.

BACKGROUND AND AIMS: Hemorrhagic stroke (HS) results in significant mortality and disability worldwide. Angiotensin Converting Enzyme (ACE) is responsible for blood pressure regulation and vascular homeostasis. Our objective was to conduct a comprehensive meta-analysis for ascertaining the association of ACE I/D polymorphism with HS since a number of studies depicted inconclusive evidence. METHODS: Literature search was performed till July 10, 2020 in PubMed, EMBASE, Cochrane, Chinese National Knowledge Information and Google Scholar databases with keywords: ('Angiotensin Converting Enzyme' OR 'ACE') AND ('Single Nucleotide polymorphisms' OR 'SNP') AND ('Hemorrhagic stroke or 'HS'). Pooled Odds Ratio (OR) and 95% Confidence Interval (CI) were determined for gene-disease association using either fixed (when I2 < 50%) or random effect (when I2 > 50%) models. Risk of bias in studies was assessed using funnel plots and sensitivity analyses. Statistical analysis was performed using STATA version 13.0 software. RESULTS: A total of 53 studies having 5186 HS and 7347 healthy control subjects were included in our meta-analysis. Pooled analyses showed that ACE I/D gene polymorphism had significant association with risk of HS in overall study population [(dominant model: OR = 1.29, 95% CI = 1.12-1.50 & recessive model: OR = 1.79, 95% CI = 1.46-2.20)]. Population subgroup analyses further revealed significant relationship of ACE I/D polymorphism with ICH in Asians (recessive: OR 1.97, 95% CI = 1.57-2.47) but not in Caucasians (recessive: OR 1.02, 95% CI = 0.76-1.36). CONCLUSION: This meta-analysis suggests that ACE I/D polymorphism may lead to risk of HS and can be a potential biomarker for HS susceptibility especially in Asian population.

Antihypertensive Drugs for Secondary Prevention After Ischemic Stroke or Transient Ischemic Attack: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Approximately 30% of ischemic strokes occur after a previous stroke or transient ischemic attack. Arterial hypertension is one of the best established risk factors for first and recurrent stroke, both ischemic and hemorrhagic. Guidelines for the secondary prevention of ischemic stroke support the use of blood pressure (BP)-lowering drugs in most patients. However, the evidence for these recommendations comes from meta-analyses that included both ischemic and hemorrhagic stroke patients, whereas these 2 conditions differ quantitatively in several aspects. With this systematic review and meta-analysis, we aimed at summarizing the current evidence on BP-lowering drugs for secondary prevention in patients with ischemic stroke or transient ischemic attack. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to January 31, 2020. We included randomized controlled trials comparing any specific BP-lowering drug, as monotherapy or combination, with either a control or another BP-lowering drug. RESULTS: Eight studies that enrolled 33 774 patients with ischemic stroke or transient ischemic attack were included in the meta-analysis. Mean follow-up was 25 months (range, 3-48). Moderate-quality evidence indicated that a subsequent stroke occurred in 7.9% (ischemic in 7.4% or hemorrhagic in 0.6%) of patients taking any type of BP-lowering drug compared with 9.7% of patients taking placebo (odds ratio, 0.79 [95% CI, 0.66-0.94]; absolute risk difference, -1.9% [95% CI, -3.1% to -0.5%]). Moderate-quality evidence indicated that mortality occurred similarly in patients taking any type of BP-lowering treatment compared with placebo, with an absolute risk of 7.3% and 7.9%, respectively (odds ratio, 1.01 [95% CI, 0.92-1.10]; absolute risk difference, 0.1% [95% CI, -0.6% to 0.7%]). CONCLUSIONS: The use of BP-lowering drugs in patients with ischemic stroke or transient ischemic attack is associated with a 1.9% risk reduction of stroke but does not affect the all-cause mortality risk.

Herpes Zoster Vaccine Live and Risk of Stroke Among Medicare Beneficiaries: A Population-Based Cohort Study.

Background and Purpose: Herpes zoster (HZ) is associated with increased risk of stroke, and zoster vaccine live (ZVL, Zostavax) reduces the risk of HZ. No study has examined the association between ZVL (Zostavax) and risk of stroke. Present study examined association between receipt of ZVL (Zostavax) and risk of stroke among older US population. Methods: Our study included 1 603 406 US Medicare fee-for-service beneficiaries aged ≥66 years without a history of stroke and who received ZVL (Zostavax) during 2008 to 2014, and 1 603 406 propensity score-matched unvaccinated beneficiaries followed through to December 31, 2017. We used Cox proportional hazard models to examine association between ZVL (Zostavax) and composite fatal or nonfatal incident stroke outcomes. Results: During a median of 5.1 years follow-up (interquartile range, 3.9­6.7), we documented 64 635 stroke events, including 43 954 acute ischemic strokes and 6727 hemorrhagic strokes, among vaccinated beneficiaries during 8 755 331 person-years. The corresponding numbers among unvaccinated beneficiaries were 73 023, 50 476, and 7276, respectively, during 8 517 322 person-years. Incidence comparing vaccinated to unvaccinated beneficiaries were 7.38 versus 8.57 per 1000 person-years for all stroke, 5.00 versus 5.90 for acute ischemic stroke, and 0.76 versus 0.84 for hemorrhagic stroke (P<0.001 for all difference). Adjusted hazard ratios comparing vaccinated to unvaccinated beneficiaries were 0.84 (95% CI, 0.83­0.85), 0.83 (0.82­0.84), and 0.88 (0.85­0.91) for all stroke, acute ischemic stroke, and hemorrhagic stroke, respectively. The association between ZVL (Zostavax) and risk of stroke appeared to be stronger among younger beneficiaries, beneficiaries who did not take antihypertensive or statin medications and who had fewer comorbid conditions (P<0.05 for interaction) but largely consistent across sex, low-income status, and racial groups. Conclusions: Among Medicare fee-for-service beneficiaries, receipt of ZVL (Zostavax) was associated with lower incidence of stroke. Our findings may encourage people to get vaccinated against HZ to reduce HZ and HZ-associated stroke risk.

Safety of antithrombotic therapy in East Asian patients.

Antithrombotic agents are widely used on the globe for prevention of thrombotic events such as atherothrombotic events and thromboembolic stroke in atrial fibrillation or for prevention and treatment of venous thromboembolism. However, the net clinical benefit of antithrombotic intervention may differ substantially in various sub-population of patients. Here, the authors attempt to address the risk of serious bleeding in East Asian as compared to the other regions of the world. The community-based epidemiological data suggest numerically higher risk of hemorrhage stroke in East Asian as compared to the globe. Importantly, the life-time risk of ischemic stroke in East Asia is higher than that of the globe. Regarding the serious bleeding risk in East Asians with the use of antithrombotic agents, various clinical trials and international registries provided conflicting information. It is hard to draw generalized conclusion, but there are some specific sub-population in East Asian with higher risk of specific serious bleeding events with the use of specific antithrombotic agents such as the risk of intra-cranial bleeding (ICH) with Vitamin K antagonists. Specific characteristics in East Asian such as higher prevalence of lacunar stroke may contribute higher risk of ICH in East Asian, but the detailed mechanism is still to be elucidated. In conclusion, further investigations are necessary to clarify the specific conditions where the risk of serious bleeding events in East Asian patients differ substantially compared to the global. In addition, further understanding of the mechanisms causing the different bleeding response in specific conditions in East Asian is awaited.