Background: Coronavirus disease 2019 (COVID-19) has become a global pandemic, affecting millions of people. However, the relationship between COVID-19 and acute cerebrovascular diseases (CVD) is unclear. Aims: We aimed to characterize the incidence, risk factors, clinical-radiological manifestations and outcome of COVID-19-associated stroke. Methods: Three medical databases were systematically reviewed for published articles on acute CVD in COVID-19 (December 2019-September 2020). The review protocol was previously registered (PROSPERO ID=CRD42020185476). Data were extracted from articles reporting 5 stroke cases in COVID-19. We complied with the PRISMA guidelines, and used the Newcastle–Ottawa Scale to assess data quality. Data were pooled using a random-effects model. Summary of review: Of 2,277 initially identified articles, 61 (2.7%) were entered in the meta-analysis. Out of 108,571 patients with COVID-19, acute CVD occurred in 1.4% (95%CI: 1.0-1.9). The most common manifestation was acute ischemic stroke (87.4%); intracerebral haemorrhage was less common (11.6%). Patients with COVID-19 developing acute CVD, compared to those who did not, were older (pooled median difference=4.8 years; 95%CI:1.7-22.4), more likely to have hypertension (OR=7.35; 95%CI:1.94-27.87), diabetes mellitus (OR=5.56; 95%CI:3.34-9.24), coronary artery disease (OR=3.12; 95%CI:1.61-6.02), and severe infection (OR=5.10; 95%CI:2.72-9.54). Compared to individuals who experienced a stroke without the infection, patients with COVID-19 and stroke were younger (pooled median difference=-6.0 years; 95%CI:-12.3 to -1.4), had higher NIHSS (pooled median difference=5; 95%CI:3-9), higher frequency of large vessel occlusion (OR=2.73; 95%CI:1.63-4.57), and higher in-hospital mortality rate (OR=5.21; 95% CI:3.43-7.90). Conclusions: Acute CVD is not uncommon in COVID-19, especially in those whom are severely infected and have pre-existing vascular risk factors. The pattern of large vessel occlusion and multi-territory infarcts suggest that cerebral thrombosis and/or thromboembolism could be possible causative pathways for the disease.

Both MSS and Activity sessions appear to be effective and appropriate therapies for people with dementia.

Objectives To investigate the association between alcohol consumption and cardiovascular disease at higher resolution by examining the initial lifetime presentation of 12 cardiac, cerebrovascular, abdominal, or peripheral vascular diseases among five categories of consumption. Design Population based cohort study of linked electronic health records covering primary care, hospital admissions, and mortality in 1997-2010 (median follow-up six years). Setting CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). Participants 1 937 360 adults (51% women), aged ≥30 who were free from cardiovascular disease at baseline. Main outcome measures 12 common symptomatic manifestations of cardiovascular disease, including chronic stable angina, unstable angina, acute myocardial infarction, unheralded coronary heart disease death, heart failure, sudden coronary death/cardiac arrest, transient ischaemic attack, ischaemic stroke, intracerebral and subarachnoid haemorrhage, peripheral arterial disease, and abdominal aortic aneurysm. Results 114 859 individuals received an incident cardiovascular diagnosis during follow-up. Non-drinking was associated with an increased risk of unstable angina (hazard ratio 1.33, 95% confidence interval 1.21 to 1.45), myocardial infarction (1.32, 1.24 to1.41), unheralded coronary death (1.56, 1.38 to 1.76), heart failure (1.24, 1.11 to 1.38), ischaemic stroke (1.12, 1.01 to 1.24), peripheral arterial disease (1.22, 1.13 to 1.32), and abdominal aortic aneurysm (1.32, 1.17 to 1.49) compared with moderate drinking (consumption within contemporaneous UK weekly/daily guidelines of 21/3 and 14/2 units for men and women, respectively). Heavy drinking (exceeding guidelines) conferred an increased risk of presenting with unheralded coronary death (1.21, 1.08 to 1.35), heart failure (1.22, 1.08 to 1.37), cardiac arrest (1.50, 1.26 to 1.77), transient ischaemic attack (1.11, 1.02 to 1.37), ischaemic stroke (1.33, 1.09 to 1.63), intracerebral haemorrhage (1.37, 1.16 to 1.62), and peripheral arterial disease (1.35; 1.23 to 1.48), but a lower risk of myocardial infarction (0.88, 0.79 to 1.00) or stable angina (0.93, 0.86 to 1.00). Conclusions Heterogeneous associations exist between level of alcohol consumption and the initial presentation of cardiovascular diseases. This has implications for counselling patients, public health communication, and clinical research, suggesting a more nuanced approach to the role of alcohol in prevention of cardiovascular disease is necessary. Registration clinicaltrails.gov (NCT01864031).

Background The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. MethodsWe did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.Findings Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 con trols, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associa ted with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP,

It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs).OBJECTIVE To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood. DESIGN, SETTING, AND PARTICIPANTS A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline.EXPOSURES Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; Ն16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; Ն3 indicates possible depressive disorder).MAIN OUTCOMES AND MEASURES Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported. RESULTS Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of (CES-D) score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and for 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors. CONCLUSIONS AND RELEVANCEIn a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that ~10% of blood monocytes in COVID-19 patients are dying and infected with SARS-CoV-2. Monocyte infection, which depends on antiviral antibodies, activates NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD cleavage and relocalization. Signs of pyroptosis (IL-1 family cytokines, LDH) in the plasma correlate with development of severe disease. Moreover, expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes triggers inflammation that contributes to severe COVID-19 disease pathogenesis.

BackgroundCysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear.MethodsCysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls.ResultsOf 200 632 participants with exome sequencing data available, 443 (~1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001).ConclusionsCysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently ‘sporadic’ stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.

Word count: 3313 excluding references ABSTRACT Aims. To systematically investigate causal relationships between circulating lipids and cardiovascular outcomes, using a Mendelian randomization approach.Methods and Results. In the primary analysis, we performed two-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188,577 participants, and genetic associations with cardiovascular outcomes from 367,703 participants in UK Biobank.For LDL-cholesterol, in addition to the expected positive associations with coronary artery disease (CAD) risk (odds ratio per 1 standard deviation increase [OR], 1.45; 95% confidence interval [95%CI] 1.35-1.57) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically-predicted LDLcholesterol with abdominal aortic aneurysm (OR 1.75; 95%CI 1.40-2.17), and aortic valve stenosis (OR 1.46; 95%CI 1.25-1.70). Genetically-predicted triglyceride levels were positively associated with CAD (OR 1.25; 95%CI 1.12-1.40), aortic valve stenosis (OR 1.29; 95%CI 1.04-1.61), and hypertension (OR 1.17; 95%CI 1.07-1.27), but inversely associated with venous thromboembolism (OR 0.79; 95%CI 0.67-0.93). The positive associations of genetically-predicted LDL-cholesterol and triglycerides with heart failure and aortic stenosis appeared to be mediated by CAD. Conclusion.Lowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis, but may increase risk of thromboembolism. KEYWORDSLipids, Cardiovascular disease, Aetiology, Epidemiology, Mendelian randomization 0 2 5 Supplementary Table S3: Estimates (odds ratio per 1 standard deviation increase in lipid fraction and 95% confidence interval) from polygenic multivariable Mendelian randomization analyses for all lipid-related variants. Estimates with p < 0.05 are reported in bold. 0.91 (0.83-1.00) 1.45 (1.35-1.57) 1.25 (1.12-1.40) Ischaemic Cerebrovascular Disease (all) 0.95 (0.86-1.05) 1.14 (1.04-1.24) 0.98 (0.87-1.10) Ischaemic Stroke 0.98 (0.86-1.12) 1.10 (0.98-1.23) 1.03 (0.87-1.20) Transient Ischaemic Attack 0.91 (0.80-1.03) 1.16 (1.04-1.29) 0.94 (0.81-1.10) Haemorrhagic Stroke (all) 0.76 (0.63-0.92) 0.90 (0.76-1.05) 0.78 (0.62-0.98) Intracerebral Haemorrhage 0.65 (0.51-0.82) 0.86 (0.70-1.05) 0.65 (0.49-0.86) Subarachnoid Haemorrhage 0.82 (0.63-1.06) 0.90 (0.72-1.12) 0.85 (0.62-1.17) Aortic Aneurysm (all) 0.79 (0.65-0.96) 1.43 (1.21-1.68) 1.06 (0.84-1.33) Abdominal Aortic Aneurysm 0.65 (0.51-0.85) 1.75 (1.40-2.17) 0.94 (0.68-1.28) Thoracic Aortic An...