Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study.

BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

The relationship between low prolactin and type 2 diabetes.

Prolactin (PRL) is secreted throughout life in men and women. At elevated levels, its physiological role in pregnancy and lactation, and pathological effects, are well known. However clinical implications of low circulating PRL are not well established. We conducted a meta-analysis to examine the relationship between low PRL levels and type 2 diabetes. Five papers included cross-sectional studies comprising 8,720 men (mean age range 51.4-60 years) and 3,429 women (49.5-61.6 years), and four papers included cohort studies comprising 2,948 men (52.1-60.0 years) and 3,203 women (49.2-60.1 years). Individuals with pregnancy, lactation and hyperprolactinemia, drugs known to alter circulating PRL levels, or pituitary diseases had been excluded. Although most studies used quartiles to categorize PRL groups for analysis, PRL cut-off values (all measured by chemiluminescence immunoassay) were variably defined between studies: the lowest PRL quartiles ranged from 3.6 ng/ml to 7.2 ng/ml in men and between 4.5 ng/ml to 8 ng/ml in women; and the highest PRL quartiles ranged from 6.9 ng/ml to 13 ng/ml in men and 9.6 ng/ml to 15.8 ng/ml in women. Type 2 diabetes was defined variably using self-reported physician's diagnosis, fasting blood glucose, oral glucose tolerance test or glycated hemoglobin (HbA1C). In cross-sectional studies, compared to individuals in the highest PRL groups (reference), those in the lowest PRL groups had greater risk of type 2 diabetes both in men: odds ratio (OR) and 95% confidence interval = 1.86 (1.56-2.22) and in women: OR = 2.15 (1.63-2.85). In cohort studies, women showed a significant association between low PRL and type 2 diabetes: OR = 1.52 (1.02-2.28) but not men: OR = 1.44 (0.46-4.57). Relatively low heterogeneity was observed (I2 = 25-38.4%) for cross-sectional studies, but higher for cohort studies (I2 = 52.8-79.7%). In conclusion, low PRL is associated with type 2 diabetes, but discrepancy between men and women in the relationship within cohort studies requires further research.

Coma in adult cerebral venous thrombosis: The BEAST study.

BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.

Direct oral anticoagulants compared to warfarin in long-term management of cerebral venous thrombosis: A comprehensive meta-analysis.

Objectives: We compared the safety and efficacy of direct oral anticoagulants (DOACs) with those of warfarin in the long-term (≥6 months) treatment of cerebral venous thrombosis (CVT). Methods: We searched electronic databases up to November 2023 to compare the use of DOACs and warfarin in CVT management. Modified Rankin scores (mRS), new intracranial hemorrhage, all-cause mortality, recurrence and nonrecanalisation events were used to assess outcome. RevMan v5.4 software and the Cochran-Mantel-Haenszel method were utilized to analyse data. Results: A total of 25 studies involving 2301 patients were identified as having treated CVT with either DOACs or warfarin. Good long-term mRS scores 0-2 (risk ratio [RR] = 1.01, 95% CI = 0.98-1.03; p = 0.61), new intracranial hemorrhage (RR = 1.00, 95% CI = 0.48-2.08; p = 0.99), all-cause mortality (RR = 1.00, 95% CI = 0.50-1.98; p = 0.99), nonrecanalisation (RR = 0.95, 95% CI = 0.77-1.18; p = 0.65) and recurrence venous thrombosis events (RR = 0.63, 95% CI = 0.33-1.22; p = 0.17) were similar between the two treatment arms. Subgroup analysis found recurrence of venous thrombosis was lower in the rivaroxaban group compared to warfarin (2.2% vs. 8.5%, RR = 0.33, 95% CI = 0.11-0.98; p = 0.05). Conclusion: DOACs and warfarin provide comparable long-term safety and efficacy profiles. DOACs may be preferred over warfarin due to their ease of clinical management.

ABO blood group associated with cerebral venous thrombosis after Oxford-AstraZeneca COVID-19 vaccination: a case-control study.

OBJECTIVES: To determine whether blood group influences development of cerebral venous thrombosis (CVT) after administration of the coronavirus disease 2019 (COVID-19) AstraZeneca ChAdOx1-S vaccine. DESIGN: A case-control study. Univariate and multivariate logistic regression was used to determine the association between blood type and COVID-19 vaccination status. SETTING: Vaccinated and unvaccinated patients recruited from the international Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis study and the Cerebral Venous Sinus Thrombosis With Thrombocytopenia Syndrome Study Group. PARTICIPANTS: All patients were of European descent and age and sex matched. Cases (n = 82) were patients ≥18 years old who suffered a CVT within 28 days of a first dose of ChAdOx1-S vaccine. Controls (n = 441) were unvaccinated CVT patients ≥18 years old. All patients were of European descent. MAIN OUTCOME MEASURES: Frequency of blood type and ABO allele distribution by vaccination status. RESULTS: Blood group O was found to be more prevalent among CVT patients with vaccine-induced thrombotic thrombocytopenia (VITT-CVT) after ChAdOx1-S vaccination compared with unvaccinated CVT cases (43% vs. 17%, respectively, p < 0.001). Blood group A was less prevalent, though still high, in the vaccinated group compared with the unvaccinated group (47% vs. 71%, respectively, p < 0.001). No significant differences were observed in the VITT-CVT non-ChAdOx1-S vaccine group and unvaccinated pre-COVID-19 CVT group for blood group. CONCLUSIONS: Blood group O is more prevalent among patients with VITT-CVT after ChAdOx1-S vaccination compared with unvaccinated cases, independent of well-established CVT risk factors. A larger dataset may be able to determine whether those of blood groups B and/or AB may be safely vaccinated with the low cost, readily available and easily transported ChAdOx1-S rather than adopting a complete ban.

Meta-analysis and construction of simple-to-use nomograms for approximating testosterone levels gained from weight loss in obese men.

BACKGROUND: Obesity-induced hypogonadism, which manifests as erectile dysfunction and a lack of libido, is a less visible and under-recognized obesity-related disorder in men. OBJECTIVE: We examined the impact of weight loss on total (TT) and free testosterone (FT) levels, and constructed nomograms to provide an easy-to-use visual aid for clinicians. MATERIALS AND METHODS: Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean differences (SMD) for testosterone. Parallel-scale nomograms were constructed from baseline and target body mass index values to estimate the gain in testosterone. RESULTS: In total, 44 studies were included, comprising 1,774 participants and 2,159 datasets, as some studies included several datasets at different time points. Weight loss was controlled by low calorie diet (LCD) in 19 studies (735 participants, 988 datasets), by bariatric surgery (BS) in 26 studies (1,039 participants, 1,171 datasets), and by both in one study. The median follow-up was 26 weeks (interquartile range = 12-52). The range of baseline mean age was 21-68 yr, BMI: 26.2-71.2 kg/m2 , TT: 7-20.2 nmol/L and FT: 140-583 pmol/L. TT levels increased after weight loss by LCD: SMD (95%CI) = 2.5 nmol/L (1.9-3.1) and by BS: SMD = 7.2 nmol/L (6.0-8.4); the combined TT gain was 4.8 nmol/L (3.9-5.6). FT levels increased after weight reduction by LCD: SMD = 19.9 pmol/L (7.3-32.5) and by BS: SMD = 58.0 pmol/L (44.3-71.7); the combined gain was 42.2 pmol/L (31.4-52.9). Greater amounts of total and free testosterone could be gained by weight loss in men with higher baseline BMI, or lower levels of SHBG, TT and FT, while gain in TT was relatively greater in older and FT in younger age. Age-stratified nomograms revealed that compared to older men (> 40 yr), younger men (≤ 40 yr) gained less TT but more FT for a given weight loss. DISCUSSION AND CONCLUSION: Both TT and FT levels increased after weight loss, relatively greater with higher baseline BMI, or lower levels of SHBG, TT and FT. Nomograms constructed from a large number of participants with a wide range of BMI and testosterone values provide an evidence-based and simple-to-use tool in clinical practice.

Diabetes mellitus and obesity among South Asians with ischemic stroke across three countries.

BACKGROUND: Diabetes mellitus and central obesity are more common among South Asian populations than among White British people. This study explores the differences in diabetes and obesity in South Asians with stroke living in the United Kingdom, India, and Qatar compared with White British stroke patients. METHODS: The study included the UK, Indian, and Qatari arms of the ongoing large Bio-Repository of DNA in Stroke (BRAINS) international prospective hospital-based study for South Asian stroke. BRAINS includes 4580 South Asian and White British recruits from UK, Indian, and Qatar sites with first-ever ischemic stroke. RESULTS: The study population comprises 1751 White British (WB) UK residents, 1165 British South Asians (BSA), 1096 South Asians in India (ISA), and 568 South Asians in Qatar (QSA). ISA, BSA, and QSA South Asians suffered from higher prevalence of diabetes compared with WB by 14.5% (ISA: 95% confidence interval (CI) = 18.6-33.0, p < 0.001), 31.7% (BSA: 95% CI = 35.1-50.2, p < 0.001), and 32.7% (QSA: 95% CI = 28.1-37.3, p < 0.001), respectively. Although WB had the highest prevalence of body mass index (BMI) above 27 kg/m2 compared with South Asian patients (37% vs 21%, p < 0.001), South Asian patients had a higher waist circumference than WB (94.8 cm vs 90.8 cm, p < 0.001). Adjusting for traditional stroke risk factors, ISA, BSA, and QSA continued to display an increased risk of diabetes compared with WB by 3.28 (95% CI: 2.53-4.25, p < 0.001), 3.61 (95% CI: 2.90-4.51, p < 0.001), and 5.24 (95% CI: 3.93-7.00, p < 0.001), respectively. CONCLUSION: South Asian ischemic stroke patients living in Britain and Qatar have a near 3.5-fold risk of diabetes compared with White British stroke patients. Their body composition may partly help explain that increased risk. These findings have important implications for public health policymakers in nations with large South Asian populations.

Cigarette smoking as a risk factor for ischaemic stroke in young South Asian male migrants to Qatar: The BRAINS study.

BACKGROUND: The incidence of stroke in the Middle East is high, given its relatively young population. Smoking is a well-recognized risk factor for ischaemic stroke, and its high regional prevalence may partly account for this increased stroke risk. This research aims to determine whether young male South Asian migrants in Qatar were adversely affected by stroke depending on their smoking status. METHODS: Data from the ongoing international prospective BRAINS study was analysed. Male South Asian migrants to Qatar with a history of ischaemic stroke were recruited. Multivariate regression analysis was used to estimate the effects of comorbidities, such as BMI, hypertension, diabetes, hypercholesterolemia, alcohol consumption, and ischemic heart disease, on the association of age of stroke onset and smoking status. RESULTS: We identified 778 (mean age 49.5±10.2) migrant male workers of South Asian descent with ischaemic stroke in Qatar, of which 41.3% of the sample were current smokers. Compared to non-smokers, current smokers suffered a stroke 2.03 years earlier (95%CI: 0.60-3.46, P=0.005). Multivariate regression analysis demonstrated that only current smoking status was associated with an earlier age of stroke onset (ß=2.03, SE=0.74, P=0.006). CONCLUSION: Smoking is associated with at least a two-year earlier onset of ischaemic stroke in male South Asian migrants to the Middle East. Our study has important implications for the public health management of migrants in host countries.

Pathophysiology, diagnosis and management of cerebral venous thrombosis: A comprehensive review.

Cerebral venous thrombosis is a rare cause of stroke in young mostly female adults which is frequently overlooked due to its variable clinical and radiological presentation. This review summarizes current knowledge on it risk factors, management and outcome in adults and highlights areas for future research. Females are 3 times more commonly affected and are significantly younger than males. The presenting symptoms can range from headache to loss of consciousness. However, the often-nebulous nature of symptoms can make the diagnosis challenging. Magnetic resonance imaging with venography is often the diagnostic imaging of choice. While unfractionated or low molecular-weight heparin is the mainstay of treatment, endovascular intervention with thrombolysis or thrombectomy and decompressive craniectomy may be required depending on clinical status. Nevertheless, approximately 80% of patients have a good recovery but mortality rates of -5% to 10% are not uncommon. Diagnosing cerebral venous thrombosis can be challenging but with vigilance and expert care patients have the best chance of a good clinical outcome.

Cerebral Venous Thrombosis Among Bangladeshi Population: A Systematic Review.

Cerebral venous thrombosis (CVT) is a rare cause of stroke which remains unsung among Bangladeshi physicians and the general population. Our objective was to provide a comprehensive review of published data on Bangladeshi CVT patients. We searched all-electronic databases for Bangladeshi studies on CVT until November 2023, including literature in all languages. This study reviews the age of onset, gender distribution, radiological characteristics, and outcomes of Bangladeshi CVT patients. We included 13 studies (two observational and 11 case reports) that evaluated 102 CVT patients and found that women suffered CVT significantly higher than men (59.8% vs 40.2%; P =0.04), respectively. The overall age of the study population was 36.6±6.8, and men were significantly older than women (45.4±12.3 vs. 32.4±8.3; P<0.001). The most commonly affected sites were the superior sagittal sinus and transverse sinus thrombosis. Rivaroxaban was primarily used for long-term anticoagulation after initial low molecular weight heparin therapy. Furthermore, most studies observed an excellent clinical outcome with completed recanalisation on early follow-up angiography in three studies. In Bangladesh, women 1.5 times more commonly suffer from CVT and 13 years earlier than men. Although this review found that prompt diagnosis and anticoagulation therapy provides good clinical outcome, we recommended further studies to evaluate the long-term outcome, especially the safety and efficacy of oral anticoagulants, with recanalisation and recurrence rate.

Blood group and ischemic stroke, myocardial infarction, and peripheral vascular disease: A meta-analysis of over 145,000 cases and 2,000,000 controls.

OBJECTIVE: Cardiovascular illnesses have been associated to ABO blood types, specifically through an effect on von Willebrand factor and factor FVIII levels. We conducted a meta-analysis to comprehensively explore the relationship between blood groups and ischemic stroke, myocardial infarction, and peripheral vascular disease. MATERIALS AND METHODS: A comprehensive meta-analysis was undertaken to investigate blood groups and ischemic stroke (IS), myocardial infarction (MI) and peripheral vascular disease (PVD). Odds ratios (OR) were used to assess the relationship between blood groups and disease. RevMan v5,4 was used to statistically analyse the results. Risk of bias was assessed using the Newcastle-Ottawa scale. RESULTS: A total of 72 studies (18 ischemic stroke, 37 myocardial infarction, 17 peripheral vascular disease) met our search criteria, totalling 145,499 cases and 2,113,736 controls. Mean age ranged between 18 and 90 years. Compared to blood group-O, non-O blood group had an increased association with IS (OR=1.13, 95%Cl: 1.07-1.21, P < 0.001), MI (OR=1.17, 95%Cl: 1.11-1.24, P < 0.001) and PVD (OR=1.15, 95%Cl: 1.04-1.28, P=0.005). Compared to blood group-O, blood group A had a stronger statistically significant association to IS (OR=1.19, P=0.001), MI (OR=1.22, P < 0.001) and PVD (OR=1.15, P=0.03). Blood group-B has the lowest risk associated with MI (OR=1.09, P=0.01). In addition, blood groups AB had a stronger statistically significant association to IS (OR=1.24, P=0.01), and MI (OR=1.20, P < 0.001) compared with the other blood groups. CONCLUSIONS: Compared to blood group-O, groups A and AB are strongly associated to ischemic stroke, myocardial infarction, and peripheral vascular disease.

Age of onset of cerebral venous thrombosis: the BEAST study.

Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset. Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females. Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35-58) years and 37 (28-47) years (p < 0.001), respectively. However, the presence of antibiotic-requiring sepsis (p = 0.03, 95% CI 27-47 years) among males and gender-specific risk factors like pregnancy (p < 0.001, 95% CI 29-34 years), puerperium (p < 0.001, 95% CI 26-34 years) and oral contraceptive use (p < 0.001, 95% CI 33-36 years) were significantly associated with earlier onset of CVT among females. CFA demonstrated a significantly earlier onset of CVT in females, ~12 years younger, in those with multiple (⩾1) compared to '0' risk factors (p < 0.001, 95% CI 32-35 years). Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors.

Atrial fibrillation in UK South Asian hospitalized ischemic stroke patients: The BRAINS study.

INTRODUCTION: South Asian diaspora comprise one of the largest ethnic minority groups in the world yet data about atrial fibrillation (AF) in this demographic is understudied. Our aim is to identify differences in AF prevalence and treatment between South Asians and white British stroke patients. METHOD: The UK arm of a prospective ongoing large international repository on stroke was analysed. Ethnic differences in AF prevalence and management in those with ischemic stroke were analysed. RESULTS: Of the 3515 individuals recruited with ischemic stroke, 1482 (men: 972, women: 510) were South Asian and 2033 (men:1141, women:892) of white British ethnicity. AF was present in 462 white British and 193 South Asians stroke patients, with South Asians displaying a lower prevalence of AF (South Asians: 13.0% vs white British 22.7%, P<0.001). Despite adjustment for traditional AF risk factors, South Asians had a significantly lower OR of AF compared to white British stroke patients (OR: 0.40, 95%CI: 0.33:0.49, P<0.001). Among confirmed AF cases, 31.8% of South Asians and 41.4% of white British were untreated at admission (P = 0.02). Antiplatelet treatment was significantly higher among South Asians at both admission (South Asian: 47.4% vs. white British: 29.9%, P<0.001) and discharge (South Asian: 49.5% vs. white British: 34.7%, P = 0.001), although anticoagulation treatment was similar across both ethnic groups at admission (South Asian: 28.5% vs white British: 28.1%, P = 0.93), and discharge (South Asian: 45.1% vs white British: 43.1%, P = 0.64). CONCLUSION: Stroke patients of South Asian descent are at significantly lower risk of AF but more likely to be on antiplatelet treatment compared to their white British counterparts.

Ischaemic stroke in South Asians: The BRAINS study.

BACKGROUND AND PURPOSE: Studies on stroke in South Asian populations are sparse. The aim of this study was to compare differences in age of onset of ischaemic stroke in South Asian patients living in the United Kingdom and South Asian patients living in India versus White British stroke patients. METHODS: We studied the UK and Indian arms of the ongoing BRAINS study, an international prospective hospital-based study of South Asian stroke patients. The BRAINS study includes 4038 South Asian and White British patients with first-ever ischaemic stroke, recruited from sites in the United Kingdom and India. RESULTS: Of the included patients, 1126 were South Asians living in India (ISA), while 1176 were British South Asian (BSA) and 1736 were White British (WB) UK residents. Patients in the ISA and BSA groups experienced stroke 19.5 years and 7.2 years earlier than their WB counterparts, respectively (mean [interquartile range] age: BSA 64.3 [22] years vs. ISA 52.0 [18] years vs. WB 71.5 [19] years; p < 0.001). Patients in the BSA group had higher rates of hypertension, diabetes mellitus and hypercholesterolaemia than those in the ISA and WB groups. After adjustment for traditional stroke risk factors, an earlier age of stroke onset of 18.9 years (p < 0.001) and 8.9 years (p < 0.001) was still observed in the ISA and BSA groups, respectively. In multivariable stepwise linear regression analysis, ethnicity accounted for 24.7% of the variance in early age onset. CONCLUSION: Patients in the BSA and ISA groups experienced ischaemic stroke approximately 9 and 19 years earlier, respectively, than their WB counterparts. Ethnicity is an independent predictor of early age of stroke onset. Our study has considerable implications for public health policymakers in countries with sizable South Asian populations.

Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis.

OBJECTIVE: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood. METHODS: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets. RESULTS: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10-24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10-16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10-16 ) increased risk of CVT compared with individuals with blood group O. INTERPRETATION: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788.

Continuous positive airway pressure therapy reduces the levels of catecholamines and blood pressure in pseudophaeochromocytoma with coexisting obstructive sleep apnoea.

BACKGROUND: Stress from obstructive sleep apnoea (OSA) stimulates catecholamine release and consequently can exacerbate hypertension, even in the absence of a catecholamine-producing tumour (phaeochromocytoma). As such, a positive screening test for suspected phaeochromocytoma may be misleading. There exists only a handful case reports, and no controlled trials, how continuous positive airway pressure (CPAP) to treat OSA influences catecholamine levels. We examined changes to levels of urinary catecholamine and blood pressure in response to CPAP treatment. METHODS: We conducted a meta-analysis of data aggregated from published case reports of individual patient data up to April 2020. The quality of the reports was evaluated using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool. RESULTS: A total of 13 cases (seven men and six women) from seven reports met our search criteria. Patients had mean age of 49.1 years (range = 36-62) and body mass index of 37.4 kg/m2 (range = 27-56). Most had moderate to severe OSA with CPAP treatment. Nine cases had 24-hour urinary noradrenaline assessment before and after CPAP treatment. CPAP treatment led to a 21% reduction (104 nmol/24-hours, 95% credible interval =59 to 148) in 24-hour urinary noradrenaline to within reference ranges, and 25% reduction (from 131 to 100 mmHg) in mean arterial pressure. The risk of overall bias evaluated by the ROBINS-I tool was found to be low in the majority of reports. CONCLUSIONS: Investigations of patients suspected of phaeochromocytoma, particularly obese individuals, should exclude OSA and treat this condition if present before performing screening tests to assess for catecholamine levels.

Markov chain Monte Carlo Gibbs sampler approach for estimating haplotype frequencies among multiple malaria infected human blood samples.

BACKGROUND: Malaria patients can have two or more haplotypes in their blood sample making it challenging to identify which haplotypes they carry. In addition, there are challenges in measuring the type and frequency of resistant haplotypes in populations. This study presents a novel statistical method Gibbs sampler algorithm to investigate this issue. RESULTS: The performance of the algorithm is evaluated on simulated datasets consisting of patient blood samples characterized by their multiplicity of infection (MOI) and malaria genotype. The simulation used different resistance allele frequencies (RAF) at each Single Nucleotide Polymorphisms (SNPs) and different limit of detection (LoD) of the SNPs and the MOI. The Gibbs sampler algorithm presents higher accuracy among high LoD of the SNPs or the MOI, validated, and deals with missing MOI compared to previous related statistical approaches. CONCLUSIONS: The Gibbs sampler algorithm provided robust results when faced with genotyping errors caused by LoDs and functioned well even in the absence of MOI data on individual patients.

Changes in cortisol levels by continuous positive airway pressure in patients with obstructive sleep apnoea: Meta-analysis of 637 individuals.

BACKGROUND: Obesity, obstructive sleep apnoea (OSA) and hypertension frequently coexist and are associated with elevated cortisol levels. Identification and treatment of such patients is important when investigating for suspected Cushing's syndrome and hypertension. Studies of the impact of continuous positive airway pressure (CPAP) on cortisol and blood pressure are limited by the small sample size and show conflicting findings. We conducted a meta-analysis to document changes in the levels of cortisol and blood pressure in response to CPAP treatment of OSA. METHODS: Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean difference (SMD) for catecholamines and mean difference for systolic (SBP) and diastolic blood pressure (DBP). The quality of the studies was evaluated using standard tools for assessing the risk of bias. RESULTS: A total of 22 studies met our search criteria; they consisted of 16 prospective cohort studies (PCS) that recruited 385 participants and six randomized control trials (RCT) totalling 252 participants. The range of mean age was 41-62 years and BMI 27.2-35.1 kg/m2 . CPAP treatment reduced plasma cortisol levels in PCS: SMD = -0.28 [95% confidence interval (95% CI) = -0.45 to -0.12], I2 = 0%, p = .79 and in RCT: SMD = -0.39 (95% CI = -0.75 to -0.03), I2 = 28.3%, p = .25. CPAP treatment reduced SBP by 5.4 mmHg (95% CI = 1.7-9.1) and DBP by 3.3 mmHg (95% CI = 1.0-5.7). Interstudy heterogeneity was low for all studies. Bias in most RCT arose from the lack of blinding of participants and personnel. CONCLUSION: CPAP treatment in individuals with OSA reduces cortisol levels and blood pressure.

SARS-CoV-2 antibody seroprevalence in NHS healthcare workers in a large double-sited UK hospital.

We determined the seroprevalence of SARS-CoV-2 antibodies in NHS healthcare workers (HCWs) in a cross-sectional study from a large general hospital located in a double-sited rural and semi-rural area. The sample size of 3,119 HCWs (mean age 43±13) consisted of 75.2% women, 61.1% White individuals and predominantly (62.4%) asymptomatic individuals. Seroprevalence of SARS-CoV-2 antibodies was 19.7%. Determinants of seropositivity were preceding symptomatic infection and non-White ethnicity. Regardless of staff role or sex, multivariate regression analysis revealed that non-White HCWs were three times (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.53-3.86, P<0.001) more likely to have antibodies than White staff, and seven times (OR 7.10, 95% CI 5.72-8.87, P<0.001) more likely if there was a history of preceding symptoms. We report relatively high rates of seropositivity in all NHS healthcare workers. Non-White symptomatic HCWs were significantly more likely to be seropositive than their colleagues, independent of age, sex or staff role.

Meta-analysis of changes in the levels of catecholamines and blood pressure with continuous positive airway pressure therapy in obstructive sleep apnea.

Stress from obstructive sleep apnea (OSA) stimulates catecholamine release consequently exacerbating hypertension. However, different studies have shown a conflicting impact of continuous positive airway pressure (CPAP) treatment in patients with OSA on catecholamine levels and blood pressure. We aimed to examine changes to catecholamine levels and blood pressure in response to CPAP treatment. We conducted a meta-analysis of data published up to May 2020. The quality of the studies was evaluated using standard tools for assessing the risk of bias. Meta-analysis was conducted using RevMan (v5.3) and expressed in standardized mean difference (SMD) for catecholamines and mean difference (MD) for systolic (SBP) and diastolic blood pressure (DBP). A total of 38 studies met our search criteria; they consisted of 14 randomized control trials (RCT) totaling 576 participants and 24 prospective cohort studies (PCS) of 547 participants. Mean age ranged between 41 and 62 year and body mass index between 27.2 and 35.1 kg/m2 . CPAP treatment reduced 24-hour urinary noradrenaline levels both in RCT (SMD = -1.1; 95% confidence interval (CI): -1.63 to - 0.56) and in PCS (SMD = 0.38 (CI: 0.24 to 0.53). SBP was also reduced by CPAP treatment in RCT (4.8 mmHg; CI: 2.0-7.7) and in PCS (7.5 mmHg; CI: 3.3-11.7). DBP was similarly reduced (3.0 mmHg; CI: 1.4-4.6) and in PCS (5.1 mmHg; CI: 2.3-8.0). In conclusion, CPAP treatment in patients with OSA reduces catecholamine levels and blood pressure. This suggests that sympathetic activity plays an intermediary role in hypertension associated with OSA-related stress.