Adherence to secondary stroke prevention medications in Singapore: a single center study.

OBJECTIVES: Recurrent strokes are associated with greater disability and mortality than first-time strokes. However, adherence to secondary stroke prevention medications has been reported to be suboptimal. We assessed medication adherence to antihypertensives, antiplatelets, and statins after acute ischemic stroke and identified factors associated with non-adherence behavior to each drug class. METHODS: This single center study is an extension of a larger prospective cohort study of ischemic stroke patients assessed at an outpatient post stroke clinic. Medication adherence behavior and medication knowledge was determined by direct questioning, and perceptions towards medications via the Beliefs about Medicines Questionnaire. Factors associated with non-adherence in each drug class were determined using logistic regression. RESULTS: Rates of adherence differed between antihypertensives (77.9%), antiplatelets (80.3%), and statins (64.7%) (p < 0.001) amongst the 193 patients surveyed. Non-adherence to antihypertensives was associated with living alone, taking < 5 medications, and stronger beliefs that medications are harmful. For antiplatelets, non-diabetic patients and patients with stronger beliefs that medications are harmful were more likely to be non-adherent. Patients non-adherent to statins were more likely to have a longer time since ischemic event and have a transient ischemic attack as the index event. CONCLUSIONS: Overall, medication adherence behavior to secondary stroke prevention medications was poor, with statins the least adhered to. Factors associated with non-adherence to each drug class could guide the development of tailored interventions to improve adherence to secondary stroke prevention medications.

Predictors of post stroke cognitive impairment: VITATOPS cognition substudy.

INTRODUCTION: Post stroke cognitive impairment (PSCI) is a common complication of ischemic stroke. PSCI can involve different depending on clinical and stroke related characteristics. The aim of this study is to determine the factors associated with impairments in specific cognitive domains. METHODS: The Vitamins to Prevent Stroke (VITATOPS) trial is a large, multinational randomised controlled trial. In this substudy, consecutive patients admitted for ischaemic stroke or transient ischaemic attack (TIA) at a tertiary hospital in Singapore were included. PSCI was defined as impairment of any of the six cognitive subgroups - visuoconstruction, attention, verbal memory, language, visual memory and visuomotor function - that were assessed annually for up to five years. Univariate and multivariate Cox proportional hazard models were used to determine factors associated with impairments in each of these cognitive domains. RESULTS: A total of 736 patients were included in this study, of which 173 (23.5 %) developed cognitive impairment. Out of the six cognitive domains, the greatest proportion of patients had an impairment in visuoconstruction (26.4 %) followed by attention (19.8 %), verbal memory (18.3 %), language (17.5 %), visual memory (17.3 %) and visuomotor function (14.8 %). Patients with posterior circulation cerebral infarction (POCI) as the index stroke subtype had higher rates of cognitive impairment. Further subgroup analyses show that Indian race and advanced age were predictive of language impairment, whilst fewer years of education and POCI were predictive of verbal memory impairment. POCI was predictive of visual memory impairment, and advanced age and POCI were predictive of visuomotor function impairment. CONCLUSION: We identified visuoconstruction and attention domains to be the most affected in our Asian cohort of PSCI. Advanced age, lower levels of education, posterior circulation strokes and concomitant comorbidities such as peripheral artery disease are independent predictors of PSCI.

Neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease is a rare genetic condition, previously diagnosed only at postmortem, but its characteristic radiological features now allow its diagnosis in life. The clinical presentation is variable and we hope this case report will raise awareness of this condition.

The Bidirectional Relationship between Vision and Cognition: A Systematic Review and Meta-analysis.

TOPIC: Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship. CLINICAL RELEVANCE: Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people. METHODS: PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity. RESULTS: Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84-3.07]; longitudinal: OR, 1.66 [95% CI, 1.46-1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48-4.01]; longitudinal: OR, 2.09 [95% CI, 1.37-3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data. DISCUSSION: Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences.

Modifiable Factors Associated with Non-Adherence to Secondary Ischaemic Stroke Prevention Strategies.

BACKGROUND: Secondary stroke-prevention strategies proven to reduce stroke recurrence include pharmaceutical agents and lifestyle modifications. AIMS: We aimed to study factors associated with adherence to medications and lifestyle modifications amongst ischaemic stroke and transient ischaemic attack (TIA) patients. METHODS: In a prospective cohort study, we surveyed 200 outpatients attending stroke clinic at a Singaporean tertiary hospital. We determined medication knowledge and lifestyle modification adherence through direct questioning. We also administered the Beliefs About Medicines Questionnaire, Trust in Physician Scale, Patient Health Questionnaire and Hospital Anxiety and Depression Scale. Multivariable logistic regression models were used to identify factors associated with adherence. RESULTS: The rates of adherence to medications, smoking cessation, dietary modification, and exercise were 52.3%, 71.0%, 80.0% and 78.5% respectively. Subjects who lacked medication knowledge (OR=3.47; 95% CI=1.55-7.74) or possessed negative medication beliefs (OR=1.20; 95% CI=0.72-0.96) were less likely to be adherent to medications. TIA as an index event (OR=5.04; 95% CI=1.39-18.32), younger age (OR=1.04; 95% CI=1.01-1.08) and higher income (OR=2.40; 95% CI=1.09-5.25) were also associated with medication non-adherence. There were no associations between adherence to medications and lifestyle modifications. Dietary adherence was independently associated with exercise adherence (OR=17.2; 95% CI=3.21-92.22). CONCLUSIONS: Our findings of suboptimal adherence to medications and lifestyle modifications show that many stroke patients are not benefitting from proven secondary stroke prevention strategies. We identified medication knowledge and medication beliefs as potential target areas for studies to improve medication adherence.

Hospitalization, surgery, and incident dementia.

INTRODUCTION: We evaluated whether hospitalization with or without surgery increases risk for dementia or Alzheimer's disease. METHODS: A clinical sample (843 clinically diagnosed dementia cases; 1686 matched nondemented individuals) was identified from Swedish Twin Registry studies. A register-based sample (4293 cases; 21,465 matched controls) was identified by linkage of Swedish Twin Registry to Swedish Patient Registry records. Apolipoprotein E (APOE) status and within-pair comparisons of dementia discordant twins indicated genetic susceptibility. RESULTS: Nonsurgical hospitalization is associated with greater dementia risk than hospitalization with surgical intervention. In the register sample, thoracic, abdominal, and major orthopedic procedures entailed dementia risk; in the clinical sample, orthopedic alone. Within-pair analyses indicate that associations in part reflect genetic susceptibility in common to hospitalization and dementia. Potential gene-environment interactions were indicated by greater risk due to hospitalization among APOE ε4 noncarriers. DISCUSSION: We confirm hospitalization as a risk factor for dementia, with repeated hospitalizations a more important risk factor than surgery.

Implementing electronic handover: interventions to improve efficiency, safety and sustainability.

PROBLEM: Effective handovers are critical for patient care and safety. Electronic handover tools are increasingly used today to provide an effective and standardized platform for information exchange. The implementation of an electronic handover system in tertiary hospitals can be a major challenge. Previous efforts in implementing an electronic handover tool failed due to poor compliance and buy-in from end-users. A new electronic handover tool was developed and incorporated into the existing electronic medical records (EMRs) for medical patients in Singapore General Hospital (SGH). INITIAL ASSESSMENT: There was poor compliance by on-call doctors in acknowledging electronic handovers, and lack of adherence to safety rules, raising concerns about the safety and efficiency of the electronic handover tool. Urgent measures were needed to ensure its safe and sustained use. SOLUTION: A quality improvement group comprising stakeholders, including end-users, developed multi-faceted interventions using rapid PDSA (P-Plan, D-Do, S-Study, A-Act ) cycles to address these issues. IMPLEMENTATION: Innovative solutions using media and online software provided cost-efficient measures to improve compliance. EVALUATION: The percentage of unacknowledged handovers per day was used as the main outcome measure throughout all PDSA cycles. Doctors were also assessed for improvement in their knowledge of safety rules and their perception of the electronic handover tool. LESSONS LEARNT: An electronic handover tool complementing daily clinical practice can be successfully implemented using solutions devised through close collaboration with end-users supported by the senior leadership. A combined 'bottom-up' and 'top-down' approach with regular process evaluations is crucial for its long-term sustainability.

Neurophysiological findings in conus medullaris infarction-a case report and systematic review of the literature.

INTRODUCTION: Conus medullaris infarction (CMI) is a rare vascular phenomenon that has been scarcely reported in the literature. While previous studies have described the clinical and radiological features of CMI, little attention has been paid to its associated neurophysiological findings. METHODS: We present a case of idiopathic CMI and its neurophysiological findings, then present our findings from a systematic review of other reports of CMI with neurophysiological features found via PubMed search. RESULTS: Nine articles describing ten cases of CMI with associated neurophysiological data were found, in addition to our case. Out of all 11 cases, 7 cases (64%) had absent F-waves on the first nerve conduction study (NCS) performed as early as 4 h after onset, 5 of whom demonstrated reappearance of F-waves on subsequent follow-up NCS. Seven patients (64%) had diminished compound muscle action potentials (CMAPs), which was usually detectable on NCS performed between day 8 and day 18 of onset. None of them showed recovery of CMAPs in follow-up studies. Four patients (36%) had absent H-reflexes and two patients (18%) had sensory abnormalities. Electromyography (EMG) was reported in seven patients (64%), showing reduced recruitment as early as day 1 of onset, and denervation potentials as early as 4 weeks after onset. CONCLUSION: Absent F-waves and diminished CMAPs are the most common NCS abnormalities in CMI. Absent F-waves are detectable very early but tend to recover on subsequent NCS, while diminished CMAPs are detectable later but do not seem to resolve. Further research to determine the utility of neurophysiological studies in CMI diagnosis and prognostication is needed.

Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack.

BACKGROUND: Patients with minor ischemic stroke or transient ischemic attacks (TIAs) are often treated with dual antiplatelet therapy regimens as part of secondary stroke prevention. Clopidogrel, an antiplatelet used in these regimens, is metabolized into its active form by the CYP2C19 enzyme. Patients with loss of function (LOF) mutations in CYP2C19 are at risk for poorer secondary outcomes when prescribed clopidogrel. AIMS: We aimed to determine the cost-effectiveness of three different treatment antiplatelet regimens in ischemic stroke populations with minor strokes or TIAs and how these treatment regimens are influenced by the LOF prevalence in the population. METHODS: Markov models were developed to look at the cost-effectiveness of empiric treatment with aspirin and clopidogrel versus empiric treatment with aspirin and ticagrelor, versus genotype-guided therapy for either 21 or 30 days. Effect ratios were obtained from the literature, and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. The primary endpoints were the incremental cost-effectiveness ratios (ICERs). RESULTS: Empiric treatment with aspirin and ticagrelor was the most cost-effective treatment. Genotype-guided therapy was more cost-effective than empiric aspirin and clopidogrel if the LOF was above 48%. Empiric ticagrelor and aspirin was cost saving when compared to genotype-guided therapy. Results in models of dual antiplatelet therapy for 30 days were similar. CONCLUSION: This study suggests that in patients with minor stroke and TIA planned for dual antiplatelet regimens, empiric ticagrelor and aspirin is the most cost-effective treatment regimen. If ticagrelor is not available, genotype-guided therapy is the most cost-effective treatment regimen if the LOF prevalence in the population is more than 48%.

Recurrent vascular events partially explain association between diabetes and poor prognosis in young ischemic stroke patients.

BACKGROUND AND AIMS: Stroke is the second leading cause of death and third leading cause of disability worldwide. There is an increasing incidence of stroke among the young. In this study, we aimed to identify factors associated with poor long-term prognosis in young stroke patients. METHODS: In this longitudinal observational study, we recruited 147 young ischemic stroke patients within one week of ischemic stroke and followed them up for functional outcome (modified Rankin score (mRS)), recurrent vascular events, and recurrent hospitalisation. Poor function was labelled as mRS score of 3 and above. We performed univariate and multivariable logistic regression analyses to determine factors associated with poor long term functional outcome. RESULTS: At a median follow-up of 7-years, 32 (22%) of the 147 patients had poor functional outcome. In multivariable analyses, diabetes mellitus (OR = 9.01, CI 3.15 to 26.92), was the only independent predictor of poor function. In analyses stratified by diabetic status, recurrent vascular events (OR = 4.47, CI 1.40 to 14.28) were associated with poor functional outcome within young diabetic patients but not in non-diabetic patients. CONCLUSIONS: Our findings suggest that diabetes mellitus affects long-term functional outcome in young ischemic stroke and that its effect is mediated partly by recurrent vascular events. DATA ACCESS STATEMENT: Data obtained from Multi-Centre Retinal study (MCRS), Singapore site. Data cannot be made publicly available due to potentially identifiable research participant information.

Associated demographic factors for the recurrence and prognosis of stroke patients within a multiethnic Asian population.

OBJECTIVE: There is a paucity of studies investigating the outcomes among Asian stroke patients. Identifying subgroups of stroke patients at risk of poorer outcomes could identify patients who would benefit from targeted interventions. Therefore, the aim of this study was to identify which ischemic stroke patients at high risk of recurrent events and mortality. METHODS: This cohort study adhered to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines. We obtained data from the Singapore Stroke Registry (SSR) from 2005 to 2016 and cross referenced to the Death Registry and the Myocardial Infarction Registry. Outcome measures included recurrent stroke, acute myocardial infarction (AMI), and all-cause and stroke-related deaths. Multivariable Cox proportional hazards regression models were performed to determine risk factors for recurrent stroke, AMI, and all-cause and stroke-related deaths. RESULTS: A total of 64,915 patients (6705 young, and 58,210 older) were included in our analysis. Older stroke patients were found to have an increased risk of recurrent stroke (hazard ratio (HR) = 1.21, 95% confidence interval (CI) = 1.12-1.30), AMI (HR = 1.73, 95% CI = 1.54-1.95), all-cause death (HR = 2.49, 95% CI = 2.34-2.64), and stroke-related death (HR = 176, 95% CI = 1.61-1.92). Among young stroke patients, males were at increased risk for recurrent stroke (HR = 1.18, 95% CI = 1.01-1.39) and AMI (HR = 1.41, 95% CI = 1.08-1.83), but at reduced risk for all-cause (HR = 0.78, 95% CI = 0.69-0.89) and stroke-related deaths (HR = 0.79, 95% CI = 0.67-0.94). Ethnicity appeared to influence outcomes, with Malay patients at increased risk of recurrent stroke (HR = 1.37, 95% CI = 1.14-1.65), AMI (HR = 2.45, 95% CI = 1.87-3.22), and all-cause (HR = 1.43, 95% CI = 1.24-1.66) and stroke-related deaths (HR = 1.34, 95% CI = 1.09-1.64). Indian patients were also at increased risk of AMI (HR = 1.96, 95% CI = 1.41-2.72). Similar findings were seen among the older stroke patients. CONCLUSION: This study found that older stroke patients are at risk of poorer outcomes. Within the young stroke population specifically, males were predisposed to recurrent stroke and AMI but were protected against all-cause and stroke-related deaths. Males were also at reduced risk of all-cause and stroke-related deaths in the older stroke population. In addition, Malay and Indian patients experience poorer outcomes after first stroke. Further optimization of risk factors targeting these high-priority populations are needed to achieve high-quality care.

Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

BACKGROUND: Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. AIMS: We applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. METHODS: We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. As replication, we tested found associations in an independent cohort of valproate users of the Mass General Brigham Biobank. RESULTS: Among 2150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12 year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per 1 standard deviation (SD), 95% confidence interval (CI) (3.45, 8.11)). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (hazard ratio (HR) per 1 SD 0.73, 95% CI (0.58, 0.91)) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p trend = 0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per 1 SD 0.53, 95% CI (0.32, 0.86)) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs 13/71, 18.3%, p trend = 0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p = 0.61), suggesting minimal pleiotropy. In 1241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per 1 SD 0.77, 95% CI (0.61, 0.97)). CONCLUSION: These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention. DATA ACCESS STATEMENT: UK Biobank participant data are available after approval of a research proposal. The weights of the used genetic scores are available in the Supplemental Tables.

Cluster analysis and visualisation of electronic health records data to identify undiagnosed patients with rare genetic diseases.

Rare genetic diseases affect 5-8% of the population but are often undiagnosed or misdiagnosed. Electronic health records (EHR) contain large amounts of data, which provide opportunities for analysing and mining. Data mining, in the form of cluster analysis and visualisation, was performed on a database containing deidentified health records of 1.28 million patients across 3 major hospitals in Singapore, in a bid to improve the diagnostic process for patients who are living with an undiagnosed rare disease, specifically focusing on Fabry Disease and Familial Hypercholesterolaemia (FH). On a baseline of 4 patients, we identified 2 additional patients with potential diagnosis of Fabry disease, suggesting a potential 50% increase in diagnosis. Similarly, we identified > 12,000 individuals who fulfil the clinical and laboratory criteria for FH but had not been diagnosed previously. This proof-of-concept study showed that it is possible to perform mining on EHR data albeit with some challenges and limitations.

Genetic and non-genetic components of family history of stroke and heart disease: a population-based study among adopted and non-adopted individuals.

Background: It is increasingly clear that genetic and non-genetic factors account for the association of family history with disease risk in offspring. We sought to distinguish the genetic and non-genetic contributions of family history of stroke and heart disease on incident events by examining adopted and non-adopted individuals. Methods: We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495,640 participants of the UK Biobank (mean age 56.5 years, 55% female) stratified by early childhood adoption status into adoptees (n=5,747) and non-adoptees (n=489,893). We estimated hazard ratios (HRs) per affected nuclear family member, and for polygenic risk scores (PRS) for stroke and MI in Cox models adjusted for baseline age and sex. Results: 12,518 strokes and 23,923 MIs occurred over a 13-year follow-up. In non-adoptees, family history of stroke and heart disease were associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR 1.16 [1.12, 1.19]) and family history of heart disease for incident MI (HR 1.48 [1.45, 1.50]). In adoptees, family history of stroke associated with incident stroke (HR 1.41 [1.06, 1.86]), but family history of heart disease did not associate with incident MI (p>0.5). PRS showed strong disease-specific associations in adoptees and non-adoptees. In non-adoptees, the stroke PRS mediated 6% risk between family history of stroke and incident stroke, and the MI PRS mediated 13% risk between family history of heart disease and MI. Conclusions: Family history of stroke and heart disease increase risk for their respective conditions. Family history of stroke contains a substantial proportion of potentially modifiable non-genetic risk, indicating a need for further research to elucidate these elements for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

Anti-NMDAR encephalitis in Southeast Asia - A single-centre, longitudinal study.

AIMS: To describe the clinical features and outcomes of anti-NMDA receptor encephalitis (ANMDARE) in Southeast Asian (SEA) patients. METHOD: SEA patients diagnosed and treated for ANMDARE at Singapore General Hospital between January 2010 and June 2020 were included in this observational study, in which their clinical features and outcomes were retrospectively analysed. RESULTS: We studied 20 patients: 11 Chinese, 3 Tagalogs, 2 Malays, 2 Indians, 1 Eurasian and 1 Javanese. Their median age was 28 years. 15 were females, amongst whom teratomas were demonstrated in 13 (12 ovarian, 1 mediastinal). Delirium and seizures were the two commonest events leading to their presentation at our facility. 1 male had biliary neuroendocrine tumour. Comparison between genders revealed a strong male predilection for early seizures and insomnia; females were four times likelier than males to develop movement disorders or have underlying neoplasms. Patients with dysautonomia required longer ICU stay beyond 14 days, but their outcomes at 1 year did not differ. When reviewed at 1 year, none had clinical relapses, and outcomes were favourable (mRS 0-2) in nearly two-thirds. CONCLUSIONS: SEA patients with ANMDARE frequently present with delirium and seizures. Underlying neoplasms are very common in females. Differences in clinical characteristics may exist between the two genders. Recognition of these can facilitate diagnosis, and permit earlier initiation of appropriate treatment strategies, and thus improve outcomes of SEA patients.

Non-Hypertensives and Those with Normal Cholesterol Are More Likely to Have Concomitant Cancer amongst Patients with Ischemic Stroke: A Retrospective Cross-Sectional Registry-Based Study.

INTRODUCTION: Patients with cancer are known to have an increased risk of ischemic stroke (IS) around the time of their diagnosis. However, there is a paucity of data in Asian populations, and as such, we aimed to determine cancer incidence rates and patterns in Asian IS patients as well as investigate the differences in vascular risk profile of IS patients with and without concomitant cancer. METHODS: We conducted a retrospective cross-sectional study using data from the Singapore Stroke and Cancer registries. We defined cases as patients with IS and a cancer diagnosis 2 years before or after the index IS. Cancer incidence was determined using the same direct age-standardization method performed for the Singapore general population in the 2015 Singapore cancer report. Multivariable logistic regression was used to analyze differences in vascular risk factors. RESULTS: Among 21,068 IS patients (mean age, 67.9 ± 13.3 years), 6.3% (1,330) were found to have concomitant cancer; 4.4% (935) had prior cancer while 1.8% (395) had cancer diagnoses within 2 years following IS. The cancer incidence among IS patients was 3,393 (95% confidence interval [CI], 1,937-4,849) per 100,000 person-years compared to 219-231 per 100,000 person-years in the general population. Older age (odds ratio [OR], 1.02 [95% CI, 1.01-1.02] per year), males (OR, 1.25 [95% CI, 1.11-1.41), Chinese ethnicity (OR, 1.61 [95% CI, 1.37-1.89]) and a lower prevalence of hypertension (OR, 0.84 [95% CI, 0.73-0.97)]), and hyperlipidemia (OR, 0.53 [95% CI, 0.45-0.62]) were independently associated with cancer-related IS. CONCLUSIONS: The age-standardized cancer incidence was 15 times higher in IS patients than the general population. IS patients with concomitant cancer were older and had a lower prevalence of vascular risk factors.

Genetic and Nongenetic Components of Stroke Family History: A Population Study of Adopted and Nonadopted Individuals.

Background Genetic and nongenetic factors account for the association of family history with disease risk. Comparing adopted and nonadopted individuals provides an opportunity to disentangle those factors. Methods and Results We examined associations between family history of stroke and heart disease with incident stroke and myocardial infarction (MI) in 495 640 UK Biobank participants (mean age, 56.5 years; 55% women) stratified by childhood adoption status (5747 adoptees). We estimated hazard ratios (HRs) per affected family member, and for polygenic risk scores in Cox models adjusted for baseline age and sex. A total of 12 518 strokes and 23 923 MIs occurred over a 13-year follow-up. In nonadoptees, family history of stroke and heart disease was associated with increased stroke and MI risk, with the strongest association of family history of stroke for incident stroke (HR, 1.16 [95% CI, 1.12-1.19]) and family history of heart disease for incident MI (HR, 1.48 [95% CI, 1.45-1.50]). In adoptees, family history of stroke associated with incident stroke (HR, 1.41 [95% CI, 1.06-1.86]), but family history of heart disease was not associated with incident MI (P>0.5). Polygenic risk scores showed strong disease-specific associations in both groups. In nonadoptees, the stroke polygenic risk score mediated 6% risk between family history of stroke and incident stroke, and the MI polygenic risk score mediated 13% risk between family history of heart disease and incident MI. Conclusions Family history of stroke and heart disease increases risk for their respective conditions. Family history of stroke contains substantial potentially modifiable nongenetic risk, indicating a need for novel prevention strategies, whereas family history of heart disease represents predominantly genetic risk.

Genetic variation supports a causal role for valproate in prevention of ischemic stroke.

Valproate is a candidate for ischemic stroke prevention due to its anti-atherosclerotic effects in vivo. Although valproate use is associated with decreased ischemic stroke risk in observational studies, confounding by indication precludes causal conclusions. To overcome this limitation, we applied Mendelian randomization to determine whether genetic variants that influence seizure response among valproate users associate with ischemic stroke. We derived a genetic score for valproate response using genome-wide association data of seizure response after valproate intake from the Epilepsy Pharmacogenomics Consortium. We then tested this score among valproate users of the UK Biobank for association with incident and recurrent ischemic stroke using Cox proportional hazard models. Among 2,150 valproate users (mean 56 years, 54% females), 82 ischemic strokes occurred over a mean 12-year follow-up. Higher valproate response genetic score was associated with higher serum valproate levels (+5.78 µg/ml per one SD, 95% CI [3.45, 8.11]). After adjusting for age and sex, higher valproate response genetic score was associated with lower ischemic stroke risk (HR per one SD 0.73, [0.58, 0.91]) with a halving of absolute risk in the highest compared to the lowest score tertile (4.8% vs 2.5%, p-trend=0.027). Among 194 valproate users with prevalent stroke at baseline, a higher valproate response genetic score was associated with lower recurrent ischemic stroke risk (HR per one SD 0.53, [0.32, 0.86]) with reduced absolute risk in the highest compared to the lowest score tertile (3/51, 5.9% vs. 13/71, 18.3%, p-trend=0.026). The valproate response genetic score was not associated with ischemic stroke among the 427,997 valproate non-users (p=0.61), suggesting minimal pleiotropy. In an independent cohort of 1,241 valproate users of the Mass General Brigham Biobank with 99 ischemic stroke events over 6.5 years follow-up, we replicated our observed associations between the valproate response genetic score and ischemic stroke (HR per one SD 0.77, 95% CI: [0.61, 0.97]). These results demonstrate that a genetically predicted favorable seizure response to valproate is associated with higher serum valproate levels and reduced ischemic stroke risk among valproate users, providing causal support for valproate effectiveness in ischemic stroke prevention. The strongest effect was found for recurrent ischemic stroke, suggesting potential dual-use benefits of valproate for post-stroke epilepsy. Clinical trials will be required in order to identify populations that may benefit most from valproate for stroke prevention.

The ABCD-GENE score influences vascular event rates in both users of clopidogrel and aspirin, as well as non-users of either drug in a population-based cohort study.

Background and Objectives: Clopidogrel is an antiplatelet used in both primary and secondary prevention of cardiovascular diseases. It is a prodrug, requiring CYP2C19 for its metabolism to the active metabolite. The ABCD-GENE score, combining clinical attributes (age, body mass index, chronic kidney disease, diabetes mellitus), with genetic information (presence of 1 or 2 loss of function (LOF) alleles in the CYP2C19 gene) has been shown to identify patients with higher risk of recurrent cardiovascular events in high-risk populations undergoing percutaneous coronary intervention. We aimed to determine if the ABCD-GENE score or LOF alleles were associated with an increased risk of vascular events among clopidogrel users in a general population. Methods: We conducted a population based cohort study with UK Biobank's primary care prescription records to identify clopidogrel users. ABCD-GENE scores were calculated with closest available data from the first date of clopidogrel prescription. The number of LOF alleles present, and the clinical component ABCD, were separate exposures. The outcome of interest was a composite endpoint of vascular events comprised of myocardial infarction, ischemic stroke, and death due to either of these. We performed Cox proportional hazards models with clopidogrel as a time varying exposure to predict hazards of these outcomes. In order to determine the drug specificity of these exposures, the analyses were repeated in aspirin users, and in non-users of either aspirin or clopidogrel. Results: Among 11,248 clopidogrel users, 3,365 (30%) developed a vascular event over a mean follow-up of 5.95±3.94 years. ABCD-GENE score ≥10 was associated with an increased risk of vascular events (HR 1.13, 95% CI 1.03-1.23). In aspirin users, and in non-users of either aspirin or clopidogrel, the ABCD-GENE score was also associated with increased risk of vascular events. In clopidogrel users, aspirin users, and non-users of either drug, the ABCD score was associated with increased risk of vascular events. The presence of two CYP2C19 LOF alleles was associated with an increased risk of vascular events in aspirin and non-users but not in clopidogrel users. Discussion: In this population-based cohort study, the ABCD-GENE score was associated with an increased risk of vascular events in clopidogrel users, aspirin users, and in non-users of either drug. The clinical component, ABCD was also associated with an increased risk of vascular events in all three groups. This suggests that the ABCD-GENE score is not specific to clopidogrel users in identifying persons at high risk of vascular events in a general sample with low baseline CYP2C19 LOF allele frequency.

Social Determinants of Health and Cerebral Small Vessel Disease: Is Epigenetics a Key Mediator?

Cerebral small vessel disease is highly prevalent, particularly in marginalized communities, and its incidence is expected to increase given the aging global population. Cerebral small vessel disease contributes to risk for stroke, vascular cognitive impairment and dementia, late-life depression, and gait disorders. A growing body of evidence suggests that adverse outcomes, including cerebral small vessel disease, caused by traditional cardiovascular risk factors are at least partly mediated by epigenetic changes, some of them already beginning during fetal development. Societal and health care access inequities, summarized under the umbrella term social determinants of health, put a higher burden of cardiovascular risk factors on marginalized populations and expose them to an increased risk for adverse outcomes. Social epigenetics has begun to deliver solid evidence that social determinants of health lead to distinct epigenetic signatures that potentially mediate the biological effect of environmental exposures on cardiovascular risk factors. Here, we provide a review of the most recent advances in the epigenetics of cerebral small vessel disease risk factors and social determinants of health and call for research efforts combining insights from both fields to reach a deeper understanding of the causal pathways, ultimately facilitating discovery of new treatment targets for a disease whose burden is magnified by existing health disparities.