Analyzing and understanding the robustness of bioprocesses.

The robustness of bioprocesses is becoming increasingly important. The main driving forces of this development are, in particular, increasing demands on product purities as well as economic aspects. In general, bioprocesses exhibit extremely high complexity and variability. Biological systems often have a much higher intrinsic variability compared with chemical processes, which makes the development and characterization of robust processes tedious task. To predict and control robustness, a clear understanding of interactions between input and output variables is necessary. Robust bioprocesses can be realized, for example, by using advanced control strategies for the different unit operations. In this review, we discuss the different biological, technical, and mathematical tools for the analysis and control of bioprocess robustness.

Fibrocartilaginous embolism: an under-recognised cause of young spinal stroke.

Fibrocartilaginous embolism is a rarely reported cause of spinal cord infarction. Seemingly innocuous activities may be associated with nucleus pulposus material embolising to the spinal cord vasculature. We describe a 36-year-old woman presenting with bilateral arm paraesthesia and chest pain that evolved into an acute cord syndrome. Initial MR scan of spine showed central spinal cord T2-weighted hyperintensity over several vertebral levels, suggesting transverse myelitis. Repeat MR scan after her symptoms persisted showed an acute cord infarction from a presumed fibrocartilaginous embolus. Clinicians should consider fibrocartilaginous embolism in patients presenting with an acute cord syndrome with supportive radiological findings.

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT).

BACKGROUND: There are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. METHODS: We pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. RESULTS: Case-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. CONCLUSION: Although age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Syphilitic meningitis presenting with multiple cranial neuropathies.

Syphilis is increasingly prevalent in the community. The protean manifestations of neurosyphilis make the recognition, diagnosis and early initiation of treatment challenging. We report a case of early syphilitic meningitis presenting with multiple cranial neuropathies. Cerebrospinal fluid (CSF) examination was inflammatory with predominant lymphocytosis. The patient was diagnosed with neurosyphilis based on serum as well as CSF testing. Intravenous benzylpenicillin treatment resulted in rapid improvement of neurological symptoms. Neurosyphilis should be considered in immunocompetent patients presenting with multiple cranial neuropathies, or isolated cranial neuropathies without vascular risk factors.

Sex Differences in Disease Profiles, Management, and Outcomes Among People with Atrial Fibrillation After Ischemic Stroke: Aggregated and Individual Participant Data Meta-Analyses.

Objectives: To examine sex differences in disease profiles, management, and survival at 1 and 5 years after ischemic stroke (IS) among people with atrial fibrillation (AF). Methods: We performed a systematic literature search of reports of AF at IS onset according to sex. We undertook an individual participant data meta-analysis (IPDMA) of nine population-based stroke incidence studies conducted in Australasia, Europe, and South America (1993-2014). Poisson regression was used to estimate women:men mortality rate ratios (MRRs). Study-specific MRRs were combined using random effects meta-analysis. Results: In our meta-analysis based on aggregated data from 101 studies, the pooled AF prevalence was 23% (95% confidence interval [CI]: 22%-25%) in women and 17% (15%-18%) in men. Our IPDMA is of 1,862 IS-AF cases, with women (79.2 ± 9.1, years) being older than men (76.5 ± 9.5, years). Crude pooled mortality rate was greater for women than for men (1-year MRR 1.24; 1.01-1.51; 5-year 1.12; 1.03-1.22). However, the sex difference was greatly attenuated after accounting for age, prestroke function, and stroke severity (1-year 1.09; 0.97-1.22; 5-year 0.98; 0.84-1.16). Women were less likely to have anticoagulant prescription at discharge (odds ratio [OR] 0.94; 95% CI: 0.89-0.98) than men when pooling IPDMA and aggregated data. Conclusions: AF was more prevalent after IS among women than among men. Among IS-AF cases, women were less likely to receive anticoagulant agents at discharge; however, greater mortality rate in women was mostly attributable to prestroke factors. Further information needs to be collected in population-based studies to understand the reasons for lower treatment of AF in women.

Sex Differences in Long-Term Quality of Life Among Survivors After Stroke in the INSTRUCT.

Background and Purpose- Women are reported to have poorer health-related quality of life (HRQoL) after stroke than men, but the underlying reasons are uncertain. We investigated factors contributing to the sex differences. Methods- Individual participant data on 4288 first-ever strokes (1996-2013) were obtained from 4 high-quality population-based incidence studies from Australasia and Europe. HRQoL utility scores among survivors after stroke (range from negative scores=worse than death to 1=perfect health) were calculated from 3 scales including European Quality of Life-5 Dimensions, Short-Form 6-Dimension, and Assessment of Quality of Life at 1 year (3 studies; n=1210) and 5 years (3 studies; n=1057). Quantile regression was used to estimate the median differences in HRQoL for women compared to men with adjustment for covariates. Study factors included sociodemographics, prestroke dependency, stroke-related factors (eg, stroke severity), comorbidities, and poststroke depression. Study-specific median differences were combined into pooled estimates using random-effect meta-analysis. Results- Women had lower pooled HRQoL than men (median differenceunadjusted 1 year, -0.147; 95% CI, -0.258 to -0.036; 5 years, -0.090; 95% CI, -0.119 to -0.062). After adjustment for age, stroke severity, prestroke dependency, and depression, these pooled median differences were attenuated, more greatly at 1 year (-0.067; 95% CI, -0.111 to -0.022) than at 5 years (-0.085; 95% CI, -0.135 to -0.034). Conclusions- Women consistently exhibited poorer HRQoL after stroke than men. This was partly attributable to women's advanced age, more severe strokes, prestroke dependency, and poststroke depression, suggesting targets to reduce the differences. There was some evidence of residual differences in HRQoL between sexes but they were small and unlikely to be clinically significant.

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke.

BACKGROUND: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline. RESULTS: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. CONCLUSIONS: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Relationship Between B-Vitamin Biomarkers and Dietary Intake with Apolipoprotein E є4 in Alzheimer's Disease.

The potential for B-vitamins to reduce plasma homocysteine (Hcy) and reduce the risk of Alzheimer's disease (AD) has been described previously. However, the role of Apolipoprotein E є4 (APOE4) in this relationship has not been adequately addressed. This case-control study explored APOE4 genotype in an Australian sample of 63 healthy individuals (female = 38; age = 76.9 ± 4.7 y) and 63 individuals with AD (female = 35, age = 77.1 ± 5.3 y). Findings revealed 55 of 126 participants expressed the APOE4 genotype with 37 of 126 having both AD and the APOE4 genotype. Analysis revealed an increased likelihood of AD when Hcy levels are >11.0 µmol/L (p = 0.012), cysteine levels were <255 µmol/L (p = 0.033) and serum folate was <22.0 nmol/L (p = 0.003; in males only). In females, dietary intake of total folate <336 µg/day (p=0.001), natural folate <270 µg/day (p = 0.011), and vitamin B2 < 1.12 mg/day (p = 0.028) was associated with an increased AD risk. These results support Hcy, Cys, and SF as useful biomarkers for AD, irrespective of APOE4 genotype and as such should be considered as part of screening and managing risk of AD.

Evaluating recruitment strategies for AUSPICE, a large Australian community-based randomised controlled trial.

OBJECTIVES: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). DESIGN, SETTING, PARTICIPANTS: Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. METHODS: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. MAIN OUTCOME: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. RESULTS: 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. CONCLUSIONS: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.

Genome-wide association meta-analysis of functional outcome after ischemic stroke.

OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8. RESULTS: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). CONCLUSIONS: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

Sex Differences in Severity of Stroke in the INSTRUCT Study: a Meta-Analysis of Individual Participant Data.

Background Women have worse outcomes after stroke than men, and this may be partly explained by stroke severity. We examined factors contributing to sex differences in severity of acute stroke assessed by the National Institutes of Health Stroke Scale. Methods and Results We pooled individual participant data with National Institutes of Health Stroke Scale assessment (N=6343) from 8 population-based stroke incidence studies (1996-2014), forming part of INSTRUCT (International Stroke Outcomes Study). Information on sociodemographics, stroke-related clinical factors, comorbidities, and pre-stroke function were obtained. Within each study, relative risk regression using log-binominal modeling was used to estimate the female:male relative risk ( RR ) of more severe stroke (National Institutes of Health Stroke Scale>7) stratified by stroke type (ischemic stroke and intracerebral hemorrhage). Study-specific unadjusted and adjusted RR s, controlling for confounding variables, were pooled using random-effects meta-analysis. National Institutes of Health Stroke Scale data were recorded in 5326 (96%) of 5570 cases with ischemic stroke and 773 (90%) of 855 participants with intracerebral hemorrhage. The pooled unadjusted female:male RR for severe ischemic stroke was 1.35 (95% CI 1.24-1.46). The sex difference in severity was attenuated after adjustment for age, pre-stroke dependency, and atrial fibrillation but remained statistically significant (pooled RR adjusted 1.20, 95% CI 1.10-1.30). There was no sex difference in severity for intracerebral hemorrhage ( RR crude 1.08, 95% CI 0.97-1.21; RR adjusted 1.08, 95% CI 0.96-1.20). Conclusions Although women presented with more severe ischemic stroke than men, much although not all of the difference was explained by pre-stroke factors. Sex differences could potentially be ameliorated by strategies to improve pre-stroke health in the elderly, the majority of whom are women. Further research on the potential biological origin of sex differences in stroke severity may also be warranted.

Factors contributing to sex differences in functional outcomes and participation after stroke.

OBJECTIVE: To examine factors contributing to the sex differences in functional outcomes and participation restriction after stroke. METHODS: Individual participant data on long-term functional outcome or participation restriction (i.e., handicap) were obtained from 11 stroke incidence studies (1993-2014). Multivariable log-binomial regression was used to estimate the female:male relative risk (RR) of poor functional outcome (modified Rankin Scale score >2 or Barthel Index score <20) at 1 year (10 studies, n = 4,852) and 5 years (7 studies, n = 2,226). Multivariable linear regression was used to compare the mean difference (MD) in participation restriction by use of the London Handicap Scale (range 0-100 with lower scores indicating poorer outcome) for women compared to men at 5 years (2 studies, n = 617). For each outcome, study-specific estimates adjusted for confounding factors (e.g., sociodemographics, stroke-related factors) were combined with the use of random-effects meta-analysis. RESULTS: In unadjusted analyses, women experienced worse functional outcomes after stroke than men (1 year: pooled RRunadjusted 1.32, 95% confidence interval [CI] 1.18-1.48; 5 years: RRunadjusted 1.31, 95% CI 1.16-1.47). However, this difference was greatly attenuated after adjustment for age, prestroke dependency, and stroke severity (1 year: RRadjusted 1.08, 95% CI 0.97-1.20; 5 years: RRadjusted 1.05, 95% CI 0.94-1.18). Women also had greater participation restriction than men (pooled MDunadjusted -5.55, 95% CI -8.47 to -2.63), but this difference was again attenuated after adjustment for the aforementioned factors (MDadjusted -2.48, 95% CI -4.99 to 0.03). CONCLUSIONS: Worse outcomes after stroke among women were explained mostly by age, stroke severity, and prestroke dependency, suggesting these potential targets to improve the outcomes after stroke in women.

Sex Differences in Long-Term Mortality After Stroke in the INSTRUCT (INternational STRoke oUtComes sTudy): A Meta-Analysis of Individual Participant Data.

BACKGROUND: Women are reported to have greater mortality after stroke than men, but the reasons are uncertain. We examined sex differences in mortality at 1 and 5 years after stroke and identified factors contributing to these differences. METHODS AND RESULTS: Individual participant data for incident strokes were obtained from 13 population-based incidence studies conducted in Europe, Australasia, South America, and the Caribbean between 1987 and 2013. Data on sociodemographics, stroke-related factors, prestroke health, and 1- and 5-year survival were obtained. Poisson modeling was used to estimate the mortality rate ratio (MRR) for women compared with men at 1 year (13 studies) and 5 years (8 studies) after stroke. Study-specific adjusted MRRs were pooled to create a summary estimate using random-effects meta-analysis. Overall, 16 957 participants with first-ever stroke followed up at 1 year and 13 216 followed up to 5 years were included. Crude pooled mortality was greater for women than men at 1 year (MRR 1.35; 95% confidence interval, 1.24-1.47) and 5 years (MRR 1.24; 95% confidence interval, 1.12-1.38). However, these pooled sex differences were reversed after adjustment for confounding factors (1 year MRR, 0.81; 95% confidence interval, 0.72-0.92 and 5-year MRR, 0.76; 95% confidence interval, 0.65-0.89). Confounding factors included age, prestroke functional limitations, stroke severity, and history of atrial fibrillation. CONCLUSIONS: Greater mortality in women is mostly because of age but also stroke severity, atrial fibrillation, and prestroke functional limitations. Lower survival after stroke among the elderly is inevitable, but there may be opportunities for intervention, including better access to evidence-based care for cardiovascular and general health.

GISCOME - Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study.

INTRODUCTION: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. METHODS: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. RESULTS: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60-190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. CONCLUSION: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.

Rationale and design of a randomized controlled trial of pneumococcal polysaccharide vaccine for prevention of cardiovascular events: The Australian Study for the Prevention through Immunization of Cardiovascular Events (AUSPICE).

BACKGROUND: Research has shown that vaccination with Streptococcus pneumoniae reduced the extent of atherosclerosis in experimental animal models. It is thought that phosphorylcholine lipid antigens in the S. pneumoniae cell wall induce the production of antibodies that cross-react with oxidized low-density lipoprotein, a component of atherosclerotic plaques. These antibodies may bind to and facilitate the regression of the plaques. Available data provide evidence that similar mechanisms also occur in humans, leading to the possibility that pneumococcal vaccination protects against atherosclerosis. A systematic review and meta-analysis, including 8 observational human studies, of adult pneumococcal polysaccharide vaccination for preventing cardiovascular disease in people older than 65 years, showed a 17% reduction in the odds (odds ratio 0.83, 95% CI 0.71-0.97) of having an acute coronary syndrome event. METHODS/DESIGN: The AUSPICE is a multicenter, randomized, placebo-controlled, double-blind, clinical trial to formally test whether vaccination with the pneumococcal polysaccharide vaccine protects against cardiovascular events (fatal and nonfatal acute coronary syndromes and ischemic strokes). Cardiovascular outcomes will be obtained during 4 to 5 years of follow-up, through health record linkage with state and national administrative data sets. CONCLUSION: This is the first registered randomized controlled trial (on US, World Health Organization, Australia and New Zealand trial registries) to be conducted to test whether vaccination with the pneumococcal polysaccharide vaccine will reduce cardiovascular events. If successful, vaccination can be readily extended to at-risk groups to reduce the risk of cardiovascular diseases.

Predictors of health-related quality of life in community-dwelling stroke survivors: a cohort study.

BACKGROUND: Impaired health-related quality of life (HRQoL) post stroke is common, though prevalence estimates vary considerably. Few longitudinal studies explore post-stroke patterns of HRQoL and factors contributing to their change over time. Accurately identifying HRQoL after stroke is essential to understanding the extent of stroke effects. OBJECTIVES: This study aimed to assess change in levels of, and identify independent predictors of, HRQoL over the first 12-months post-stroke. METHODS: Design. A prospective cohort study. SETTING AND PARTICIPANTS: Community-dwelling stroke survivors in metropolitan Newcastle, New South Wales (NSW), Australia. Consecutively recruited stroke patients (n = 134) participated in face-to-face interviews at baseline, 3, 6, 9 and 12 months. OUTCOME MEASURE: HRQoL (measured using the Assessment Quality-of-life).Independent measures. Physical and psycho-social functioning, including depression and anxiety (measured via Hospital Anxiety and Depression Scale), disability (Modified Rankin Scale), social support (Multi-dimensional Scale Perceived Social Support) and community participation (Adelaide Activities Profile). ANALYSES: A linear mixed model was used to establish the predictors of, change in HRQoL over time. RESULTS: On multivariable analysis, HRQOL did not change significantly with time post-stroke. Higher HRQoL scores were independently associated with higher baseline HRQoL (P = 0.03), younger age (P = 0.006), lower disability (P = 0.003), greater community participation (P ≤ 0.001) and no history of depression (P = 0.03). CONCLUSION: These results contribute to an understanding of HRQoL in the first year post-stroke. Community participation and stroke-related disability are potentially modifiable risk factors affecting post-stroke HRQoL. Interventions aimed at addressing participation and disability post-stroke should be developed and tested.

Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO). CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

STroke imAging pRevention and treatment (START): A longitudinal stroke cohort study: Clinical trials protocol.

RATIONALE: Stroke and poststroke depression are common and have a profound and ongoing impact on an individual's quality of life. However, reliable biological correlates of poststroke depression and functional outcome have not been well established in humans. AIMS: Our aim is to identify biological factors, molecular and imaging, associated with poststroke depression and recovery that may be used to guide more targeted interventions. DESIGN: In a longitudinal cohort study of 200 stroke survivors, the START-STroke imAging pRevention and Treatment cohort, we will examine the relationship between gene expression, regulator proteins, depression, and functional outcome. Stroke survivors will be investigated at baseline, 24 h, three-days, three-months, and 12 months poststroke for blood-based biological associates and at days 3-7, three-months, and 12 months for depression and functional outcomes. A sub-group (n = 100), the PrePARE: Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke cohort, will also be investigated for functional and structural changes in putative depression-related brain networks and for additional cognition and activity participation outcomes. Stroke severity, diet, and lifestyle factors that may influence depression will be monitored. The impact of depression on stroke outcomes and participation in previous life activities will be quantified. STUDY OUTCOMES: Clinical significance lies in the identification of biological factors associated with functional outcome to guide prevention and inform personalized and targeted treatments. Evidence of associations between depression, gene expression and regulator proteins, functional and structural brain changes, lifestyle and functional outcome will provide new insights for mechanism-based models of poststroke depression.

Polygenic overlap between kidney function and large artery atherosclerotic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. METHODS: Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. RESULTS: Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). CONCLUSIONS: This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.