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Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the resultsremain inconclusive. The EFFECTS (Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke) reached itsrecruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to theprotocol and describe how we formed the EFFECTS trial collaboration in Sweden. In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had aclinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits.Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. Seven amendments were made and included clarification of drug interaction between fluoxetine andmetoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data fromcentral Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, andclarification of design of some sub-studies.EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan tounblind the data in January 2020 and report the primary outcome in May 2020. EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine afterstroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient datameta-analysis.

BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium. METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries. RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH. CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.

OBJECTIVES: To study the associations of pre-stroke cognitive performance with mortality after first-ever stroke or transient ischaemic attack (TIA). DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: In participants having first-ever stroke or TIA during up to 14 years of post-test follow-up (n=155), we investigated the associations of pre-stroke variables and cognitive test results with post-stroke survival. The study is based on those participants of the Uppsala Longitudinal Study of Adult Men who performed cognitive function tests at approximately age 70 (n=919). PRIMARY OUTCOME MEASURES: Mortality after first-ever stroke or TIA related to pre-stroke executive performance. RESULTS: Eighty-four (54%) of the first-ever stroke/TIA patients died under a median follow-up of 2.5 years after the event. In Cox proportional hazard analyses adjusting for age, education, social group and traditional stroke risk factors, poor performance in Trail Making Test (TMT)-A was related to mortality (HR 1.88 per SD, 95% CI 1.31 to 2.71, p=0.001). The risk of mortality was approximately threefold higher in the highest tertile compared with the lowest tertile (HR TMT-A= 2.90 per SD, 95% CI 1.24 to 6.77, p=0.014). A similar pattern was seen for TMT-B, but Mini-Mental State Examination results were not related to risk of post-stroke mortality. CONCLUSION: Executive performance measured by TMT-A and -B before stroke was independently associated with long-term risk of mortality, after first-ever stroke or TIA in a population-based study of older men.

OBJECTIVE: Vascular risk factors are associated with ischemic changes in the cerebral white matter. We studied the predictive value of cognitive test performance especially related to subcortico-frontal pathways, together with a cognitive screening test, for later incidence of fatal or nonfatal stroke or TIAs and stroke subtypes. METHODS: A sample of 930 70-year-old men without previous stroke/TIA from the community-based Uppsala Longitudinal Study of Adult Men was investigated at baseline using Trail Making Tests (TMT) A and B and the Mini-Mental State Examination (MMSE). RESULTS: During up to 13 years of follow-up, 166 men developed a stroke or TIA; 105 participants had a brain infarction. In Cox proportional hazards analyses adjusting for education, social group, and traditional cardiovascular risk factors, a 1-SD increase in TMT-B time was associated with a higher risk for brain infarction (hazard ratio 1.48, 95% confidence interval 1.11-1.97). The risk of brain infarction was more than threefold higher in the highest (TMT-B = 146-240 s) compared to the lowest (TMT-B = 43-84 s) TMT-B quartile. TMT-A and MMSE results were not consistently related to stroke outcomes. CONCLUSION: Impaired performance in elderly men measured by Trail Making Test B, a cognitive test especially reflecting subcortico-frontal activities, was an independent predictor of subsequent brain infarction in this community-based sample of elderly men. Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit.

AIMS/HYPOTHESIS: Our aim was to investigate the predictive power of a panel of variables in glucose and insulin metabolism for the incidence of stroke or transient ischaemic attacks (TIA). We hypothesised that proinsulin and insulin resistance contributes to an increase of risk for fatal and non-fatal stroke/TIA, independently of diabetes and established risk factors. METHODS: The study is based on the Uppsala Longitudinal Study of Adult Men cohort. The examinations were performed at age 70 years. RESULTS: In 1,151 men free from stroke at baseline, 150 developed stroke or TIA during a median follow-up of 8.8 years. In unadjusted Cox proportional hazards analyses, a 1 SD increase of a predictor variable was associated with an increased risk for stroke/TIA, e.g. plasma insulin (HR 1.19, 95% CI 1.01-1.40), fasting intact proinsulin (HR 1.28, 95% CI 1.09-1.49); whereas a 1 SD increase in insulin sensitivity measured by the euglycaemic insulin clamp method decreased the risk for stroke/TIA (HR 0.81, 95% CI 0.68-0.96). The predictive values of fasting intact proinsulin and insulin sensitivity endured but not that of plasma insulin when adjusting for diabetes. In models adjusting for diabetes, hypertension, atrial fibrillation, electrocardiographic left ventricular hypertrophy, serum cholesterol and smoking, proinsulin remained as a significant predictor of later stroke/TIA (HR 1.22, 95% CI 1.00-1.48) whereas clamp insulin sensitivity did not (HR 0.87, 95% CI 0.71-1.07). CONCLUSIONS/INTERPRETATION: Fasting intact proinsulin level and insulin sensitivity at clamp predicted subsequent fatal and non-fatal stroke/TIA, independently of diabetes in elderly men whereas fasting insulin did not.

OBJECTIVES: To explore whether the predictive power of mid-life ECG abnormalities and conventional cardiovascular risk factors for future stroke change over a 30-year follow-up period, and whether a repeated examination improves their predictive power. DESIGN AND SETTING: Longitudinal population-based study. PARTICIPANTS: 2,322 men aged 50 years, with a follow-up period of 30 years. 1,221 subjects were re-examined at age 70 years MAIN OUTCOME MEASURE: Risk for fatal and non-fatal stroke during three decades of follow-up. Investigations included resting ECG and traditional cardiovascular risk factors. RESULTS: When measured at age 50 years, ST segment depression and T wave abnormalities, together with ECG-left ventricular hypertrophy, were of importance only during the first 20 years, but regained importance when re-measured at age 70 years. Blood pressure was a significant predictor for stroke over all three decades of follow-up. In elderly people only, there is evidence that apolipoprotein A1 may protect from future stroke. CONCLUSION: Mid-life values for blood pressure and ECG abnormalities retain their predictive value over long follow-up periods even though they improved in predictive power when re-measured in elderly people. Despite lower prevalence, ECG abnormalities had greater impact at age 50 years than at age 70 years. By contrast, apolipoprotein A1 was protective for future stroke only at age 70 years.