Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors’ knowledge, no randomized clinical trial has been conducted. To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization. This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center. Participants received either 23-valent PPV (PPV23) or placebo (saline). The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification ( ICD-10-AM ) codes. A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power. Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered. ANZCTR Identifier: ACTRN12615000536561

Importance:Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors' knowledge, no randomized clinical trial has been conducted. Objective:To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization. Design, Setting, and Participants:This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center. Interventions:Participants received either 23-valent PPV (PPV23) or placebo (saline). Main Outcomes and Measures:The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes. Results:A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power. Conclusions and Relevance:Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered. Trial Registration:ANZCTR Identifier: ACTRN12615000536561.

generalized estimating equations using log-binomial models respectively at multi-ple 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 sever-ity (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.

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.

Objectives Fibrocartilaginous embolism is a rarely reported cause of spinal cord infarction.1 The embolism arises from cartilaginous nucleus pulposus material entering the spinal cord vasculature usually after a Valsalva manoeuvre.2 Case A 36-year-old woman presented with sudden onset bilateral arm paraesthesia and chest pain soon after cleaning her fish tank without heavy lifting. 24 hours later, she developed bilateral upper and lower limb weakness with diminished deep tendon reflexes, and sensory loss to pinprick in the right C4/C5 distribution but with no sensory level. Vibration and position sense were normal. After a brief resolution of symptoms, she deteriorated to tetraparesis, with some retained distal movement. Results MRI of brain and whole spine 48 hours after symptom onset showed central T2-hyperintensity in the cervical cord extending from C4/C5 to T1, with possible restricted diffusion, associated central and left paracentral disc protrusion at C6/C7 and a mild central posterior disc protrusion at C5/C6 with preserved CSF space surrounding the cord. Vasculitic, thrombophilia and cardiac investigations were unremarkable. CSF oligoclonal bands and aquaporin-4 antibodies were negative. Repeat MRI confirmed true restricted diffusion and aspirin was commenced. A disc protrusion at the level of cord infarction was in keeping with fibrocartilaginous embolism as the primary cause, alternative causes having been excluded. Conclusions This case illustrates a rare but potentially underreported cause of spinal cord infarct. It should be considered when a patient with few vascular risk factors presents with an acute cord syndrome. References AbdelRazek MA, Mowla A, Farooq S, Silvestri N, Sawyer R, Wolfe G. Fibrocartilaginous embolism: a comprehensive review of an under-studied cause of spinal cord infarction and proposed diagnostic criteria. J Spinal Cord Med. 2016;39(2):146–54. Kepes JJ, Reynard JD. Infarction of spinal cord and medulla oblongata caused by fibrocartilaginous emboli. Virchows Archiv A. 1973;361(3):185–93.

Background: Outcomes after subarachnoid hemorrhage (SAH) have been rarely examined in large cohorts. Methods: This is an extension of the International Stroke Outcomes Study (INSTRUCT) pooling 13 ‘ideal’ stroke incidence studies (n=657 with SAH from 1993-2017, median age 56 years; 46% men). The primary outcomes were mortality and functional outcome (mRS score 3-5). Harmonized study factors included age, sex, behaviors (current smoking, alcohol intake), comorbidities (history of hypertension, ischemic heart disease, atrial fibrillation), stroke severity (e.g. NIHSS score) and year of stroke. In the pooled dataset, we estimated predictors of mortality using Poisson regression, to estimate incidence rate ratio (IRR) at 1 month (11 studies), 1 year (12 studies) and 5 years (7 studies). Generalized equation estimates in the log-binomial family were used to calculate risk ratios (RRs) for predictors of poor functional outcome at 1 month (5 studies) and 1 year (8 studies). Results: Mortality was 33% at 1 month, 43% at 1 year, and 47% at 5 years (Fig 1). Poor functional outcome was 25% at 1 month and 15% at 1 year (Fig 1). In multivariable analysis, age and stroke severity were associated with mortality at all time points, together with current smoking at 1 and 5 years, and history of hypertension at 5 years (Fig 2). Poor functional outcome was predicted by age (RR 1.03; 95% CI 1.01-1.04) at 1 month and by age (RR 1.04; 95% CI 1.00-1.08) and stroke severity (RR 1.94; 95% CI 1.02-2.87) at 1 year. Conclusion: Risk factors that predict SAH incidence including hypertension and smoking make outcomes worse. Better management of older patients and those with severe strokes could improve outcomes after SAH.

Background Syphilis is increasing in prevalence in the community.1 2 Neurosyphilis has protean manifestations making recognition, diagnosis and early initiation of treatment challenging. Methods/Results We present a case of early syphilitic meningitis in a 37-year-old female presenting with multiple cranial neuropathies (V, VI, VII, VIII and XII) developing over the course of two weeks. This began with a sensation of disequilibrium and unsteady gait, and progressed to difficulty closing both eyes, right lip numbness, bilateral hearing impairment (right, followed by left), and dysarthria. She did not report headache, meningism, features of primary syphilis infection or risk factors for sexually transmitted infections (STIs). Examination confirmed the presence of right-sided trigeminal, bilateral abducens, facial, vestibulocochlear and hypoglossal nerve palsies. Cerebrospinal fluid (CSF) examination was inflammatory (protein 1.28 g/L, glucose 3.8mmol/L) with predominant lymphocytosis (76%, WCC 441 x 106/L). Magnetic resonance imaging (MRI) demonstrated post-contrast enhancement of the trigeminal nerve at the pons, as well as facial and vestibulocochlear nerves at the geniculate ganglion with no leptomeningeal enhancement. Our patient was diagnosed with neurosyphilis on serum and CSF serological testing (Serum Treponema pallidum particle agglutination assay (TPPA) positive, chemiluminescent microparticle immunoassay (CMIA) IgG and IgM positive, rapid plasma reagen 1:32. CSF TPPA positive, Venereal Disease Research Laboratory test titre of 1:8). She was treated with intravenous benzylpenicillin with rapid improvement in her cranial neuropathies. Conclusions This is the most extensive cranial neuropathy reported with syphilitic infections to date. Neurosyphilis should be considered as a differential in patients presenting with multiple cranial neuropathies. References Kojima N, Klausner J. An update on the global epidemiology of syphilis. Curr Epidemiol Rep 2018;5(1):24–38. Ghanem K, Ram S, Rice P. The modern epidemic of syphilis. N Engl J Med 2020;382(24):2379–80.

Objectives Vitamin B12 is crucial for neurologic function, red blood cell production, and DNA synthesis. Deficiency can lead to a wide spectrum of haematologic and neuropsychiatric disorders including subacute combined degeneration of the cord. This report presents a case of a 47 y.o female who presented with subacute combined degeneration of the spinal cord with a normal active B12 level. Results MRI demonstrated high T2 signal throughout the dorsal columns of the cervical and upper thoracic cord without enhancement consistent with subacute combined degeneration of the cord. Her blood count revealed a mild macrocytic anaemia. Total vitamin B12 was <80 pmol/L and active B12 was >128 pmol/L, confirmed on repeat testing. Functional vitamin B12 deficiency was confirmed by an elevated homocysteine level of 38.6 umol/L (reference range 4.4 to 13.6 umol/L) and elevated serum methylmalonic acid of 20.75 umol/L (reference range <0.32 umol/L). Intrinsic factor and gastric parietal cell antibodies were detected. Conclusion Our patient had a clinical presentation consistent with B12 deficiency with an erroneously high active B12 level. Functional assays confirmed B12 deficiency, and a serological diagnosis of pernicious anaemia was made. This case illustrates the importance of not relying on any single test to exclude B12 deficiency.

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.

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.

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.

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.

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 difference(unadjusted) 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.

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 x 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 x 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.

Objective To determine whether early and more frequent mobilization after stroke affects health-related quality of life. Methods A Very Early Rehabilitation Trial (AVERT) was an international, multicenter (56 sites), phase 3 randomized controlled trial, spanning 2006–2015. People were included if they were aged ≥18 years, presented within 24 hours of a first or recurrent stroke (ischemic or hemorrhagic), and satisfied preordained physiologic criteria. Participants were randomized to usual care alone or very early and more frequent mobilization in addition to usual care. Quality of life at 12 months was a prespecified secondary outcome, evaluated using the Assessment of Quality of Life 4D (AQoL-4D). This utility-weighted scale has scores ranging from −0.04 (worse than death) to 1 (perfect health). Participants who died were assigned an AQoL-4D score of 0. Results No significant difference in quality of life at 12 months between intervention (median 0.47, interquartile range [IQR] 0.07–0.81) and usual care (median 0.49, IQR 0.08–0.81) groups was identified (p = 0.86), nor were there any group differences across the 4 AQoL-4D domains. The same lack of group difference in quality of life was observed at 3 months. When cohort data were analyzed (both groups together), quality of life was strongly associated with acute length of stay, independence in activities of daily living, cognitive function, depressive symptoms, and anxiety symptoms (all p < 0.001). Quality of life in AVERT participants was substantially lower than population norms, and the gap increased with age. Conclusions Earlier and more frequent mobilization after stroke did not influence quality of life. Clinical trial registration anzctr.org.au; ACTRN12606000185561 Classification of evidence This study provides Class II evidence that for people with stroke, earlier and more frequent mobilization did not influence quality of life over the subsequent year.

ObjectivesTo 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, participantsMen 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. MethodsInvitations 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 outcomeProportions of invitees completing screening questionnaire and recruited for participation in the RCT. Results21526 of 154992 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. ConclusionsTrial 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 registrationAustralian New Zealand Clinical Trials Registry, ACTRN12615000536561.

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.