BACKGROUND:Evidence is lacking on whether support and education programs, facilitated by mobile technology, benefit people with stroke. AIMS:The primary aim was to determine the effectiveness of a co-designed, eHealth self-management intervention for reducing unplanned hospital presentations. METHODS:Prospective, multicenter randomized controlled trial with blinded outcome assessment and intention-to-treat analysis. Randomization (1:1, stratified by age and level of disability at baseline) within 2 weeks of hospital discharge. Participants aged ⩾18 years with modified Rankin Scale (mRS) score 0-4 were recruited from 11 Australian hospitals. To maintain blinding, all participants co-developed three to five self-management goals with a trained clinician-researcher, using a standardized approach. Following randomization, participants were allocated to receive personalized, goal-centered electronic messages (intervention) or administrative messages (active control) over 12 weeks via text or email. The groups were not informed about the number of messages they would receive and were unaware that only the intervention group had their messages tailored to their goals. The primary outcome was unplanned hospital presentations (emergency department/admission) within 90 days post-randomization. Secondary outcomes included goal attainment, self-efficacy, and various health outcomes. We used generalized mixed-effects regression model with a logistic link for categorical outcomes and Cohen's d (0.2 considered small effect, 0.5 moderate-1.0 large) to assess within-group change. RESULTS:The trial was impacted by COVID-19 and ceased with 556/890 planned participants; 465 were randomized (n = 234 control, n = 231 experimental), a median of 10 days post-discharge (median age 67.2 years, 67.1% male, median 3 goals/participant). Primary outcome assessments for 222 control and 218 experimental participants showed no between-group differences for unplanned hospital presentations (odds ratio (OR): 1.32; 95% confidence interval (CI): 0.52-3.34). Compared to controls at 90 days, a larger proportion of the experimental group had >3 unmet needs and slight to severe disability (both <8% difference). Both groups showed non-significant improvements in goal attainment at 90 days post-randomization; overall attainment was stronger among intervention participants (within-group change Cohen's d intervention 0.76 vs 0.61). CONCLUSION:We found no evidence that tailored, electronic messaging over 12 weeks, in addition to structured goal-setting reduced unplanned hospital presentations. Future research is needed to understand the role of disability and unmet needs, and factors that influence goal attainment. TRIAL REGISTRATION:ACTRN12618001468213, U1111-1206-7237.

Abstract Background and aims Dornase-alpha, a recombinant human deoxyribonuclease-I, can potentiate alteplase-mediated clot lysis via breakdown of neutrophil extracellular traps in stroke clots. We aimed to determine if dornase potentiates clot lysis in combination with tenecteplase ex-vivo in thrombectomy clots retrieved from stroke patients. Methods Forty-two thrombectomy clots were divided and suspended in buffer, pooled citrated or heparinised plasma and incubated with 15nM tenecteplase or in combination with either 10U/ml or 100U/ml of dornase. Clot weight was measured over 120-minutes, and treated clots underwent immunofluorescence. Statistical significance was assessed using linear mixed-effects modelling. Results Addition of tenecteplase to retrieved clots in buffer resulted in a median percentage reduction to 40.7% (IQR:17.0-53.7%) of the initial clot weight after 120-minutes. The addition of 100U/ml of dornase led to significant clot weight reduction to 17.5% (IQR:8.8-27.2%) while the addition of 10U/ml of dornase led to a non-significant reduction to 28.0% (IQR:7.4-45.7%) compared to tenecteplase alone. Further, incubation in citrated and heparinised plasma resulted in a clot weight reduction to 55.7% (IQR:21.6-70.7) and 58.5% (IQR:45.3-73.2) in the presence of tenecteplase respectively, with a non-statistically significant reduction with addition of Dornase. However, there was a significant attenuation in clot weight reduction in plasma compared to buffer in clots treated with tenecteplase and Dornase. Conclusions 100U/ml dornase potentiated ex-vivo tenecteplase mediated clot lysis in buffer but was less effective at lower doses and in plasma. Further studies need to assess ex-vivo lytic activity in plasma to allow for greater clinical translation. Conflict of interest Oshi Swarup: nothing to disclose, Joanne Chia: nothing to disclose, Zikou Liu: nothing to disclose, Tammy Lam: nothing to disclose, Anna Balabanski: nothing to disclose, Geoffrey Cloud: nothing to disclose, Bruce Campbell: nothing to disclose, Robert Medcalf: nothing to disclose

Aim:The global population of older adults is growing, and older age is linked to higher bleeding risk. Although guidelines discourage aspirin for primary prevention in healthy older adults due to bleeding harms outweighing benefits, many continue taking it without a clear indication. It remains unclear whether all older adults face uniform aspirin-related bleeding risk or if certain subgroups are more vulnerable. Methods:We analyzed data from 19,114 ASPREE trial participants to develop machine learning models using 116 baseline variables. Random forest (RF) and random survival forest (RSF) models predicted 5-year bleeding risk, and participants were stratified into low, intermediate, and high-risk groups based on the 20th and 80th percentiles of predicted risk. We assessed heterogeneity of treatment effect (HTE) by testing treatment-by-risk group interactions on the relative scale using Fine-Gray models, and on the absolute scale using observed 5-year cumulative incidence rates. Results:Over a median follow-up of 4.7 years, 626 major bleeding events occurred. The RF model had moderate discrimination (AUC = 0.65, 95% CI: 0.63-0.67) and good calibration (Brier = 0.032, 95% CI: 0.029-0.034). Statistically significant HTE was observed on the relative scale, with the greatest relative increase in bleeding risk seen in the low-risk group (subdistribution hazard ratio = 2.26, 95% CI: 1.27-4.01). On the absolute scale, low-risk participants experienced higher bleeding with aspirin (absolute risk difference (ARD) = 1.17%, 95% CI: 0.37-1.95), but heterogeneity in ARDs was not statistically significant (Cochran's Q p > 0.45). Similar findings were observed when using the RSF model. Conclusion:Participants at lowest baseline bleeding risk experienced the greatest relative increase in bleeding risk with aspirin therapy. We found statistically significant heterogeneity in treatment effects on the relative but not absolute scale. These findings support an individualized, risk-based approach to aspirin therapy decision-making in older adults.

Abstract Background and aims Endovascular clot retrieval (ECR) has revolutionised acute ischaemic stroke management. While procedural safety is well established, little attention has been paid to vascular responses to hydrophilic polymer coatings used on retrieval devices. This report presents post-mortem histopathological findings implicating a foreign body giant cell reaction secondary to hydrophilic polymer exposure as a cause of recurrent stroke following ECR. Methods A detailed clinical and neuropathological review was conducted on a 72-year-old patient who experienced three sequential, ischaemic strokes within four months following ECR and angioplasty of a right middle cerebral artery (M2) occlusion. Limited post-mortem examination of the heart and brain was undertaken with histopathological and immunoperoxidase staining to assess potential vascular inflammatory mechanisms. Results Post-mortem examination demonstrated multiple infarcts of differing ages, diffuse atherosclerotic change, and a florid multinucleated giant cell reaction containing non-polarisable basophilic material along the luminal surface of the right M2 segment and adjacent vessels. The internal elastic lamina remained intact, with only focal fibrinoid necrosis and sparse medial inflammation. No amyloid angiopathy, vasculitis, or cardiac embolic source was identified. The morphological features were consistent with a chronic inflammatory response to embolised hydrophilic polymer coating material from prior endovascular instrumentation Conclusions This case highlights an under-recognised mechanism of post-ECR recurrent stroke linked to hydrophilic polymer-induced vascular inflammation. If recognised antemortem, immunosuppression maybe more effective than usual secondary stroke prevention treatments Conflict of interest Kanila Perera - Nothing to Disclose

Abstract Background and aims Women remain underrepresented in stroke clinical trials despite a higher lifetime risk of stroke and poorer post-stroke outcomes. Although sex differences in trial participation have been reported, the influence of trial design and the timing of enrolment within the stroke pathway on sex-specific non-participation remains unclear. To examine whether trial design (Drug RCTs,non- drug RCTs, and observational trials) and stroke phase (hyperacute, acute, sub-acute, and chronic) are associated with sex differences in non-participation in stroke clinical trials. Methods Retrospective observational study of adult stroke patients aged ≥18 years and older admitted to The Alfred Health Comprehensive Stroke Centre between February 2019 and March 2025. Results Among 494 eligible patients (235 females, 259 males), 340 (68.8%) consented, with lower consent rates among females than males (57.0% vs 79.5%, p < 0.001). Declines were higher among females than males (26.8% vs 17.8%). Non-participation varied by trial design, with the largest sex differences observed in drug RCTs, where decline rates were higher among females than males (28.1% vs 18.4%). Declines were also more frequent among females in non-drug RCTs (23.9% vs 17%) and observational trials (33.3% vs 22.2%). Across stroke phases, non-participation was most frequent in acute and chronic trials, with higher female decline rates in the chronic phase (29.3% vs 17.3%). Conclusions Sex differences in non-participation varied by trial design and stroke phase, suggesting that disparities in stroke trial participation are influenced by structural and temporal features of trial design rather than solely by patient preference. Conflict of interest Pamela Galindo: Nothing to disclose; Mycah Astrera-Sgro: Nothing to dislcose; Professor Geoffrey Cloud: Nothing to disclose; Dr Vimal Stanisalus: Nothing to disclose

Background and aims Endovascular clot retrieval (ECR) has revolutionised acute ischaemic stroke management. While procedural safety is well established, little attention has been paid to vascular responses to hydrophilic polymer coatings used on retrieval devices. This report presents postmortem histopathological findings implicating a foreign body giant cell reaction secondary to hydrophilic polymer exposure as a cause of recurrent stroke following ECR.Methods A detailed clinical and neuropathological review was conducted on a 72-year-old patient who experienced three sequential ischaemic strokes within 4 months following ECR and angioplasty of a right middle cerebral artery (M2) occlusion. Limited postmortem examination of the heart and brain was undertaken with histopathological and immunoperoxidase staining to assess potential vascular inflammatory mechanisms.Results Postmortem examination demonstrated multiple infarcts of differing ages, diffuse atherosclerotic change and a florid multinucleated giant cell reaction containing non-polarisable basophilic material along the luminal surface of the right M2 segment and adjacent vessels. The internal elastic lamina remained intact, with only focal fibrinoid necrosis and sparse medial inflammation. No amyloid angiopathy, vasculitis or cardiac embolic source was identified. The morphological features were consistent with a chronic inflammatory response to embolised hydrophilic polymer coating material from prior endovascular instrumentation.Conclusions This case highlights an under-recognised mechanism of post-ECR recurrent stroke linked to hydrophilic polymer-induced vascular inflammation. If recognised antemortem, immunosuppression may be more effective than usual secondary stroke prevention treatments.

In the investigation of the stroke patient chapter, investigations to confirm or refute the diagnosis of stroke are discussed including brain imaging with computed tomography and magnetic resonance imaging and blood test laboratory investigations. The importance of vascular and cardiac investigations is discussed, especially with regard to diagnosing the aetiological cause of stroke. Investigations performed to anticipate potential complications from stroke are also reviewed.

Background Blunt cerebrovascular injuries (BCVIs) are associated with high risk of ischaemic strokes during hospital admission. Understanding of high-risk factors associated with inpatient stroke and treatment characteristics may help with preventing stroke outcomes. The aim of this study was to report the incidence, risk factors and treatment characteristics of inpatient stroke outcomes in patients diagnosed with BCVI at an adult level 1 trauma centre.Methods All patients from Alfred Health Trauma Registry who presented from January 2014 to June 2021 and recorded to have BCVI were included in the study. Patient and trauma characteristics, clinical measures on admission and grades of vessel injuries were recorded. Choice and duration of treatment and inpatient stroke outcomes were also extracted.Results There were 300 BCVI patients during the study period and 56 patients had stroke on arrival. Of the remaining 244 patients, 24 patients had stroke during admission and thus the incidence of inpatient stroke in BCVI patients was 9.8%. Eighteen patients died during admission, of which five patients had stroke. Severe trauma, low Glasgow Coma Scale and higher grade BCVIs were associated with the increased risk of ischaemic stroke. Anti-thrombotic therapy was associated with reduced stroke outcomes.Conclusions The incidence of inpatient stroke in BCVI patients is high and potentially preventable. The risk of stroke was highest in the first 72 h and associated with several high-risk features. Blunt cerebrovascular injuries involving these high-risk features should alert the clinician to strongly consider initiating anti-thrombotic therapy. Early anti-thrombotic therapy may reduce stroke outcomes although often challenged by concurrent bleeding risks.

Introduction: Hematoma expansion (HE) is strongly associated with mortality and disability in intracerebral hemorrhage (ICH). While it is accepted that the majority of this expansion occurs early after onset, there is limited data on HE and associations with outcome in the ultra-early time window (within 3 hours of symptom onset). We aimed to (a) estimate the incidence of HE within the ultra-early period of ICH, (b) describe hematoma growth dynamics over time, and (c) investigate the associations between ultra-early HE and clinical outcomes after ICH. Methods: We performed a planned secondary analysis of the STOP-MSU international multicenter randomized controlled trial. The trial compared tranexamic acid (TXA) with placebo in 201 patients with primary ICH presenting within 2 hours of symptom onset. Repeat CT imaging 1 hour after treatment commencement was optional, and patients who underwent this ultra-early re-imaging were included in this descriptive study. Hematoma expansion was defined as growth by either >33% or >6ml from the baseline hematoma volume. Results: We included 105 patients with ultra-early re-imaging (median age 66 years, 40% female, 53% TXA). Median time from onset to baseline imaging was 74min (IQR 56-87min), and between baseline and ultra-early re-imaging was 95min (IQR 74-132min). Forty-one patients (39%) had ultra-early HE. These patients had larger baseline hematoma volumes (15.9ml vs 9.1ml, p=0.03) and similar rates of intraventricular hemorrhage (22% vs 29.7%, p=0.38), compared to those without ultra-early HE. No effect of TXA on ultra-early HE was observed (TXA 41.1% vs placebo 36.5%, p=0.61). Of 92 patients with both ultra-early and 24 hour re-imaging available, 31 patients had ultra-early HE. Of these, 9 (29%) had further growth at 24 hours, compared to 4/61 patients (6.6%) with no ultra-early growth (p<0.01). Median hematoma growth rate significantly reduced over time compared to the onset-to-baseline imaging period (clustered median regression p<0.01) (Figure 1). Ultra-early hematoma expansion was associated with poor functional outcomes (mRS 3-6; aOR 3.87 [1.21-12.40], p=0.02) and mortality (aOR 6.16 [95% CI 2.15-17.68], p<0.01), adjusted for treatment group. Conclusions: Most hematoma growth occurs in the ultra-early period. The presence of ultra-early HE is associated with ongoing hematoma growth, poor functional outcomes and mortality, and could be a therapeutic target for clinical trials.

BACKGROUND:Rinvecalinase alfa (DM199), a recombinant form of human tissue kallikrein-1 (KLK1), aims to promote local vasodilation to ischemic brain and enhance collateral blood flow. The ReMEDy1 trial tested the safety and tolerability of rinvecalinase alfa in ischemic stroke. METHODS:ReMEDy1 was a phase II, randomized, double-blind, placebo-controlled, study conducted at 13 Australian sites. Ninety-two patients with NIH Stroke Scale (NIHSS) 6-25 were enrolled within 24 h of ischemic stroke onset. Patients were randomized 1:1 to receive rinvecalinase alfa (1 µg/kg intravenous infusion followed by 3 µg/kg subcutaneously every 3 days for 22 days) or placebo. The primary outcome was safety, assessed by adverse events (AEs) and serious adverse events (SAEs). Secondary outcomes included changes in NIHSS, modified Rankin Scale (mRS), and Barthel Index (BI) at Days 22 and 90. Post hoc analyses excluded patients who underwent endovascular therapy (EVT). RESULTS:The median age was 72, NIHSS 10, and onset-to-randomization was 19.5 h. SAEs were reported in 20/47 (43.5%) rinvecalinase alfa patients and 14/45 (31.1%) placebo patients. Most patients experienced at least one AE; the most common in the rinvecalinase alfa group were constipation (60.9%), oral candidiasis (23.9%), and nausea (17.4%). Stroke-in-evolution by Day 90 occurred in 0 (0%) rinvecalinase alfa patients versus 6 (13.3%) placebo patients; 4/6 (66.7%) placebo patients with stroke-in-evolution died. No significant differences were observed in secondary efficacy outcomes at Day 90. Post hoc analyses in patients not treated with EVT suggested a tendency toward improved excellent global outcomes with rinvecalinase alfa. CONCLUSIONS:Rinvecalinase alfa appeared to be safe and generally well-tolerated in ischemic stroke patients, with potential efficacy in reducing stroke progression. Further studies are needed to confirm efficacy and long-term benefits in patients without EVT. REGISTRATIONS:https://www. CLINICALTRIALS:gov/study/NCT03290560.

In this secondary prevention of stroke chapter, the case is made for preventing recurrent stroke by targeted evidence-based interventions founded on the aetiological cause of stroke. Lifestyle measures such as healthy eating, exercise and smoking cessation, as well as pharmacological prevention strategies are discussed. Blood pressure treatment, lipid-lowering, diabetic control, and the latest recommended antiplatelet therapy regimens are all discussed. The early management of atrial fibrillation has been updated as new trials have changed practice. Surgical and endovascular interventions for extracranial and intracranial stenosis are also outlined, including carotid endarterectomy, carotid stenting, extracranial-intracranial bypass, and intervention for vertebral artery disease.

In this opening chapter on the epidemiology and risk factors for stroke, the ‘size of the problem’ in public health terms both in the United Kingdom and worldwide is set out. Incidence, prevalence, and mortality of stroke are discussed. Epidemiological terms and definitions as applied to stroke care are reviewed and illustrated, including absolute and relative risk reduction and numbers needed to treat. This chapter also discusses aetiological subtyping of stroke which represents a syndrome caused by multiple different underlying pathologies. It ends with a comprehensive review of the major and minor modifiable and non-modifiable risk factors for stroke disease.

BACKGROUND:Mobile stroke units (MSUs) accelerate prehospital acute stroke care and improve outcomes. Both onboard and telemedicine neurologist models of care are used but have not been directly compared. METHODS:MSU-TELEMED was a randomized, open-label, blinded-endpoint trial comparing onboard neurologist care to a telemedicine care model for people presenting to an MSU with suspected stroke. MSU care was prospectively randomized by day to onboard versus telemedicine care. The primary outcome was a hierarchical composite outcome using a win-odds approach that prioritized: (1) safety, (2) scene-to-treatment-decision time, and (3) percentage of the total case time the neurologist spent in direct care (higher values denote better resource use). Every participant in each group was compared to those in the other, resulting in a "win/tie/loss" distribution for telemedicine compared to onboard. RESULTS:A total of 275 participants were assigned to telemedicine (n=135) or onboard (n=140) neurologist care groups. The primary outcome of win/tie/loss distribution favored the telemedicine model (76%/4%/20%) with an adjusted win odds of 3.5 (95% confidence interval [CI], 2.4-5.1). Safety events were similar (13% telemedicine vs. 12% onboard, risk ratio 0.9; 95% CI, 0.5-1.8). Median scene-to-treatment-decision time was 19 minutes in the telemedicine group and 13 minutes in the onboard group (adjusted difference in median time 4 minutes; 95% CI, 1.9-5.9). The median percentage of the neurologist's time directly involved in patient care was 100% in the telemedicine group and 33% in the onboard group (adjusted difference in median percentage 63 percentage points; 95% CI, 53-74). CONCLUSIONS:Compared to an onboard model, an MSU telemedicine model of care was superior based on a composite hierarchical outcome of safety, scene-to-treatment-decision time, and percentage of the neurologist's time spent in direct care. (Funded by the Sylvia and Charles Viertel Charitable Foundation and the Medical Research Future Fund "Golden Hour"; ClinicalTrials.gov number, NCT05991310.).

The STAREE randomised controlled trial of 9971 community-dwelling older adults without cardiovascular disease, diabetes or dementia is designed to compare daily 40mg atorvastatin to placebo. We present a statistical analysis plan to pre-specify the analytical approaches that will be taken when reporting the main findings from the trial. The plan describes the analysis approach for the co-primary endpoints: (a) death, dementia, and persistent physical disability; (b) major cardiovascular events; and all secondary endpoints. A pre-specified economic evaluation is also included as part of this plan. ### Competing Interest Statement Trevor Chong has received honoraria from Roche for lectures. Mark Nelson has received a speaker's fee from MEDTRONIC. Stephen Nicholls has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx and Sanofi-Regeneron and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Daiichi Sankyo, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron, Novo Nordisk, CSL Sequiris, and Vaxxinity. Sophia Zoungas receives funding from NHMRC, MRFF, and the Commonwealth Department of Health and Aged Care. She reports previous payments to institution (Monash University) from AstraZeneca, Boehringer Ingelheim, CSL Seqirus, Eli Lilly Australia, Moderna, MSD Australia, Sanofi and Novo Nordisk for participation in advisory and educational meetings. The remaining authors have no disclosures to report. ### Clinical Trial NCT02099123 ### Clinical Protocols ### Funding Statement STAREE is sponsored by Monash University and has received funding from the National Health and Medical Research Council (NHMRC APP1068146 and APP1161503) and the Heart Foundation of Australia (HF Stroke Prevention grant). STAREE MIND and STAREE HEART have been awarded NHMRC grant funding (#2006611 and #1165440). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional ethics approval has been obtained from the following: Monash University Human Research Ethics Committee (Project ID 2787 and 21528). Curtin University Human Research Ethics Committee (HR113/2015). RACGP National Research and Evaluation Ethics Committee (14 017). Tasmanian Health and Medical Research Ethics Committee (H0014918). University of Newcastle Human Research Ethics Committee (H 2016 0266). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes On completion of the trial, and after publication of the primary and secondary outcomes of the study, requests for access to de-identified data (to be provided through a secure online environment) may be submitted to the researchers located at the School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Imaging plays a key role in the investigation in stroke, both to confirm the diagnosis and rule out other causes, and also to determine the underlying aetiology. This chapter covers the different imaging techniques which are commonly used in stroke care. It discusses the use of computed tomography and magnetic resonance imaging in diagnosis of both ischaemic and haemorrhagic stroke. It also covers the various angiographic imaging techniques that can be used to identify the presence of extra- and intracranial stenoses.

Clinical examination identifies the neuroanatomical deficit. This chapter provides a reference as to how to perform the neurological examination in a suspected stroke patient. It also covers assessment of conscious level and cognition and the key features of the systemic examination.