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Purpose. To summarize qualitative studies from the last decade that focus on experiences of caring for stroke survivors and to describe challenges, satisfactions and coping strategies. Methods. A systematic review of qualitative studies identified from English language medicine, nursing and psychology databases from 1996-2006 was undertaken. Results. Seventeen qualitative studies fitting the inclusion and exclusion criteria, mostly from the USA, were identified. All used carer interviews. These studies corroborate the quantitative research, commonly describing difficulties including emotional responses, uncertainty and associated information and training needs. However, compared with quantitative research, qualitative studies provide a more detailed, complete picture of carers' experiences and identify additional areas including role and relationship changes, positive outcomes and coping strategies. Conclusions. Qualitative studies add significantly to our understanding of carers' experiences. Caring for stroke survivors is often challenging but focusing on the difficulties and not drawing attention to successful management strategies and satisfaction reported by carers, limits understanding and reduces the chances of providing appropriate support. Future qualitative research should consider the implications of the timing of collection more carefully and should move away from simple content or thematic analysis which tends to emphasize similarities amongst carers and should now focus on understanding carer diversity. Acknowledging this diversity should maximize the chances of providing appropriate support. [ABSTRACT FROM AUTHOR]

Purpose. Despite increasing evidence of adverse effects on informal carers of caring for stroke survivors, little is known about the characteristics of carers and survivors that influence carer outcomes. The purpose of this review is to summarize factors influencing outcomes in carers of stroke survivors. Methods. A systematic review of studies identified from English language medicine, nursing and psychology databases from 1996 - 2006 was carried out. Results. Thirty-nine studies were identified. Studies from Europe and the USA investigating negative carer outcomes dominated. Carer psychological characteristics and survivor disability were shown to influence carer outcomes. However, the diversity of carers and outcomes investigated and differences in study timing post-stroke make generalizations difficult. Conclusions. Despite improvements in study design over the last two decades, atheoretical studies employing overlapping concepts and poorly defined participants still dominate. Future studies should have theoretical underpinning and should acknowledge the diversity of carers, survivors and their situations. In addition, future emphasis on positive carer outcomes may improve understanding of protective carer factors. [ABSTRACT FROM AUTHOR]

Case report: an 83-year-old heterosexual man with malaise tested positive for HIV infection antibodies and has responded well to triple antiretroviral therapy. DISCUSSION: HIV should not be discounted on the basis of age when an elderly patient presents for the investigation of illness. [ABSTRACT FROM AUTHOR]

Purpose of Review: Recent stroke treatment advances have necessitated agile, broad-scale healthcare system redesign, to achieve optimal patient outcomes and access equity. Optimised hyperacute stroke care requires integrated pre-hospital, emergency department, stroke specialist, radiology, neurosurgical and endovascular neurointervention services, guided by a population-wide needs analysis. In this review, we survey system integration efforts, providing case studies, and identify common elements of successful initiatives., Recent Findings: Different regions and nations have evolved varied acute stroke systems depending on geography, population density and workforce. However, common facilitators to these solutions have included stroke unit care as a foundation, government-clinician synergy, pre-hospital pathway coordination, service centralisation, and stroke data guiding system improvement. Further technological advantages will minimize the geographical distance disadvantages and facilitate virtual expertise redistribution to remote areas. Continued treatment advances necessitate an integrated, adaptable, population-wide trans-disciplinary approach. A well-designed clinician-led and government-supported system can facilitate hyperacute care and scaffold future system enhancements., (© 2024. Crown.)

Rationale: A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments., Aim: Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke., Methods and Design: PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo., Study Outcomes: The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events., Sample Size Target: A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha., Discussion: PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This is an academic investigator- initiated trial:Vincent Thijs: VT reports no direct conflicts related to this publication. VT reports speaker fees for Amgen, Allergan, Astra Zeneca, Atricure, BMS, Bayer, Boehringer Ingelheim, Medtronic, unrelated to this publication. VT is on the editorial board for the following journals Annals of Neurology, Neurology, International Journal of Stroke and the European Stroke Journal. He is on the steering committee of the Librexia trial for which he receives modest compensation.Geoffrey Cloud: None Nigel Gilchrist: None Brooke Parsons: None Forum Tilvawala: None Jan Ho: NoneLara Ruthnam: None Vimal Stanislaus: None Nikola Spriggs: None Marion Walker: NonePhilip M Bath: PMB is Stroke Association Professor of Stroke Medicine and an emeritus NIHR Senior Investigator. He has consulted and received honoraria from CoMind, DiaMedica, Phagenesis and Roche.Leonid Churilov: None Julie Bernhardt: None

Background: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses., Case Presentation: A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone., Conclusion: Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties., (© 2024. Crown.)

Background: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo., Methods: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete., Findings: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98])., Interpretation: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings., Funding: Australian Government Medical Research Future Fund., Competing Interests: Declaration of interests HZ is a board member of the Pre-hospital Stroke Treatment Organization. GCC has received honoraria from AstraZeneca for lectures and advisory board participation. HM has received honoraria for lectures from the Indonesia Stroke Society Meeting and is the co-chair of the scientific committee for the Asia Pacific Stroke Conference (2024). AM has received consulting fees and participated on an advisory board for Boehringer Ingelheim, and is a member of the board of the World Stroke Organisation. AR has received grants from the Health Research Council of New Zealand, New Zealand Ministry of Health, and Australian and New Zealand Association of Neurologists; participated in a Data Safety Monitoring Board for Argenica Therapeutics; is secretary of the Australia and New Zealand Stroke Organisation; and board member of the World Stroke Organisation and New Zealand Stroke Foundation. VT has received honoraria from Boehringer Ingelheim, Bayer, and Medtronic, and participated in a Data Safety Monitoring Board for EMVision and Itreas. BY has received institutional research grants and honoraria for lectures and conference attendance from Stryker and Medtronic. LMS has received honoraria for lectures and educational materials from Biogen, Pfizer, and AbbVie, and support for conference attendance from Abbott. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals., Methods: 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke., Results: During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants., Conclusions: These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention., (© 2024. The Author(s).)

Implementation of evidence-informed rehabilitation of the upper limb is variable, and outcomes for stroke survivors are often suboptimal. We established a national partnership of clinicians, survivors of stroke, researchers, healthcare organizations, and policy makers to facilitate change. The objectives of this study are to increase access to best-evidence rehabilitation of the upper limb and improve outcomes for stroke survivors. This prospective pragmatic, knowledge translation study involves four new specialist therapy centers to deliver best-evidence upper-limb sensory rehabilitation (known as SENSe therapy) for survivors of stroke in the community. A knowledge-transfer intervention will be used to upskill therapists and guide implementation. Specialist centers will deliver SENSe therapy, an effective and recommended therapy, to stroke survivors in the community. Outcomes include number of successful deliveries of SENSe therapy by credentialled therapists; improved somatosensory function for stroke survivors; improved performance in self-selected activities, arm use, and quality of life; treatment fidelity and confidence to deliver therapy; and for future implementation, expert therapist effect and cost-effectiveness. In summary, we will determine the effect of a national partnership to increase access to evidence-based upper-limb sensory rehabilitation following stroke. If effective, this knowledge-transfer intervention could be used to optimize the delivery of other complex, evidence-based rehabilitation interventions.

Tranexamic acid (TXA) is a widely used antifibrinolytic agent that has been used since the 1960's to reduce blood loss in various conditions. TXA is a lysine analogue that competes for the lysine binding sites in plasminogen and tissue-type plasminogen activator impairing its interaction with the exposed lysine residues on the fibrin surface. The presence of TXA therefore, impairs the plasminogen and tPA engagement and subsequent plasmin generation on the fibrin surface, protecting fibrin clot from proteolytic degradation. However, critical lysine binding sites for plasmin(ogen) also exist on other proteins and on various cell-surface receptors allowing plasmin to exert potent effects on other targets that are unrelated to classical fibrinolysis, notably in relation to immunity and inflammation. Indeed, TXA was reported to significantly reduce post-surgical infection rates in patients after cardiac surgery unrelated to its haemostatic effects. This has provided an impetus to consider TXA in other indications beyond inhibition of fibrinolysis. While there is extensive literature on the optimal dosage of TXA to reduce bleeding rates and transfusion needs, it remains to be determined if these dosages also apply to blocking the non-canonical effects of plasmin., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Symptomatic intracerebral hemorrhage (sICH) commonly occurs in patients with cerebral amyloid angiopathy (CAA). Amyloid also initiates plasminogen activation and might promote sICH., Objectives: As amyloid-driven plasmin formation can be blocked by tranexamic acid (TXA), we aimed to evaluate the biodistribution and long-term consequences of TXA on brain amyloid-beta (Aβ) levels, inflammation, and neurologic function in APP/PS1 mice., Methods: APP/PS1 mice overexpressing the mutant human amyloid precursor protein and wild-type littermates were randomized to TXA (20 mg/mL) or placebo in the drinking water for 6 months. TXA in plasma and various organs was determined by liquid chromatography-mass spectrometry. Plasmin activity assays were performed to evaluate changes in fibrinolytic activity. Neurologic function was evaluated by Y-maze and parallel rod floor testing. Proximity ligation-based immunoassays were used to quantitate changes of 92 biomarkers of inflammation. Brain Aβ levels were assessed by immunohistochemistry., Results: Long-term oral TXA administration inhibited fibrinolysis. TXA accumulated in the kidney (19.4 ± 11.2 μg/g) with 2- to 5-fold lower levels seen in the lung, spleen, and liver. TXA levels were lowest in the brain (0.28 ± 0.01 μg/g). Over 6 months, TXA had no discernible effect on motor coordination, novelty preference, or brain Aβ levels. TXA reduced plasma levels of epithelial cell adhesion molecule and increased CCL20., Conclusion: Long-term TXA treatment does not alter brain Aβ levels or impact neurologic behavior in mice predisposed to amyloid deposition and had minor effects on the levels of inflammatory mediators. This finding supports the safety of TXA and lays the foundation for TXA as a novel treatment to reduce sICH in patients with CAA., (© 2023 The Author(s).)

Background: Neuroprotective agents have the potential to improve the outcomes of revascularisation therapies in acute ischemic stroke patients (AIS) and in those unable to receive revascularisation. Afamelanotide, a synthetic α-melanocyte stimulating hormone analogue, is a potential novel neuroprotective agent. We set out to assess the feasibility and safety of afamelanotide for the first time in AIS patients., Methods: AIS patients within 24 h of onset, with perfusion abnormality on imaging (Tmax) and otherwise ineligible for revascularisation therapies were enrolled. Afamelanotide 16 mg implants were administered subcutaneously on Day 0 (D0, day of recruitment), D1 and repeated on D7 and D8, if not well recovered. Treatment emergent adverse events (TEAEs) and neurological assessments were recorded regularly up to D42. Magnetic resonance imaging (MRI) with FLAIR sequences were also performed on D3 and D9., Results: Six patients (5 women, median age 81, median NIHSS 6) were recruited. Two patients received 4 doses and four patients received 2. One patient (who received 2 doses), suffered a fatal recurrent stroke on D9 due to a known complete acute internal carotid artery occlusion, assessed as unrelated to the study drug. There were no other local or major systemic TEAEs recorded. In all surviving patients, the median NIHSS improved from 6 to 2 on D7. The median Tmax volume on D0 was 23 mL which was reduced to a FLAIR volume of 10 mL on D3 and 4 mL on D9., Conclusions: Afamelanotide was well tolerated and safe in our small sample of AIS patients. It also appears to be associated with good recovery and radiological improvement of salvageable tissue which needs to be tested in randomized studies., Gov Identifier: NCT04962503, First posted 15/07/2021., (© 2023. The Author(s).)

Importance: Low-dose aspirin has been widely used for primary and secondary prevention of stroke. The balance between potential reduction of ischemic stroke events and increased intracranial bleeding has not been established in older individuals., Objective: To establish the risks of ischemic stroke and intracranial bleeding among healthy older people receiving daily low-dose aspirin., Design, Setting, and Participants: This secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, double-blind, placebo-controlled trial of daily low-dose aspirin was conducted among community-dwelling people living in Australia or the US. Participants were older adults free of symptomatic cardiovascular disease. Recruitment took place between 2010 and 2014, and participants were followed up for a median (IQR) of 4.7 (3.6-5.7) years. This analysis was completed from August 2021 to March 2023., Interventions: Daily 100-mg enteric-coated aspirin or matching placebo., Main Outcomes and Measures: Stroke and stroke etiology were predetermined secondary outcomes and are presented with a focus on prevention of initial stroke or intracranial bleeding event. Outcomes were assessed by review of medical records., Results: Among 19 114 older adults (10 782 females [56.4%]; median [IQR] age, 74 [71.6-77.7] years), 9525 individuals received aspirin and 9589 individuals received placebo. Aspirin did not produce a statistically significant reduction in the incidence of ischemic stroke (hazard ratio [HR], 0.89; 95% CI, 0.71-1.11). However, a statistically significant increase in intracranial bleeding was observed among individuals assigned to aspirin (108 individuals [1.1%]) compared with those receiving placebo (79 individuals [0.8%]; HR, 1.38; 95% CI, 1.03-1.84). This occurred by an increase in a combination of subdural, extradural, and subarachnoid bleeding with aspirin compared with placebo (59 individuals [0.6%] vs 41 individuals [0.4%]; HR, 1.45; 95% CI, 0.98-2.16). Hemorrhagic stroke was recorded in 49 individuals (0.5%) assigned to aspirin compared with 37 individuals (0.4%) in the placebo group (HR, 1.33; 95% CI, 0.87-2.04)., Conclusions and Relevance: This study found a significant increase in intracranial bleeding with daily low-dose aspirin but no significant reduction of ischemic stroke. These findings may have particular relevance to older individuals prone to developing intracranial bleeding after head trauma., Trial Registration: ISRCTN.org Identifier: ISRCTN83772183.

Introduction: Data on the association between chronic kidney disease (CKD) and major hemorrhage in older adults are lacking., Methods: We used data from a double-blind randomized controlled trial of aspirin in persons aged ≥ 70 years with prospective capture of bleeding events, including hemorrhagic stroke and clinically significant bleeding. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m 2 and/or urinary albumin-to-creatinine ratio (UACR) ≥ 3 mg/mmol (26.6 mg/g). We compared bleeding rates in those with and without CKD, undertook multivariable analyses, and explored effect modification with aspirin., Results: Of 19,114 participants, 17,976 (94.0%) had CKD status recorded, of whom 4952 (27.5%) had CKD. Participants with CKD had an increased rate of major bleeding events compared with those without CKD (10.4/1000 vs. 6.3/1000 person-years [py], respectively) and increased bleeding risk (risk ratio [RR] 1.60; 95% confidence interval [CI]: 1.40, 1.90 for eGFR < 60 ml/min per 1.73 m 2 ) and RR (2.10; 95% CI: 1.70, 2.50) for albuminuria. In adjusted analyses, CKD was associated with a 35% increased risk of bleeding (hazard ratio [HR] 1.37; 95% CI: 1.15, 1.62; P  < 0.001). Other risk factors were older age, hypertension, smoking, and aspirin use. There was no differential effect of aspirin on bleeding by CKD status (test of interaction P  = 0.65)., Conclusion: CKD is independently associated with an increased risk of major hemorrhage in older adults. Increased awareness of modifiable risk factors such as discontinuation of unnecessary aspirin, blood pressure control, and smoking cessation in this group is warranted., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Background: Mobile stroke units (MSUs) equipped with a CT scanner reduce time to thrombolytic treatment and improve patient outcomes. We tested the hypothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival, when compared with alteplase., Methods: The TASTE-A trial is a phase 2, randomised, open-label trial at the Melbourne MSU and five tertiary hospitals in Melbourne, VIC, Australia. Patients (aged ≥18 years) with ischaemic stroke who were eligible for thrombolytic treatment were randomly allocated in the MSU to receive, within 4·5 h of symptom onset, either standard-of-care alteplase (0·9 mg/kg [maximum 90 mg], administered intravenously with 10% as a bolus over 1 min and 90% as an infusion over 1 h), or the investigational product tenecteplase (0·25 mg/kg [maximum 25 mg], administered as an intravenous bolus over 10 s), before being transported to hospital for ongoing care. The primary outcome was the volume of the perfusion lesion on arrival at hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were modified Rankin Scale (mRS) score of 5 or 6 at 90 days, symptomatic intracerebral haemorrhage and any haemorrhage within 36 h, and death at 90 days. Assessors were masked to treatment allocation. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov, NCT04071613, and is completed., Findings: Between June 20, 2019, and Nov 16, 2021, 104 patients were enrolled and randomly allocated to receive either tenecteplase (n=55) or alteplase (n=49). The median age of patients was 73 years (IQR 61-83), and the median NIHSS at baseline was 8 (5-14). On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3-28]) than with alteplase (35 mL [18-76]; adjusted incidence rate ratio 0·55, 95% CI 0·37-0·81; p=0·0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0·70, 95% CI 0·23-2·16; p=0·54). Five (9%) patients allocated to tenecteplase and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1·12, 95% CI 0·26-4·90; p=0·88). No cases of symptomatic intracerebral haemorrhage were reported within 36 h with either treatment. Up to day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase, and eight (8%) in patients treated with alteplase., Interpretation: Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted. This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care., Funding: Melbourne Academic Centre for Health., Competing Interests: Declaration of interests All authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: In search of Kipling's six honest serving men in upper limb rehabilitation after stroke, we sought to investigate clinicians' perspective of when and where to begin therapy, how much and what therapy to provide, and who and why (or not) to provide therapy. Materials & methods: Within-participant case cross-over experiments were nested within an anonymous web-based questionnaire (21 questions, three cases). Graph theory-based voting to produce ranked ordered lists and mixed-effect logistic regression were performed., Results: In total, 225 Australian stroke clinicians responded: 53% occupational therapists, 61% working in acute/inpatient stroke setting. Most respondents indicated they did not have a protocol/expectation regarding when (62%), how much (84%) or what (60%) therapy to provide in their setting. Respondents ranked 24-h to 7-days post-stroke as the optimal time to commence therapy, and 30- to 60-min per day as the optimal dose to provide. Within-participant experiments demonstrated that greater motor recovery as time progressed increased the odds of offering therapy, while lack of motor recovery, shoulder pain, neurological decline and sole therapist reduced the odds., Conclusion: We need to develop an evidence base concerning Kipling's six honest serving men and equip clinicians with clinical decision-making skills aligned with this focus.IMPLICATIONS FOR REHABILITATIONMost clinicians did not have access to a protocol / clinical pathway which defines when, how much and what upper limb therapy to provide after stroke, which may be improved by providing individual clinicians with organisational support to make therapy decisions.To improve the personalisation of upper limb rehabilitation in clinical practice, we need to understand when and where after stroke to begin therapy, how much and what therapy to provide, as well as who and why (clinical decision-making) to provide therapy.Clinicians perceive clinical trials as successful if the therapy can demonstrate recovery that is greater than a minimal clinical important difference (MCID).

Background: Urinary and fecal incontinence are disabling impairments after stroke that can be clinically managed with electrical stimulation., Aim: The purpose of this systematic review was to determine the effectiveness of non-implanted electrical stimulation to reduce the severity of post-stroke incontinence., Summary of Review: Clinical trials of non-implanted electrical stimulation applied for the purposes of treating post-stroke incontinence were searched in MEDLINE, EMBASE, CINAHL, PEDro, and CENTRAL. From a total of 5043 manuscripts, 10 trials met the eligibility criteria ( n  = 894 subjects). Nine trials reported urinary incontinence severity outcomes enabling meta-analysis of transcutaneous electrical nerve stimulation (TENS; five trials) and electroacupuncture (four trials). Studies provide good-to-fair quality evidence that TENS commenced <3 months post-stroke has a large effect on urinary continence ( SMD  = -3.40, 95% CI -4.46 to -2.34) and a medium effect when commenced >3 months after stroke ( SMD  = -0.67, 95% CI -1.09 to -0.26). Electroacupuncture has a large effect when administered >5 times a week ( SMD  = -2.32, 95% CI -2.96 to -1.68) and a small effect when administered five times a week ( SMD  = -0.44, 95% CI -0.69 to -0.18). Only one trial reported the effect of non-implanted electrical stimulation on post-stroke fecal incontinence., Conclusions: Published trials evaluating the effect of non-implanted electrical stimulation on post-stroke incontinence are few and heterogenous. Synthesized trials suggest that early and frequent treatment using electrical stimulation is probably more effective than sham or no treatment. Further trials measuring incontinence in an objective manner are required.

Rationale: Haematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth., Methods and Design: Stopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework., Hypothesis: In patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo., Sample Size Estimates: A sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients., Intervention: Participants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo., Primary Efficacy Measure: The primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan., Discussion: We describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments., Competing Interests: Competing interests: Henry Zhao has received grant funding from the Medical Research Future Fund (Commonwealth Government of Australia). Leonid Churilov is co-chairperson of the Australasian Stroke Trials Network (unpaid). Andrew Cheung has received honoraria for lectures/presentations from Medtronic and Stryker and support for attending meetings and/or travel from Stryker. Rohan Grimley is a member of the Clinical Council, Stroke Foundation (Australia). Chung Hsu has received grants from the Ministry of Health and Welfare in Taiwan. Peter Mitchell has received institutional research grants from Stryker and Medtronic, travel support for attendance of international conferences and honoraria for speaking at symposia from Stryker, and is an executive member and immediate past president of the Australian and New Zealand Society of Neuroradiology (ANZSNR)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This paper describes an Experience-based Co-design (EBCD) project that aimed to increase patient activity within an acute stroke unit. We apply the concept of liminality to explore ways in which the EBCD process, a form of Participatory Action Research, may dilute or even dissolve social hierarchies and challenge assumptions about practices and constraints in this care setting, thereby opening up possibilities for transformation that enhances the therapeutic value of the space for patients and care providers alike. By occasioning a liminal phase of possibility for change, the work of one co-design group explored in detail here suggests that, in this process, the sociomaterial interactions involving patients, family members, staff, and the physical space are refashioned and re-inscribed in transformed 'emplaced' relationships of care., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cerebral amyloid angiopathy is a devastating cause of intracerebral hemorrhage for which there is no specific secondary stroke prevention treatment. Here we review the current literature regarding cerebral amyloid angiopathy pathophysiology and treatment, as well as what is known of the fibrinolytic pathway and its interaction with amyloid. We postulate that tranexamic acid is a potential secondary stroke prevention treatment agent in sporadic cerebral amyloid angiopathy, although further research is required.

Background and Purpose: Polygenic risk scores (PRSs) can be used to predict ischemic stroke (IS). However, further validation of PRS performance is required in independent populations, particularly older adults in whom the majority of strokes occur., Methods: We predicted risk of incident IS events in a population of 12 792 healthy older individuals enrolled in the ASPREE trial (Aspirin in Reducing Events in the Elderly). The PRS was calculated using 3.6 million genetic variants. Participants had no previous history of cardiovascular events, dementia, or persistent physical disability at enrollment. The primary outcome was IS over 5 years, with stroke subtypes as secondary outcomes. A multivariable model including conventional risk factors was applied and reevaluated after adding PRS. Area under the curve and net reclassification were evaluated., Results: At baseline, mean population age was 75 years. In total, 173 incident IS events occurred over a median follow-up of 4.7 years. When PRS was added to the multivariable model as a continuous variable, it was independently associated with IS (hazard ratio, 1.41 [95% CI, 1.20–1.65] per SD of the PRS; P<0.001). The PRS alone was a better discriminator for IS events than most conventional risk factors. PRS as a categorical variable was a significant predictor in the highest tertile (hazard ratio, 1.74; P=0.004) compared with the lowest. The area under the curve of the conventional model was 66.6% (95% CI, 62.2–71.1) and after inclusion of the PRS, improved to 68.5 ([95% CI, 64.0–73.0] P=0.095). In subgroup analysis, the continuous PRS remained an independent predictor for large vessel and cardioembolic stroke subtypes but not for small vessel stroke. Reclassification was improved, as the continuous net reclassification index after adding PRS to the conventional model was 0.25 (95% CI, 0.17–0.43)., Conclusions: PRS predicts incident IS in a healthy older population but only moderately improves prediction over conventional risk factors., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Background: Limb-shaking transient ischaemic attacks (TIAs) are an under recognised presentation of severe cerebrovascular disease resulting from cerebral hypoperfusion. Patients present with jerking, transitory limb movements precipitated by change in position or exercise that are often confused with seizure. Cerebral perfusion imaging studies are an important tool available to aid diagnosis., Case Presentation: We present the case of a young female who developed limb-shaking TIA in the context of progressive severe intracranial atherosclerotic disease (ICAD). Previous cortical infarction raised suspicion for seizure as a cause of her symptoms. However, single photon emission CT (SPECT) with CT acetazolamide challenge identified severe left hemisphere cerebral hypoperfusion and a diagnosis of limb-shaking TIA was made. Symptoms improved with maximal medical management., Conclusions: This case highlights the importance of cerebral perfusion imaging for diagnostic confirmation as well as therapeutic options available to alleviate symptoms and reduce stroke risk in patients with limb-shaking TIA.

Background: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking., Objective: Compare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people., Design: Prospective cohort study., Setting: Primary care (Australia and USA)., Participants: 19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100., Measurements: Baseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition., Results: At baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications., Limitations: Residual confounding and reverse causality are possible. Assessment of dose or duration was not possible., Conclusions: High anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.

We present information on acute stroke care for the first wave of the COVID-19 pandemic in Australia using data from the Australian Stroke Clinical Registry (AuSCR). The first case of COVID-19 in Australia was recorded in late January 2020 and national restrictions to control the virus commenced in March. To account for seasonal effects of stroke admissions, patient-level data from the registry from January to June 2020 were compared to the same period in 2019 (historical-control) from 61 public hospitals. We compared periods using descriptive statistics and performed interrupted time series analyses. Perceptions of stroke clinicians were obtained from 53/72 (74%) hospitals participating in the AuSCR (80% nurses) via a voluntary, electronic feedback survey. Survey data were summarized to provide contextual information for the registry-based analysis. Data from the registry covered locations that had 91% of Australian COVID-19 cases to the end of June 2020. For the historical-control period, 9,308 episodes of care were compared with the pandemic period (8,992 episodes). Patient characteristics were similar for each cohort (median age: 75 years; 56% male; ischemic stroke 69%). Treatment in stroke units decreased progressively during the pandemic period (control: 76% pandemic: 70%, p < 0.001). Clinical staff reported fewer resources available for stroke including 10% reporting reduced stroke unit beds. Several time-based metrics were unchanged whereas door-to-needle times were longer during the peak pandemic period (March-April, 2020; 82 min, control: 74 min, p = 0.012). Our data emphasize the need to maintain appropriate acute stroke care during times of national emergency such as pandemic management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cadilhac, Kim, Tod, Morrison, Breen, Jaques, Grimley, Jones, Cloud, Kleinig, Hillier, Castley, Lindley, Lannin, Middleton, Yan, Hill, Clissold, Mitchell, Anderson, Faux, Campbell and the AuSCR COVID-19 Reporting Consortium Group.)

The role of aspirin for primary prevention in older adults with chronic kidney disease (CKD) is unclear. Therefore, post hoc analysis of the randomized controlled trial ASPirin in Reducing Events in the Elderly (ASPREE) was undertaken comparing 100 mg of enteric-coated aspirin daily against matching placebo. Participants were community dwelling adults aged 70 years and older in Australia, 65 years and older in the United States, all free of a history of dementia or cardiovascular disease and of any disease expected to lead to death within five years. CKD was defined as present at baseline if either eGFR under 60mL/min/1.73m 2 or urine albumin to creatinine ratio 3 mg/mmol or more. In 4758 participants with and 13004 without CKD, the rates of a composite endpoint (dementia, persistent physical disability or death), major adverse cardiovascular events and clinically significant bleeding in the CKD participants were almost double those without CKD. Aspirin's effects as estimated by hazard ratios were generally similar between CKD and non-CKD groups for dementia, persistent physical disability or death, major adverse cardiovascular events and clinically significant bleeding. Thus, in our analysis aspirin did not improve outcomes in older people while increasing the risk of bleeding, with mostly consistent effects in participants with and without CKD., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage., Methods: We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636)., Findings: Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication., Interpretation: Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified., Funding: National Health and Medical Research Council, Royal Melbourne Hospital Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To determine if Victorian State of Emergency (SOE) measures to combat COVID-19 were associated with delayed presentations or management of acute stroke and acute myocardial infarction (AMI)., Methods: This was a retrospective, pre- and post-implementation study using data from an adult, tertiary cardiology and neurosciences centre with 24-h capacity for endovascular procedures. All primary presentations with acute stroke or AMI during the first 28 days of stage 2 and stage 3 SOE restrictions (26 March to 23 April 2020) were compared to an equivalent period without restrictions (26 March to 23 April 2019). The primary outcome variable was time from onset of symptoms to ED presentation., Results: There were 52 (1.6% of all ED presentations) patients who met inclusion criteria during the SOE period and 57 (1.0%) patients in the comparator period. Patients were equally matched for demographics, disease severity and prior history of stroke or AMI. Median time from symptom onset to presentation was 227 (93-1183) min during the SOE period and 342 (119-1220) min during the comparator period (P = 0.24). Among eligible patients with ischaemic stroke or ST-elevation AMI, median time to primary reperfusion intervention was 65 (37-78) min during SOE and 44 (39-60) min in the comparator period (P = 0.54). There were no differences in mortality at hospital discharge (9.6% vs 10.5%) and hospital length of stay (5.4 vs 4.3 days)., Conclusions: In the first 28 days, SOE measures to combat COVID-19 were not associated with delays in presentation or life-saving interventions for patients with acute stroke and AMI., (© 2020 Australasian College for Emergency Medicine.)

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase., Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke., Design, Setting, and Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria., Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy., Main Outcomes and Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death., Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%])., Conclusions and Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned., Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.

Neurological conditions such as traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis, and Alzheimer's disease are serious clinical problems that affect millions of people worldwide. The majority of clinical trials for these common conditions have failed, and there is a critical need to understand why treatments in preclinical animal models do not translate to patients. Many patients with these conditions are middle-aged or older, however, the majority of preclinical studies have used only young-adult animals. Considering that aging involves biological changes that are relevant to the pathobiology of neurological diseases, the lack of aged subjects in preclinical research could contribute to translational failures. This paper details how aging affects biological processes involved in neurological conditions, and reviews aging research in the context of traumatic brain injury, stroke, Parkinson's disease, epilepsy, multiple sclerosis, and Alzheimer's disease. We conclude that aging is an important, but often overlooked, factor that influences biology and outcomes in neurological conditions, and provide suggestions to improve our understanding and treatment of these diseases in aged patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Importance: Reperfusion is a key factor for clinical outcome in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (EVT) for large-vessel intracranial occlusion. However, data are scarce on the association between the time from onset and reperfusion results., Objective: To analyze the rate of reperfusion after EVT started at different intervals after symptom onset in patients with AIS., Design, Setting, and Participants: We conducted a meta-analysis of individual patient data from 7 randomized trials of the Highly Effective Reperfusion Using Multiple Endovascular Devices (HERMES) group. This is a multicenter cohort study of the intervention arm of randomized clinical trials included in the HERMES group. Patients with anterior circulation AIS who underwent EVT for M1/M2 or intracranial carotid artery occlusion were included. Each trial enrolled patients according to its specific inclusion and exclusion criteria. Data on patients eligible but not enrolled (eg, refusals or exclusions) were not available. All analyses were performed by the HERMES biostatistical core laboratory using the pooled database. Data were analyzed between December 2010 and April 2015., Main Outcomes and Measures: Successful reperfusion was defined as a modified thrombolysis in cerebral infarction score of 2b/3 at the end of the EVT procedure adjusted for age, occlusion location, pretreatment intravenous thrombolysis, and clot burden score and was analyzed in relation to different intervals (onset, emergency department arrival, imaging, and puncture) using mixed-methods logistic regression., Results: Among the 728 included patients, with a mean (SD) age of 65.4 (13.5) years and of whom 345 were female (47.4%), decreases in rates of successful reperfusion defined as a thrombolysis in cerebral infarction score of 2b/3 were observed with increasing time from admission or first imaging to groin puncture. The magnitude of effect was a 22% relative reduction (odds ratio, 0.78; 95% CI, 0.64-0.95) per additional hour between admission and puncture and a 26% relative reduction (odds ratio, 0.74; 95% CI, 0.59-0.93) per additional hour between imaging and puncture., Conclusions and Relevance: Because the probability of reperfusion declined significantly with time between hospital arrival and groin puncture, we provide additional arguments for minimizing the intervals after symptom onset in anterior circulation acute ischemic stroke.

Background and Purpose- Hyperglycemia is a negative prognostic factor after acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy (EVT) in patients with large-vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of EVT in acute stroke. Methods- Seven randomized trials compared EVT with standard care between 2010 and 2017 (HERMES Collaboration [highly effective reperfusion using multiple endovascular devices]). One thousand seven hundred and sixty-four patients with large-vessel stroke were allocated to EVT (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome (modified Rankin Scale range, 0-6; lower scores indicating less disability) at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level. Results- Median (interquartile range) serum glucose on admission was 120 (104-140) mg/dL (6.6 mmol/L [5.7-7.7] mmol/L). EVT was better than standard care in the overall pooled-data analysis adjusted common odds ratio (acOR), 2.00 (95% CI, 1.69-2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose < or >90 mg/dL (5.0 mmol/L; P=0.019 for interaction; acOR, 3.81; 95% CI, 1.73-8.41 for patients < 90 mg/dL versus 1.83; 95% CI, 1.53-2.19 for patients >90 mg/dL), and glucose < or >100 mg/dL (5.5 mmol/L; P=0.004 for interaction; acOR, 3.17; 95% CI, 2.04-4.93 versus acOR, 1.72; 95% CI, 1.42-2.08) but not between subgroups above these levels of glucose. Conclusions- EVT improved stroke outcomes compared with standard treatment regardless of glucose levels, but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100 mg/dL (5.0-5.5 mmol/L). Whether tight control of glucose improves the efficacy of EVT after large-vessel stroke warrants appropriate testing.

Objective: The Pragmatic Ischaemic Thrombectomy Evaluation (PISTE) trial was a multicentre, randomised, controlled clinical trial comparing intravenous thrombolysis (IVT) alone with IVT and adjunctive intra-arterial mechanical thrombectomy (MT) in patients who had acute ischaemic stroke with large artery occlusive anterior circulation stroke confirmed on CT angiography (CTA)., Design: Eligible patients had IVT started within 4.5 hours of stroke symptom onset. Those randomised to additional MT underwent thrombectomy using any Conformité Européene (CE)-marked device, with target interval times for IVT start to arterial puncture of <90 min. The primary outcome was the proportion of patients achieving independence defined by a modified Rankin Scale (mRS) score of 0-2 at day 90., Results: Ten UK centres enrolled 65 patients between April 2013 and April 2015. Median National Institutes of Health Stroke Scale score was 16 (IQR 13-21). Median stroke onset to IVT start was 120 min. In the intention-to-treat analysis, there was no significant difference in disability-free survival at day 90 with MT (absolute difference 11%, adjusted OR 2.12, 95% CI 0.65 to 6.94, p=0.20). Secondary analyses showed significantly greater likelihood of full neurological recovery (mRS 0-1) at day 90 (OR 7.6, 95% CI 1.6 to 37.2, p=0.010). In the per-protocol population (n=58), the primary and most secondary clinical outcomes significantly favoured MT (absolute difference in mRS 0-2 of 22% and adjusted OR 4.9, 95% CI 1.2 to 19.7, p=0.021)., Conclusions: The trial did not find a significant difference between treatment groups for the primary end point. However, the effect size was consistent with published data and across primary and secondary end points. Proceeding as fast as possible to MT after CTA confirmation of large artery occlusion on a background of intravenous alteplase is safe, improves excellent clinical outcomes and, in the per-protocol population, improves disability-free survival., Trial Registration Number: NCT01745692; Results., Competing Interests: The Trial Steering Committee was chaired by GAF (Stroke Association funded phase) and by H Markus (HTA phase). JF was the lay representative on the Trial Steering Committee and participated in all trial design and management decisions. The Data Monitoring Committee was chaired by K R Lees (Stroke Association phase) and by T Robinson (HTA phase); and included S Lewis (Stroke Association phase), J Norrie (HTA phase) and A Molyneux (throughout)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: There is no robust evidence that screening patients with acute stroke for dysphagia reduces the risk of stroke-associated pneumonia (SAP), or of how quickly it should be done after admission. We aimed to identify if delays in bedside dysphagia screening and comprehensive dysphagia assessments by a speech and language therapist (SALT) were associated with patients' risk of SAP., Methods: Nationwide, registry-based, prospective cohort study of patients admitted with acute stroke in England and Wales. Multilevel multivariable logistic regression models were fitted, adjusting for patient variables and stroke severity. The exposures were time from (1) admission to bedside dysphagia screen, and (2) admission to comprehensive dysphagia assessment., Results: Of 63 650 patients admitted with acute stroke, 55 838 (88%) had a dysphagia screen, and 24 542 (39%) a comprehensive dysphagia assessment. Patients with the longest delays in dysphagia screening (4th quartile adjusted OR 1.14, 1.03 to 1.24) and SALT dysphagia assessment (4th quartile adjusted OR 2.01, 1.76 to 2.30) had a higher risk of SAP. The risk of SAP increased in a dose-response manner with delays in SALT dysphagia assessment, with an absolute increase of pneumonia incidence of 1% per day of delay., Conclusions: Delays in screening for and assessing dysphagia after stroke, are associated with higher risk of SAP. Since SAP is one of the main causes of mortality after acute stroke, early dysphagia assessment may contribute to preventing deaths from acute stroke and could be implemented even in settings without access to high-technology specialist stroke care., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Stroke services have been centralised in several countries in recent years. Diagnosing acute stroke is challenging and a high proportion of patients admitted to stroke units are diagnosed as a non-stroke condition (stroke mimics). This study aims to describe the stroke mimic patient group, including their impact on stroke services. We analysed routine clinical data from 2,305 consecutive admissions to a stroke unit at St George's Hospital, London. Mimic groupings were derived from 335 individual codes into 17 groupings. From 2,305 admissions, 555 stroke mimic diagnoses were identified (24.2%) and 72% of stroke mimics had at least one stroke risk factor. Common mimic diagnoses were headache, seizure and syncope. Medically unexplained symptoms and decompensation of underlying conditions were also common. Median length of stay was 1 day; a diagnosis of dementia (p=0.028) or needing MRI (p=0.006) was associated with a longer stay. Despite emergency department assessment by specialist clinicians and computed tomography brain, one in four suspected stroke patients admitted to hospital had a non-stroke diagnosis. Stroke mimics represent a heterogeneous patient group with significant impacts on stroke services. Co-location of stroke and acute neurology services may offer advantages where service reorganisation is being considered., (© Royal College of Physicians 2016. All rights reserved.)

Background: Studies in many health systems have shown evidence of poorer quality health care for patients admitted on weekends or overnight than for those admitted during the week (the so-called weekend effect). We postulated that variation in quality was dependent on not only day, but also time, of admission, and aimed to describe the pattern and magnitude of variation in the quality of acute stroke care across the entire week., Methods: We did this nationwide, registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. We included all adult patients (aged >16 years) admitted to hospital with acute stroke (ischaemic or primary intracerebral haemorrhage) in England and Wales between April 1, 2013, and March 31, 2014. Our outcome measure was 30 day post-admission survival. We estimated adjusted odds ratios for 13 indicators of acute stroke-care quality by fitting multilevel multivariable regression models across 42 4-h time periods per week., Findings: The study cohort comprised 74,307 patients with acute stroke admitted to 199 hospitals. Care quality varied across the entire week, not only between weekends and weekdays, with different quality measures showing different patterns and magnitudes of temporal variation. We identified four patterns of variation: a diurnal pattern (thrombolysis, brain scan within 12 h, brain scan within 1 h, dysphagia screening), a day of the week pattern (stroke physician assessment, nurse assessment, physiotherapy, occupational therapy, and assessment of communication and swallowing by a speech and language therapist), an off-hours pattern (door-to-needle time for thrombolysis), and a flow pattern whereby quality changed sequentially across days (stroke-unit admission within 4 h). The largest magnitude of variation was for door-to-needle time within 60 min (range in quality 35-66% [16/46-232/350]; coefficient of variation 18·2). There was no difference in 30 day survival between weekends and weekdays (adjusted odds ratio 1·03, 95% CI 0·95-1·13), but patients admitted overnight on weekdays had lower odds of survival (0·90, 0·82-0·99)., Interpretation: The weekend effect is a simplification, and just one of several patterns of weekly variation occurring in the quality of stroke care. Weekly variation should be further investigated in other health-care settings, and quality improvement should focus on reducing temporal variation in quality and not only the weekend effect., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Prognosis after intracerebral hemorrhage (ICH) is poor and care-limiting decisions may worsen outcomes., Aims: To determine whether in current UK stroke practice, key acute care decisions are associated with stroke subtype (ICH/ischemic) and whether these decisions are independently associated with survival., Methods: We extracted data describing all stroke patients included in a UK quality register between 1 April 2013 and 31 March 2014. Key care decisions in our analyses were transfer to higher level care on admission and palliation in the first 72 h. We used multivariable regression models to test for associations between stroke subtype (ICH/ischemic), key care decisions, and survival., Results: A total of 65,818 patients were included in the final analysis. After ICH (n = 7020/65,818, 10.7%), 10.5% were palliated on the day of admission and 19.3% by 72 h (vs. 0.7% and 3.3% for ischemic stroke). Although a greater proportion were admitted directly to higher level care after ICH (3.7% vs. 1.5% for ischemic stroke), ICH was not independently associated with the decision to admit to higher level care (adjusted odds ratio (OR): 1.12, 95% confidence interval (95%CI): 0.95-1.31, p = 0.183). However, ICH was strongly associated with the decision to commence palliative care on the day of admission (OR: 7.27, 95%CI: 6.31-8.37, p < 0.001). Palliative care was independently associated with risk of death by 30 days regardless of stroke subtype., Conclusions: When compared to ischemic stroke, patients with ICH are much more likely to commence palliative care during the first 72 h of their care, independent of level of consciousness, age, and premorbid health., (© 2016 World Stroke Organization.)

Background and Purpose: Case mix adjustment is required to allow valid comparison of outcomes across care providers. However, there is a lack of externally validated models suitable for use in unselected stroke admissions. We therefore aimed to develop and externally validate prediction models to enable comparison of 30-day post-stroke mortality outcomes using routine clinical data., Methods: Models were derived (n=9000 patients) and internally validated (n=18 169 patients) using data from the Sentinel Stroke National Audit Program, the national register of acute stroke in England and Wales. External validation (n=1470 patients) was performed in the South London Stroke Register, a population-based longitudinal study. Models were fitted using general estimating equations. Discrimination and calibration were assessed using receiver operating characteristic curve analysis and correlation plots., Results: Two final models were derived. Model A included age (<60, 60-69, 70-79, 80-89, and ≥90 years), National Institutes of Health Stroke Severity Score (NIHSS) on admission, presence of atrial fibrillation on admission, and stroke type (ischemic versus primary intracerebral hemorrhage). Model B was similar but included only the consciousness component of the NIHSS in place of the full NIHSS. Both models showed excellent discrimination and calibration in internal and external validation. The c-statistics in external validation were 0.87 (95% confidence interval, 0.84-0.89) and 0.86 (95% confidence interval, 0.83-0.89) for models A and B, respectively., Conclusions: We have derived and externally validated 2 models to predict mortality in unselected patients with acute stroke using commonly collected clinical variables. In settings where the ability to record the full NIHSS on admission is limited, the level of consciousness component of the NIHSS provides a good approximation of the full NIHSS for mortality prediction., (© 2014 American Heart Association, Inc.)