Learning together for better health using an evidence-based Learning Health System framework: a case study in stroke.

BACKGROUND: In the context of expanding digital health tools, the health system is ready for Learning Health System (LHS) models. These models, with proper governance and stakeholder engagement, enable the integration of digital infrastructure to provide feedback to all relevant parties including clinicians and consumers on performance against best practice standards, as well as fostering innovation and aligning healthcare with patient needs. The LHS literature primarily includes opinion or consensus-based frameworks and lacks validation or evidence of benefit. Our aim was to outline a rigorously codesigned, evidence-based LHS framework and present a national case study of an LHS-aligned national stroke program that has delivered clinical benefit. MAIN TEXT: Current core components of a LHS involve capturing evidence from communities and stakeholders (quadrant 1), integrating evidence from research findings (quadrant 2), leveraging evidence from data and practice (quadrant 3), and generating evidence from implementation (quadrant 4) for iterative system-level improvement. The Australian Stroke program was selected as the case study as it provides an exemplar of how an iterative LHS works in practice at a national level encompassing and integrating evidence from all four LHS quadrants. Using this case study, we demonstrate how to apply evidence-based processes to healthcare improvement and embed real-world research for optimising healthcare improvement. We emphasize the transition from research as an endpoint, to research as an enabler and a solution for impact in healthcare improvement. CONCLUSIONS: The Australian Stroke program has nationally improved stroke care since 2007, showcasing the value of integrated LHS-aligned approaches for tangible impact on outcomes. This LHS case study is a practical example for other health conditions and settings to follow suit.

Antithrombotic Treatment for Cervical Artery Dissection: A Systematic Review and Individual Patient Data Meta-Analysis.

Importance: Cervical artery dissection is the most common cause of stroke in younger adults. To date, there is no conclusive evidence on which antithrombotic therapy should be used to treat patients. Objective: To perform an individual patient data meta-analysis of randomized clinical trials comparing anticoagulants and antiplatelets in prevention of stroke after cervical artery dissection. Data Sources: PubMed.gov, Cochrane database, Embase, and ClinicalTrials.gov were searched from inception to August 1, 2023. Study Selection: Randomized clinical trials that investigated the effectiveness and safety of antithrombotic treatment (antiplatelets vs anticoagulation) in patients with cervical artery dissection were included in the meta-analysis. The primary end point was required to include a composite of (1) any stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up. Data Extraction/Synthesis: Two independent investigators performed a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and inconsistencies were resolved by a principal investigator. Main Outcomes and Measures: The primary outcome was a composite of (1) ischemic stroke, (2) death, or (3) major bleeding (extracranial or intracranial) at 90 days of follow-up. The components of the composite outcome were also secondary outcomes. Subgroup analyses based on baseline characteristics with a putative association with the outcome were performed. Logistic regression was performed using the maximum penalized likelihood method including interaction in the subgroup analyses. Results: Two randomized clinical trials, Cervical Artery Dissection in Stroke Study and Cervical Artery Dissection in Stroke Study and the Biomarkers and Antithrombotic Treatment in Cervical Artery Dissection, were identified, of which all participants were eligible. A total of 444 patients were included in the intention-to-treat population and 370 patients were included in the per-protocol population. Baseline characteristics were balanced. There were fewer primary end points in those randomized to anticoagulation vs antiplatelet therapy (3 of 218 [1.4%] vs 10 of 226 [4.4%]; odds ratio [OR], 0.33 [95% CI, 0.08-1.05]; P = .06), but the finding was not statistically significant. In comparison with aspirin, anticoagulation was associated with fewer strokes (1 of 218 [0.5%] vs 10 of 226 [4.0%]; OR, 0.14 [95% CI, 0.02-0.61]; P = .01) and more bleeding events (2 vs 0). Conclusions and Relevance: This individual patient data meta-analysis of 2 currently available randomized clinical trial data found no significant difference between anticoagulants and antiplatelets in preventing early recurrent events.

Bushfire-smoke trigger hospital admissions with cerebrovascular diseases: Evidence from 2019-20 bushfire in Australia.

INTRODUCTION: Exposure to ambient air pollution is strongly associated with increased cerebrovascular diseases. The 2019-20 bushfire season in Australia burnt 5.4 million hectares of land in New South Wales alone, with smoke so severe it affected cities in Argentina, 11,000 km away. The smoke emitted by bushfires consists of both gaseous and particle components. It is important to note that exposure to particulate matter has been shown to be linked to a heightened risk of stroke, which is the primary kind of cerebrovascular illness, as well as an increased likelihood of hospitalisations and mortality. However, the available data is inadequate in terms of documenting the response of patients diagnosed with a proven cerebrovascular illness to bushfire smoke. Additionally, there is a lack of information about the health effects associated with particulate matter throughout the bushfire season and on days when smoke was present in 2019 and 2020.Therefore, we aimed to determine the effects of (i) short-term air pollution triggered by bushfires and (ii) high smoke days in increasing the daily number of hospital admissions with cerebrovascular diseases. MATERIALS AND METHODS: Hospitalisation data were accessed from the admitted patient dataset from seven local Government areas of Hunter New England Local Health District. The bushfire period was defined from 1 October 2019 to 10 February 2020, and a same period from 2018-19 as the control. High bushfire smoke days were days when the average daily concentration of particulate matter was higher than the 95th percentile of the control period. Poisson regression models and fixed effect meta-analysis were used to analyse the data. RESULTS: In total, 275 patients with cerebrovascular admissions were identified, with 147 (53.5%) during the bushfire (2019-20) and 128 (46.5%) in the control period (2018-19). There was no significant increase in daily admissions for cerebrovascular disease (Incidence Rate Ratio, IRR: 1.04; 95% CI: 0.81-1.34; p-value: 0.73), acute stroke (IRR: 1.15; 95% CI: 0.88-1.50; p-value: 0.29) or acute ischaemic stroke (IRR: 1.18; 95% CI: 0.87-1.59; p-value: 0.28), over the entire bushfire period. However, the high bushfire smoke days were associated with increased acute ischaemic stroke-related hospital admissions across lead 0-3 and the highest cumulative effect was observed with lead 0 (IRR:1.52; 95% CI: 1.01-2.29; p-value: 0.04). In addition, during the bushfire period, particulate matter, both PM10 and PM2.5 (defined as particulates that have an effective aerodynamic diameter of 10, and 2.5 microns, respectively), were also associated with increased acute ischaemic stroke admissions with a lag of 0-3 days. DISCUSSION AND CONCLUSION: The results suggested a possible association between particulate matter and high smoke days with increased hospital admissions due to acute ischaemic stroke during the recent Australian bushfire season.

Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study.

BACKGROUND: The optimal time to commence anticoagulation in patients with atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA) is unclear, with guidelines differing in recommendations. A limitation of previous studies is the focus on clinically overt stroke, rather than radiologically obvious diffusion-weighted imaging ischaemic lesions. We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1 month in patients commenced on early (<4 days) vs late (≥4 days) anticoagulation. We hypothesised that there would be fewer ischaemic lesions and more haemorrhages in the early anticoagulant group at 1-month MRI. METHODS: A prospective multicentre, observational cohort study was performed at 11 Australian stroke centres. Clinical and MRI data were collected at baseline and follow-up, with blinded imaging assessment performed by two authors. Timing of commencement of anticoagulation was at the discretion of the treating stroke physician. RESULTS: We recruited 276 patients of whom 208 met the eligibility criteria. The average age was 74.2 years (SD±10.63), and 79 (38%) patients were female. Median National Institute of Health Stroke Scale score was 5 (IQR 1-12). Median baseline ischaemic lesion volume was 5 mL (IQR 2-17). There were a greater number of new ischaemic lesions on follow-up MRI in patients commenced on anticoagulation ≥4 days after index event (17% vs 8%, p=0.04), but no difference in haemorrhage rates (22% vs 32%, p=0.10). Baseline ischaemic lesion volume of ≤5 mL was less likely to have a new haemorrhage at 1 month (p=0.02). There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of >5 mL, regardless of anticoagulation timing. CONCLUSION: Commencing anticoagulation <4 days after stroke or TIA is associated with fewer ischaemic lesions at 1 month in AF patients. There is no increased rate of haemorrhage with early anticoagulation. These results suggest that early anticoagulation after mild-to-moderate acute ischaemic stroke associated with AF might be safe, but randomised controlled studies are needed to inform clinical practice.

Development of a diagnostic support tool for predicting cervical arterial dissection in primary care.

OBJECTIVES: Cervical arterial dissection (CAD) is an important cause of stroke in young people which may be missed because early features may mimic migraine or a musculoskeletal presentation. The study aimed to develop a diagnostic support tool for early identification of CAD. DESIGN: Retrospective observational study. SETTING: Tertiary hospital. PARTICIPANTS: Radiologically confirmed CAD cases (n = 37), non-CAD stroke cases (n = 20), and healthy controls (n = 100). MAIN OUTCOME MEASURES: The presence of CAD is confirmed with imaging. Predictive variables included risk factors and clinical characteristics of CAD. Variables with a p-value <0.2 included in a multivariable model. Predictive utility of the model is assessed by calculating area underthe ROC curve (AUC). RESULTS: The model including four variables: age 40-55 years (vs < 40), trauma, recent onset headache, and > 2 neurological features, demonstrated excellent discrimination: AUC of 0.953 (95% CI: 0.916, 0.987). A predictive scoring system (total score/7) identified an optimal threshold of ≥ 3 points, with a sensitivity of 87% and specificity of 79%. CONCLUSIONS: The study identified a diagnostic support tool with four variables to predict increased risk of CAD. Validation in a clinical sample is needed to confirm variables and refine descriptors to enable clinicians to efficiently apply the tool.Optimum cutoff scores of ≥ 3/7 points will help identify those in whom CAD should be considered and further investigation instigated. The potential impact of the tool is to improve early recognition of CAD in those with acute headache or neck pain, thereby facilitating more timely medical intervention, preventing inappropriate treatment, and improving patient outcomes.Wordcount: 3195.

Role of cardiac computed tomography in hyperacute stroke assessment.

BACKGROUND: Incorporating cardiac CT with hyperacute stroke imaging may increase the yield for cardioembolic sources. It is not clarified whether stroke severity influences on rates of intracardiac thrombus. We aimed to investigate a National Institutes of Health Stroke Scale (NIHSS) threshold below which acute cardiac CT was unnecessary. METHODS: Consecutive patients with suspected stroke who underwent multimodal brain imaging and concurrent non-gated cardiac CT with delayed timing were prospectively recruited from 1st December 2020 to 30th November 2021. We performed receiver operating characteristics analysis of the NIHSS and intracardiac thrombus on hyperacute cardiac CT. RESULTS: A total of 314 patients were assessed (median age 69 years, 61% male). Final diagnoses were ischemic stroke (n=205; 132 etiology-confirmed stroke, independent of cardiac CT and 73 cryptogenic), transient ischemic attack (TIA) (n=21) and stroke-mimic syndromes (n=88). The total yield of cardiac CT was 8 intracardiac thrombus and 1 dissection. Cardiac CT identified an intracardiac thrombus in 6 (4.5%) with etiology-confirmed stroke, 2 (2.7%) with cryptogenic stroke, and none in patients with TIA or stroke-mimic. All of those with intracardiac thrombus had NIHSS ≥4 and this was the threshold below which hyperacute cardiac CT was not justified (sensitivity 100%, specificity 38%, positive predictive value 4.0%, negative predictive value 100%). CONCLUSIONS: A cutoff NIHSS ≥4 may be useful to stratify patients for cardiac CT in the hyperacute stroke setting to optimize its diagnostic yield and reduce additional radiation exposure.

TACTICS VR Stroke Telehealth Virtual Reality Training for Health Care Professionals Involved in Stroke Management at Telestroke Spoke Hospitals: Module Design and Implementation Study.

BACKGROUND: Stroke management in rural areas is more variable and there is less access to reperfusion therapies, when compared with metropolitan areas. Delays in treatment contribute to worse patient outcomes. To improve stroke management in rural areas, health districts are implementing telestroke networks. The New South Wales Telestroke Service provides neurologist-led telehealth to 23 rural spoke hospitals aiming to improve treatment delivery and patient outcomes. The training of clinical staff was identified as a critical aspect for the successful implementation of this service. Virtual reality (VR) training has not previously been used in this context. OBJECTIVE: We sought to develop an evidence-based VR training module specifically tailored for stroke telehealth. During implementation, we aimed to assess the feasibility of workplace deployment and collected feedback from spoke hospital staff involved in stroke management on training acceptability and usability as well as perceived training impact. METHODS: The TACTICS VR Stroke Telehealth application was developed with subject matter experts. During implementation, both quantitative and qualitative data were documented, including VR use and survey feedback. VR hardware was deployed to 23 rural hospitals, and use data were captured via automated Wi-Fi transfer. At 7 hospitals in a single local health district, staff using TACTICS VR were invited to complete surveys before and after training. RESULTS: TACTICS VR Stroke Telehealth was deployed to rural New South Wales hospitals starting on April 14, 2021. Through August 20, 2023, a total of 177 VR sessions were completed. Survey respondents (n=20) indicated a high level of acceptability, usability, and perceived training impact (eg, accuracy and knowledge transfer; mean scores 3.8-4.4; 5=strongly agree). Furthermore, respondents agreed that TACTICS VR increased confidence (13/18, 72%), improved understanding (16/18, 89%), and improved awareness (17/18, 94%) regarding stroke telehealth. A comparison of matched pre- and posttraining responses revealed that training improved the understanding of telehealth workflow practices (after training: mean 4.2, SD 0.6; before training: mean 3.2, SD 0.9; P<.001), knowledge on accessing stroke telehealth (mean 4.1, SD 0.6 vs mean 3.1, SD 1.0; P=.001), the awareness of stroke telehealth (mean 4.1, SD 0.6 vs mean 3.4, SD 0.9; P=.03), ability to optimally communicate with colleagues (mean 4.2, SD 0.6 vs mean 3.7, SD 0.9; P=.02), and ability to make improvements (mean 4.0, SD 0.6 vs mean 3.5, SD 0.9; P=.03). Remote training and deployment were feasible, and limited issues were identified, although uptake varied widely (0-66 sessions/site). CONCLUSIONS: TACTICS VR Stroke Telehealth is a new VR application specifically tailored for stroke telehealth workflow training at spoke hospitals. Training was considered acceptable, usable, and useful and had positive perceived training impacts in a real-world clinical implementation context. Additional work is required to optimize training uptake and integrate training into existing education pathways.

Management of Poststroke Hyperglycemia: Results of the TEXAIS Randomized Clinical Trial.

BACKGROUND: Hyperglycemia in acute ischemic stroke reduces the efficacy of stroke thrombolysis and thrombectomy, with worse clinical outcomes. Insulin-based therapies are difficult to implement and may cause hypoglycemia. We investigated whether exenatide, a GLP-1 (glucagon-like peptide-1) receptor agonist, would improve stroke outcomes, and control poststroke hyperglycemia with minimal hypoglycemia. METHODS: The TEXAIS trial (Treatment With Exenatide in Acute Ischemic Stroke) was an international, multicenter, phase 2 prospective randomized clinical trial (PROBE [Prospective Randomized Open Blinded End-Point] design) enrolling adult patients with acute ischemic stroke ≤9 hours of stroke onset to receive exenatide (5 µg BID subcutaneous injection) or standard care for 5 days, or until hospital discharge (whichever sooner). The primary outcome (intention to treat) was the proportion of patients with ≥8-point improvement in National Institutes of Health Stroke Scale score (or National Institutes of Health Stroke Scale scores 0-1) at 7 days poststroke. Safety outcomes included death, episodes of hyperglycemia, hypoglycemia, and adverse event. RESULTS: From April 2016 to June 2021, 350 patients were randomized (exenatide, n=177, standard care, n=173). Median age, 71 years (interquartile range, 62-79), median National Institutes of Health Stroke Scale score, 4 (interquartile range, 2-8). Planned recruitment (n=528) was stopped early due to COVID-19 disruptions and funding constraints. The primary outcome was achieved in 97 of 171 (56.7%) in the standard care group versus 104 of 170 (61.2%) in the exenatide group (adjusted odds ratio, 1.22 [95% CI, 0.79-1.88]; P=0.38). No differences in secondary outcomes were observed. The per-patient mean daily frequency of hyperglycemia was significantly less in the exenatide group across all quartiles. No episodes of hypoglycemia were recorded over the treatment period. Adverse events of mild nausea and vomiting occurred in 6 (3.5%) exenatide patients versus 0 (0%) standard care with no withdrawal. CONCLUSIONS: Treatment with exenatide did not reduce neurological impairment at 7 days in patients with acute ischemic stroke. Exenatide did significantly reduce the frequency of hyperglycemic events, without hypoglycemia, and was safe to use. Larger acute stroke trials using GLP-1 agonists such as exenatide should be considered. REGISTRATION: URL: www.australianclinicaltrials.gov.au; Unique identifier: ACTRN12617000409370. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03287076.

Effect of short-term exposure to air pollution on daily cardio- and cerebrovascular hospitalisations in areas with a low level of air pollution.

Exposure to air pollution is associated with increased cardio- and cerebrovascular diseases. However, the evidence regarding the short-term effect of air pollution on cardio- and cerebrovascular hospitalisations in areas with relatively low air pollution levels is limited. This study aims to examine the effect of short-term exposure to different air pollutants on hospital admissions due to cardio- and cerebrovascular diseases in rural and regional Australia with low air pollution. The study was conducted in five local Government areas of Hunter New England Local Health District (HNE-LHD). Hospitalisation data from January 2018 to February 2020 (820 days) were accessed from the HNE-LHD admitted patients' dataset. Poisson regression model was used to examine the association between the exposure (air pollutants) and outcome variables (hospitalisation due to cardio- and cerebrovascular disease). The concentrations of gaseous air pollutants, Sulphur Dioxide (SO2), Nitrogen Dioxide (NO2), Ozone (O3), Carbon Monoxide (CO), and Ammonia (NH3) were below national benchmark concentrations for every day of the study period. In single pollutant models, SO2 and NO2 significantly increased the daily number of cardio- and cerebrovascular hospitalisations. The highest cumulative effect for SO2 was observed across lag 0-3 days (Incidence Rate Ratio, IRR: 1.77; 95% Confidence Interval, CI: 1.18-2.65; p-value: 0.01), and for NO2, it was across lag 0-2 days (IRR: 1.13; 95% CI: 1.02-1.25; p-value: 0.02). In contrast, higher O3 was associated with decreased cardio- and cerebrovascular hospitalisations, with the largest effect observed at lag 0 (IRR: 0.94; 95% CI: 0.89-0.98; p-value: 0.02). In the multi-pollutant model, the effect of NO2 remained significant at lag 0 and corresponded to a 21% increase in cardio- and cerebrovascular hospitalisation (95% CI: 1-44%; p-value = 0.04). Thus, the study revealed that gaseous air pollutants, specifically NO2, were positively related to increased cardio- and cerebrovascular hospitalisations, even at concentrations below the national standards.

Translation of nurse-initiated protocols to manage fever, hyperglycaemia and swallowing following stroke across Europe (QASC Europe): A pre-test/post-test implementation study.

Introduction: Poor adoption of stroke guidelines is a problem internationally. The Quality in Acute Stroke Care (QASC) trial demonstrated significant reduction in death and disability with facilitated implementation of nurse-initiated. Methods: This was a multi-country, multi-centre, pre-test/post-test study (2017-2021) comparing post implementation data with historically collected pre-implementation data. Hospital clinical champions, supported by the Angels Initiative conducted multidisciplinary workshops discussing pre-implementation medical record audit results, barriers and facilitators to FeSS Protocol implementation, developed action plans and provided education, with ongoing support co-ordinated remotely from Australia. Prospective audits were conducted 3-month after FeSS Protocol introduction. Pre-to-post analysis and country income classification comparisons were adjusted for clustering by hospital and country controlling for age/sex/stroke severity. Results: Data from 64 hospitals in 17 countries (3464 patients pre-implementation and 3257 patients post-implementation) showed improvement pre-to-post implementation in measurement recording of all three FeSS components, all p < 0.0001: fever elements (pre: 17%, post: 51%; absolute difference 33%, 95% CI 30%, 37%); hyperglycaemia elements (pre: 18%, post: 52%; absolute difference 34%; 95% CI 31%, 36%); swallowing elements (pre: 39%, post: 67%; absolute difference 29%, 95% CI 26%, 31%) and thus in overall FeSS Protocol adherence (pre: 3.4%, post: 35%; absolute difference 33%, 95% CI 24%, 42%). In exploratory analysis of FeSS adherence by countries' economic status, high-income versus middle-income countries improved to a comparable extent. Discussion and conclusion: Our collaboration resulted in successful rapid implementation and scale-up of FeSS Protocols into countries with vastly different healthcare systems.

Machine learning segmentation of core and penumbra from acute stroke CT perfusion data.

Introduction: Computed tomography perfusion (CTP) imaging is widely used in cases of suspected acute ischemic stroke to positively identify ischemia and assess suitability for treatment through identification of reversible and irreversible tissue injury. Traditionally, this has been done via setting single perfusion thresholds on two or four CTP parameter maps. We present an alternative model for the estimation of tissue fate using multiple perfusion measures simultaneously. Methods: We used machine learning (ML) models based on four different algorithms, combining four CTP measures (cerebral blood flow, cerebral blood volume, mean transit time and delay time) plus 3D-neighborhood (patch) analysis to predict the acute ischemic core and perfusion lesion volumes. The model was developed using 86 patient images, and then tested further on 22 images. Results: XGBoost was the highest-performing algorithm. With standard threshold-based core and penumbra measures as the reference, the model demonstrated moderate agreement in segmenting core and penumbra on test images. Dice similarity coefficients for core and penumbra were 0.38 ± 0.26 and 0.50 ± 0.21, respectively, demonstrating moderate agreement. Skull-related image artefacts contributed to lower accuracy. Discussion: Further development may enable us to move beyond the current overly simplistic core and penumbra definitions using single thresholds where a single error or artefact may lead to substantial error.

Prior anticoagulation and bridging thrombolysis improve outcomes in patients with atrial fibrillation undergoing endovascular thrombectomy for anterior circulation stroke.

BACKGROUND: Where stroke occurs with pre-existing atrial fibrillation (AF)studies validating the safety and efficacy of bridging thrombolysis, and the use of endovascular thrombectomy (EVT) in the setting of prior anticoagulation, are limited to single-center reports. METHODS: In a retrospective analysis, AF patients undergoing EVT for anterior circulation large vessel occlusion stroke enrolled in a prospectively-maintained, international multicenter database (International Stroke Perfusion Imaging Registry (INSPIRE)) between 2016 and 2019 were studied. Patients were categorized by anticoagulation status: anticoagulated (warfarin/non-vitamin K oral anticoagulants) versus not anticoagulated. Patients not anticoagulated were further divided into intravenous thrombolysis versus no thrombolysis. Outcomes compared between groups included 90-day modified Rankin Scale, 90-day mortality, rates of symptomatic intracerebral hemorrhage (sICH), and good reperfusion (modified Thrombolysis In Cerebral Infarction (mTICI) 2b-3). RESULTS: Of 563 AF patients, 118 (21%) were on anticoagulation. AF patients on anticoagulation showed improved 90-day functional outcomes (adjusted odds ratio (aOR) 1.68, 95% confidence interval (95% CI) 1.00 to 2.82). Mortality (26.3% vs 23.8%), sICH (4.5% vs 3.9%), and rates of good reperfusion (91.3% vs 88.0%) were similar between those anticoagulated and those not anticoagulated. Thrombolysis before EVT in AF patients was independently associated with improved 90-day functional outcomes (aOR 1.81, 95% CI 1.18 to 2.79) and reduced mortality (aOR 0.51, 95% CI 0.31 to 0.84), with similar sICH rates (3.4% vs 4.5%). CONCLUSIONS: Anticoagulated patients with AF who underwent EVT had improved 90-day functional outcomes and similar sICH rates. Thrombolysis before EVT in AF patients was associated with improved 90-day functional outcomes and reduced mortality.

Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36 h. Mean achieved systolic blood pressures over 1-24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36 h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Tenecteplase versus alteplase for stroke thrombolysis evaluation (TASTE): A multicentre, prospective, randomized, open-label, blinded-endpoint, controlled phase III non-inferiority trial protocol.

RATIONALE: Alteplase is the only approved thrombolytic agent for acute stroke. An alternative plasminogen activator, tenecteplase, has been previously shown to increase early biological effectiveness (reperfusion) resulting in early clinical recovery in acute stroke patients with target mismatch on perfusion imaging; however, phase III data are lacking. AIM AND HYPOTHESIS: In this study, we assess the efficacy and safety of tenecteplase compared to alteplase in acute stroke patients with target mismatch on perfusion imaging. METHODS AND DESIGN: Tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) for Stroke Thrombolysis Evaluation (TASTE) is a multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE), controlled phase III non-inferiority trial (2 arms with 1:1 randomization) with an adaptive sample size re-estimation in patients with acute ischemic stroke meeting target mismatch criteria on perfusion imaging. SAMPLE SIZE ESTIMATES: Recruiting 728 patients (1:1 tenecteplase vs alteplase) would yield 90% power (two-sided alpha 0.05) to detect a treatment effect of 8% (26% modified Rankin scale (mRS) 0-1 in alteplase arm and 34% mRS 0-1 in tenecteplase arm), with an absolute non-inferiority margin of 3%. Following the pre-planned "promising zone" adaptive sample size re-estimation, the final sample size was set at 832 patients. STUDY OUTCOMES: The primary outcome measure is the proportion of patients with an mRS score of 0-1 at 3 months. Secondary outcomes include the categorical shift in mRS at 3 months; the proportion of patients with: mRS 0-2, 5-6, and 6; reduction of the National Institutes of Health Stroke Scale (NIHSS) by 8 or more points or reaching 0-1 at 24 h; symptomatic intracerebral hemorrhage within 36 h; and death. DISCUSSION: This pivotal trial will provide important data on the role of tenecteplase in acute ischemic stroke, and the use of imaging-based treatment decision-making for stroke thrombolysis. CLINICAL TRIAL PROTOCOL: Trial Registration: ACTRN12613000243718, EudraCT 2015-002657-36.

From Hair to the Brain: The Short-Term Therapeutic Potential of Human Hair Follicle-Derived Stem Cells and Their Conditioned Medium in a Rat Model of Stroke.

The short-term therapeutic impacts of stem cells and their derivatives were frequently reported in preclinical investigations of ischemic stroke (IS); however, several drawbacks including accessibility, abundancy, and ethical concerns limited their clinical application. We describe here for the first time the therapeutic potential of human hair follicle-derived stem cells (hHFSCs) and their conditioned medium (CM) in a rat model of IS. Furthermore, we hypothesized that a combination of cell therapy with repeated CM administration might enhance the restorative efficiency of this approach compared to each treatment alone. Middle cerebral artery occlusion was performed for 30 min to induce IS. Immediately after reperfusion, hHFSCs were transplanted through the intra-arterial route and/or hHFSC-CM administered intranasally. The neurological outcomes, short-term spatial working memory, and infarct size were evaluated. Furthermore, relative expression of seven target genes in three categories of neuronal markers, synaptic markers, and angiogenic markers was assessed. The hHFSCs and hHFSC-CM treatments improved neurological impairments and reduced infarct size in the IS rats. Moreover, molecular data elucidated that IS was accompanied by attenuation in the expression of neuronal and synaptic markers in the evaluated brain regions and the interventions rescued these expression changes. Although there was no considerable difference between hHFSCs and hHFSC-CM treatments in the improvement of neurological function and decrement of infarct size, combination therapy was more effective to reduce infarction and elevation of target gene expression especially in the hippocampus. These findings highlight the curative potential of hHFSCs and their CM in a rat model of IS.

Modelling the Long-Term Health Outcome and Costs of Thrombectomy in Treating Stroke Patients with Large Ischaemic Core: Comparison between Clinical Trials and Real-World Data.

INTRODUCTION: We aimed to assess the long-term health outcomes and costs of endovascular thrombectomy (EVT) using clinical trials and real-world evidence in patients with large ischaemic core. METHODS: Both clinical trials and the INternational Stroke Perfusion Imaging REgistry (INSPIRE) were used. Patients with acute computed tomography perfusion scan with an ischaemic core of ≥70 mL were included. A Markov model was constructed to simulate the long-term costs and health outcomes (quality-adjusted life year) post-index stroke. Effectiveness of EVT (modified Rankin scale score at 3 months) was derived from the trials and INSPIRE registry (compared to matched patients not treated with EVT), respectively. RESULTS: Based on the trial and real-world data, the overall results revealed varied health benefits and costs due to EVT, with reduced health benefits and increased costs from EVT treatment in everyday practice. The long-term simulation estimated that offering EVT to large vessel occlusion stroke patients with large ischaemic core was associated with greater benefits (1.12 vs. 0.25 quality-adjusted life year gains) and lower (-A$19,320) or higher costs (A$11,278), using trial and real-world data, respectively. The incremental cost of the EVT procedure (i.e., A$14,356) could be primarily offset to a different extent by the reduction in costs related to the nursing home care (-$31,986 vs. -A$1,874) in the clinical trial and real-world practice. CONCLUSIONS: Our results highlight the potential gaps when implementing an effective intervention in the real world and the importance of the rigorous selection of large infarct core patients for EVT.

Ultra-Long Transfers for Endovascular Thrombectomy-Mission Impossible?: The Australia-New Zealand Experience.

BACKGROUND: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. METHODS: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). RESULTS: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P<0.01). CONCLUSIONS: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of poststroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age." We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of patients with stroke will be associated with cardiovascular risk factors and worse functional outcomes. METHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison with chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs and a logistic regression model of favorable functional outcomes taking RBA as input. RESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age = 62.8 years, 42.0% female patients). T2-FLAIR radiomics predicted chronological ages (mean absolute error = 6.9 years, r = 0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted odds ratios: 0.58, 0.76, 0.48, 0.55; all p-values < 0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. DISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older-appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.

Rural versus metropolitan comparison of processes of care in the community-based management of TIA and minor stroke in Australia (an analysis from the INSIST study).

OBJECTIVES: To compare processes of care and clinical outcomes of community-based management of TIAs and minor strokes (TIAMS) between rural and metropolitan Australia. DESIGN: Inception cohort study between 2012 and 2016 with 12-month follow-up after index event (sub-study of INSIST). SETTING: Hunter and Manning valley regions of New South Wales, within the referral territory of the John Hunter Hospital Acute Neurovascular Clinic (JHHANC). PARTICIPANTS: Consecutive patients of 16 participating general practices, presenting with possible TIAMS to either primary or secondary care. MAIN OUTCOME MEASURES: Processes of care (referrals, key management processes, time-based metrics) and clinical outcomes. RESULTS: Of 613 participants with possible TIAMS who completed the baseline interview, 298 were adjudicated as having TIAMS (119 from rural, 179 from metropolitan). Mean age was 72.3 years (SD, 10.7) and 127 (43%) were women. Rural participants were more likely to be managed solely by a general practitioner (GP) than metropolitan participants (34% v 20%) and less likely to be referred to a JHHANC specialist (13% v 38%) or have brain magnetic resonance imaging (MRI) [24% v 51%]. Those rural participants who were referred, also waited longer (both p < 0.001). Recurrent stroke, myocardial infarction and death at 12 months were not significantly different between rural and metropolitan participants. CONCLUSIONS: Although TIAMS prognosis in rural settings where solely GP care is common is very good, the processes of care in such areas are inferior to metropolitan. This suggests there is further scope to support rural GPs to optimise care of TIAMS patients.