Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

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.

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.

"Are we there yet?" expectations and experiences with lower limb robotic exoskeletons: a qualitative evaluation of the therapist perspective.

PURPOSE: Lower limb robotic exoskeletons can assist movement, however, clinical uptake in neurorehabilitation is limited. The views and experiences of clinicians are pivotal to the successful clinical implementation of emerging technologies. This study investigates therapist perspectives of the clinical use and future role of this technology in neurorehabilitation. METHODS: Australian and New Zealand-based therapists with lower limb exoskeleton experience were recruited to complete an online survey and semi-structured interview. Survey data were transposed into tables and interviews transcribed verbatim. Qualitative data collection and analysis were guided by qualitative content analysis and interview data were thematically analysed. RESULTS: Five participants revealed that the use of exoskeletons to deliver therapy involves the interplay of human elements - experiences and perspectives of use, and mechanical elements - the device itself. Two overarching themes emerged: the "journey", with subthemes of clinical reasoning and user experience; and the "vehicle" with design features and cost as subthemes, to explore the question "Are we there yet?" CONCLUSION: Therapists expressed positive and negative perspectives from their experiences with exoskeletons, giving suggestions for design features, marketing input, and cost to enhance future use. Therapists are optimistic that this journey will see lower limb exoskeletons integral to rehabilitation service delivery.

Further innovation of design features, marketing, and cost are needed to enhance ongoing development and integration.Routine clinical implementation of lower limb exoskeletons is unlikely at this time in Australia and New Zealand.Therapists do expect lower limb exoskeletons to have an ongoing role in future rehabilitation.

Secondary prevention of stroke. A telehealth-delivered physical activity and diet pilot randomized trial (ENAbLE-pilot).

BACKGROUND: Improving physical activity levels and diet quality are important for secondary stroke prevention. AIM: To test the feasibility and safety of 6-month, co-designed telehealth-delivered interventions to increase physical activity and improve diet quality. METHODS: A 2 × 2 factorial trial (physical activity (PA); diet (DIET); PA + DIET; control) randomized, open-label, blinded endpoint trial. Primary outcomes were feasibility and safety. Secondary outcomes included stroke risk factors (blood pressure, self-report PA (International Physical Activity Questionnaire (IPAQ)) and diet quality (Australian Recommended Food Score (ARFS)), and quality of life. Between-group differences were analyzed using linear-mixed models. RESULTS: Over 23 months, 99 people were screened for participation and 40 (40%) randomized (3 months to 10 years post-stroke, mean age 59 (16) years). Six participants withdrew, and an additional five were lost to follow-up. Fifteen serious adverse events were reported, but none were deemed definitely or probably related to the intervention. Median attendance was 32 (of 36) PA sessions and 9 (of 10) DIET sessions. The proportion of missing primary outcome data (blood pressure) was 3% at 3 months, 11% at 6 months, and 14% at 12 months. Between-group 95% confidence intervals showed promising, clinically relevant differences in support of the interventions across the range of PA, diet quality, and blood pressure outcomes. CONCLUSION: Our telehealth PA and diet interventions were safe and feasible and may have led to significant behavior change. TRIAL REGISTRATION: ACTRN12620000189921.

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.

Blood pressure variability is associated with Infarct Growth in Acute Ischemic Stroke.

Introduction Evidence based blood pressure (BP) targets in acute ischemic stroke are lacking. Previous observational studies have focused on single baseline BP and clinical outcomes, without consideration for dynamic changes. We aim to determine the association between BP parameters including variability, peak, nadir, median and mean during stroke and infarct growth (primary outcome), risk of haemorrhagic transformation and functional outcome (secondary outcomes). Methods Suspected stroke patients were prospectively recruited from a single comprehensive stroke centre. Multimodal computed tomography imaging was used to define infarct core. BP was recorded as per national stroke guidelines during the initial 24-hours. Infarct growth and evidence of parenchymal haemorrhage were determined by follow-up magnetic resonance imaging at 24 hours. Functional outcome at 3-months was assessed using the modified Rankin Scale. Subgroup analysis was performed according to stroke etiology and treatment for the association between BP, infarct volume growth and risk of hemorrhagic transformation. The association between BP parameters and outcomes were determined using regression modelling. Results A total of 229 patients were included in this study. The median age was 67.4, 64.4% were male and the baseline National Institutes of Health Stroke Scale was 8. Blood pressure variability (BPV) was independently associated with increased infarct growth (multivariate coefficient 1.60, 95% CI 0.27-2.94, P=0.019) and an increased odds of parenchymal haemorrhage (adjusted OR 1.21, 95% CI 1.02-1.44, P= 0.028). The odds of a favourable outcome at 90 days were inversely associated with BPV on simple, but not adjusted logistic regression. On subgroup analysis, only in patients with large vessel occlusions undergoing endovascular clot retrieval was BPV associated with infarct growth (multivariate adjusted coefficient 2.62, 95% CI 0.53-4.70, P=0.014) and an increased odds of hemorrhagic transformation (adjusted OR 1.26, 95% CI 1.01-1.57, P=0.045). Conclusions: An increase in BPV was associated with infarct expansion, increased risk of haemorrhagic transformation, and was negatively associated with favourable functional outcomes at 3-months.

Whole Blood Viscosity and Cerebral Blood Flow in Acute Ischemic Stroke.

Existing effective treatments for ischemic stroke restore blood supply to the ischemic region using thrombolysis or mechanical removal of clot. However, it is increasingly recognized that successful removal of occlusive thrombus from the large artery-recanalization, may not always be accompanied by successful restoration of blood flow to the downstream tissues-reperfusion. Ultimately, brain tissue survival depends on cerebral perfusion, and a functioning microcirculation. Because capillary diameter is often equal to or smaller than an erythrocyte, microcirculation is largely dependent on erythrocyte rheological (hemorheological) factors such as whole blood viscosity (WBV). Several studies in the past have demonstrated elevated WBV in stroke compared with healthy controls. Also, elevated WBV has shown to be an independent risk factor for stroke. Elevated WBV leads to endothelial dysfunction, decreases nitric oxide-dependent flow-mediated vasodilation, and promotes hemostatic alterations/thrombosis, all leading to microcirculation sludging. Compromised microcirculation further leads to decreased cerebral perfusion. Hence, modulating WBV through pharmacological agents might be beneficial to improve cerebral perfusion in stroke. This review discusses the effect of elevated WBV on endothelial function, hemostatic alterations, and thrombosis leading to reduced cerebral perfusion in stroke.

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.

"Wasting time": a qualitative study of stroke survivors' experiences of boredom in non-therapy time during inpatient rehabilitation.

PURPOSE: Stroke survivors regularly report experiencing boredom during inpatient rehabilitation which may detrimentally affect mood, learning and engagement in activities important for functional recovery. This study explores how stroke survivors meaningfully occupy their non-therapy time and their experiences of boredom, to further our understanding of this complex phenomenon. METHODS: Secondary analysis of transcripts from semi-structured interviews with stroke survivors exploring activity during non-therapy time. Transcripts were coded and analysed using a hybrid approach of inductive and deductive thematic analysis, guided by a published boredom framework. RESULTS: Analysis of 58 interviews of 36 males and 22 females, median age 70 years, revealed four main themes: (i) Resting during non-therapy time is valued, (ii) Managing "wasted" time, (iii) Meaningful environments support autonomy and restore a sense of normality, and (iv) Wired to be social. Whilst limited therapy, social opportunities and having "nothing to do" were common experiences, those individuals who felt in control and responsible for driving their own stroke recovery tended to report less boredom during their rehabilitation stay. CONCLUSION: Creating rehabilitation environments that support autonomy, socialisation and opportunities to participate in activity are clear targets to reduce boredom during non-therapy time, increase meaningful engagement and possibly improve rehabilitation outcomes post-stroke.

Stroke survivors with a low sense of autonomy are at greater risk of boredom and may benefit from person-centred strategies to support participation in meaningful activities during non-therapy time whilst undertaking inpatient rehabilitation.Review and reduction of paternalistic practices within traditional models of care, to increase patient autonomy, may empower stroke survivors to drive their own activity and reduce boredom.The redesign and reorganisation of rehabilitation environments to increase opportunities for socialisation and access to nature and the outdoors may reduce boredom during inpatient rehabilitation.

A method for rapid machine learning development for data mining with doctor-in-the-loop.

Classifying free-text from historical databases into research-compatible formats is a barrier for clinicians undertaking audit and research projects. The aim of this study was to (a) develop interactive active machine-learning model training methodology using readily available software that was (b) easily adaptable to a wide range of natural language databases and allowed customised researcher-defined categories, and then (c) evaluate the accuracy and speed of this model for classifying free text from two unique and unrelated clinical notes into coded data. A user interface for medical experts to train and evaluate the algorithm was created. Data requiring coding in the form of two independent databases of free-text clinical notes, each of unique natural language structure. Medical experts defined categories relevant to research projects and performed 'label-train-evaluate' loops on the training data set. A separate dataset was used for validation, with the medical experts blinded to the label given by the algorithm. The first dataset was 32,034 death certificate records from Northern Territory Births Deaths and Marriages, which were coded into 3 categories: haemorrhagic stroke, ischaemic stroke or no stroke. The second dataset was 12,039 recorded episodes of aeromedical retrieval from two prehospital and retrieval services in Northern Territory, Australia, which were coded into 5 categories: medical, surgical, trauma, obstetric or psychiatric. For the first dataset, macro-accuracy of the algorithm was 94.7%. For the second dataset, macro-accuracy was 92.4%. The time taken to develop and train the algorithm was 124 minutes for the death certificate coding, and 144 minutes for the aeromedical retrieval coding. This machine-learning training method was able to classify free-text clinical notes quickly and accurately from two different health datasets into categories of relevance to clinicians undertaking health service research.

Endovascular thrombectomy for acute ischaemic stroke improves and maintains function in the very elderly: A multicentre propensity score matched analysis.

Introduction: The very elderly (⩾80 years) are under-represented in randomised endovascular thrombectomy (EVT) clinical trials for acute ischaemic stroke. Rates of independent outcome in this group are generally lower than the less-old patients but the comparisons may be biased by an imbalance of non-age related baseline characteristics, treatment related metrics and medical risk factors. Patients and methods: We compared outcomes between very elderly (⩾80) and the less-old (<80 years) using retrospective data from consecutive patients receiving EVT from four comprehensive stroke centres in New Zealand and Australia. We used propensity score matching or multivariable logistic regression to account for confounders. Results: We included 600 patients (300 in each age cohort) after propensity score matching from an initial group of 1270 patients. The median baseline National Institutes of Health Stroke Scale was 16 (11-21), with 455 (75.8%) having symptom free pre-stroke independent function, and 268 (44.7%) receiving intravenous thrombolysis. Good functional outcome (90-day modified Rankin Scale 0-2) was achieved in 282 (46.8%), with very elderly patients having less proportion of good outcome compared to the less-old (118 (39.3%) vs 163 (54.3%), p < 0.01). There was no difference between the very elderly and the less-old in the proportion of patients who returned to baseline function at 90 days (56 (18.7%) vs 62 (20.7%), p = 0.54). All-cause 90-day mortality was higher in the very elderly (75 (25%) vs 49 (16.3%), p < 0.01), without a difference in symptomatic haemorrhage (very elderly 11 (3.7%) vs 6 (2.0%), p = 0.33). In the multivariable logistic regression models, the very elderly were significantly associated with reduced odds of good 90-day outcome (OR 0.49, 95% CI 0.34-0.69, p < 0.01) but not with return to baseline function (OR 0.85, 90% CI 0.54-1.29, p = 0.45) after adjusting for confounders. Conclusion: Endovascular thrombectomy can be successfully and safely performed in the very elderly. Despite an increase in all-cause 90-day mortality, selected very elderly patients are as likely as younger patients with similar baseline characteristics to return to baseline function following EVT.

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.

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.

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.

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.

Ischemic Lesion Growth in Patients with a Persistent Target Mismatch After Large Vessel Occlusion.

BACKGROUND: Failure to reperfuse a cerebral occlusion resulting in a persistent penumbral pattern has not been fully described. METHODS: We retrospectively reviewed patients with anterior large vessel occlusion who did not receive reperfusion, and underwent repeated perfusion imaging, with baseline imaging < 6 h after onset and follow-up scans from 16-168 h. A persistent target mismatch (PTM) was defined as core volume of < 100 mL, mismatch ratio > 1.2, and mismatch volume > 10 mL on follow-up imaging. Patients were divided into PTM or non-PTM groups. Ischemic core and penumbral volumes were compared between baseline and follow-up imaging between the two groups, and collateral flow status assessed using CT perfusion collateral index. RESULTS: A total of 25 patients (14 PTM and 11 non-PTM) were enrolled in the study. Median core volumes increased slightly in the PTM group, from 22 to 36 ml. There was a much greater increase in the non-PTM group, from 57 to 190 ml. Penumbral volumes were stable in the PTM group from a median of 79 ml at baseline to 88 ml at follow-up, whereas penumbra was reduced in the non-PTM group, from 120 to 0 ml. Collateral flow status was also better in the PTM group and the median collateral index was 33% compared with 44% in the non-PTM group (p = 0.043). CONCLUSION: Multiple patients were identified with limited core growth and large penumbra (persistent target mismatch) > 16 h after stroke onset, likely due to more favorable collateral flow.

Depression and a lack of socialization are associated with high levels of boredom during stroke rehabilitation: An exploratory study using a new conceptual framework.

This exploratory sub-study aimed to develop a framework to conceptualize boredom in stroke survivors during inpatient rehabilitation, establish the effect of an activity promotion intervention on boredom, and to investigate factors that are associated with boredom. A framework was developed and explored within a cluster non-randomised controlled trial. Self-reported boredom was measured in 160 stroke survivors 13 (±5) days after rehabilitation admission; 91 participants received usual-care (control) and 69 had access to a patient-driven model of activity promotion (intervention). Individuals with pre-existing dementia or unable to participate in standard rehabilitation were excluded. Hierarchical logistic regression analysis was used to identify demographic, health and activity measures associated with boredom. Results indicated 39% of participants were highly bored. There was no statistically significant difference in boredom levels between treatment groups (difference -11%, 95% CI -26% to 4%). The presence of depression (OR 6.17, 95% CI 2.57-14.79) and lower levels of socialization (OR 0.96, 95% CI 0.92-0.99) predicted high boredom levels. This comprehensive framework provides a foundation for understanding the many interacting factors associated with boredom. Results suggest managing depression and improving opportunities for socialization may support meaningful engagement in rehabilitation to optimize recovery following stroke.