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Thrombosis and inflammation are primary contributors to the onset and progression of ischemic stroke. The contact-kinin pathway, initiated by plasma kallikrein (PK) and activated factor XII (FXIIa), functions bidirectionally with the coagulation and inflammation cascades, providing a novel target for therapeutic drug development in ischemic stroke. In this study, we identified a bat-derived oligopeptide from Myotis myotis (Borkhausen, 1797), designated LE6 (Leu-Ser-Glu-Glu-Pro-Glu, 702 Da), with considerable potential in stroke therapy due to its effects on the contact kinin pathway. Notably, LE6 demonstrated significant inhibitory effects on PK and FXIIa, with inhibition constants of 43.97 μmol/L and 6.37 μmol/L, respectively. In vitro analyses revealed that LE6 prolonged plasma recalcification time and activated partial thromboplastin time. In murine models, LE6 effectively inhibited carrageenan-induced mouse tail thrombosis, FeCl 3 -induced carotid artery thrombosis, and photochemically induced intracerebral thrombosis. Furthermore, LE6 significantly decreased inflammation and stroke injury in transient middle cerebral artery occlusion models. Notably, the low toxicity, hemolytic activity, and bleeding risk of LE6, along with its synthetic simplicity, underscore its clinical applicability. In conclusion, as an inhibitor of FXIIa and PK, LE6 offers potential therapeutic benefits in stroke treatment by mitigating inflammation and preventing thrombus formation.

Despite the protective nature of the blood-brain barrier (BBB) and brain-protecting tissues, some types of CNS injury or stress can cause cerebral cytokine production and profound alterations in brain function. Neuroinflammation, which can also be accompanied by increased cerebral cytokine production, has a remarkable impact on the pathogenesis of many neurological illnesses, including loss of BBB integrity and ischemic stroke, yet effective treatment choices for these diseases are currently lacking. Although little is known about the brain effects of Metformin (MF), a commonly prescribed first-line antidiabetic drug, prior research suggested that it may be useful in preventing BBB deterioration and the increased risk of stroke caused by tobacco smoking (TS). Therefore, reducing neuroinflammation by escalating anti-inflammatory cytokine production and declining pro-inflammatory cytokine production could prove an effective therapeutic strategy for ischemic stroke. Hence, the current investigation was planned to explore the potential role of MF against stroke and TS-induced neuroinflammation and reactive oxygen species (ROS) production. Our studies revealed that MF suppressed releasing pro-inflammatory mediators like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) by aiming at the nuclear factor kappa B (NF-κB) signaling pathway in primary neurons and astrocytes. MF also upregulated anti-inflammatory mediators, like interleukin-10 (IL-10), and interleukin-4 (IL-4), by upregulating the Nrf2-ARE signaling pathway. Adolescent mice receiving MF along with TS exposure also showed a notable decrease in NF-κB expression compared to the mice not treated with MF and significantly decreased the level of TNF-α, IL-1β, MCP-1, and MIP-2 and increased the levels of IL-10 and IL-4 through the activation of Nrf2-ARE signaling pathway. These results suggest that MF has anti-neuroinflammatory effects via inhibiting NF-κB signaling by activating Nrf2-ARE. These studies support that MF could be a strong candidate drug for treating and or preventing TS-induced neuroinflammation and ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study assesses the safety and efficacy of tirofiban for patients with large vessel occlusion stroke after intravenous thrombolysis., Methods: This study data was from SUSTAIN, DEVT, and RESCUE BT trials. According to whether the use of tirofiban who underwent endovascular treatment and preceding intravenous thrombolysis was divided into the tirofiban group and the no-tirofiban group. The safety outcomes were symptomatic intracranial hemorrhage, any intracranial hemorrhage within 48 h, and 3-month mortality. The efficacy outcome was defined as a score of 0-2 on the modified Rankin Scale scores at 3 months., Results: A total of 372 patients with intravenous thrombolysis were included in these SUSTAIN, DEVT, and RESCUE BT trials. Adjusted multivariate analysis showed that tirofiban with intravenous thrombolysis was not associated with symptomatic intracranial hemorrhage (aOR, 0.87; 95 % CI, 0.49-1.57; P=0.65), any intracranial hemorrhage within 48 h (aOR, 1.00; 95 % CI, 0.60-1.66; P=1.00), 3-month mortality (aOR, 1.10; 95 % CI, 0.56-2.19; P=0.78) and 3-month modified Rankin Scale scores 0-2 (aOR, 0.72; 95 % CI, 0.42-1.25; P=0.25) in patients with acute large vessel occlusion. In the subgroup analysis, we found that tirofiban was not recommended for females (aOR, 0.34; 95 % CI, 0.12-0.93), baseline Alberta Stroke Program Early CT Score≤9 (aOR, 0.37; 95 % CI, 0.18-0.76), and cardiogenic embolism (aOR, 0.36; 95 % CI, 0.14-0.97)., Conclusion: Tirofiban combined with intravenous thrombolysis in patients with acute large vessel occlusion may be safe. Further studies need to confirm the effectiveness of tirofiban after intravenous thrombolysis in different stroke etiology., Competing Interests: Declaration of Competing Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Despite substantial improvement of acute ischemic stroke (AIS) care with the advent of extended time windows for intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), a substantial portion of patients still suffer poor outcomes. Additional adjuvant therapies are needed but pharmacologic interactions among therapies may dictate how they could be used. We conducted a survey to determine physician decision-making regarding the use of cytoprotective agents in patients presenting with AIS., Methods: The survey was structured, web-based, anonymous, and invite-only among physicians across the world treating patients presenting with AIS. Respondents were asked about the use of a hypothetical cytoprotective agent (that provided an added 10% benefit) in the context of a treatment interaction with IVT or its timing in relation to IVT., Results: A total of 282 stroke physicians (74.9% males, mean age 46 years) participated in the survey. When the respondent could give both the cytoprotective agent and IVT with no treatment interaction, 177 (78.0%) chose to administer both. In the presence of treatment interaction, 88 (38.3%) would withhold IVT, 83 (36.1%) would withhold the cytoprotective agent and 56 (24.4%) were uncertain. Lastly, 111 (48.9%) were willing to administer the cytoprotective agent if it meant a necessary 10-minute delay in IVT administration., Conclusions: Pharmacologic interactions result in major uncertainty about cytoprotective treatment choices., Competing Interests: Declaration of competing interest The authors have do not have any competing interests to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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

Ischemic stroke is a disease associated with high morbidity and disability rates; however, its pathogenesis remains elusive, and treatment options are limited. Ferroptosis, an iron-dependent form of cell death, represents a novel avenue for investigation. The objective of this study was to explore the role of melatonin in MCAO-induced ferroptosis and elucidate its underlying molecular mechanism. To simulate brain damage and neuronal injury caused by ischemic stroke, we established a mouse model of MCAO and an HT-22 cell model of OGD/R. The therapeutic efficacy of melatonin was assessed through measurements of infarct size, brain edema, and neurological scores. Additionally, qRT-PCR, WB analysis, and Co-IP assays were employed to investigate the impact of melatonin on ferroptosis markers such as NCOA4 and FTH1 expression levels. Confocal microscopy was utilized to confirm the colocalization between ferritin and lysosomes. Furthermore, we constructed a SIRT6 siRNA model to validate the regulatory effect exerted by SIRT6 on NCOA4 as well as their binding interaction. The present study provides initial evidence that melatonin possesses the ability to mitigate neuronal damage induced by MCAO and OGD/R. Assessment of markers for oxidative damage and ferroptosis revealed that melatonin effectively inhibits intracellular Fe2+ levels, thereby suppressing ferroptosis. Additionally, our findings demonstrate that melatonin modulates the interaction between FTH1 and NCOA4 via SIRT6, influencing ferritin autophagy without affecting cellular macroautophagy. These findings provide reliable data support for the promotion and application of melatonin in clinical practice., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Inc.)

Background and Purpose: Thrombo-inflammation is a key feature of stroke pathophysiology and provides multiple candidate drug targets. Thrombin exerts coagulation-independent actions via protease-activated receptors (PAR), of which PAR1 has been implicated in stroke-associated neuroinflammation. The role of PAR4 in this context is less clear. This study examined if the selective PAR4 antagonist ML354 provides neuroprotection in experimental stroke and explored the underlying mechanisms., Experimental Approach: Mouse primary cortical neurons were exposed to oxygen-glucose deprivation (OGD) and simulated reperfusion ± ML354. For comparison, functional Ca 2+ -imaging was performed upon acute stimulation with a PAR4 activating peptide or glutamate. Male mice underwent sham operation or transient middle cerebral artery occlusion (tMCAO), with ML354 or vehicle treatment beginning at recanalization. A subset of mice received a platelet-depleting antibody. Stroke size and functional outcomes were assessed. Abundance of target genes, proteins, and cell markers was determined in cultured cells and tissues by qPCR, immunoblotting, and immunofluorescence., Key Results: Stroke up-regulated PAR4 expression in cortical neurons in vitro and in vivo. OGD augments spontaneous and PAR4-mediated neuronal activity; ML354 suppresses OGD-induced neuronal excitotoxicity and apoptosis. ML354 applied in vivo after tMCAO reduced infarct size, apoptotic markers, macrophage accumulation, and interleukin-1β expression. Platelet depletion did not affect infarct size in mice with tMCAO ± ML354., Conclusions and Implications: Selective PAR4 inhibition during reperfusion improves infarct size and neurological function after experimental stroke by blunting neuronal excitability, apoptosis, and local inflammation. PAR4 antagonists may provide additional neuroprotective benefits in patients with acute stroke beyond their canonical antiplatelet action., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Purpose: A mobile stroke unit (MSU) reduces delays in stroke treatment by allowing thrombolysis on board and avoiding secondary transports. Due to the beneficial effect in comparison to conventional emergency medical services, current guidelines recommend regional evaluation of MSU implementation., Methods: In a descriptive study, current pathways of patients requiring a secondary transport for mechanical thrombectomy were reconstructed from individual patient records within a Danish (n = 122) and an adjacent German region (n = 80). Relevant timestamps included arrival times (on site, primary hospital, thrombectomy centre) as well as the initiation of acute therapy. An optimal MSU location for each region was determined. The resulting time saving was translated into averted disability-adjusted life years (DALYs)., Results: For each region, the optimal MSU location required a median driving time of 35 min to a stroke patient. Time savings in the German region (median [Q1; Q3]) were 7 min (-15; 31) for thrombolysis and 35 min (15; 61) for thrombectomy. In the Danish region, the corresponding time savings were 20 min (8; 30) and 43 min (25; 66). Assuming 28 thrombectomy cases and 52 thrombolysis cases this would translate to 9.4 averted DALYs per year justifying an annual net MSU budget of $0.8M purchasing power parity dollars (PPP-$) in the German region. In the Danish region, the MSU would avert 17.7 DALYs, justifying an annual net budget of PPP-$1.7M., Conclusion: The effects of an MSU can be calculated from individual patient pathways and reflect differences in the hospital infrastructure between Denmark and Germany., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide. Although most mouse models of atherosclerosis develop lesions in the aorta and carotid arteries, they do not develop advanced coronary artery lesions. Moreover, they do not undergo spontaneous plaque rupture with MI and stroke or do so at such a low frequency that they are not viable experimental models to study late-stage thrombotic events or to identify novel therapeutic approaches for treating atherosclerotic disease. This has stymied the development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Here, we describe a diet-inducible mouse model that develops widespread advanced atherosclerosis in coronary, brachiocephalic, and carotid arteries with plaque rupture, MI, and stroke., Methods: We characterized a novel mouse model with a C-terminal mutation in the scavenger receptor class B, type 1 (SR-BI), combined with Ldlr knockout (designated SR-BI ∆CT/∆CT / Ldlr -/- ). Mice were fed Western diet (WD) for 26 weeks and analyzed for MI and stroke. Coronary, brachiocephalic, and carotid arteries were analyzed for atherosclerotic lesions and indices of plaque stability. To validate the utility of this model, SR-BI ∆CT/∆CT / Ldlr -/- mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme produced by activated neutrophils that predicts rupture of human atherosclerotic lesions., Results: SR-BI ∆CT/∆CT / Ldlr -/- mice show high (>80%) mortality rates after 26 weeks of WD feeding because of major adverse cardiovascular events, including spontaneous plaque rupture with MI and stroke. Moreover, WD-fed SR-BI ∆CT/∆CT / Ldlr -/- mice displayed elevated circulating high-sensitivity cardiac troponin I and increased neutrophil extracellular trap formation within lesions compared with control mice. Treatment of WD-fed SR-BI ∆CT/∆CT / Ldlr -/- mice with AZM198 showed remarkable benefits, including >90% improvement in survival and >60% decrease in the incidence of plaque rupture, MI, and stroke, in conjunction with decreased circulating high-sensitivity cardiac troponin I and reduced neutrophil extracellular trap formation within lesions., Conclusions: WD-fed SR-BI ∆CT/∆CT / Ldlr -/- mice more closely replicate late-stage clinical events of advanced human atherosclerotic disease than previous models and can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events.

In the last decade, mobile stroke units (MSUs) have shown the potential to transform prehospital stroke care, marking a paradigm shift in delivering ultra-rapid thrombolysis and streamlining triage processes. These units bring acute stroke care directly to patients, significantly shortening treatment times. This review outlines the rationale for MSU care and discusses the potential applications beyond the original purpose of delivering thrombolysis, including large vessel occlusion detection, intracerebral hemorrhage management, and innovative forms of prehospital research., Competing Interests: Declaration of Competing Interest None of the authors declare conflicts of interest related to this data. In the early stages of drafting, we used Chat-GPT (version 3.5) to aid with grammar and readability of select sections. All conceptualization, literature review, development of the ideas discussed in the article, and revisions were carried out by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cerebral stroke is a pressing global health concern, ranking as the second leading cause of mortality and resulting in persistent neurobehavioral impairments. Cerebral strokes, triggered by various embolic events, initiate complex signaling pathways involving neuroexcitotoxicity, ionic imbalances, inflammation, oxidative stress, acidosis, and mitochondrial dysfunction, leading to programmed cell death. Currently, the FDA has approved tissue plasminogen activator as a relatively benign intervention for cerebral stroke, leaving a significant treatment gap. However, a promising avenue has emerged from Earth's toxic creatures. Animal venoms harbor bioactive molecules, particularly neuropeptides, with potential in innovative healthcare applications. These venomous components, affecting ion channels, receptors, and transporters, encompass neurochemicals, amino acids, and peptides, making them prime candidates for treating cerebral ischemia and neurological disorders. This review explores the composition, applications, and significance of toxin-derived peptides as viable therapeutic agents. It also investigates diverse toxins from select venomous creatures, with the primary objective of shedding light on current stroke treatments and paving the way for pioneering therapeutic strategies capable of addressing neurobehavioral deficits., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

There is no effective and noninvasive solution for thrombolysis because the mechanism by which certain thrombi become tissue plasminogen activator (tPA)-resistant remains obscure. Endovascular thrombectomy is the last option for these tPA-resistant thrombi, thus a new noninvasive strategy is urgently needed. Through an examination of thrombi retrieved from stroke patients, we found that neutrophil extracellular traps (NETs), ε-(γ-glutamyl) lysine isopeptide bonds and fibrin scaffolds jointly comprise the key chain in tPA resistance. A theranostic platform is designed to combine sonodynamic and mechanical thrombolysis under the guidance of ultrasonic imaging. Breakdown of the key chain leads to a recanalization rate of more than 90% in male rat tPA-resistant occlusion model. Vascular reconstruction is observed one month after recanalization, during which there was no thrombosis recurrence. The system also demonstrates noninvasive theranostic capabilities in managing pigs' long thrombi (>8 mm) and in revascularizing thrombosis-susceptible tissue-engineered vascular grafts, indicating its potential for clinical application. Overall, this noninvasive theranostic platform provides a new strategy for treating tPA-resistant thrombi., (© 2024. The Author(s).)

We conducted a multicenter and retrospective study to describe the use of botulinum toxin type A (BoNT-A) to treat post-stroke spasticity (PSS). Data were extracted from free-text in electronic health records (EHRs) in five Spanish hospitals. We included adults diagnosed with PSS between January 2015 and December 2019, stratified into BoNT-A-treated and untreated groups. We used EHRead ® technology, which incorporates natural language processing and machine learning, as well as SNOMED CT terminology. We analyzed demographic data, stroke characteristics, BoNT-A use patterns, and other treatments. We reviewed the EHRs of 1,233,929 patients and identified 2190 people with PSS with a median age of 69 years; in total, 52.1% were men, 70.7% had cardiovascular risk factors, and 63.2% had suffered an ischemic stroke. Among the PSS patients, 25.5% received BoNT-A at least once. The median time from stroke to spasticity onset was 205 days, and the time from stroke to the first BoNT-A injection was 364 days. The primary goal of BoNT-A treatment was pain control. Among the study cohort, rehabilitation was the most common non-pharmacological treatment (95.5%). Only 3.3% had recorded monitoring scales. In conclusion, a quarter of patients with PSS received BoNT-A mainly for pain relief, typically one year after the stroke. Early treatment, disease monitoring, and better data documentation in EHRs are crucial to improve PSS patients' care.

Background and Objective: Metformin pretreatment might have neuroprotective effects. We aimed to determine the therapeutic effects of the antidiabetic medication metformin on ischemic stroke severity and discharge outcomes., Methods: We analyzed data on 1303 ischemic stroke patients who were on antidiabetic medications from the Massachusetts General Hospital (MGH) Advanced Comprehensive Stroke Center dataset (n = 8943, 2012-2022). We applied propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analyses to investigate the effect of current usage of metformin (versus alternate antidiabetic treatment) on acute stroke clinical severity and discharge outcomes., Results: Of the 1303 patients who were on antidiabetic medications at the time of stroke admission, 730 (56%) were taking metformin. Metformin users were younger and more frequently had hypertension, whereas less frequently had prior CAD, AFib, and chronic kidney disease. The clinical features and laboratory values of the two groups were evenly distributed after PSM. Metformin-treated patients had statistically significant lower stroke severity on admission [National Institutes of Health Stroke Scale (NIHSS) (median, interquartile range) 3.0 (1.0-8.0) vs. 4.0 (2.0-11.3), p = 0.011], better functional independence at discharge (modified Rankin scale score 0-2, 36.3% vs. 25.4%, p < 0.001) and less in-hospital mortality (4.5% vs. 11.3%, p = 0.018). IPTW analysis results were consistent with PSM results., Conclusions: Among diabetic patients with acute ischemic stroke, metformin appears to confer neuroprotection. Our results extend previous findings to the general stroke population. Stroke patients with diabetes mellitus who were treated with metformin prior to stroke, even when combined with additional antidiabetic medications, experienced less severe strokes upon admission and had better functional outcomes during hospitalization., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Recent hypertension guidelines for the general population have included race-specific recommendations for antihypertensives, whereas current stroke-specific recommendations for antihypertensives do not vary by race. The impact of these guidelines on antihypertensive regimen changes over time, and if this has varied by prevalent stroke status, is unclear., Methods: The use of antihypertensive medications was studied cross-sectionally among self-identified Black and White participants, aged ≥45 years, with and without history of stroke, from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Participants completed an in-home examination in 2003-2007 (visit 1) with/without an examination in 2013-2016 (visit 2). Stratified by prevalent stroke status, logistic regression mixed models examined associations between antihypertensive class use for visit 2 versus visit 1 and Black versus White individuals with an interaction adjusted for demographics, socioeconomic status, and vascular risk factors/vital signs., Results: Of 17 244 stroke-free participants at visit 1, Black participants had greater adjusted odds of angiotensin-converting enzyme inhibitor usage than White participants (odds ratio [OR], 1.51 [95% CI, 1.30-1.77]). This difference was smaller in the 7476 stroke-free participants at visit 2 (OR, 1.16 [95% CI, 1.08-1.25]). In stroke-free participants at visit 1, Black participants had lower odds of calcium channel blocker (CCB) usage than White participants (OR, 0.47 [95% CI, 0.41-0.55]), but CCB usage did not differ significantly between Black and White stroke-free participants at visit 2 (OR, 1.02 [95% CI, 0.95-1.09]). Among 1437 stroke survivor participants at visit 1, Black participants had lower odds of CCB use than White participants (OR, 0.34 [95% CI, 0.26-0.45]). In 689 stroke survivor participants at visit 2, CCB use did not differ between Black and White participants (OR, 0.80 [95% CI, 0.61-1.06])., Conclusions: Racial differences in the use of guideline-recommended antihypertensives decreased between 2003-2007 and 2013-2016 in stroke-free individuals. In stroke survivors, racial differences in CCB usage narrowed over the time periods. These findings suggest there is still a mismatch between race-specific hypertension guidelines and recent clinical practice., Competing Interests: Dr Royan receives salary support as an Assistant Editor at JAMA Network Open. Dr Long receives grant/contract support from the Centers for Disease Control and Prevention, the National Institutes of Health, Patient-Centered Outcomes Research Institute, and Amgen, and reports employment by West Virginia University. Dr Levine receives grant/contract support from the National Institutes of Health and compensation from Northwestern University for consultant services. Dr Gorelick receives consultant support from AbbVie and End Point Review Committee support from Bausch Health US, LLC, ICON Pharma, LabCorp (aka Lab Corporation), Pharmaceutical Research Associates, Sanofi and Genzyme US Companies, Takeda Pharmaceutical Company, and Union Chimique Belge (UCB). The other authors report no conflicts.

The transplantation of bone marrow mesenchymal stem cells (MSCs) in stroke is hindered by the restricted rates of survival and differentiation. Ginsenoside compound K (CK), is reported to have a neuroprotective effect and regulate energy metabolism. We applied CK to investigate if CK could promote the survival of MSCs and differentiation into brain microvascular endothelial-like cells (BMECs), thereby alleviating stroke symptoms. Therefore, transwell and middle cerebral artery occlusion (MCAO) models were used to mimic oxygen and glucose deprivation (OGD) in vitro and in vivo, respectively. Our results demonstrated that CK had a good affinity for GLUT1, which increased the expression of GLUT1 and the production of ATP, facilitated the proliferation and migration of MSCs, and activated the HIF-1α/VEGF signaling pathway to promote MSC differentiation. Moreover, CK cooperated with MSCs to protect BMECs, promote angiogenesis and vascular density, enhance neuronal and astrocytic proliferation, thereby reducing infarct volume and consequently improving neurobehavioral outcomes. These results suggest that the synergistic effects of CK and MSCs could potentially be a promising strategy for stroke., (© 2024 John Wiley & Sons Ltd.)

Introduction: United States stroke systems are increasingly transitioning from alteplase (TPA) to tenecteplase (TNK). Real-world data on the safety and effectiveness of replacing TPA with TNK before large vessel occlusion (LVO) stroke endovascular treatment (EVT) are lacking., Methods: Four Pennsylvania stroke systems transitioned from TPA to TNK during the study period 01/2020-06/2023. LVO stroke patients who received intravenous thrombolysis with TPA or TNK before EVT were reviewed. Multivariate logistic analysis was conducted adjusting for age, sex, National Institute of Health Stroke Scale (NIHSS), occlusion site, last-known-well-to-intravenous thrombolysis time, interhospital-transfer and stroke system., Results: Of 635 patients, 309 (48.7%) received TNK and 326 (51.3%) TPA prior to EVT. The site of occlusion was the M1 middle cerebral artery (MCA) (47.7%), M2 MCA (25.4%), internal carotid artery (14.0%), tandem carotid with M1 or M2 MCA (9.8%) and basilar artery (3.1%). A favorable functional outcome (90-day mRS ≤ 2) was observed in 47.6% of TNK and 49.7% of TPA patients (p = 0.132). TNK versus TPA groups had similar rates of early recanalization (11.9% vs. 8.4%, p = 0.259), successful endovascular reperfusion (93.5% vs. 89.3%, p = 0.627), symptomatic intracranial hemorrhage (3.2% vs. 3.4%, p = 0.218) and 90-day all-cause mortality (23.1% vs. 21.5%, p = 0.491)., Conclusions: This U.S. multicenter real-world clinical experience demonstrated that switching from TPA to TNK before EVT for LVO stroke resulted in similar endovascular reperfusion, safety, and functional outcomes., (© 2024. The Author(s).)

Angioedema without concomitant urticaria is a well-known complication of treatment with the recombinant tissue-type plasminogen activator (r-tPA) alteplase and its genetically modified variant tenecteplase. It is potentially lethal when causing airway obstruction and can require intubation. The latest guideline for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association advises to treat this complication initially by interfering with the histamine pathway. This article aims to clarify the pathophysiological mechanism of r-tPA-induced angioedema and provides several arguments that this condition is primarily bradykinin-mediated and hence should be treated initially by intervening with the bradykinin pathway. Second, other-less frequently reported-adverse symptoms after r-tPA therapy and their proposed pathophysiological mechanisms leading to specific treatment are described. This manuscript describes the need for an update of the section "3.5 IV alteplase" from the American Heart Association/American Stroke Association guideline to treat this r-tPA-induced angioedema adequately and prevent potentially fatal outcomes., Competing Interests: None.

Post-stroke emotional disorders such as post-stroke anxiety and post-stroke depression are typical symptoms in patients with stroke. They are closely associated with poor prognosis and low quality of life. The State Food and Drug Administration of China has approved DL-3-n-butylphthalide (NBP) as a treatment for ischemic stroke (IS). Clinical research has shown that NBP alleviates anxiety and depressive symptoms in patients with IS. Therefore, this study explored the role and molecular mechanisms of NBP in cases of post-stroke emotional disorders using network pharmacology and experimental validation. The results showed that NBP treatment significantly increased the percentage of time spent in the center of the middle cerebral artery occlusion (MCAO) rats in the open field test and the percentage of sucrose consumption in the sucrose preference test. Network pharmacology results suggest that NBP may regulate neuroinflammation and cell death. Further experiments revealed that NBP inhibited the toll-like receptor 4/nuclear factor kappa B signaling pathway, decreased the level of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, and M1-type microglia markers (CD68, inducible nitric oxide synthase), and reduced the expression of PANoptosis-related molecules including caspase-1, caspase-3, caspase-8, gasdermin D, and mixed lineage kinase domain-like protein in the hippocampus of the MACO rats. These findings demonstrate that the mechanisms through which NBP ameliorates post-stroke emotional disorders in rats are associated with inhibiting neuroinflammation and PANoptosis, providing a new strategy and experimental basis for treating post-stroke emotional disorders., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: None.

Neuronal ferroptosis plays a key role in neurologic deficits post intracerebral hemorrhage (ICH). However, the endogenous regulation of rescuing ferroptotic neurons is largely unexplored. Here, we analyzed the integrated alteration of metabolomic landscape after ICH using LC-MS and MALDI-TOF/TOF MS, and demonstrated that aconitate decarboxylase 1 (Irg1) and its product itaconate, a derivative of the tricarboxylic acid cycle, were protectively upregulated. Deficiency of Irg1 or depletion of neuronal Irg1 in striatal neurons was shown to exaggerate neuronal loss and behavioral dysfunction in an ICH mouse model using transgenic mice. Administration of 4-Octyl itaconate (4-OI), a cell-permeable itaconate derivative, and neuronal Irg1 overexpression protected neurons in vivo. In addition, itaconate inhibited ferroptosis in cortical neurons derived from mouse and human induced pluripotent stem cells in vitro. Mechanistically, we demonstrated that itaconate alkylated glutathione peroxidase 4 (GPx4) on its cysteine 66 and the modification allosterically enhanced GPx4's enzymatic activity by using a bioorthogonal probe, itaconate-alkyne (ITalk), and a GPx4 activity assay using phosphatidylcholine hydroperoxide. Altogether, our research suggested that Irg1/itaconate-GPx4 axis may be a future therapeutic strategy for protecting neurons from ferroptosis post ICH., (© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: I have received a research grant from Boehringer Ingelheim for the RECCA registry (paid to Clinica Alemana de Santiago, Chile) and honoraria from Novo Nordisk for a stroke lecture.

Competing Interests: I am principal investigator for the T-FLAVOR trial (funded by AMED: JP24lk0221186) and the BAT2 study (funded by JSPS KAKENHI: JP23H02831). I report honoraria from Otsuka Pharmaceutical, Daiichi-Sankyo, Bristol-Myers-Squibb, Bayer Yakuhin, and Janssen.

Background and Purpose: This systematic review examines the effectiveness of motivational interviewing (MI) on medication adherence for preventing recurrent stroke and transient ischemic attack (TIA)., Methods: MEDLINE (via PubMed), CINAHL, PsycINFO, CENTRAL, and ClinicalTrials.gov were searched from inception to 12 June 2023. Randomized controlled trials comparing MI with usual care or interventions without MI in participants with any stroke type were identified and summarized descriptively. Primary outcome was medication adherence. Secondary outcomes were quality of life (QoL) and different clinical outcomes. We assessed risk of bias with RoB 2 (revised Cochrane risk-of-bias tool) and intervention complexity with the iCAT&#95;SR (intervention Complexity Assessment Tool for Systematic Reviews)., Results: We screened 691 records for eligibility and included four studies published in five articles. The studies included a total of 2751 participants, and three were multicentric. Three studies had a high risk of bias, and interventions varied in complexity. Two studies found significantly improved medication adherence, one at 9 (96.9% vs. 88.2%, risk ratio = 1.098, 95% confidence interval = 1.03-1.17) and one at 12 months (97.0% vs. 95.0%, p = 0.026), but not at other time points, whereas two other studies reported no significant changes. No significant differences were found in QoL or clinical outcomes., Conclusions: Evidence on MI appears inconclusive for improving medication adherence for recurrent stroke and TIA prevention, with no benefits on QoL and clinical outcomes. There is a need for robustly designed studies and process evaluations of MI as a complex intervention for people with stroke., Registration: PROSPERO (CRD42023433284)., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data., Methods: Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined., Findings: The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results., Interpretation: Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Alteplase (rtPA) remains the standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules, such as tenecteplase (TNK), with prolonged half-lives following a single bolus administration, have been developed. Although TNK is currently under clinical evaluation, the limited preclinical data highlight the need for additional studies to elucidate its benefits. The toxicities of rtPA and TNK were evaluated in endothelial cells, astrocytes, and neuronal cells. In addition, their in vivo efficacy was independently assessed at two research centers using an ischemic thromboembolic mouse model. Both therapies were tested via early (20 and 30 min) and late administration (4 and 4.5 h) after stroke. rtPA, but not TNK, caused cell death only in neuronal cultures. Mice were less sensitive to thrombolytic therapies than humans, requiring doses 10-fold higher than the established clinical dose. A single bolus dose of 2.5 mg/kg TNK led to an infarct reduction similar to perfusion with 10 mg/kg of rtPA. Early administration of TNK decreased the hemorrhagic transformations compared to that by the early administration of rtPA; however, this result was not obtained following late administration. These two independent preclinical studies support the use of TNK as a promising reperfusion alternative to rtPA., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To provide an update on the effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on stroke in patients with type 2 diabetes (T2D)., Methods: PubMed, Embase, and Cochrane Library were systematically searched for randomized controlled trials (RCTs) comparing SGLT2 inhibitors versus placebo or other therapies in patients with T2D and reporting stroke endpoint. We computed the risk ratios (RRs) to binary endpoints, with 95 % confidence intervals (CIs)., Results: A total of 71 RCTs and 105,914 patients were included, of whom 62,488 (59 %) were randomized to the SGLT2 inhibitors group. The follow-up ranged from 12 weeks to 4.2 years. There were no significant differences between groups in all types of stroke (RR 0.96; 95 % CI 0.89-1.04), ischemic stroke (RR 0.89; 95 % CI 0.76-1.04), and transient ischemic attack (RR 0.96; 95 % CI 0.79-1.16). Patients on SGLT2 inhibitors experienced lower rates of hemorrhagic stroke (RR 0.62; 95 % CI 0.39-0.98). In the subgroup analysis of the type of drug, sotagliflozin significantly reduced all types of stroke (RR 0.74; 95 % CI 0.56-0.97)., Conclusion: In this meta-analysis of 71 RCTs comprising 105,914 patients with T2D, SGLT2 inhibitors were not associated with a reduced risk of stroke and transient ischemic attack compared to placebo or other therapies; however, there was a trend toward reduced risk of hemorrhagic stroke. Among all SGLT2 inhibitors, sotagliflozin significantly reduced the risk of stroke., Competing Interests: Declaration of competing interest Dr. Sur has served as a consultant for Medtronic; receives research funding as the Evelyn F. McKnight Brain Institute Neurocognitive Scholar and the Florida Stroke Registry COHAN A-2; and serves on the editorial board for Stroke, JACC: Advances, and the Journal of Clinical and Translational Investigation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: To investigate the cost-avoidance associated with implementation of an overnight emergency medicine pharmacist (EMP) through documented clinical interventions., Design: Retrospective evaluation of prospectively tracked interventions in a single Level I Trauma, Comprehensive Stroke Center, from November 25, 2020 through March 12, 2021 during expanded emergency medicine service hours (2300-0700)., Interventions: One of 45 clinical patient-care recommendations associated with cost-avoidance were available to be selected and documented by the EMP; more than one intervention was allowed per patient, though one clinical intervention could not be counted as multiple items. Documented services were associated with monetary cost avoidance based upon available literature assessing pharmacy clinical interventions. Differences in time from imaging to systemic thrombolytics and percentage of patients meeting door-to-alteplase benchmarks were compared with and without the availability of EMPs., Results: Overnight EMPs documented 820 interventions during 107 overnight shifts with a cost avoidance of $612,974. The most common interventions were bedside monitoring (n = 127; $50,694), drug information consultation (97; $11,269), and antimicrobial therapy initiation and streamlining (95; $60,101). When categorizing interventions, 378 (46%; $292,484) were input as hands-on care, 216 (26%; $94,899) as individualization of patient care, 135 (17%; $25,897) as administrative and supportive tasks, 84 (10%; $121,746) as adverse drug event prevention, and 7 (1%; $77,964) as resource utilization. All patients (n = 6) with an acute ischemic stroke during the evaluation period received systemic thrombolytics ≤45 min in the presence of EMPs compared with 50% receiving thrombolytics ≤45 min without EMPs., Conclusions: Expanded overnight coverage by EMPs provided clinical bedside pharmacotherapy expertise to critically ill patients otherwise not available prior to study implementation. Clinical interventions were associated with substantial cost-avoidance., Competing Interests: Declaration of competing interest Gabriel V. Fontaine, PharmD, MBA: AstraZeneca, Chiesi, Anticoagulation Forum – consultant, speakers bureau; Marinus Pharmaceuticals – consultant., (Copyright © 2024. Published by Elsevier Inc.)

Stroke, the leading cause of disability and cognitive impairment, is also the second leading cause of death worldwide. The drugs with multi-targeted brain cytoprotective effects are increasingly being advocated for the treatment of stroke. Irisin, a newly discovered myokine produced by cleavage of fibronectin type III domain 5, has been shown to regulate glucose metabolism, mitochondrial energy, and fat browning. A large amount of evidence indicated that irisin could exert anti-inflammatory, anti-apoptotic, and antioxidant properties in a variety of diseases such as myocardial infarction, inflammatory bowel disease, lung injury, and kidney or liver disease. Studies have found that irisin is widely distributed in multiple brain regions and also plays an important regulatory role in the central nervous system. The most common cause of a stroke is a sudden blockage of an artery (ischemic stroke), and in some circumstances, a blood vessel rupture can also result in a stroke (hemorrhagic stroke). After a stroke, complicated pathophysiological processes lead to serious brain injury and neurological dysfunction. According to recent investigations, irisin may protect elements of the neurovascular unit by acting on multiple pathological processes in stroke. This review aims to outline the currently recognized effects of irisin on stroke and propose possible directions for future research., Competing Interests: Declaration of competing interest 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 © 2024. Published by Elsevier Ltd.)

GluN2B-induced activation of NMDA receptors plays a key function in central nervous system (CNS) disorders, including Parkinson, Alzheimer, and stroke, as it is strongly involved in excitotoxicity, which makes selective NMDA receptor antagonists one of the potential therapeutic agents for the treatment of neurodegenerative diseases, especially stroke. The present study aims to examine a structural family of thirty brain-penetrating GluN2B N-methyl-D-aspartate (NMDA) receptor antagonists, using virtual computer-assisted drug design (CADD) to discover highly candidate drugs for ischemic strokes. Initially, the physicochemical and ADMET pharmacokinetic properties confirmed that C13 and C22 compounds were predicted as non-toxic inhibitors of CYP2D6 and CYP3A4 cytochromes, with human intestinal absorption (HIA) exceeding 90%, and designed to be as efficient central nervous system (CNS) agents due to the highest probability to cross the blood-brain barrier (BBB). Compared to ifenprodil, a co-crystallized ligand complexed with the transport protein encoded as 3QEL.pdb, we have noticed that C13 and C22 chemical compounds were defined by good ADME-Toxicity profiles, meeting Lipinski, Veber, Egan, Ghose, and Muegge rules. The molecular docking results indicated that C22 and C13 ligands react specifically with the amino acid residues of the NMDA receptor subunit GluN1 and GluN2B. These intermolecular interactions produced between the candidate drugs and the targeted protein in the B chain remain stable over 200 nanoseconds of molecular dynamics simulation time. In conclusion, C22 and C13 ligands are highly recommended as anti-stroke therapeutic drugs due to their safety and molecular stability towards NMDA receptors.Communicated by Ramaswamy H. Sarma.

Salvianolic acid A (SalA), a bioactive compound extracted from Salvia miltiorrhiza, has garnered considerable interest for its potential in ameliorating the post-stroke neuroinflammation. This review delineates the possible molecular underpinnings of anti-inflammatory and neuroprotective roles of SalA, offering a comprehensive analysis of its therapeutic efficacy in preclinical studies of ischemic stroke. We explore the intricate interplay between post-stroke neuroinflammation and the modulatory effects of SalA on pro-inflammatory cytokines, inflammatory signaling pathways, the peripheral immune cell infiltration through blood-brain barrier disruption, and endothelial cell function. The pharmacokinetic profiles of SalA in the context of stroke, characterized by enhanced cerebral penetration post-ischemia, makes it particularly suitable as a therapeutic agent. Preliminary clinical findings have demonstrated that salvianolic acids (SA) has a positive impact on cerebral perfusion and neurological deficits in stroke patients, warranting further investigation. This review emphasizes SalA as a potential anti-inflammatory agent for the advancement of innovative therapeutic approaches in the treatment of ischemic stroke., 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 © 2024 Yang, Ibrahim, Zhang, Sun, Chang, Qi and Yang.)

Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is a pleiotropic peptide known to promote many beneficial processes following neural damage and cell death after stroke. Despite PACAP's known neurotrophic and anti-inflammatory properties, it has not realized its translational potential due to a poor pharmacokinetic profile (non-linear PK/PD), and limited Blood-Brain Barrier Penetration (BBB) permeability. We have previously shown that glycosylation of PACAP increases stability and enhances BBB penetration. In addition, our prior studies showed reduced neuronal cell death and neuroinflammation in models of Parkinson's disease and Traumatic Brain Injury (TBI). In this study we show that a PACAP (1-27) glucoside retains the known neurotrophic activity of native PACAP (1-27) in vitro and a 5-day daily treatment regimen (100 nM) leads to neurite-like extensions in PC12 cells. In addition, we show that intraperitoneal injection of a PACAP (1-27) lactoside (10 mg/kg) with improved BBB-penetration, given 1-hour after reperfusion in a Transient Middle Cerebral Artery Occlusion (tMCAO) mouse model, reduces the infarct size after the ischemic injury in males significantly by ∼ 36 %, and the data suggest a dose-dependency. In conclusion, our data support further development of PACAP glycopeptides as promising novel drug candidates for the treatment of stroke, an area with an urgent clinical need., Competing Interests: Declaration of Competing Interest MLH, TF, and RP hold patents related to the content. MLH, TF, and RP have equity in Teleport Pharmaceuticals, LLC, a UArizona biotech startup. This interest played no role in the design of the studies; in the collection, analyses, or interpretation of data; in the writing of the Paper, or in the decision to present the results. The remaining 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 © 2024 Elsevier B.V. All rights reserved.)

Objectives: After introducing a team simulation training programme at our hospital, we saw a reduction in door-to-needle times (DNT) for stroke thrombolysis but persisting variability prompting further investigation. Our objective is to examine this gap through assessing: (1) whether there is an association between DNT and the clinical experience of neurology registrars and (2) whether experience influences the benefits from attending simulation., Design: Prospective cohort study., Setting and Participants: Patients treated with intravenous thrombolysis between January 2016 and 2020 at a Norwegian stroke centre., Primary and Secondary Outcome Measures: Using DNT and prior intravenous thrombolysis administrations (case-based definition of clinical experience) as continuous variables, a mixed effects linear regression model was performed to examine the association between clinical experience, DNT and simulation attendance. For dichotomised analyses, neurology registrars with 15 or more prior treatments were defined as experienced., Results: A total of 532 patients treated by 36 neurology registrars from January 2016 to 2020 were included. There was a linear association between clinical experience and DNT (test for non-linearity p=0.479). Each prior intravenous thrombolysis administration was associated with a significant 1.1% decrease in DNT in the adjusted analysis (ΔDNT -1.1%; 95% CI, -2.2% to -0.0%; p=0.048). The interaction between effects of clinical experience and simulation on DNT was not statistically significant (p=0.150). In the dichotomised analysis, experienced registrars had similar gains from attending simulation sessions (mean DNT from 18.5 min to 13.5 min) compared with less experienced registrars (mean DNT from 22.4 min to 17.4 min)., Conclusions: Less experienced registrars had longer DNT in stroke thrombolysis. Attending team simulation training was associated with similar improvements for experienced and inexperienced neurology registrars. We suggest a focus on high-quality onboarding programmes to close the experience-related quality gap. Our findings suggest that both inexperienced and experienced neurology registrars might benefit from team simulation training for stroke thrombolysis., Competing Interests: Competing interests: SCA is a research fellow funded by a Safer Healthcare Grant (University Research Fund). The remaining authors report no disclosures., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy. Nevertheless, there is limited evidence regarding the clinical profile of antiseizure medications (ASMs) in PSE. This study aims to evaluate the 12-month effectiveness and tolerability of perampanel (PER) used as only add-on treatment in patients with PSE in a real-world setting., Methods: We performed a subgroup analysis of PSE patients included in a previous retrospective, longitudinal, multicentre observational study on adults. Treatment discontinuation, seizure frequency and adverse events were collected at 3, 6 and 12 months. Sub-analyses by early (≤1 previous ASM) or late PER add-on were also conducted., Results: Our analysis included 56 individuals with PSE, characterized by varying initial treatment modalities and timeframes relative to disease onset. We found notable retention rates (92.8%, 83.7%, and 69% at 3, 6, and 12 months), with treatment withdrawal mainly due to poor tolerability. One year after PER introduction, seizure frequency significantly reduced, with a responder rate (≥50% reduction) of 83.9% and a seizure-free rate of 51.6%. Adverse events occurred in 25 (46.3%) patients, mainly dizziness, irritability, and behavioural disorders. No major statistical differences were found between early (30 patients, 53.6%) and late add-on groups, except for a higher 6-month responder rate in the early add-on group., Conclusion: Adjunctive PER was effective and well-tolerated in patients with PSE in a real-world setting. Perampanel demonstrated good efficacy and safety as both early and late add-on treatment, making it a compelling option for this unique patient population., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Stroke is responsible for 11% of all deaths worldwide, the majority of which are caused by ischemic strokes, thus making the need to urgently find safe and effective therapies. Today, these can be cured either by mechanical thrombectomy when the thrombus is accessible, or by intravenous injection of fibrinolytics. However, the latter present several limitations, such as potential severe side effects, few eligible patients and low rate of partial and full recovery. To design safer and more effective treatments, nanomedicine appeared in this medical field a few decades ago. This review will explain why nanoparticle-based therapies and imaging techniques are relevant for ischemic stroke management. Then, it will present the different nanoparticle types that have been recently developed to treat this pathology. It will also study the various targeting strategies used to bring nanoparticles to the stroke site, thereby limiting side effects and improving the therapeutic efficacy. Finally, this review will present the few clinical studies testing nanomedicine on stroke and discuss potential causes for their scarcity., (Copyright © 2023 IBRO. Published by Elsevier Inc. All rights reserved.)

Animal models are an indispensable tool in the study of ischaemic stroke with hundreds of drugs emerging from the preclinical pipeline. However, all of these drugs have failed to translate into successful treatments in the clinic. This has brought into focus the need to enhance preclinical studies to improve translation. The confounding effects of anaesthesia on preclinical stroke modelling has been raised as an important consideration. Various volatile and injectable anaesthetics are used in preclinical models during stroke induction and for outcome measurements such as imaging or electrophysiology. However, anaesthetics modulate several pathways essential in the pathophysiology of stroke in a dose and drug dependent manner. Most notably, anaesthesia has significant modulatory effects on cerebral blood flow, metabolism, spreading depolarizations, and neurovascular coupling. To minimise anaesthetic complications and improve translational relevance, awake stroke induction has been attempted in limited models. This review outlines anaesthetic strategies employed in preclinical ischaemic rodent models and their reported cerebral effects. Stroke related complications are also addressed with a focus on infarct volume, neurological deficits, and thrombolysis efficacy. We also summarise routinely used focal ischaemic stroke rodent models and discuss the attempts to induce some of these models in awake rodents., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Systolic blood pressure (SBP) was a predictor of early neurological deterioration (END) in stroke. We performed a secondary analysis of ARAMIS trial to investigate whether baseline SBP affects the effect of dual antiplatelet versus intravenous alteplase on END., Methods: This post hoc analysis included patients in the as-treated analysis set. According to SBP at admission, patients were divided into SBP ≥140 mmHg and SBP <140 mmHg subgroups. In each subgroup, patients were further classified into dual antiplatelet and intravenous alteplase treatment groups based on study drug actually received. Primary outcome was END, defined as an increase of ≥2 in the NIHSS score from baseline within 24 h. We investigated effect of dual antiplatelet vs intravenous alteplase on END in SBP subgroups and their interaction effect with subgroups., Results: A total of 723 patients from as-treated analysis set were included: 344 were assigned into dual antiplatelet group and 379 into intravenous alteplase group. For primary outcome, there was more treatment effect of dual antiplatelet in SBP ≥140 mmHg subgroup (adjusted RD, -5.2%; 95% CI, -8.2% to -2.3%; p < 0.001) and no effect in SBP <140 mmHg subgroup (adjusted RD, -0.1%; 95% CI, -8.0% to 7.7%; p = 0.97), but no significant interaction between subgroups was found (adjusted p = 0.20)., Conclusions: Among patients with minor nondisabling acute ischemic stroke, dual antiplatelet may be better than alteplase with respect to preventing END within 24 h when baseline SBP ≥140 mmHg., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to investigate the factors influencing good outcomes in patients receiving only intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke., Methods: Post hoc exploratory analysis using the RESCUE BT trial identified consecutive patients who received intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke in 55 comprehensive stroke centers from October 2018 to January 2022 in China., Results: A total of 521 patients received intravenous tirofiban, 253 of whom achieved a good 90-day outcome (modified Rankin Scale [mRS] 0-2). Younger age (adjusted odds ratio [aOR]: 0.965, 95% confidence interval [CI]: 0.947-0.982; p < 0.001), lower serum glucose (aOR: 0.865, 95%CI: 0.807-0.928; p < 0.001), lower baseline National Institutes of Health Stroke Scale (NIHSS) score (aOR: 0.907, 95%CI: 0.869-0.947; p < 0.001), fewer total passes (aOR: 0.791, 95%CI: 0.665-0.939; p = 0.008), shorter punctures to recanalization time (aOR: 0.995, 95%CI:0.991-0.999; p = 0.017), and modified Thrombolysis in Cerebral Infarction (mTICI) score 2b to 3 (aOR: 8.330, 95%CI: 2.705-25.653; p < 0.001) were independent predictors of good outcomes after intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke., Conclusion: Younger age, lower serum glucose level, lower baseline NIHSS score, fewer total passes, shorter punctures to recanalization time, and mTICI scores of 2b to 3 were independent predictors of good outcomes after intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke., Chinese Clinical Trial Registry Identifier: ChiCTR-IOR-17014167., (© 2024. The Author(s).)

Background: AST-004, a small molecule agonist of the adenosine A1 and A3 receptors, is a potential cerebroprotectant for patients with acute stroke and is currently in clinical trials. Drug-drug interactions are critically important to assess in the context of acute stroke care. Lytic therapy with tPA (tissue-type plasminogen activator)-induced plasmin formation (alteplase) is the only available pharmacotherapy for acute stroke. Consequently, it is imperative to evaluate potential interactions between AST-004 and tPAs such as alteplase and tenecteplase., Methods: The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi., Results: Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood., Conclusions: These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy., Competing Interests: Disclosures Drs Liston and Korinek are employees of Astrocyte Pharmaceuticals Inc. Dr Lechleiter is a co-founder of Astrocyte Pharmaceuticals Inc, and a science advisor. D. Solt is an employee of Thrombodyne MDEC, LLC.

Background: The dramatic clinical improvement offered by mechanical thrombectomy raised questions about the relevance of prior intravenous thrombolysis in large-vessel occlusion strokes. Hence, studying intravenous thrombolysis susceptibility and its dependence on thrombus composition is crucial. We used an observational proteomic study of whole thrombi retrieved by mechanical thrombectomy to identify factors associated with fibrin content and fibrinolytic activity (FA)., Methods: In 104 stroke patients, the thrombi proteome was established by mass spectrometry coupled to liquid chromatography. FA was estimated in clots both outside (FA out ) by measuring D-dimer levels at the blood-thrombus interface and inside (FA in ) by evaluating the ratio of fibrinogen α to its plasmin-cleaved forms using proteomics coupled with protein electrophoresis. The factors associated with fibrin content, FA in , and FA out were determined by intravenous thrombolysis-adjusted linear regression., Results: FA out ( P <0.0001) and FA in ( P =0.0147) were driven by recombinant tissue-type plasminogen activator (r-tPA) administration (47/104) and thrombus composition. Indeed, FA out was greater with fibrin-rich than erythrocyte-rich thrombi, presumably because of more (r)tPA substrates. Thus, FA out was increased with cardioembolic thrombi (72/104), which are rich in fibrin ( P =0.0300). Opposite results were found inside the thrombus, suggesting that (r)tPA penetrability was hampered by the density of the fibrinous cap. Moreover, blood cells had a strong impact on thrombus structure and susceptibility to (r)tPA. Indeed, fibrin content was negatively associated with erythrocyte-specific proteins in the thrombus, admission hematocrit ( P =0.0139), and hemoglobin level ( P =0.0080), which underlines the key role of erythrocytes in thrombus composition. Also, an increased number of neutrophils impaired FA out ( P =0.0225), which suggests that their aggregation around the thrombus prevented the (r)tPA attack. Only FA out was significantly associated with reduced thrombus weight ( P =0.0310), increased recanalization rate ( P =0.0150), good clinical outcome ( P =0.0480), and reduced mortality ( P =0.0080)., Conclusions: Proteomics can offer new insights into the close relationship between thrombus composition and susceptibility to fibrinolysis, paving the way for new adjuvant therapies., Competing Interests: Disclosures None.

Background: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS., Methods: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors., Results: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P =0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P <0.01). The P value was 0.56 for the treatment × ESUS status interaction effect., Conclusions: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737., Competing Interests: Disclosures Dr Johnston has received support from SANOFI US SERVICES Inc, compensation from Johnson and Johnson International, AstraZeneca AB, and Bristol Myers Squibb Company for consultant services. Dr Bath reports compensation from DiaMedica, F. Hoffmann-La Roche AG, and Phagenesis for consultant services, and World Stroke Organisation for other services; stock options in CoMind; employment by University Of Nottingham; and grants from British Heart Foundation and National Institute for Health and Care Research. The other authors report no conflicts.

Meta-analysis was used to analyze the efficacy of conventional western medicine plus Buyanghuanwu Decoction in the treatment of convalescent patients with stroke, and to observe its influence on the neurological function and condition of patients. According to the research direction and set keywords, the research literature was retrieved from Wanfang Medical Science, CNKI, VIP, PubMed and other domestic and foreign literature databases. A total of 13 articles with 1023 patients were included in this meta-analysis, with a large sample size. Outcome measures of the meta-analysis included efficacy, National Institutes of Health Stroke Scale (NIHSS) score, Barthel Index Rating Scale (BI) score, C-reactive protein (CRP) and homocysteine (Hcy) score. Compared with western medicine group, the increase of BI score and the decrease of NIHSS score, CRP and Hcy in combined medicine group were greater (P < .05). Conventional Western medicine combined with Buyang Huanwu Decoction can improve the rehabilitation effect, living ability and neurological function of patients with stroke, and reducing the inflammatory response, it is beneficial to create favorable conditions for patients' rehabilitation and improve prognosis, which is worthy of clinical application. The effect of this protocol on long-term survival of patients can be further analyzed in the future.

Growing evidence has demonstrated that gut microbiota could be developed as a therapeutic target due to its contribution to microglia activation in the pathological process of ischemic stroke. Acorus tatarinowii oils (AT oils), which is considered as the active fraction of a traditional Chinese herbal medicine Acorus tatarinowii, exerts various bioactivities and prebiotic effects. However, it remains unclear that the effect of AT oils on inflammatory response after ischemic stroke and whether its underlying mechanism is associated to gut microbiota and the intestinal barrier. In the current study, we aim to investigate the anti-microglial neuroinflammation mechanism of AT oils in a middle cerebral artery occlusion model of ischemic stroke. The compositions of AT oils were identified by GC-MS. Our results demonstrated that AT oils could effectively relieve cerebral infarction, inhibit neuronal apoptosis, degrade the release of pro-inflammatory factors (TNF-α, IL-17, IL-6 and IFN-γ), and mediate the polarization of microglia. Moreover, AT oils restored the composition and the balance of gut microbiota in stroke rats, and reduced abundance of opportunistic genera including Verrucomicrobia, Akkermansia and Tenericutes, as well as increased beneficial bacteria abundance such as Tenericutes and Prevotella&#95;copri. To investigate the role of gut microbiota on AT oils against ischemic stroke, we conducted the fecal microbiota transplantation (FMT) experiments with gut microbiota consumption, which suggested that the depletion of gut microbiota took away the protective effect of AT oils, confirming the importance of gut microbiota in the protective effect of AT oils on ischemic stroke. FMT experiments have demonstrated that AT oils preserved the gut permeability and blood-brain barrier, as well as mediated the microglial phenotype under the intervention of gut microbiota. In summary, AT oils could efficaciously moderate neuronal damage and intervene microglial phenotype by reversing gut microbiota disorder in ischemic stroke rats., Competing Interests: Declaration of Competing Interest The authors confirm that the research was conducted without any existing commercial or financial relationships that could be perceived as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It is uncertain whether antiplatelets or anticoagulants are more effective in preventing early recurrent stroke in patients with cervical artery dissection. Following the publication of the observational Antithrombotic for STOP-CAD (Stroke Prevention in Cervical Artery Dissection) study, which has more than doubled available data, we performed an updated systematic review and meta-analysis comparing antiplatelets versus anticoagulation in cervical artery dissection., Methods: The systematic review was registered in PROSPERO (CRD42023468063). We searched 5 databases using a combination of keywords that encompass different antiplatelets and anticoagulants, as well as cervical artery dissection. We included relevant randomized trials and included observational studies of dissection unrelated to major trauma. Where studies were sufficiently similar, we performed meta-analyses for efficacy (ischemic stroke) and safety (major hemorrhage, symptomatic intracranial hemorrhage, and death) outcomes using relative risks., Results: We identified 11 studies (2 randomized trials and 9 observational studies) that met the inclusion criteria. These included 5039 patients (30% [1512] treated with anticoagulation and 70% [3527]) treated with antiplatelets]. In meta-analysis, anticoagulation was associated with a lower ischemic stroke risk (relative risk, 0.63 [95% CI, 0.43 to 0.94]; P =0.02; I 2 =0%) but higher major bleeding risk (relative risk, 2.25 [95% CI, 1.07 to 4.72]; P =0.03, I 2 =0%). The risks of death and symptomatic intracranial hemorrhage were similar between the 2 treatments. Effect sizes were larger in randomized trials. There are insufficient data on the efficacy and safety of dual antiplatelet therapy or direct oral anticoagulants., Conclusions: In this study of patients with cervical artery dissection, anticoagulation was superior to antiplatelet therapy in reducing ischemic stroke but carried a higher major bleeding risk. This argues for an individualized therapeutic approach incorporating the net clinical benefit of ischemic stroke reduction and bleeding risks. Large randomized clinical trials are required to clarify optimal antithrombotic strategies for management of cervical artery dissection., Competing Interests: Disclosures Dr Henninger has received funding from the National Institutes of Health ([NIH]; NS131756, NR020231) during the conduct of this study, unrelated to the present work. Dr Nguyen discloses advisory board for Brainomix and Aruna and is an Associate Editor for Stroke. Dr Siegler has served as a consultant for AstraZeneca and has received funding from the NIH (R61NS135583), vizai, Philips, and Medtronic, unrelated to this work. Dr Field has received in-kind study medication from Bayer and discloses advisory board participation for Bayer, AstraZeneca, Roche, HLS Therapeutics, and Novartis, is on the board of DESTINE Health, and has served as an expert witness. Dr Mistry receives funding from the NIH/National Institute of Neurological Disorders and Stroke and Patient Centered Outcomes Research Institute. She serves as a consultant for AbbVie and RAPID AI and serves on the steering committee for SilverCreek Pharmaceuticals. She reports a nonfinancial relationship with Translational Sciences Inc. She is also an Associate Editor for Stroke and is employed by the University of Cincinnati. Dr de Havenon is a consultant for Integra, TitinKM, and Novo Nordisk, own stocks in Certus, and receives grant support from the NIH. Dr Fletcher received funds from the Library association and is an officer of the Association of College and Research Libraries and the Medical Library Association. Dr Furie is a consultant for Janssen Biotech. Dr Markus receives infrastructural support provided by the Cambridge British Heart Foundation Centre of Research Excellence (RE/18/1/34212) and by the Cambridge University Hospitals NIHR Biomedical Research Centre (NIHR203312).