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Stroke is one of the most devastating pathologies in terms of mortality, cause of dementia, major adult disability, and socioeconomic burden worldwide. Despite its severity, treatment options remain limited, with no pharmacological therapies available for hemorrhagic stroke (HS) and only fibrinolytic therapy or mechanical thrombectomy for ischemic stroke (IS). In the pathophysiology of stroke, after the acute phase, many patients develop systemic immunosuppression, which, combined with neurological dysfunction and hospital management, leads to the onset of stroke-associated infections (SAIs). These infections worsen prognosis and increase mortality. Recent evidence, particularly from experimental studies, has highlighted alterations in the microbiota-gut-brain axis (MGBA) following stroke, which ultimately disrupts the gut flora and increases intestinal permeability. These changes can result in bacterial translocation (BT) from the gut to sterile organs, further contributing to the development of SAIs. Given the novelty and significance of these processes, especially the role of BT in the development of SAIs, this review summarizes the latest advances in understanding these phenomena and discusses potential therapeutic strategies to mitigate them, ultimately reducing post-stroke complications and improving treatment outcomes.

The Stroke Treatment Academic Industry Roundtable (STAIR) convened a session and workshop regarding enrollment in acute stroke trials during the STAIR XII meeting on March 22, 2023. This forum brought together stroke physicians and researchers, members of the National Institute of Neurological Disorders and Stroke, industry representatives, and members of the US Food and Drug Administration to discuss the current status and opportunities for improving enrollment in acute stroke trials. The workshop identified the most relevant issues impacting enrollment in acute stroke trials and addressed potential action items for each. Focus areas included emergency consent in the United States and other countries; careful consideration of eligibility criteria to maximize enrollment and representativeness; investigator, study coordinator, and pharmacist availability outside of business hours; trial enthusiasm/equipoise; site start-up including contractual issues; site champions; incorporation of study procedures into standard workflow as much as possible; centralized enrollment at remote sites by study teams using telemedicine; global trials; and coenrollment in trials when feasible. In conclusion, enrollment of participants is the lifeblood of acute stroke trials and is the rate-limiting step for testing an exciting array of new approaches to improve patient outcomes. In particular, efforts should be undertaken to broaden the medical community's understanding and implementation of emergency consent procedures and to adopt designs and processes that are easily incorporated into standard workflow and that improve trials' efficiencies and execution. Research and actions to improve enrollment in ongoing and future trials will improve stroke outcomes more broadly than any single therapy under consideration., Competing Interests: Disclosures Dr Broderick receives monies from National Institute of Neurological Disorders and Stroke (NINDS) for research grants, receives study medication and monies for temperature monitoring and after-business hour enrollments from Novo Nordisk for NINDS-funded FASTEST Trial (rFVIIa for Acute Hemorrhagic Stroke Administered at Earliest Time Trial). The Department of Neurology receives monies to an educational/research fund from Genentech for his role on Executive Committee of Timeless Trial; from Roche Pharmaceuticals for consulting, from BrainsGate Ltd for consulting; from Basking Biosciences, from Kroger Prescription Plans Inc’s Pharmacy &Therapeutics Committee as voting member of committee. Dr Silva reports funding from the Brazilian Ministry of Health for the Resilient and OPTIMAL trials; consulting and speaker fees from AstraZeneca, Biogen, Boehringer Ingelheim, and Pfizer; consulting fees from IschemaView and Bayer, and speaker fees from Abbott. Dr Selim receives grant funding from the NINDS and NIA (related to and outside of the current work), and royalties from Up to Date and Cambridge University Press and is on the Advisory Board of MedRhythms Inc. Dr Kasner has received grant funding (to institution) from Genentech, Diamedica, Bristol-Myers Squibb, Bayer, Stryker, and Medtronic; consulting fees from Shionogi, Abbvie, Artivion, AstraZeneca, and NeuExcell; and royalties from UpToDate and Elsevier. Dr Adeoye receives funding from NINDS and has equity in and is the Chief Medical Officer for Sense Diagnostics, Inc and receives compensation from NICO Corporation for data and safety monitoring services. Dr Hill reports grants from MicroVention Inc; employment by University of Calgary; grants from Medtronic; grants from Boehringer Ingelheim; grants from Medtronic; grants from Medtronic; grants from Canadian Institutes of Health Research; grants from Biogen Inc; compensation from Brainsgate Ltd for consultant services; and grants from NoNO Inc. Dr Mistry receives funding from National Institutes of Health/NINDS and Patient-Centered Outcomes Research Institute (PCORI) and receives monies for consulting for RAPID AI, Abbvie, and the American Heart Association. Dr Smith is an employee of AbbVie Inc, and holds AbbVie stock and stock options. All inputs to this article are based on personal experiences and opinions, and do not necessarily reflect AbbVie’s views. J. Sutherland is the Clinical Operations Manager for Revalesio. Dr Lyden receives royalty Income for “Thrombolytic Therapy for Acute Stroke” Third Edition Springer Press, is the PI for NINDS grants U24 NS13006000 and UG3 NS119199, and monies for consulting for Apex Innovations. Dr Jauch receives monies for consulting for RapidAI, and reports compensation from Schultz & Pogue, LLP, and McLeod Law Group for expert witness services. Dr Hernandez-Jimenez works for aptaTargets Dr Mocco receives grant funding from Stryker Neurovascular, Penumbra, and Microvention, as well as a research award from PCORI. Dr Mocco reports stock holdings in Endostream; stock holdings in Viz.ai; stock options in Neuroradial Technologies; stock options in Echovate; compensation from CVAid for consultant services; compensation from Penumbra Inc for other services; stock options in Whisper; compensation from RIST Neurovascular, Inc, for consultant services; stock options in Neurotechnology Investors, LLC, Managers; stock holdings in Q’Apel; grants from PCORI; compensation from Stryker for other services; compensation from MicroVention Inc for other services; stock holdings in Vastrax; stock holdings in Imperative Care Inc; compensation from Synchron for consultant services; stock holdings in Blinktbi; stock holdings in Cerebrotech; stock options in Sim&Cure; stock holdings in Spinaker; stock options in Spinaker; compensation from CVAid for consultant services; stock options in Songbird; stock options in E8; compensation from Perflow for consultant services; employment by Mount Sinai Health System; stock options in Tulavi; stock options in Borvo; stock holdings in Viseon Inc; stock options in Radical; and stock options in Neurolutions. E. Deljkich is Vice President, Clinical Affairs, Imperative Care. Dr Kamel is the PI for the ARCADIA trial (Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke; NIH/NINDS U01NS095869), which received in-kind study drug from the BMS-Pfizer Alliance for Eliquis and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); Deputy Editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; end point adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group.

Experimental evidence indicates that the control of the inflammatory response after myocardial infarction is a key strategy to reduce cardiac injury. Cellular damage after blood flow restoration in the heart promotes sterile inflammation through the release of molecules that activate pattern recognition receptors, among which TLR4 is the most prominent. Transient regulation of TLR4 activity has been considered one of the potential therapeutic interventions with greater projection towards the clinic. In this regard, the characterization of an aptamer (4FT) that acts as a selective antagonist for human TLR4 has been investigated in isolated macrophages from different species and in a rat model of cardiac ischemia/reperfusion (I/R). The binding kinetics and biological responses of murine and human macrophages treated with 4FT show great affinity and significant inhibition of TLR4 signaling including the NF-κB pathway and the LPS-dependent increase in the plasma membrane currents (Kv currents). In the rat model of I/R, administration of 4FT following reoxygenation shows amelioration of cardiac injury function and markers, a process that is significantly enhanced when the second dose of 4FT is administered 24 h after reperfusion of the heart. Parameters such as cardiac injury biomarkers, infiltration of circulating inflammatory cells, and the expression of genes associated with the inflammatory onset are significantly reduced. In addition, the expression of anti-inflammatory genes, such as IL-10, and pro-resolution molecules, such as resolvin D1 are enhanced after 4FT administration. These results indicate that targeting TLR4 with 4FT offers new therapeutic opportunities to prevent cardiac dysfunction after infarction., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Toll-like receptor 4 (TLR4) contributes to the pathogenesis of coronary ischemia/reperfusion (IR). To test whether the new TLR4 antagonist, ApTOLL, may prevent coronary IR damage, we administered 0.078 mg/kg ApTOLL or Placebo in pigs subjected to IR, analyzing the levels of cardiac troponins, matrix metalloproteinases, pro-, and anti-inflammatory cytokines, heart function, and tissue integrity over a period of 7 days after IR. Our results show that ApTOLL reduced cardiac troponin-1 24 h after administration, improving heart function, as detected by a significant recovery of the left ventricle ejection fraction (LVEF) and the shortening fraction (FS) cardiac parameters. The extension of necrotic and fibrotic areas was also reduced, as detected by Evans blue/2,3,5-triphenyltetrazolium chloride (TTC) staining, Hematoxylin/Eosine, and Masson Trichrome staining of heart sections, together with a significant reduction in the expression of the extracellular matrix-degrading, matrix metalloproteinase 9. Finally, the expression of the following cytokines, CCL1, CCL2, MIP1-A-B, CCL5, CD40L, C5/C5A, CXCL1, CXCL10, CXCL11, CXCL12, G-CSF, GM-CSF, ICAM-1, INF-g, IL1-a, ILI-b, IL-1Ra, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, IL16, IL17-A, IL17- E, IL18, IL21, IL27, IL32, MIF, SERPIN-E1, TNF-a, and TREM-1, were also assayed, detecting a pronounced decrease of pro-inflammatory cytokines after 7 days of treatment with ApTOLL. Altogether, our results show that ApTOLL is a promising new tool for the treatment of acute myocardial infarction (AMI).

Baseline chest computed tomography (BCT) in high-risk hematology patients allows for the early diagnosis of invasive pulmonary aspergillosis (IPA). The distribution of BCT implementation in hematology departments and impact on outcome is unknown. A web-based questionnaire was designed. International scientific bodies were invited. The estimated numbers of annually treated hematology patients, chest imaging timepoints and techniques, IPA rates, and follow-up imaging were assessed. In total, 142 physicians from 43 countries participated. The specialties included infectious diseases ( n = 69; 49%), hematology ( n = 68; 48%), and others ( n = 41; 29%). BCT was performed in 57% ( n = 54) of 92 hospitals. Upon the diagnosis of malignancy or admission, 48% and 24% performed BCT, respectively, and X-ray was performed in 48% and 69%, respectively. BCT was more often used in hematopoietic cell transplantation and in relapsed acute leukemia. European centers performed BCT in 59% and non-European centers in 53%. Median estimated IPA rate was 8% and did not differ between BCT (9%; IQR 5-15%) and non-BCT centers (7%; IQR 5-10%) (p = 0.69). Follow-up computed tomography (CT) for IPA was performed in 98% ( n = 90) of centers. In high-risk hematology patients, baseline CT is becoming a standard-of-care. Chest X-ray, while inferior, is still widely used. Randomized, controlled trials are needed to investigate the impact of BCT on patient outcome.

Background and Purpose: Methamphetamine is a powerful addictive, which has been associated with ischemic stroke and brain hemorrhage in humans. Whether and how methamphetamine influences the expression of tight junctions and adenosine triphosphate-binding cassette transporters, which have previously been shown to be regulated by apolipoprotein-E (ApoE) under conditions of brain ischemia, was unknown., Methods: C57BL/6J mice received intraperitoneal injections of methamphetamine (3 times 4 mg/kg separated by 3 hours) either alone or in combination with the ApoE receptor-2 inhibitor receptor-associated protein (40 μg/kg) or the inducible nitric oxide synthase inhibitor 1400W (5 mg/kg). Animals were euthanized 3 or 24 hours after methamphetamine exposure. Tissue responses were evaluated with Western blots, immunoprecipitation, and immunohistochemistry using total brain and cerebral microvessel extracts., Results: Methamphetamine induced a transient activation of stress kinases c-Jun N-terminal kinase 1/2 and p38 in the brain parenchyma and increased intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression on cerebral microvessels without inducing loss of tight junction proteins and without inducing IgG extravasation. Methamphetamine transiently increased the expression of the luminal adenosine triphosphate-binding cassette transporter ABCB1 on cerebral microvessels and reduced the expression of the abluminal transporter ABCC1. Elevated expression of ApoE was noted in the brain parenchyma by methamphetamine, activating ApoE receptor-2 on brain capillaries, deactivating c-Jun N-terminal kinase 1/2 and c-Jun, and regulating ABCB1 and ABCC1 expression. Indeed, ApoE receptor-2 and inducible nitric oxide synthase inhibition prevented the ABCB1 and ABCC1 expression changes., Conclusions: Acute exposure to methamphetamine at doses comparable to those consumed in drug addiction does not induce tight junction breakdown but differentially regulates adenosine triphosphate-binding cassette transporters through the ApoE/ApoE receptor-2/c-Jun N-terminal kinase 1/2 pathway.