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Background: Direct oral anticoagulants (DOACs) reduce the rate of thromboembolism in patients with atrial fibrillation but the benefits and risks in survivors of intracerebral haemorrhage are uncertain. We aimed to determine whether DOACs reduce the risk of ischaemic stroke without substantially increasing the risk of recurrent intracerebral haemorrhage., Methods: PRESTIGE-AF is a multicentre, open-label, randomised, phase 3 trial conducted at 75 hospitals in six European countries. Eligible patients were aged 18 years or older with spontaneous intracerebral haemorrhage, atrial fibrillation, an indication for anticoagulation, and a score of 4 or less on the modified Rankin Scale. Patients were randomly assigned (1:1) to a DOAC or no anticoagulation, stratified by intracerebral haemorrhage location and sex. Only the events adjudication committee was masked to treatment allocation. The coprimary endpoints were first ischaemic stroke and first recurrent intracerebral haemorrhage. Hierarchical testing for superiority and non-inferiority, respectively, was performed in the intention-to-treat population. The margin to establish non-inferiority regarding intracerebral haemorrhage was less than 1·735. The safety analysis was done in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03996772, and is complete., Findings: Between May 31, 2019, and Nov 30, 2023, 319 participants were enrolled and 158 were randomly assigned to the DOAC group and 161 to the no anticoagulant group. Patients' median age was 79 years (IQR 73-83). 113 (35%) of 319 patients were female and 206 (65%) were male. Median follow-up was 1·4 years (IQR 0·7-2·3). First ischaemic stroke occurred less frequently in the DOAC group than in the no anticoagulant group (hazard ratio [HR] 0·05 [95% CI 0·01-0·36]; log-rank p<0·0001). The rate of all ischaemic stroke events was 0·83 (95% CI 0·14-2·57) per 100 patient-years in the DOAC group versus 8·60 (5·43-12·80) per 100 patient-years in the no anticoagulant group. For first recurrent intracerebral haemorrhage, the DOAC group did not meet the prespecified HR for the non-inferiority margin of less than 1·735 (HR 10·89 [90% CI 1·95-60·72]; p=0·96). The event rate of all intracerebral haemorrhage was 5·00 (95% CI 2·68-8·39) per 100 patient-years in the DOAC group versus 0·82 (0·14-2·53) per 100 patient years in the no anticoagulant group. Serious adverse events occurred in 70 (44%) of 158 patients in the DOAC group and 89 (55%) of 161 patients in the no anticoagulant group. 16 (10%) patients in the DOAC group and 21 (13%) patients in the no anticoagulant group died. No patients died in the placebo group., Interpretation: DOACs effectively prevent ischaemic strokes in survivors of intracerebral haemorrhage with atrial fibrillation but a part of this benefit is offset by a substantially increased risk of recurrent intracerebral haemorrhage. To optimise stroke prevention in these vulnerable patients, further evidence from ongoing trials and a meta-analysis of randomised data is needed, as well as the evaluation of safer medical or mechanical alternatives for selected patients., Funding: European Commission., Competing Interests: Declaration of interests RV reports research support from Bayer, BMS-Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, and Biogen; honoraria for consultancies and lectures from AstraZeneca, Bayer, BMS-Pfizer, Javelin, and Portola; and being an investigator of the Imperial BRC. EK reports honoraria for lectures or participation on advisory boards from Amgen, AstraZeneca, Bayer, Elpen, Innovis, Pfizer, and Sanofi. VCas reports consultancy work for Bayer as a member of the Steering Committee for OCEANIC-AF; speakers bureau for Bayer, BMS-Pfizer alliance, and Daiichi-Sankyo; and a leadership role for WSO Treasurer. PR reports payment to the institution for consulting from Bayer and Boehringer Ingelheim; lecture fees paid to the institution from Bayer, Boehringer Ingelheim, and Pfizer; travel support from Boehringer Ingelheim; participation on a data and safety monitoring board or advisory board for the NISCI study and Closure-AF study. VR reports grants or contracts from the University Hospital Wuerzburg, Universitätsklinikum Essen. TD reports funding from PIA3 for the Digital Public Health Program. SF-H reports lecture fees from AstraZeneca. YW and HAW report grants for applied research from the National Institute for Health and Care Research. DAL reports investigator-initiated quality improvement grants from Bristol-Myers Squibb and Pfizer (paid to the institution); being a co-applicant on the AFFIRMO project on multimorbidity in atrial fibrillation, ARISTOTELES project on artificial intelligence for management of chronic long term conditions, and the TARGET project on digital twins for personalised management of atrial fibrillation and stroke, all of which are funded by the Horizon Europe Research & Innovation programme; and being a co-chair of European Heart Rhythm Association Advocacy, Quality Improvement, and Health Economics Committee. WEH reports grants or contracts from ABDA—Bundesvereinigung Deutscher Apothekerverbände, ABF Pharmaceutical Services, AOK Thüringen und Sachsen, Bayoonet, BioNTech, Boehringer Ingelheim, Bundesinstitut für Arzneimittel und Medizinprodukte, Bundesministerium für Bildung und Forschung, Bundesverwaltungsamt, Chiesi, Christophsbad, Daiichi Sankyo, Deutsche Forschungsgemeinschaft, Deutsches Krebsforschungszentrum, Dietmar Hopp Stiftung, Dosing, Dr Falk Pharma, Else Kröner-Fresenius Stiftung, Förderinitiative Pharmazeutische Betreuung, Goethe Universität Frankfurt, Gilead, Heidelberg ImmunoTherapeutics, Hepatera, Innovationsfonds des Gemeinsamen Bundesausschusses, Innovative Molecules, Janssen, Kassenärztliche Vereinigung Baden-Württemberg, Landesapothekerkammer Baden-Württemberg, Lesmüller-Stiftung, Martin-Luther Universität Halle, Medizinische Fakultät Heidelberg, MYR, Parexel Intern, Pharmtrace Klinische Entwicklung, Röchling, Sanofi, and Universität Maastricht; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Deutsches Ärzteblatt, Landgericht Hannover, Landesapothekerkammer Baden-Württemberg, Med Fakultät Heidelberg, Regierungspräsidium Stuttgart, Thieme Verlag, and Thieme Compliance; support for attending meetings or travel from Abschiedssymposium Basel and Universitätsklinikum Dresden; patents planned, issued, or pending from Universitätsklinikum Heidelberg, LipOra, Universitätsklinikum Heidelberg, Doxapram, Universitätsklinikum Heidelberg, and Task-1-Inhibitoren zur Behandlung von atrialer Arrhythmie; and participation on a data and safety monitoring board for MYR safety advisory committee. PBN reports research grants and consultant fees from Daiichi-Sankyo, grants from BMS/Pfizer, and grants and consultant fees from Bayer. SP reports grants or contracts from BMS/Pfizer (for the ATTICUS trial), Boehringer-Ingelheim (REVISION trial), Daiichi Sankyo (SPOCT-DOAC 1 study), European Union (PROOF trial), German Federal Joint Committee Innovation Fund (APICES project), German Federal Ministry of Education and Research (APICES project), German Federal Ministry of Education and Research (REVISION trial), Helena Laboratories (SPOCT-DOAC 1 study), and Werfen (SPOCT-DOAC 1 study); consulting fees from Alexion, AstraZeneca, Daiichi Sankyo, and Werfen; and non-significant payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alexion, Bayer, Boehringer-Ingelheim, BMS/Pfizer, and Portola. JP reports grants or contracts and payment for lecture fees from Abbott, Akcea, Daiichi Sankyo, and BMS Pfizer, and grants from the Federal Joint Committee. MLai reports lecture fees from AstraZeneca. PM-S reports lecture fees from Daiichi Sankyo. BN reports personal honoraria for work on a data and safety monitoring board from Simbec-Orion. GP reports research grants from Sanofi and Bayer and honoraria and consulting fees from Amgen, Bayer, Novartis, and Sanofi. RW reports research grants from Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft, European Union, and Medtronic to his institution and personal honoraria for lectures or participation on advisory boards from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, CVRX, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Servier. GN reports honoraria for lectures or participation on advisory boards from AstraZeneca, Bayer, Ferrer, Javelin, Novartis, Pfizer, Sanofi, and Winmedica (all paid to the University of Thessaly). PUH reports research grants from the European Union, German Ministry of Research and Education, German Research Foundation, Federal Joint Committee (G-BA) within the Innovation fund, German Cancer Aid, German Heart Foundation, Bavarian State, Robert Koch Institute, and University Hospital Heidelberg (within RASUNOA-prime); support from an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, and Daiichi Sankyo; and participation on a data and safety monitoring board in publicly funded studies (by German Research Foundation, German Ministry of Research, and Foundations). All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In recent years, telestroke programmes have been established as a fundamental tool for extending acute stroke care to hospitals that lack an on-call neurology service. The main objective of this study is to describe the existence and functioning of the different telestroke systems and networks (TS) in Spain., Methods: We conducted a cross-sectional study to analyse the current situation of TS in Spain using a structured survey distributed among the members of the Stroke Study Group of the Spanish Society of Neurology., Results: Responses were received from 12 of the 17 Spanish autonomous communities, of which 10 had implemented TS. In addition, a literature search revealed that 2 other systems were in operation. Twelve of the 17 regions in the country have TS, achieving coverage of at least 20% of the Spanish population. Of these 10 TS, organisation was regional in 7, provincial in 2, and hospital-based in one. Most TS (9) included at least simple CT and angio-CT studies; 4 also included perfusion imaging. Nine TS operated with professional videoconferencing equipment. However, the suboptimal quality of examination via videoconferencing scan was the main problem identified in 50% of TS. Other problems detected are difficulty obtaining data from registries and the transfer of images between hospitals., Conclusion: In recent years, a significant expansion of telestroke programmes has taken place in Spain, which has improved the accessibility of specialised care in patients with symptoms of acute stroke. This study allows us to describe the different types of TS in Spain and to detect areas for improvement and expansion, and could contribute to defining regional telestroke implementation strategies to offer quality care to the whole population., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: Blood-biomarkers have the potential to aid clinicians in pediatric emergency departments (PED) in managing children with mild traumatic brain injury (mTBI) acutely. However, studies focusing on pediatric populations remain limited. We aim to assess the performances of two routinely used biomarkers in other fields: the neurofilament light chain protein (NfL), and the N-terminal prohormone of brain natriuretic peptide (NTproBNP), to safely discharge children without intracranial injuries (ICIs)., Methods: A prospective multicenter cohort study was conducted, enrolling children suffering from mTBI, both with and without imaging during their acute management in the PED. A blood sample was collected within 24 h post-trauma for biomarker analysis. Inclusion criteria followed the PECARN (Pediatric Emergency Care Applied Research Network) guidelines for the diagnosis of mTBI and for ICI on CT as the primary outcome (CT+)., Results: A total of 302 mTBI patients were analyzed comparing children with ICI (18 CT+) versus all the other children without ICI (54 CT- and 230 in-hospital-observation patients without CT). NfL and NTproBNP were increased in the CT+ group and their performances to safely rule-out patient without ICI reached up to 30% specificity with 100% sensitivity. Equivalent performances were observed whether selecting patients with blood collection within 6 h or 24 h post-trauma., Conclusion: NfL and NTproBNP were described for the first time in children suffering mTBI. Their performances were comparable to well-known biomarkers, such as S100b, GFAP, or HFABP, with the benefit of already being used in routine tests for other diseases. Further large-scale studies are necessary to verify and validate these results., 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 © 2025 Chiollaz, Pouillard, Seiler, Habre, Romano, Ritter Schenck, Spigariol, Korff, Maréchal, Wyss, Gruaz, Montaner, Sanchez and Manzano.)

Adequate secondary prevention in survivors of intracerebral hemorrhage (ICH) who also have atrial fibrillation (AF) is a long-standing clinical dilemma because these patients are at increased risk of recurrent ICH as well as of ischemic stroke. The efficacy and safety of oral anticoagulation, the standard preventive medication for ischemic stroke patients with AF, in ICH patients with AF are uncertain. PRESTIGE-AF is an international, phase 3b, multi-center, randomized, open, blinded end-point assessment (PROBE) clinical trial that compared the efficacy and safety of direct oral anticoagulants (DOACs) with no DOAC (either no antithrombotic treatment or any antiplatelet drug). Randomization occurred in a 1:1 ratio and stratification was based on ICH location and sex. The two co-primary binary endpoints included ischemic stroke and recurrent ICH which will be analyzed hierarchically according to the intention-to-treat principle. Secondary efficacy endpoints encompassed all-stroke and systemic embolism, all-cause and cardiovascular mortality, major adverse cardiac events, and net clinical benefit. Secondary safety endpoints included any major hemorrhage and intracranial hemorrhage. All outcome events were adjudicated by an independent committee. Results of PRESTIGE-AF are expected to support risk-adjusted secondary prevention in ICH survivors with AF and to inform clinical guideline recommendations., Competing Interests: All the authors are a part of European Union's Horizon 2020 research and innovation program under grant agreement No. 754517 (PRESTIGE-AF). E.K. received Speaker Honoraria/Advisory boards/Travel grants from Amgen, AstraZeneca, Bayer, Elpen, Innovis, Pfizer, Sanofi. All outside the submitted work. P.H. received Institutional Research Grants by German Ministry of Research and Education, German Research Foundation, Federal Joint Committee (G-BA) within the Innovation fond, German Cancer Aid, German Heart Foundation, Bavarian State, Robert Koch Institute, University Hospital Heidelberg. Y.W. received support from The National Institute for Health and Care Research (NIHR) under its Program Grants for Applied Research (NIHR202339). P.B.N. received Institutional support by grants of Daiichi Sankyo; Consultancy: Daiichi-Sankoy, Bayer; Speaker Honoraria/Advisory boards: SERVIER, Baye. V.C. received consultancy fees from Bayer Steering Committee Oceanic AF; Speakers: Bayer, BMS-Pfizer alliance and Daiichi-Sankyo. Leadership Role: WSO Treasurer. D.L. received institutional support for investigator-initiated quality improvement grants: Bristol-Myers Squibb and Pfizer; Speaker: Bayer, Boehringer Ingelheim, and Bristol-Myers Squibb/Pfizer; Consultancy: Bristol-Myers Squibb and Boehringer Ingelheim; all outside the submitted work. P.R. received institution support by: Boehringer Ingelheim, Bayer; Speaker: Boehringer Ingelheim, Bayer, Pfizer. Participation on Data Safety: CLOSURE-AF (Institution) NISCI (no payment). W.H. received institutional support by grants from Boehringer Ingelheim and Daiichi-Sankyo. R. V. received speaker Honoraria/Advisory boards: AstraZeneca, Bayer, BMS-Pfizer alliance. Research support: Bayer, BMS-Pfizer alliance, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, Biogen. All other authors declare no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine (HCys) levels, is associated with increased risks of neurovascular diseases such as stroke or hydrocephalus. HHcy promotes oxidative stress, neuroinflammation, and endothelial dysfunction, disrupting the blood-brain barrier and accelerating neurodegeneration. These processes highlight HCys as both a biomarker and a potential therapeutic target in vascular-related neurological disorders. Current research suggests that polyphenols, known for their antioxidant and anti-inflammatory properties, may reduce HCys levels and offer neuroprotection. Polyphenols have demonstrated effectiveness in modulating oxidative stress and inflammatory pathways triggered by HHcy. These compounds may also upregulate enzymatic functions involved in HCys metabolism, thus reducing neurotoxicity. Furthermore, polyphenol-rich diets, like the Mediterranean diet, have been linked to lower HCys levels and a reduced incidence of neurovascular disorders. This review provides an overview of HHcy's role in neurovascular pathologies and examines the therapeutic potential of polyphenols in managing HCys levels and preventing HCys-induced neurovascular damage.

Transient ischemic attack (TIA) is a well-established risk factor for future strokes, making interventions that target recovery and vascular risk crucial. This study aimed to assess the safety and clinical effects of a polyphenol-rich Salicornia ramosissima extract in post-TIA patients. A randomized, triple-blind, placebo-controlled trial was conducted with participants who had a history of TIA or minor stroke and who received 1 g of Salicornia extract or placebo over 11 months. Biochemical analyses, neuropsychological assessments (MOCA test), and gait and aerobic performance tests were conducted at the beginning and the end of the study. A total of 118 individuals were screened, with 80 finally included. Importantly, no significant adverse events were reported throughout the study. A neurological analysis showed an improvement in MOCA scores in patients treated with the Salicornia extract for 11 months. The treatment did not affect spatiotemporal gait parameters, but it significantly reduced blood pressure at baseline and after the aerobic performance test. Biochemically, both groups exhibited mild hyperhomocysteinemia at baseline; however, Salicornia treatment significantly lowered homocysteine levels, bringing them within the normal range. These findings highlight the safety of the Salicornia extract in patients at a high cerebrovascular risk and suggest it as a potential therapeutic option for managing vascular risk factors, such as hyperhomocysteinemia and hypertension. However, further studies are required to confirm the underlying mechanisms and explore broader clinical applications.

Objectives: The objective of this study was to evaluate the feasibility of point-of-care testing (POCT) devices for N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement in prehospital settings, with the aim of improving the speed and accuracy of stroke diagnosis, thereby facilitating quicker and more effective patient care., Methods: Prehospital blood samples were collected from suspected stroke patients, and NT-proBNP levels were measured using a POCT device in ambulances and hospitals. Results from the NT-proBNP POCT and smartphone images were analyzed. Plasma samples underwent Elecsys proBNP II immunoassay after storage at -80ºC., Results: A total of 121 suspected stroke patients were included in the study. The correlation between POCT measured by the POCT and immunoassay for NT-proBNP was strong ( R  = 0.926). Smartphone images also strongly correlated with POCT values at 10 min ( R ²=0.9716) and 15 min ( R ²=0.9405). Stability analysis of samples showed consistent NT-proBNP results and a high correlation ( R  = 0.907) was observed between plasma and whole blood samples for NT-proBNP POCT., Conclusions: This study highlights the potential of NT-proBNP POCT devices in ambulances to expedite stroke diagnosis and management within 10 min. Smartphone integration further enhances efficiency, adding advancement in prehospital stroke management.

Background and Aims: Acute ischemic stroke (AIS) outcome prognostication remains challenging despite available prognostic models. We investigated whether a biomarker panel improves the predictive performance of established prognostic scores., Methods: We investigated the improvement in discrimination, calibration, and overall performance by adding five biomarkers (procalcitonin, copeptin, cortisol, mid-regional pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)) to the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) and age/NIHSS scores using data from two prospective cohort studies (SICFAIL, PREDICT) and one clinical trial (STRAWINSKI). Poor outcome was defined as mRS > 2 at 12 (SICFAIL, derivation dataset) or 3 months (PREDICT/STRAWINSKI, pooled external validation dataset)., Results: Among 412 SICFAIL participants (median age 70 years, quartiles 59-78; 63% male; median NIHSS score 3, quartiles 1-5), 29% had a poor outcome. Area under the curve of the ASTRAL and age/NIHSS were 0.76 (95% CI 0.71-0.81) and 0.77 (95% CI 0.73-0.82), respectively. Copeptin (0.79, 95% CI 0.74-0.84), NT-proBNP (0.80, 95% CI 0.76-0.84), and MR-proANP (0.79, 95% CI 0.75-0.84) significantly improved ASTRAL score's discrimination, calibration, and overall performance. Copeptin improved age/NIHSS model's discrimination, copeptin, MR-proANP, and NT-proBNP improved its calibration and overall performance. In the validation dataset (450 patients, median age 73 years, quartiles 66-81; 54% men; median NIHSS score 8, quartiles 3-14), copeptin was independently associated with various definitions of poor outcome and also mortality. Copeptin did not increase model's discrimination but it did improve calibration and overall model performance., Discussion: Copeptin, NT-proBNP, and MR-proANP improved modest but consistently the predictive performance of established prognostic scores in patients with mild AIS. Copeptin was most consistently associated with poor outcome in patients with moderate to severe AIS, although its added prognostic value was less obvious., 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: F.A.M., V.R., K.U, A.P., D.M., B.H., M.G., W.N.W, C.K., A.M., and J.M. have nothing to disclose. S.W. reports grants from the German Ministry of Research and Education and Deutsche Herzstiftung e.V. C.M. is supported by the IZKF, University Hospital Würzburg (advanced clinician-scientist program, ADVCSP-3) and the German Research Foundation (Comprehensive Research Center 1525 “Cardio-immune interfaces,” #453989101, project C5). CM reports research cooperation with the University of Würzburg and Tomtec Imaging Systems funded by the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany; travel grants, advisory and speakers honoraria from Amgen, Tomtec, Orion Pharma, Alnylam, AKCEA, Sobi, Alexion, Janssen, Pfizer, and EBR Systems; principal investigator in trials sponsored by Alnylam, AstraZeneca, and Bayer. St.St. reports grants, personal fees, non-financial support, and/or other from Boehringer, Bayer, Thermo Fisher, and Pfizer; AstraZeneca, Sanofi, Servier, Alnylam, Ionis, Akcea; and Novartis, outside the submitted work. S.F. reports grants from the German Ministry of Research and Education during the conduct of the study. KGH reports speaker’s honoraria, consulting fees, lecture honoraria, and/or study grants from Abbott, Amarin, AstraZeneca, Bayer Healthcare, Biotronik, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Edwards Lifesciences, Medtronic, Novartis, Pfizer, Portola, Premier Research, Sanofi, SUN Pharma, W.L. Gore and Associates. P.U.H. reports grants from German Ministry of Research and Education, during the conduct of the study; grants from German Ministry of Research and Education, European Union, Charité-Universitätsmedizin Berlin, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationfond, German Research Foundation, Bavarian State, German Cancer Aid, Charité-Universitätsmedizin Berlin (within Mondafis; supported by an unrestricted research grant to the Charité from Bayer), University Göttingen (within FIND-AF randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim), University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), outside the submitted work.

Background: Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction., Methods: Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship., Results: There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P <0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19-1.41], per unit log e IL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98-1.25]; P interaction =0.03). After adjustment for risk factors/medication, the association remained for postacute IL-6 when analyzed per log e unit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP., Conclusions: Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies., Competing Interests: Dr McCabe is supported by grant funding from Irish Institute for Clinical Neuroscience. Dr Woodward performs consultancy work for Freeline. Dr Katan received funding from the Swiss national Science Foundation; grants from the Swiss Heart Foundation and USZ Foundation; participated on advisory boards and speaker honoraria for Medtronic, BMS Pfizer/Jansen, and Astra Zeneca; and in kind contributions from Roche Diagnostics, and Brahms Thermo Fisher Scientific. Dr Rothwell performed consultancy work for Abbott, Bayer, and Sanofi; and data/safety monitoring for Bristol-Myers Squibb. Dr Sudlow received grant support from Asthma Lung UK, British Heart Foundation, Medical Research Council, Kidney Research UK, the Stroke Association, and Diabetes UK. Dr Whiteley performed consultancy work for Bayer and Viatris, data/safety monitoring for several clinical trials (CATIS-ICAD [Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease], TEMPO-2 [Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion], PROTECT-U [Prospective Randomized Open-Label Trial to Evaluate Risk Factor Management in Patients With Unruptured Intracranial Aneurysms], and INTERACT-3 [The Third Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]); and received compensation from UK Courts for expert witness services. Dr Kelly is the principal investigator of the CONVINCE trial (Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke). The other authors report no conflicts.

Introduction: Access to and engagement with primary healthcare can be difficult for marginalized low-income populations residing in inner cities in high-income countries. We designed a study to examine retention in primary care among clients of a novel interdisciplinary primary care clinic in the Downtown Eastside of Vancouver, Canada who did not previously have access to care., Methods: Beginning in June 2021, clients of the Hope to Health clinic were offered enrolment in a cohort study which involved a baseline and follow-up surveys every six months, and linking their data to information from the clinic's electronic medical records. We used Chi-square or Fisher's Exact test and Wilcoxon rank sum test to compare clients who were lost to follow-up (LTFU) or deceased, with clients who were retained in care at the end of follow-up, Cox proportional hazards modeling was used to examine independent associations with mortality or LTFU., Results: Among 425 participants enrolled, the median age was 50 years (IQR 40-59), 286 (67.3%) participants were men and 128 (25.4%) were unstably housed at enrollment. Among 338 participants with at least six months of follow-up after enrolment, 262 participants (67.5%) were retained in care, 20 (5.2%) had moved, 57 (14.7%) were classified as LTFU, and 28 (7.2%) had died with a median of 19.9 months of follow-up time. The risk of death or LTFU was independently associated diagnosed with alcohol use disorder (AUD) (adjusted hazard ratio [AHR] = 2.23 vs. not; 1.38-3.60), frequency of medical doctor visits (AHR = 0.69 per visit per 3 months; 0.60-0.79) and social work visits (AHR = 0.73 per visit per 3 months; 0.59-0.90. Stimulant use disorder or asthma were not significantly associated with retention in care., Conclusion: We found that a primary healthcare model of care was successful in retaining over two-thirds of clients in primary healthcare after more than 18 months of follow-up. Additional supports for those diagnosed with alcohol use disorder are needed to retain them in care., Competing Interests: Declarations. Ethics approval and consent to participate: The study received scientific and ethics approval from the University of British Columbia Research Ethics Board at the St. Paul’s Hospital site (REB number H20-03256). All participants provided informed consent prior to enrolling in the study and all study procedures were in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: JSGM has received limited unrestricted funding, paid to his institution, from Gilead Sciences, Merck, and ViiV Healthcare. All other authors declare that they have no competing interests., (© 2024. The Author(s).)

Objective: Stroke is the leading cause of death and disability. Timely differentiation between ischemic stroke, hemorrhagic stroke, and stroke mimics is critical for tailored treatment and triage. To accelerate the identification of stroke's subtype, we propose to use the levels of circulating tPA as a biomarker., Methods: Biostroke is an observational study performed at the Caen Hospital. We quantified tPA levels in 110 patients with ischemic strokes, 30 patients with hemorrhagic strokes, and 67 stroke mimic patients upon their arrival at the emergency. Two logistic regression models were formulated: one with parameters measurable in an ambulance (Model A) and one with parameters measurable at the hospital (Model H). These models were both tested with or without plasma tPA measurements. Our initial assessment involved evaluating the effectiveness of both models in distinguishing between hemorrhagic strokes, ischemic strokes, and stroke mimics within our study cohort., Results: Plasmatic tPA levels exhibit significant distinctions between hemorrhagic, ischemic, and mimic stroke patients (1.8; 2.5; 2.4 ng/mL, respectively). The inclusion of tPA in model A significantly enhances the classification accuracy of hemorrhagic patients only, increasing identification from 0.67 (95% CI, 0.59 to 0.75) to 0.78 (95% CI, 0.7 to 0.85) (p = 0.0098). Similarly, in model H, classification accuracy of hemorrhagic patients significantly increased with the addition of tPA, rising from 0.75 (95% CI, 0.67 to 0.83) without tPA to 0.86 (95% CI, 0.81 to 0.91) with tPA (p = 0.024)., Interpretations: Our findings underscore the valuable role of tPA levels in distinguishing between stroke subtypes., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking., Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data., Results: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P =4.34×10 -8 ). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings., Conclusions: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice., Competing Interests: Dr Arenillas reports compensation from Medtronic, Daiichi Sankyo, Boehringer Ingelheim, and Pfizer for consultant services; grants from AstraZeneca, Instituto de Salud Carlos III, European Commission and Gerencia de Salud Castilla y León; compensation from Philips for data and safety monitoring services; travel support from Daiichi Sankyo Company. Dr Ribo reports stock holdings in Methinks, Nora, and Ancaonda Biomed; compensation from Cerenovus, Vesalio, Stryker Corporation, Philips, Rapid Pulse, AptaTargets, and Medtronic MiniMed Inc for consultant services; compensation from Sensome for data and safety monitoring services. Dr Heitsch reports employment by Washington University School of Medicine in St. Louis; reports funding from National Institutes of Health and American Heart Association. Dr Dhar reports grants from National Institute of Neurological Disorders and Stroke. The other authors report no conflicts.

Purpose: Carotid artery stenting (CAS) is an effective and minimally invasive method for the treatment of extracranial carotid artery stenosis. The aim of the present study was to explore independent risk factors to predict cerebrovascular events following CAS to identify high-risk patients and improve the safety of CAS in this population., Materials and Methods: HISPANIAS is a national prospective multicenter study that included 14 hospitals that collected data from patients who underwent CAS. We analyzed morbidity and mortality within 30 days after CAS, looking for factors that might be associated with cerebrovascular events (stroke and transient ischemic attack [TIA])., Results: The HISPANIAS cohort included 757 patients: 80.32% were men, the mean age was 70.73 years, and 82.96% underwent symptomatic CAS. Cerebrovascular complications occurred in 42 patients (5.6%), including TIA in 24 patients (70.8% ipsilateral; mean 2.79 days after CAS) and stroke in 18 patients (72.2% ipsilateral; mean 6.72 days after CAS). The main independent clinical predictors of stroke/TIA identified by logistic regression were female sex (odds ratio [OR] 2.29, 95% CI 1.15-4.54) and diabetes (OR 3.29, 95% CI 1.71-6.40). Survival analysis showed that diabetic women, compared with the rest of the patients, had a higher number of events concentrated mainly in the first days after the intervention (p=0.003)., Conclusion: Cerebrovascular ischemic complications after CAS continue to be a challenge for the management of these patients. Although there are other factors, female sex and the presence of diabetes are emerging as strong risk factors for the development of complications after symptomatic CAS., Clinical Impact: Carotid artery stenting (CAS) is an effective and minimally invasive method for the treatment of extracranial carotid artery stenosis. Although CAS has been regarded as a reliable and safety approach, some studies reported that CAS was associated with a higher risk of procedure-related stroke. Cerebrovascular complications after CAS continue to be a main problem and a challenge for the management of these patients. Therefore, it is essential to identify the factors involved in the development of these complications. Our study shows that the combination of female sex and diabetes is associated with a clearly worse outcome, with a greater number of events concentrated mainly in the first days. This is different from other studies that have explored each factor separately. It would be interesting to perform separate interventions for this group given the increased risk of complications., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The long term benefit of carotid angioplasty and stenting (CAS) can be reduced by recurrent stroke related to in stent re-stenosis (ISR). An individualised predictive tool is needed to identify ISR events. A nomogram for individual risk assessment of ISR ≥ 70% after CAS is proposed., Methods: A national observational, prospective, multicentre registry was conducted between January 2015 and December 2020. Cohorts of patients with symptomatic or asymptomatic severe carotid stenosis who underwent CAS with a follow up of at least one year after CAS were included. Duplex ultrasound was used to assess in stent re-stenosis. Pre-operative factors were compared between the non-ISR and ISR groups. Kaplan-Meier and Cox regression were used for variable selection. The nomogram was formulated and validated by concordance indices and calibration curves. An in stent re-stenosis risk table was generated for risk stratification., Results: A total of 354 patients were included in the analysis. The ISR rate of ≥ 70% was 7.6% (n = 27). Peripheral arterial disease (hazard ratio [HR] 3.18, 95% confidence interval [CI] 1.23 - 8.24, p = .017), anterior communicating artery absence (HR 3.38, 95% CI 1.27 - 8.94, p = .016), diabetes mellitus (HR 3.34, 95% CI 1.21 - 9.26, p = .020), female sex (HR 2.99, 95% CI 1.04 - 8.60, p = .041), and pre-procedure pathological ultrasound vasoreactivity (HR 3.87, 95% CI 1.43 -10.50, p = .008), as independent risk factors for ISR of ≥ 70%, were included in the nomogram. The concordance index at 12 and 24 months was 0.83. In low risk groups, ISR of ≥ 70% occurred in 4.8% of patients during follow up compared with 56.2% of patients in the high risk groups (p < .001)., Conclusion: The nomogram and risk evaluation score have good predictive ability for ISR. They can be used as practical clinical tools for individualised risk assessment., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to review the varied 1-4 gastrointestinal (GI) system surgical outcomes among people living with Human Immunodeficiency Virus (PLWH) in the HAART-era., Methods: MEDLINE and EMBASE were searched for primary publications on GI surgery outcomes exclusively in HAART-treated HIV patients. NSQIP-reported complications (NRCs), all-cause complications (ACC) and HIV disease parameters were extracted., Results: 12 studies met study inclusion criteria, examining bowel (4), bariatric (5), cholecystectomy (1), appendectomy (1), and other general abdominal operations (1). The NRC rate was 0%, ≥44.4% and 13.3% in bariatric, bowel and appendix surgeries, respectively. Over half of NRCs were infectious. HAART-treated patients had lower ACC, LOS, and sepsis versus untreated-HIV, and higher ACC, LOS and reoperation rates versus HIV-negative patients., Conclusion: HAART use is associated with markedly improved NRC outcomes post GI surgery among PLWH; however, these remained inferior to those documented among HIV uninfected individuals., Competing Interests: Declaration of competing interest The authors do not report any conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: In addition to stent retrievers, direct aspiration has become a reasonable thrombectomy strategy., Objectives: We carried out the thrombectomy by guiding the aspiration catheter fully over the clot and performing immediate manual aspiration; we call this procedure "embed aspiration"., Methods: In this prospective, non-randomised, single-centre study, we included all patients treated at a high volume-of-care stroke centre between 2017 and 2018 for the TRIANA (Thrombectomy in Andalusia using Aspiration) registry. Thrombectomy was carried out by embed aspiration. Patients were classified according to the success (eTICI 2b67-2c-3) or failure (eTICI 0-1-2a-2b50) of the procedure. Baseline clinical data and outcomes were compared, and multivariate analysis was performed., Results: The embed aspiration technique was used in 370 patients. Treatment was successful in 90.3% of patients. Mean puncture-to-recanalisation time was 25 minutes. The overall rate of good outcomes (mRS 0-2) at 3 months was 64%., Conclusions: This study supports real-life evidence that standardised embed aspiration may be an alternative to stent retrievers for thrombectomy., (Copyright © 2021 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: In addition to clinical factors, blood-based biomarkers can provide useful information on the risk of developing post-stroke epilepsy (PSE). Our aim was to identify serum biomarkers at stroke onset that could contribute to predicting patients at higher risk of PSE., Patients and Methods: From a previous study in which 895 acute stroke patients were followed-up, 51 patients developed PSE. We selected 15 patients with PSE and 15 controls without epilepsy. In a biomarker discovery setting, 5 Olink panels of 96 proteins each, were used to determine protein levels. Biomarkers that were down-regulated and overexpressed in PSE patients, and those that showed the strongest interactions with other proteins were validated using an enzyme-linked immunosorbent assay in samples from 50 PSE patients and 50 controls. A ROC curve analysis was used to evaluate the predictive ability of significant biomarkers to develop PSE., Results: Mean age of the PSE discovery cohort was 68.56 ± 15.1, 40% women and baseline NIHSS 12 [IQR 1-25]. Nine proteins were down-expressed: CASP-8, TNFSF-14, STAMBP, ENRAGE, EDA2R, SIRT2, TGF-alpha, OSM and CLEC1B. VEGFa, CD40 and CCL4 showed greatest interactions with the remaining proteins. In the validation analysis, TNFSF-14 was the single biomarker showing statistically significant downregulated levels in PSE patients ( p  = 0.006) and it showed a good predictive capability to develop PSE (AUC 0.733, 95% CI 0.601-0.865)., Discussion and Conclusion: Protein expression in PSE patients differs from that of non-epileptic stroke patients, suggesting the involvement of several different proteins in post-stroke epileptogenesis. TNFSF-14 emerges as a potential biomarker for predicting PSE., 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: L. Abraira has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals, EISAI Inc, Neuraxpharm, Exeltis, Angelini Pharma and Esteve Laboratorios. E. Fonseca has received funding and speaker fees from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals, EISAI Inc, Neuraxpharm, Sanofi Genzyme, Angelini Pharma and Esteve Laboratorios. M. Toledo has received research funding and speaking fees from UCB Pharma, Angelini, Arvelle, Jazz Pharma, BIAL Pharmaceutical, EISAI Inc and Esteve Laboratorios. E. Santamarina has received research funding and speaking fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc and Esteve Laboratorios. D. Campos has received travel support from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals and Angelini Pharma S. Lallana has received travel support from UCB Pharma, BIAL Pharmaceutical, Jazz Pharmaceuticals and Angelini Pharma. The remaining authors have no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Introduction: Inflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear., Materials and Methods: We did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup analysis according to timing of phlebotomy after the index event., Results: Eleven studies were included (14,002 patients, 42,800 follow-up years), of which seven provided IPD. Fibrinogen was associated with recurrent MACE on unadjusted (RR 1.35, 95% CI 1.17-1.57, supra-median vs sub-median) and adjusted models (RR 1.21, 95% CI 1.06-1.38). Fibrinogen was associated with recurrent stroke on univariate analysis (RR 1.19, 95% CI 1.03-1.39), but not after adjustment (RR 1.11, 95% CI 0.94-1.31). The association with recurrent MACE was consistently observed in patients with post-acute (⩾14 days) fibrinogen measures (RR 1.29, 95% CI 1.16-1.45), but not in those with early phlebotomy (<14 days) (RR 0.98, 95% CI 0.82-1.18) ( P interaction  = 0.01). Similar associations were observed for recurrent stroke., Discussion and Conclusion: Fibrinogen was independently associated with recurrence after stroke, but the association was modified by timing of phlebotomy. Fibrinogen measurements might be useful to identify patients who are more likely to derive benefit from anti-inflammatory therapies after 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: M. Woodward has done consultancy work for Amgen and Freeline. W. Whiteley has done consultancy work for Bayer and Viatris, data/safety monitoring for several clinical trials (ICAD-CATIS, TEMPO-2, PROTECT-U, CHOSEN, PAX-D, INTERACT-3), is a clinical lead for the Scotish Stroke Research Network, and received compensation from UK Courts for expert witness services. P.J. Kelly is the principal investigator of the CONVINCE trial. P.Rothwell reports compensation from Bristol-Myers Squibb for data and safety monitoring services; compensation from Abbott Vascular, Sanofi US Services Inc. and Bayer for consultant services.

The study investigates the utility of heart fatty-acid binding protein (H-FABP) in distinguishing TIA from mimics. Data from 175 patients from the StrokeChip multicenter study was retrospectively analyzed. H-FABP level was measured using a rapid point-of-care test. Findings revealed that H-FABP levels were higher in individuals with TIA compared to mimics [3.10 ng/mL (IQR 2.13-4.78) vs. 1.70 ng/mL (IQR 1.23-2.38)] (p < 0.001). The diagnostic performance of H-FABP, assessed using the area under the curve operating characteristic curve (AUC) was 0. 83 (95% CI = 0.76-0.90) for the final model, indicating good discriminative ability. The PanelomiX determined that a combined cutoff of > 1.85 ng/ml for H-FABP, age > 42.5 years, and baseline NIHSS > 3.5 had a 100% of sensitivity and 23.30% of specificity. The study suggests that H-FABP has potential as a TIA diagnostic biomarker. The rapid application of POCT's for H-FABP measurement supports its potential use in emergency departments and primary care settings., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hypoxic-ischemic (HI) encephalopathy is a cerebrovascular injury caused by oxygen deprivation to the brain and remains a major cause of neonatal mortality and morbidity worldwide. Therapeutic hypothermia is the current standard of care but it does not provide complete neuroprotection. Our aim was to investigate the neuroprotective effect of oleuropein (Ole) in a neonatal (seven-day-old) mouse model of HI. Ole, a secoiridoid found in olive leaves, has previously shown to reduce damage against cerebral and other ischemia/reperfusion injuries. Here, we administered Ole as a pretreatment prior to HI induction at 20 or 100 mg/kg. A week after HI, Ole significantly reduced the infarct area and the histological damage as well as white matter injury, by preserving myelination, microglial activation and the astroglial reactive response. Twenty-four hours after HI, Ole reduced the overexpression of caspase-3 and the proinflammatory cytokines IL-6 and TNF-α. Moreover, using UPLC-MS/MS we found that maternal supplementation with Ole during pregnancy and/or lactation led to the accumulation of its metabolite hydroxytyrosol in the brains of the offspring. Overall, our results indicate that pretreatment with Ole confers neuroprotection and can prevent HI-induced brain damage by modulating apoptosis and neuroinflammation., 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.

Background and Objectives: Prolonged cardiac monitoring (PCM) increases atrial fibrillation (AF) detection after ischemic stroke, but access is limited, and it is burdensome for patients. Our objective was to assess whether midregional proatrial natriuretic peptide (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) could classify people who are unlikely to have AF after ischemic stroke and allow better targeting of PCM., Methods: We analyzed people from the Biomarker Signature of Stroke Aetiology (BIOSIGNAL) study with ischemic stroke, no known AF, and ≥3 days cardiac monitoring. External validation was performed in the Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) study of 28 days of cardiac monitoring in people with ischemic stroke or transient ischemic attack and no known AF. The main outcome is no AF detection. We assessed the discriminatory value of MR-proANP and NT-proBNP combined with clinical variables to identify people with no AF. A decision curve analysis was performed with combined data to determine the net reduction in people who would undergo PCM using the models based on a 15% threshold probability for AF detection., Results: We included 621 people from the BIOSIGNAL study. The clinical multivariable prediction model included age, NIH Stroke Scale score, lipid-lowering therapy, creatinine, and smoking status. The area under the receiver-operating characteristic curve (AUROC) for clinical variables was 0.68 (95% CI 0.62-0.74), which improved with the addition of log 10 MR-proANP (0.72, 0.66-0.78; p = 0.001) or log 10 NT-proBNP (0.71, 0.65-0.77; p = 0.009). Performance was similar for the models with log 10 MR-proANP vs log 10 NT-proBNP ( p = 0.28). In 239 people from the PRECISE study, the AUROC for clinical variables was 0.68 (0.59-0.76), which improved with the addition of log 10 NT-proBNP (0.73, 0.65-0.82; p < 0.001) or log 10 MR-proANP (0.79, 0.72-0.86; p < 0.001). Performance was better for the model with log 10 MR-proANP vs log 10 NT-proBNP ( p = 0.03). The models could reduce the number of people who would undergo PCM by 30% (clinical and log 10 MR-proANP), 27% (clinical and log 10 NT-proBNP), or 20% (clinical only)., Discussion: MR-proANP and NT-proBNP help classify people who are unlikely to have AF after ischemic stroke. Measuring MR-proANP or NT-proBNP could reduce the number of people who need PCM by 30%, without reducing the amount of AF detected., Trial Registration Information: NCT02274727; clinicaltrials.gov/study/NCT02274727.

A budget impact analysis estimates the short-term difference between the cost of the current treatment strategy and a new treatment strategy, in this case to implement population screening for atrial fibrillation (AF). The aim of this study is to estimate the financial impact of implementing population-based AF-screening of 75-year-olds compared with the current setting of no screening from a healthcare payer perspective in eight European countries. The net budget impact of AF-screening was estimated in country-specific settings for Denmark, Germany, Ireland, Italy, Netherlands, Serbia, Spain, and Sweden. Country-specific parameters were used to allow for variations in healthcare systems and to reflect the healthcare sector in the country of interest. Similar results can be seen in all countries AF-screening incurs savings of stroke-related costs since AF treatment reduces the number of strokes. However, the increased number of detected AF and higher drug acquisition will increase the drug costs as well as the costs of physician- and control visits. The net budget impact per invited varied from €10 in Ireland to €122 in the Netherlands. The results showed the increased costs of implementing AF-screening were mainly driven by increased drug costs and screening costs. In conclusion, across Europe, though the initial cost of screening and more frequent use of oral anti-coagulants will increase the healthcare payers' costs, introducing population screening for AF will result in savings of stroke-related costs., Competing Interests: Conflict of interest: M.E., J.L., L.B., and K.A. report no conflicts of interest. L.Å.L. has received lecture fees and advisory board fees from BMS/Pfizer, Bayer, Boehringer Ingelheim, and Zenicor and own stocks in Astra Zeneca. J.H.S. reports to be a member of Medtronic and Vital Beats advisory boards and to have received speaker honoraria and research grants from Medtronic. R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer and Bayer outside this work. D.E. reports no conflicts of interest. C.M. and C.W. are employees of the Institute for Epidemiology, Statistics and Informatics GmbH. The Institute for Epidemiology, Statistics and Informatics GmbH has received grants from Astra Zeneca, Bayer, Bristol-Myers Squibb and CSL Behring outside the submitted work. S.Z.D. reports consultancy fees from VitalBeats, BMS/Pfizer, Cortrium, and Acesion Pharma, speaker grants from BMS/Pfizer and Bayer, and travel grants from Abbott and Boston Scientific. G.B. reports speaker’s fees of small amount from Bayer, Boehringer Ingelheim, Boston, Daiichi Sankyo, Janssen, and Sanofi outside of the submitted work. C.M.B. reports no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Inflammatory biomarkers, as indicators of biological states, provide a valuable approach for accurate and reproducible measurements, crucial for the effective management of mild traumatic brain injury (mTBI) in pediatric patients. This study aims to assess the diagnostic utility of blood-based inflammatory markers IL6, IL8, and IL10 in children with mTBI, including those who did not undergo computed tomography (CT) scans., Methods: A prospective multicentric cohort study involving 285 pediatric mTBI patients was conducted, stratified into CT-scanned and non-CT-scanned groups within 24 h post-trauma, alongside 74 control subjects. Biomarker levels were quantitatively analyzed using ELISA. Sensitivity and specificity metrics were calculated to determine the diagnostic efficacy of each biomarker., Results: A total of 223 mTBI patients (78%) did not undergo CT scan examination but were kept in observation for symptoms monitoring at the emergency department (ED) for more than 6 h (in-hospital-observation patients). Among CT-scanned patients ( n = 62), 14 (23%) were positive (CT+). Elevated levels of IL6 and IL10 were found in mTBI children compared to controls. Within mTBI patients, IL6 was significantly increased in CT+ patients compared to both CT- and in-hospital-observation patients. No significant differences were observed for IL8 among the compared groups. IL6 yielded a specificity of 48% in identifying CT- and in-hospital-observation patients, with 100% sensitivity in excluding all CT+ cases. These performances were maintained whether IL6 was measured within 6 h or within 24 h after the trauma., Conclusion: The inflammatory marker IL6 emerges as a robust biomarker, showing promising stratification value for pediatric mTBI patients undergoing CT scans or staying in observation in a pediatric ED., 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 Chiollaz, Pouillard, Habre, Seiler, Romano, Spigariol, Ritter Schenk, Korff, Maréchal, Wyss, Gruaz, Montaner, Manzano and Sanchez.)

Background: DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. We investigated whether bronchoalveolar lavage (BAL) cells of people living with HIV (PLWH) demonstrate epigenetic disruptions and advanced epigenetic aging., Methods: BAL cell DNA methylation from 25 PLWH and 16 HIV-uninfected individuals were tested for differential methylation of Alu and LINE-1 sites, markers of aging. We used a weighted gene correlation network analysis to identify HIV- and age-associated co-methylation networks. We tested the effect of HIV on DNA methylation using a robust linear model (false discovery rate < 0.10)., Results: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways (e.g., Ras signaling and T-cell receptors). We identified 6428 CpG sites associated with HIV., Conclusions: We have shown here for the first time that alterations in the DNA methylation of BAL cells in the lung with HIV show a pattern of advanced aging. This study strongly supports that HIV may contribute to an increased the risk of lung comorbidities through the epigenetics of aging.

Background/Objectives : Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease leading to significant morbidity and mortality. Despite advances in genetic diagnosis, the underlying pathophysiology remains incompletely understood. Proteomic studies offer insights into disease mechanisms by identifying altered protein expression patterns. Here, we conducted a proteomic analysis to elucidate molecular pathways associated with CADASIL. Methods : We enrolled genetically diagnosed CADASIL patients and healthy, genetically related controls. Plasma samples were subjected to proteomic analysis using the Olink platform, measuring 552 proteins across six panels. The data were analyzed from several approaches by using three different statistical methods: Exploratory Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA), differential expression with moderated t -test, and gene set enrichment analysis (GSEA). In addition, bioinformatics analysis, including volcano plot, heatmap, and Variable Importance on Projection (VIP) scores from the PLS-DA model were drawn. Results : Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels ( p < 0.05), while PPY showed downregulation ( p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. Furthermore, MIC-A/B expression varied significantly between patients with mutations in exon 4 versus exon 11 of the NOTCH3 gene ( p < 0.05), highlighting potential immunological mechanisms underlying CADASIL. We identified altered pathways using GSEA, applied after ranking the study data. Conclusions : Our study provides novel insights into the proteomic profile of CADASIL, identifying dysregulated proteins associated with vascular pathology, metabolic dysregulation, and immune activation. These findings contribute to a deeper understanding of CADASIL pathophysiology and may inform the development of targeted therapeutic strategies. Further research is warranted to validate these biomarkers and elucidate their functional roles in disease progression.

Background: The evolution of ischemic stroke is different accordin'g to sex and is one of the main causes of death in women. Previous studies have shown that women are less likely to receive acute treatment, and stroke center type is an important predictor of door-to-needle times. We investigated whether women are attended in a similar way to men in the telestroke network with specialized stroke physicians., Methods: A prospective registry of ischemic strokes recorded in the centralized Andalusian telestroke network was analyzed, focusing on sex differences. Demographic data, clinical characteristics, neuroimaging data, treatment intervals, follow-up visits, and clinical outcomes were collected., Results: A total of 3009 suspected stroke patients were attended to in the telestroke network from 2019 to 2023, of which 42.74% were women. Women were older ( p < 0.001) and less independent upon arrival ( p = 0.006) than men. There was no difference in the treatment received or in the treatment time intervals between the groups. Importantly, there was no difference in modified Rankin scale scores at 3 months between sexes. At 3 months post-stroke follow-up, women had fewer imaging tests ( p = 0.018) and fewer outpatient visits ( p < 0.001) than men., Conclusions: No significant difference between men and women has been found in the acute treatment of stroke in a large telestroke network. However, the same is not true for the follow-up and management of patients after the acute phase. This fact supports that strict adherence to protocols and specialization of care lead to equal care that avoids sex differences in stroke treatment and functional outcomes., (© Soledad Pérez-Sánchez et al., 2024; Published by Mary Ann Liebert, Inc.)

Background: The issue of sex differences in stroke has gained concern in the past few years. However, multicenter studies are still required in this field. This study explores sex variation in a large number of patients and compares stroke characteristics among women in different age groups and across different countries., Methods: This multicenter retrospective cross-sectional study aimed to compare sexes regarding risk factors, stroke severity, quality of services, and stroke outcome. Moreover, conventional risk factors in women according to age groups and among different countries were studied., Results: Eighteen thousand six hundred fifty-nine patients from 9 countries spanning 4 continents were studied. The number of women was significantly lower than men, with older age, more prevalence of AF, hypertension, and dyslipidemia. Ischemic stroke was more severe in women, with worse outcomes among women (p: < 0.0001), although the time to treatment was shorter. Bridging that was more frequent in women (p:0.002). Analyzing only women: ischemic stroke was more frequent among the older, while hemorrhage and TIA prevailed in the younger and stroke of undetermined etiology. Comparison between countries showed differences in age, risk factors, type of stroke, and management., Conclusion: We observed sex differences in risk factors, stroke severity, and outcome in our population. However, access to revascularization was in favor of women., (© 2023. The Author(s).)

Objective: The modified Centers for Disease Control and Prevention (mCDC) criteria have been proposed for diagnosing and managing stroke-associated pneumonia (SAP). The objective was to investigate the impact of SAP on stroke outcome depending on whether or not it conforms to mCDC criteria. Our secondary objective was to identify the responsible factors for antibiotic initiation in stroke patients., Methods: We conducted a prospective, multicenter, observational study of ischemic stroke patients with moderate to severe stroke (NIHSS≥4) admitted within 24 h. For 7 days, mCDC criteria were assessed daily, and infections and antibiotics were recorded. Pneumonias were divided into those fulfilling mCDC criteria (mCDC-SAP) or not (other pneumonias, OPn). The effect of each type of pneumonia on 3-month outcome was evaluated in separated logistic regression models. Factors associated with antibiotic initiation were explored using a random forest analysis., Results: Of the 342 patients studied, infections were diagnosed in 72 (21.6%), including 39 (11.7%) cases of pneumonia. Of them, 25 (7.5%) fulfilled mCDC criteria. Antibiotics were used in 92% of mCDC-SAP and 64.3% of OPn. In logistic regression analysis, mCDC-SAP, but not OPn, was an independent predictor of poor outcome [OR, 4.939 (1.022-23.868)]. The random forest analysis revealed that fever had the highest importance for antibiotic initiation., Interpretation: The mCDC criteria might be useful for detecting clinically relevant SAP, which is associated with poor outcomes. Isolated signs of infection were more important for antibiotic initiation than compliance with pre-defined criteria. Therefore, adherence to mCDC criteria might result in antibiotic saving without compromising clinical outcome., 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 Rabaneda-Lombarte, Faura, Ezcurra-Díaz, Olivé-Gadea, Álvarez-Larruy, Vidal-de Francisco, Domínguez-Mayoral, Avellaneda, Freijo, Zapata-Arriaza, Serrano-Heras, Alcahut-Rodríguez, Fernández-Pérez, Moniche, Pérez-Sánchez, Millán, Rubiera, Dorado, Maisterra, Montaner and Bustamante.)

Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, β-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery., (© 2024. The Author(s).)

Plant extracts rich in phenolic compounds have been reported to exert different bioactive properties. Despite the fact that there are plant extracts with completely different phenolic compositions, many of them have been reported to have similar beneficial properties. Thus, the structure-bioactivity relationship mechanisms are not yet known in detail for specific classes of phenolic compounds. In this context, this work aims to demonstrate the relationship of extracts with different phenolic compositions versus different bioactive targets. For this purpose, five plant matrices ( Theobroma cacao , Hibiscus sabdariffa , Silybum marianum , Lippia citriodora , and Olea europaea ) were selected to cover different phenolic compositions, which were confirmed by the phytochemical characterization analysis performed by HPLC-ESI-qTOF-MS. The bioactive targets evaluated were the antioxidant potential, the free radical scavenging potential, and the inhibitory capacity of different enzymes involved in inflammatory processes, skin aging, and neuroprotection. The results showed that despite the different phenolic compositions of the five matrices, they all showed a bioactive positive effect in most of the evaluated assays. In particular, matrices with very different phenolic contents, such as T. cacao and S. marianum, exerted a similar inhibitory power in enzymes involved in inflammatory processes and skin aging. It should also be noted that H. sabdariffa and T. cacao extracts had a low phenolic content but nevertheless stood out for their bioactive antioxidant and anti-radical capacity. Hence, this research highlights the shared bioactive properties among phenolic compounds found in diverse matrices. The abundance of different phenolic compound families highlights their elevated bioactivity against diverse biological targets.

Introduction: Acute ischemic stroke (AIS) is a time-critical medical emergency. For patients with large-vessel occlusions (LVO), mechanical thrombectomy (MT) is the gold-standard treatment. Mobile Stroke Units (MSUs) provide on-site diagnostic capabilities via computed tomography (CT) and have been shown to improve functional outcomes in stroke patients, but are cost-efficient only in urban areas. Blood biomarkers have recently emerged as possible alternative to cerebral imaging for LVO diagnosis. Prehospital LVO diagnosis offers the potential to transport patients directly to centers that have MT treatment available. In this study, we assess the accuracy of combining two biomarkers, HFABP and NT-proBNP, with clinical indicators to detect LVO using ultra-early prehospital blood samples. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00030399)., Methods and Analysis: We plan a multicenter prospective observational study with 800 patients with suspected stroke enrolled within 24 h of symptom onset. Study participants will be recruited at three sites (MSUs) in Berlin, Germany. Blood-samples will be taken pre-hospitally at the scene and tested for HFABP and NT-proBNP levels. Additional clinical data and information on final diagnosis will be collected and documented in an electronic case report form (eCRF). Sensitivity and specificity of the combination will be calculated through iterative permutation-response calculations., Discussion: This study aims to evaluate the diagnostic capabilities of a combination of the biomarkers HFABP and NT-proBNP in LVO prediction. In contrast to most other biomarker studies to date, by employing MSUs as study centers, ultra-early levels of biomarkers can be analyzed. Point-of-care LVO detection in suspected stroke could lead to faster treatment in both urban and rural settings and thus improve functional outcomes on a broader scale., Clinical Trial Registration: Deutsches Register klinischer Studien https://drks.de/search/de/trial/DRKS00030399, DRKS00030399., Competing Interests: HA reports Presidency in the PREhospital Stroke Organization (PRESTO) and having received consultancy fees from Roche Diagnostics and NovoNordisk. FG owns stocks in JNJ, ABBV, BMY, and PFE. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kaffes, Bondi, Geisler, Grittner, Haacke, Ihl, Lorenz, Schehadat, Schwabauer, Wendt, Zuber, Kübler-Weller, Lorenz-Meyer, Sanchez, Montaner, Audebert and Weber.)

Background and Objectives: Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention., Methods: Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after log e transformation. We then did study-level meta-analysis with comparable published studies not providing IPD. Preferred Reporting Items for Systematic Review and Meta-Analyses IPD guidelines were followed., Results: IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, p = 0.01), stroke of undetermined cause (UND) (RR 1.78, 1.19-2.66, p = 0.005), and small vessel occlusion (SVO) (RR 1.71, 0.99-2.96, p = 0.053) (quarter 4 [Q4] vs quarter 1 [Q1]). No association was observed for stroke due to cardioembolism or other determined cause. Similar results were seen for recurrent stroke and when analyzed per log e unit increase for MACE (LAA, RR 1.26 [1.06-1.50], p = 0.009; SVO, RR 1.22 [1.01-1.47], p = 0.04; UND, RR 1.18 [1.04-1.34], p = 0.01). High-sensitivity CRP was associated with recurrent MACE in UND stroke only (Q4 vs Q1 RR 1.45 [1.04-2.03], p = 0.03). Findings were consistent on study-level meta-analysis of the IPD results with 2 other comparable studies (20,136 patients)., Discussion: Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.

Rationale: In-stent reocclusion after endovascular therapy has a negative impact on outcomes in acute ischemic stroke (AIS) due to tandem lesions (TL). Optimal antiplatelet therapy approach in these patients to avoid in-stent reocclusion is yet to be elucidated., Aims: To assess efficacy and safety of intravenous tirofiban versus intravenous aspirin in patients undergoing MT plus carotid stenting in the setting of AIS due to TL., Sample Size Estimates: Two hundred forty patients will be enrolled, 120 in every treatment arm., Methods and Design: A multicenter, prospective, randomized, controlled (aspirin group), assessor-blinded clinical trial will be conducted. Patients fulfilling the inclusion criteria will be randomized at MT onset to the experimental or control group (1:1). Intravenous aspirin will be administered at a 500-mg single dose and tirofiban at a 500-mcg bolus followed by a 200-mcg/h infusion during the first 24 h. All patients will be followed for up to 3 months., Study Outcomes: Primary efficacy outcome will be the proportion of patients with carotid in-stent thrombosis within the first 24 h after MT. Primary safety outcome will be the rate of symptomatic intracranial hemorrhage., Discussion: This will be the first clinical trial to assess the best antiplatelet therapy to avoid in-stent thrombosis after MT in patients with TL., Trial Registration: The trial is registered as NCT05225961. February, 7th, 2022., (© 2024. The Author(s).)

Objective: To understand the similarities and differences between acute ischemic stroke and acute myocardial infarction (AMI) to help in the development of specific or common treatment strategies., Methods: Using an aptamer-based proteomic array, we measured and compared 1310 circulating proteins in the blood of 40 patients with AIS, 9 patients with AMI, and 31 healthy controls. Pathway enrichment analysis was performed using GSEA and g:profiler., Results: Ninety-four proteins were differentially expressed in AIS, and 284 were differentially expressed in AMI. Of these, 8 were specific to cerebral ischemia, and 197 were specific to myocardial infarction. Forty-two proteins were altered in both ischemia processes. Most altered pathways in AIS could be classified as immune response, cell cycle processing, molecular transport, or signaling. Pathways altered in AMI were mostly related to lipid metabolism and transport, highlighting cholesterol metabolic processes and estrogen signaling. In both types of ischemia, we found pathways related to metabolism, specifically purine metabolism, and signaling processes, such as TNF signaling or MAPK1/3., Conclusions: The present study revealed proteins and pathways that were specifically altered in cerebral ischemia, in cardiac ischemia, or in both diseases, providing information on the similarities and differences of ischemic conditions. The role of common and specific proteins and pathways should be explored in detail to find possible therapeutic targets., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs., Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion., Methods and Design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial., Study Outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted., Sample Size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation., Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia., Trial Registrations: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31., 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.

Background: Predicting a challenging clot when performing mechanical thrombectomy in acute stroke can be difficult. One reason for this difficulty is a lack of agreement on how to precisely define these clots. We explored the opinions of stroke thrombectomy and clot research experts regarding challenging clots, defined as difficult to recanalize clots by endovascular approaches, and clot/patient features that may be indicative of such clots., Methods: A modified DELPHI technique was used before and during the CLOTS 7.0 Summit, which included experts in thrombectomy and clot research from different specialties. The first round included open-ended questions and the second and final rounds each consisted of 30 closed-ended questions, 29 on various clinical and clot features, and 1 on number of passes before switching techniques. Consensus was defined as agreement ≥ 50%. Features with consensus and rated ≥ 3 out of 4 on the certainty scale were included in the definition of a challenging clot., Results: Three DELPHI rounds were performed. Panelists achieved consensus on 16/30 questions, of which 8 were rated 3 or 4 on the certainty scale, namely white-colored clots (mean certainty score 3.1), calcified clots under histology (3.7) and imaging (3.7), stiff clots (3.0), sticky/adherent clots (3.1), hard clots (3.1), difficult to pass clots (3.1) and clots that are resistant to pulling (3.0). Most panelists considered switching endovascular treatment (EVT) techniques after 2-3 unsuccessful attempts., Conclusion: This DELPHI consensus identified 8 distinct features of a challenging clot. The varying degree of certainty amongst the panelists emphasizes the need for more pragmatic studies to enable accurate a priori identification of such occlusions prior to EVT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background and Objectives: Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy., Methods: We searched articles until January 25, 2022, in MEDLINE, Embase, PsycInfo, Web of Science, and Cochrane. The primary outcome was the difference in mean biomarker levels in patients with and without post-brain injury epilepsy. We used the modified quality score on prognostic studies for risk of bias assessment. We calculated each biomarker's pooled standardized mean difference (SMD) and 95% CI. Molecular interaction network and enrichment analyses were conducted in Cytoscape (PROSPERO CRD42021297110)., Results: We included 22 studies with 1,499 cases with post-brain injury epilepsy and 7,929 controls without post-brain injury epilepsy. Forty-five biomarkers in the blood or CSF were investigated with samples collected at disparate time points. Of 22 studies, 21 had a moderate-to-high risk of bias. Most of the biomarkers (28/45) were investigated in single studies; only 9 provided validation data, and studies used variable definitions for early-onset and late-onset seizures. A meta-analysis was possible for 19 biomarkers. Blood glucose levels in 4 studies were significantly higher in patients with poststroke epilepsy (PSE) than those without PSE (SMD 0.44; CI 0.19-0.69). From individual studies, 15 biomarkers in the blood and 7 in the CSF were significantly associated with post-brain injury epilepsy. Enrichment analysis identified that the significant biomarkers (interleukin [IL]-6, IL-1β]) were predominantly inflammation related., Discussion: We cannot yet recommend using the reported biomarkers for designing antiepileptogenesis trials or use in the clinical setting because of methodological heterogeneity, bias in the included studies, and insufficient validation studies. Although our analyses indicate the plausible role of inflammation in epileptogenesis, this is likely not the only mechanism. For example, an individual's genetic susceptibilities might contribute to his/her risk of epileptogenesis after brain injury. Rigorously designed biomarker studies with methods acceptable to the regulatory bodies should be conducted., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Introduction: Therapeutic hypothermia is a promising candidate for stroke treatment although its efficacy has not yet been demonstrated in patients. Changes in blood molecules could act as surrogate markers to evaluate the efficacy and safety of therapeutic cooling., Methods: Blood samples from 54 patients included in the EuroHYP-1 study (27 treated with hypothermia, and 27 controls) were obtained at baseline, 24 ± 2 h, and 72 ± 4 h. The levels of a panel of 27 biomarkers, including matrix metalloproteinases and cardiac and inflammatory markers, were measured., Results: Metalloproteinase-3 (MMP-3), fatty-acid-binding protein (FABP), and interleukin-8 (IL-8) increased over time in relation to the hypothermia treatment. Statistically significant correlations between the minimum temperature achieved by each patient in the hypothermia group and the MMP-3 level measured at 72 h, FABP level measured at 24 h, and IL-8 levels measured at 24 and 72 h were found. No differential biomarker levels were observed in patients with poor or favorable outcomes according to modified Rankin Scale scores., Conclusion: Although the exact roles of MMP3, FABP, and IL-8 in hypothermia-treated stroke patients are not known, further exploration is needed to confirm their roles in brain ischemia., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: The secondary impacts of the COVID-19 pandemic may disproportionately affect gay, bisexual, and other men who have sex with men (GBM), particularly related to HIV prevention and treatment outcomes. We applied syndemic theory to examine PrEP disruptions during the during the height of the COVID-19 pandemic in Vancouver, Canada., Methods: Sexually-active GBM, aged 16 + years, were enrolled through respondent-driven sampling (RDS) from February 2017 to August 2019. Participants completed a Computer-Assisted Self-Interview every six months and data were linked to the BC PrEP Program (program responsible for publicly funded PrEP in the province) to directly measure PrEP disruptions. The analysis period for this study was from March 2018-April 2021. We used univariable generalized linear mixed models to examine (1) six-month trends for syndemic conditions: the prevalence of moderate/severe depressive or anxiety symptoms, polysubstance use, harmful alcohol consumption, intimate partner violence, and (2) six-month trends for PrEP interruptions among HIV-negative/unknown GBM. We also applied 3-level mixed-effects logistic regression with RDS clustering to examine whether syndemic factors were associated with PrEP interruptions., Results: Our study included 766 participants, with 593 participants who had at least one follow-up visit. The proportion of respondents with abnormal depressive symptoms increased over the study period (OR = 1.35; 95%CI = 1.17, 1.56), but we found decreased prevalence for polysubstance use (OR = 0.89; 95%CI = 0.82, 0.97) and binge drinking (OR = 0.74; 95%CI = 0.67, 0.81). We also found an increase in PrEP interruptions (OR = 2.33; 95%CI = 1.85, 2.94). GBM with moderate/severe depressive symptoms had higher odds (aOR = 4.80; 95%CI = 1.43, 16.16) of PrEP interruptions, while GBM with experiences of IPV had lower odds (aOR = 0.38; 95%CI = 0.15, 0.95) of PrEP interruptions. GBM who met clinical eligibility for PrEP had lower odds of experiencing PrEP interruptions (aOR = 0.25; 95%CI = 0.11, 0.60)., Conclusion: There were increasing PrEP interruptions since March 2020. However, those most at risk for HIV were less likely to have interruptions. Additional mental health services and targeted follow-up for PrEP continuation may help to mitigate the impacts of the COVID-19 pandemic on GBM., (© 2023. The Author(s).)

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated ( p -value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p -value = 2.3 × 10 -2 , se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p -value = 1.3 × 10 -3 , se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p -value = 3.6 × 10 -4 , se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p -value = 1.0 × 10 -2 , se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Importance: ApTOLL is a TLR4 antagonist with proven preclinical neuroprotective effect and a safe profile in healthy volunteers., Objective: To assess the safety and efficacy of ApTOLL in combination with endovascular treatment (EVT) for patients with ischemic stroke., Design, Setting, and Participants: This phase 1b/2a, double-blind, randomized, placebo-controlled study was conducted at 15 sites in Spain and France from 2020 to 2022. Participants included patients aged 18 to 90 years who had ischemic stroke due to large vessel occlusion and were seen within 6 hours after stroke onset; other criteria were an Alberta Stroke Program Early CT Score of 6 to 10, estimated infarct core volume on baseline computed tomography perfusion of 5 to 70 mL, and the intention to undergo EVT. During the study period, 4174 patients underwent EVT., Interventions: In phase 1b, 0.025, 0.05, 0.1, or 0.2 mg/kg of ApTOLL or placebo; in phase 2a, 0.05 or 0.2 mg/kg of ApTOLL or placebo; and in both phases, treatment with EVT and intravenous thrombolysis if indicated., Main Outcomes and Measures: The primary end point was the safety of ApTOLL based on death, symptomatic intracranial hemorrhage (sICH), malignant stroke, and recurrent stroke. Secondary efficacy end points included final infarct volume (via MRI at 72 hours), NIHSS score at 72 hours, and disability at 90 days (modified Rankin Scale [mRS] score)., Results: In phase Ib, 32 patients were allocated evenly to the 4 dose groups. After phase 1b was completed with no safety concerns, 2 doses were selected for phase 2a; these 119 patients were randomized to receive ApTOLL, 0.05 mg/kg (n = 36); ApTOLL, 0.2 mg/kg (n = 36), or placebo (n = 47) in a 1:1:√2 ratio. The pooled population of 139 patients had a mean (SD) age of 70 (12) years, 81 patients (58%) were male, and 58 (42%) were female. The primary end point occurred in 16 of 55 patients (29%) receiving placebo (10 deaths [18.2%], 4 sICH [7.3%], 4 malignant strokes [7.3%], and 2 recurrent strokes [3.6%]); in 15 of 42 patients (36%) receiving ApTOLL, 0.05 mg/kg (11 deaths [26.2%], 3 sICH [7.2%], 2 malignant strokes [4.8%], and 2 recurrent strokes [4.8%]); and in 6 of 42 patients (14%) receiving ApTOLL, 0.2 mg/kg (2 deaths [4.8%], 2 sICH [4.8%], and 3 recurrent strokes [7.1%]). ApTOLL, 0.2 mg/kg, was associated with lower NIHSS score at 72 hours (mean difference log-transformed vs placebo, -45%; 95% CI, -67% to -10%), smaller final infarct volume (mean difference log-transformed vs placebo, -42%; 95% CI, -66% to 1%), and lower degrees of disability at 90 days (common odds ratio for a better outcome vs placebo, 2.44; 95% CI, 1.76 to 5.00)., Conclusions and Relevance: In acute ischemic stroke, 0.2 mg/kg of ApTOLL administered within 6 hours of onset in combination with EVT was safe and associated with a potential meaningful clinical effect, reducing mortality and disability at 90 days compared with placebo. These preliminary findings await confirmation from larger pivotal trials., Trial Registration: ClinicalTrials.gov Identifier: NCT04734548.

Objectives: Stroke treatment with intravenous tissue-type plasminogen activator (tPA) is effective and efficient, but as its benefits are highly time dependent, it is essential to treat the patient promptly after symptom onset. This study evaluates the cost-effectiveness of a blood biomarker test to differentiate ischemic and hemorrhagic stroke to guide pre-hospital treatment with tPA in patients with suspected stroke, compared with standard hospital management. The standard care for patients suffering stroke consists mainly in diagnosis, treatment, hospitalization and monitoring., Methods: A Markov model was built with four health states according to the modified Rankin scale, in adult patients with suspected moderate to severe stroke (NIHSS 4-22) within 4.5 hours after symptom onset. A Spanish Health System perspective was used. The time horizon was 15 years. Quality-adjusted life-years (QALYs) and life-years gained (LYGs) were used as a measure of effectiveness. Short- and long-term direct health costs were included. Costs were expressed in Euros (2022). A discount rate of 3% was used. Probabilistic sensitivity analysis and several one-way sensitivity analyses were conducted., Results: The use of a blood-test biomarker compared with standard care was associated with more QALYs (4.87 vs. 4.77), more LYGs (7.18 vs. 7.07), and greater costs (12,807€ vs. 12,713€). The ICER was 881€/QALY. Probabilistic sensitivity analysis showed that the biomarker test was cost-effective in 82% of iterations using a threshold of 24,000€/QALY., Conclusions: The use of a blood biomarker test to guide pre-hospital thrombolysis is cost-effective compared with standard hospital care in patients with ischemic stroke., (© 2022. The Author(s).)

Aims: Carotid reocclusion (CRO) after mechanical thrombectomy (MT) in acute ischemic stroke (AIS) due to tandem lesion (TL) or isolated internal carotid occlusion (ICO) is associated with worse clinical outcomes. Our aim was to analyze the predictors and clinical impact of CRO., Methods: A retrospective single-center analysis of all patients with anterior circulation strokes who underwent MT prospectively included in a registry between 2017 and 2020 was performed. ICO and TL as stroke causes were included. Stent deployment was left to the discretion of the interventionist. All patients received at least intravenous aspirin during MT. CRO was assessed using ultrasound within the first 24 h after MT. Efficacy and safety of stenting were assessed., Results: Among 1304 AIS cases, 218 (16.7%) were related to TL or ICO. Of them, 5% (n=11) were associated with internal CRO 24 h after the endovascular procedure. After adjusting per confounders, multivariate analysis showed that the independent variables associated with CRO were the TICI recanalization grade [TICI 2b-3; OR 0.1, 95% confidence interval (CI) 0.01-0.89, p=0.040], pial collateral circulation presence (OR 0.09, 95% CI 0.02-0.45, p=0.03), stent deployment during MT (OR 0.17, 95% CI 0.03-0.84, p=0.030), and general anesthesia use (OR 2.92, 95% CI 1.13-7.90, p=0.034). CRO showed a trend toward worst outcomes (modified Rankin scale 3-6) at 3 months (OR 3.4, 95% CI 0.96-12, p=0.057). After multivariate analysis, variables independently associated with worse outcomes at 90 days were intrastent platelet aggregation phenomena during endovascular therapy, admission National Institute of Health Stroke Scale, and age. Conversely, intravenous thrombolysis and TICI 2b-3 recanalization grade were identified as independent predictors of good outcomes at 90 days., Conclusions: CRO has a relevant clinical impact in our study, associating lower rates of good functional outcomes at 3 months. Independent factors of CRO were the recanalization degree, presence of pial collateral circulation, use of a stent as a protective factor, and use of general anesthesia during thrombectomy.

Background: People living with HIV (PLWH) are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) independent of cigarette smoking. We hypothesized that dysbiosis in PLWH is associated with epigenetic and transcriptomic disruptions in the airway epithelium., Methods: Airway epithelial brushings were collected from 18 COPD + HIV + , 16 COPD - HIV + , 22 COPD + HIV - and 20 COPD - HIV - subjects. The microbiome, methylome, and transcriptome were profiled using 16S sequencing, Illumina Infinium Methylation EPIC chip, and RNA sequencing, respectively. Multi 'omic integration was performed using Data Integration Analysis for Biomarker discovery using Latent cOmponents. A correlation > 0.7 was used to identify key interactions between the 'omes., Results: The COPD + HIV -, COPD -HIV + , and COPD + HIV + groups had reduced Shannon Diversity (p = 0.004, p = 0.023, and p = 5.5e-06, respectively) compared to individuals with neither COPD nor HIV, with the COPD + HIV + group demonstrating the most reduced diversity. Microbial communities were significantly different between the four groups (p = 0.001). Multi 'omic integration identified correlations between Bacteroidetes Prevotella, genes FUZ, FASTKD3, and ACVR1B, and epigenetic features CpG-FUZ and CpG-PHLDB3., Conclusion: PLWH with COPD manifest decreased diversity and altered microbial communities in their airway epithelial microbiome. The reduction in Prevotella in this group was linked with epigenetic and transcriptomic disruptions in host genes including FUZ, FASTKD3, and ACVR1B., (© 2023. The Author(s).)

Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines., Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis., Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase log e IL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase log e hsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43])., Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid-β (Aβ) in brain vessels and is a main cause of lobar intracerebral hemorrhage (ICH) in the elderly. CAA is associated with magnetic resonance imaging (MRI) markers of small vessel disease (SVD). Since Aβ is also accumulated in Alzheimer's disease (AD) in the brain parenchyma, we aimed to study if several single nucleotide polymorphisms (SNPs) previously associated with AD were also associated with CAA pathology. Furthermore, we also studied the influence of APOE and CLU genetic variants in apolipoprotein E (ApoE) and clusterin/apolipoprotein J (ApoJ) circulating levels and their distribution among lipoproteins., Methods: The study was carried out in a multicentric cohort of 126 patients with lobar ICH and clinical suspicion of CAA., Results: We observed several SNPs associated with CAA neuroimaging MRI markers [cortical superficial siderosis (cSS), enlarged perivascular spaces in the centrum semiovale (CSO-EPVS), lobar cerebral microbleeds (CMB), white matter hyperintensities (WMH), corticosubcortical atrophy and CAA-SVD burden score]. Concretely, ABCA7 (rs3764650), CLU (rs9331896 and rs933188), EPHA1 (rs11767557), and TREML2 (rs3747742) were significantly associated with a CAA-SVD burden score. Regarding circulating levels of apolipoproteins, protective AD SNPs of CLU [rs11136000 (T) and rs9331896 (C)] were significantly associated with higher HDL ApoJ content in the lobar ICH cohort. APOEε2 carriers presented higher plasma and LDL-associated ApoE levels whereas APOEε4 carriers presented lower plasma ApoE levels. Additionally, we observed that lower circulating ApoJ and ApoE levels were significantly associated with CAA-related MRI markers. More specifically, lower LDL-associated ApoJ and plasma and HDL-associated ApoE levels were significantly associated with CSO-EPVS, lower ApoJ content in HDL with brain atrophy and lower ApoE content in LDL with the extent of cSS., Discussion: This study reinforces the relevance of lipid metabolism in CAA and cerebrovascular functionality. We propose that ApoJ and ApoE distribution among lipoproteins may be associated with pathological features related to CAA with higher ApoE and ApoJ levels in HDL possibly enhancing atheroprotective, antioxidative, and anti-inflammatory responses in cerebral β-amyloidosis., 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 © 2023 Bonaterra-Pastra, Benítez, Pancorbo, Rodríguez-Luna, Vert, Rovira, Freijo, Tur, Martínez-Zabaleta, Cardona Portela, Vera, Lebrato-Hernández, Arenillas, Pérez-Sánchez, Domínguez-Mayoral, Fàbregas, Mauri, Montaner, Sánchez-Quesada and Hernández-Guillamon.)

In this work, we studied the combined effect of increased temperature and atmospheric CO 2 , salt and drought stress, and inoculation with plant-growth-promoting rhizobacteria (PGPR) on the growth and some nutritional parameters of the edible halophyte Salicornia ramosissima . We found that the increase in temperature and atmospheric CO 2 , combined with salt and drought stresses, led to important changes in S. ramosissima fatty acids (FA), phenols, and oxalate contents, which are compounds of great importance for human health. Our results suggest that the S. ramosissima lipid profile will change in a future climate change scenario, and that levels of oxalate and phenolic compounds may change in response to salt and drought stress. The effect of inoculation with PGPR depended on the strains used. Some strains induced the accumulation of phenols in S. ramosissima leaves at higher temperature and CO 2 while not altering FA profile but also led to an accumulation of oxalate under salt stress. In a climate change scenario, a combination of stressors (temperature, salinity, drought) and environmental conditions (atmospheric CO 2, PGPR) will lead to important changes in the nutritional profiles of edible plants. These results may open new perspectives for the nutritional and economical valorization of S. ramosissima .