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Study Design: A methodological study., Objectives: To establish the criterion-related validity of the Nepali version of the Spinal Cord Independence Measure Self-Report (SCIM-SR)., Setting: Outpatient Department of the Spinal Injury Rehabilitation Center and community of Province no. 3, Nepal., Methods: Community-dwelling individuals with spinal cord injury were enrolled. Participants self-administered the Nepali version of the SCIM-SR while a clinician concurrently administered the SCIM III. Descriptive statistics characterized the sample, while Spearman's rank correlation coefficient and Intraclass correlation coefficient assessed the association between the SCIM III and the Nepali version of the SCIM-SR. Bland Altman's analysis determined the differences., Results: The Spearman's rank correlation coefficient for the total score was 0.961, self-care subscale was 0.590, respiration and sphincter management subscale was 0.897, and mobility subscale was 0.891. The ICC (2,1) and confidence interval for the total score, self-care subscale, respiration and sphincter management subscale, and mobility subscale were 0.989 (0.983-0.993), 0.873 (0.804-0.918), 0.955 (0.931-0.971) and 0.991 (0.987-0.994), respectively. The SCIM-SR scores were lower than the SCIM III in total and all subscale scores. The Bland-Altman's difference for the total score, self-care subscale, respiration and sphincter management subscale, and mobility subscale were 2.55, 1.34, 0.83, and 0.38, respectively., Conclusions: The Nepali version of the SCIM-SR was validated and can be used to evaluate the functional status of individuals with spinal cord injury in the community setting of Nepal., Competing Interests: Competing interests The authors declare no competing interest. Ethics approval The study was approved by the Nepal Health Research Council. We certify that all applicable institutional and government regulations concerning the ethical use of human volunteers were followed during this research., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

While most respiratory viral infections resolve with little harm to the host, severe symptoms arise when infection triggers an aberrant inflammatory response that damages lung tissue. Host regulators of virally induced lung inflammation have not been well defined. Here, we show that enrichment for sialylated, but not asialylated immunoglobulin G (IgG), predicted mild influenza disease in humans and was broadly protective against heterologous influenza viruses in a murine challenge model. Mechanistic studies show that sialylated IgG mediated this protection by inducing the transcription factor repressor element-1 silencing transcription factor (REST), which repressed nuclear factor κB (NF-κB)-driven responses, preventing severe lung inflammation and protecting lung function during influenza infection. Therapeutic administration of a recombinant, sialylated Fc molecule in clinical development similarly activated REST and protected against severe influenza disease, demonstrating that this pathway could be clinically harnessed. Overall, induction of REST through sialylated IgG signaling is a strategy to limit inflammatory disease sequelae in infections caused by antigenically distinct influenza strains., Competing Interests: Declaration of interests T.T.W. is a scientific advisor for Nuvig Therapeutics. M.S.D. is a consultant or on the Scientific Advisory Board for Inbios, Vir Biotechnology, Topspin Therapeutics, Akagera Medicines, Merck, GlaxoSmithKline, and Moderna. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Emergent BioSolutions, Moderna, Topspin Therapeutics, and Vir Biotechnology., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Little scientific evidence exists on maternal and fetal outcomes in aplastic anemia (AA) during pregnancy., Aim: The review was conducted to assess the maternal and fetal outcomes due to AA during pregnancy., Data Sources: Web of Science, EMBASE, PubMed, Scopus, Cochrane CENTRAL, and registries until May 5, 2024., Study Eligibility Criteria: Studies (prospective, retrospective cohort, cross-sectional, one arm, survey, follow-up studies) evaluating AA during pregnancy were searched as per PROSPERO registered protocol (CRD42024506668). Case reports, case series, expert opinion letters, and studies assessing less than or equal to 10 pregnant women were not considered. The primary outcome was the prevalence of preeclampsia in AA pregnancies. The secondary outcomes included spontaneous abortion, preterm premature rupture of membranes, premature rupture of membranes, fetal growth restriction, type of delivery, intrauterine fetal death, maternal and neonatal mortality, and pre and post-pregnancy remission status comparison., Methods: The quality of research was checked using the New Castle-Ottawa risk-of-bias tool. A meta-analysis model with a random effect distribution, coupled with meta-regression, sensitivity analysis, and publication bias assessment, was used in the statistical software R. Standard Equator network study reporting guidelines were followed., Results: Seven (one prospective and six retrospective cohort) studies included patients with confirmed AA diagnosis in 248 pregnancies. The pooled prevalence of preeclampsia was 13% (95% CI, 8%-20%). Heterogeneity was low in the present meta-analysis (I 2  = 26%). The secondary outcome evaluation showed a pooled prevalence of 5% (95% CI, 3%-11%) for spontaneous abortion, 4% (95% CI, 1%-11%) for preterm premature rupture of membranes, 10% (95% CI, 3%-28%) for premature rupture of membranes, 6% (95% CI, 3%-11%) for fetal growth restriction, 5% (95% CI, 2%-13%) for intrauterine fetal death, 12% (95% CI, 5%-26%) for post-partum hemorrhage, 74% (95% CI, 45%-91%) for intrapartum transfusion requirement, and 55% (95% CI, 27%-80%) for the cesarean delivery opting. The maternal mortality in pregnancies with AA was 4% (95% CI, 0.01-0.14), whereas neonatal mortality was 7% (95% CI, 0.03-0.18). The odds of AA complete remission were better in pre-pregnancy than post-pregnancy (OR = 0.36; 95% CI = 0.08-1.66), although the results remain insignificant. The leave-one-out sensitivity analysis did not change the pooled estimates for the primary outcome., Conclusion: A risk of developing preeclampsia was observed in every eighth pregnant woman with an AA diagnosis. AA remission status might worsen after undergoing pregnancy, considering the significant obstetric morbidity and mortality burden., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Inclusion of adaptive design features in a clinical trial provides preplanned flexibility to dynamically modify a trial during its conduct while preserving validity and integrity. Adaptive trials are needed to accelerate the conduct of more efficient, informative, and ethical clinical research in the field of neurology. Stroke is a natural candidate for adoption of these innovative approaches to trial design. This Research Methods in Neurology article is informed by a scoping review that identified 45 completed or ongoing adaptive clinical trials in stroke that were appraised: 15 trials had published results with or without a published protocol and 30 ongoing trials (14 trials had a published protocol, and 16 trials were registered only). Interventions spanned acute (n = 28), rehabilitation (n = 8), prevention (n = 8), and rehabilitation and prevention (n = 1). A subsample of these trials was selected to illustrate the utility of adaptive design features and discuss why each adaptive feature was incorporated in the design to best achieve the aim; whether each individual feature was used and whether it resulted in expected efficiencies; and any learnings during preparation, conduct, or reporting. We then discuss the operational, ethical, and regulatory considerations that warrant careful consideration during adaptive trial planning and reflect on the workforce readiness to deliver adaptive trials in practice. We conclude that adaptive trials can be designed, funded, conducted, and published for a wide range of research questions and offer future directions to support adoption of adaptive trial designs in stroke and neurologic research more broadly.

Medical progress is reflected in the advance from broad clinical syndromes to mechanistically coherent diagnoses. By this metric, research in sepsis is far behind other areas of medicine-the word itself conflates multiple different disease mechanisms, whilst excluding noninfectious syndromes (e.g., trauma, pancreatitis) with similar pathogenesis. New technologies, both for deep phenotyping and data analysis, offer the capability to define biological states with extreme depth. Progress is limited by a fundamental problem: observed groupings of patients lacking shared causal mechanisms are very poor predictors of response to treatment. Here, we discuss concrete steps to identify groups of patients reflecting archetypes of disease with shared underlying mechanisms of pathogenesis. Recent evidence demonstrates the role of causal inference from host genetics and randomised clinical trials to inform stratification analyses. Genetic studies can directly illuminate drug targets, but in addition they create a reservoir of statistical power that can be divided many times among potential patient subgroups to test for mechanistic coherence, accelerating discovery of modifiable mechanisms for testing in trials. Novel approaches, such as subgroup identification in-flight in clinical trials, will improve efficiency. Within the next decade, we expect ongoing large-scale collaborative projects to discover and test therapeutically relevant sepsis archetypes., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Hyperkalemia is frequently encountered and associated with cardio-vascular mortality in chronic hemodialysis (HD) patients. While online hemodiafiltration (OL-HDF) is thought to offer clinical benefit over high-flux HD, the impact of convective clearance on intra-dialytic potassium removal is unknown., Methods: Chronic dialysis patients undergoing outpatient HD or OL-HDF at a single center attached to a university hospital were recruited in a prospective observational study. Spent dialysate along with clinical and biological variables were collected during a single mid-week session., Results: We included 141 patients, with 21 treated with HD and 120 with OL-HDF. Mean age was 65.7 ± 15.6 years with 87 (61.7%) men. Mean intra-dialytic potassium removal was 69.9 ± 34.2 mmol. Patients on OL-HDF and HD have similar intra-dialytic potassium removal, with mean values of 69.1 ± 34.2 and 74.3 ± 35.0, respectively. In multivariate analysis, factors associated with intra-dialytic potassium removal were (decreasing order of effect size): dialysate potassium (β -15.5, p < 0.001), pre-HD serum potassium (β 9.1, p < 0.001), and session time (β 7.8, p = 0.003). In OL-HDF patients, substitution flow was not associated with potassium removal., Conclusion: In chronic dialysis patients, convective therapy provided by OL-HDF does not affect potassium removal when compared with high-flux HD. Moreover, the importance of convective volume is not associated with potassium clearance in OL-HDF. Overall, session length and serum-to-dialysate potassium gradient are the main determinants of potassium clearance regardless of dialysis modality. Those results should inform clinicians on the optimal therapy in chronic dialysis patients in the era of OL-HDF., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Just as the value of crude oil is unlocked through refining, the true potential of air quality data is realized through systematic processing, analysis, and application. This refined data is critical for making informed decisions that may protect health and the environment. Perhaps ground-based air quality monitoring data often face quality control issues, notably outliers. The outliers in air quality data are reported as error and event-based. The error-based outliers are due to instrument failure, self-calibration, sensor drift over time, and the event based focused on the sudden change in meteorological conditions. The event-based outliers are meaningful while error-based outliers are noise that needs to be eliminated and replaced post-detection. In this study, we address error-based outlier detection in air quality data, particularly targeting particulate pollutants (PM 2.5 and PM 10 ) across various monitoring sites in Delhi. Our research specifically examines data from sites with less than 5% missing values and identifies four distinct types of error-based outliers: extreme values due to measurement errors, consecutive constant readings and low variance due to instrument malfunction, periodic outliers from self-calibration exceptions, and anomalies in the PM 2.5 /PM 10 ratio indicative of issues with the instruments' dryer unit. We developed a robust methodology for outlier detection by fitting a non-linear filter to the data, calculating residuals between observed and predicted values, and then assessing these residuals using a standardized Z-score to determine their probability. Outliers are flagged based on a probability threshold established through sensitivity testing. This approach helps distinguish normal data points from suspicious ones, ensuring the refined quality of data necessary for accurate air quality modeling. This method is essential for improving the reliability of statistical and machine learning models that depend on high-quality environmental data., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Tuberculosis (TB) is a disease with social issue. Tribal people are disproportionately affected by TB. There is a scarcity of data on issues of TB management among the tribal groups of India. The objective of this study was to get in-depth understanding of the issues hindering TB management among the tribal communities of Rajasthan, India., Methods: We conducted qualitative study involving in-depth interviews with purposively selected healthcare service providers of the selected tribal areas of Rajasthan. Beside this, in-depth interviews and focus group discussions were also conducted among the purposively selected tribal people of these tribal areas. Data was collected using predesigned interview guides and a focus group discussion guide in their local setting in the local language. Information obtained were transcribed and translated into English language before analysing. Translated data was then coded and thematically organized. Inductive coding was used to identify emerging themes and sub-themes relevant to issues that occur during TB management., Results: Several locally relevant issues were identified which negatively affected TB management in tribal areas of Rajasthan, India. Substance abuse, lack of awareness, discriminative behaviour, poor accessibility, exposure to mine dust, economic burden, migration, lack of training, irregular disbursement of incentive and staff behaviour emerged as major issues., Conclusion: This study identified the issues which hamper TB management in tribal population of Rajasthan, India. Result of this study can be useful in designing a tribal-centric approach to adequately manage TB among tribal population of Rajasthan., Competing Interests: Conflicts of interest The authors have none to declare., (Copyright © 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19., Methods: This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774., Findings: The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis., Interpretation: SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19., Funding: National Institutes of Health., Competing Interests: Declaration of interests MNK has received research grant support from University of Pittsburgh, AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, Regeneron, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca and Vifor Pharma; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. He holds stock options from Artera Health and Saghmos Therapeutics. OV has received institutional research support from AstraZeneca, Bayer, and Cardurion, and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi. JSB reports research grants from National Institutes of Health and American Heart Association and has consulted for Janssen. HRR reports receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study, as well as nonfinancial support from Abbott Vascular, SHL Telemedicine, Siemens, and Phillips outside the submitted work. ADA is an employee of Medtronic. SDS has received research grants from Alexion, Alnylam, AstraZeneca, Bellerophon, Bayer, BMS, Cytokinetics, Eidos, Gossamer, GSK, Ionis, Lilly, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI, and has consulted for Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. ASB has received research grant support to his institution from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention. AP reports a research grant from the German Research Foundation. MNG reports receiving grants from National Institutes of Health, Agency for Healthcare Research and Quality, and the US Centers for Disease Control and Prevention and receiving personal fees from Regeneron for serving on the data safety monitoring board for monoclonal antibody trials in COVID-19. LZK reports receiving personal fees from Cerus Corp, University of Maryland, Coagulant Therapeutics, Haemonetics, and Gamma Diagnostics. PK receives grant funding as a principal investigator from NIH and Cerenovus; consulting fees as a scientific advisor to Basking Biosciences, Bayer, Lumosa, and Shionogi; and royalties for online publication from UpToDate. KSK reports grants from National Institutes of Health during the conduct of the study, funding from Eisai outside the submitted work, and personal fees from National Institutes of Health for committee service indirectly related to the research. LBK reports that her institution received funding from National Institutes of Health to perform the study. AJ reports receiving funding from AstraZeneca to study mechanisms of action of dapagliflozin. LW reports funding from the National Institutes of Health for ACTIV-4A and ACTIV-4C. JLSM reports receiving honoraria from Roche la Hoffman and Novartis. MQH reports receiving research funding from National Institutes of Health and NIAID. JLS reports research grants or contracts from Amgen, BMS, GSK, Medtronic, Pfizer, Sanofi-Aventis; funding for educational activities or lectures from Pfizer, BMS, Novo Nordisk, AstraZeneca, and funding for consulting from Bayer, Boehringer Ingelheim, BMS, Novo Nordisk, and AstraZeneca. RDL has received grants from Amgen, BMS, and GSK; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, and NovoNordisk; and Honoraria from AstraZeneca, Daiichi Sankyo, NovoNordisk and Pfizer. JLC reports direct support for this project from National Institutes of Health/National Heart, Lung, and Blood Institute; grants from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/NIAID, the Department of Defense, the Department of Veterans Affairs, and the COPD Foundation, outside of this project; and support paid to his institution outside this project from CDL Behring, LLC, AstraZeneca, and Novartis, GBMH. B-AK (through SOCAR Research) received grants from National Institutes of Health. MWG reports funding in part by the National Institutes of Health Agreement 1OT2HL156812 through the National Heart, Lung, and Blood Institute CONNECTS programme. MDN serves as chief medical officer for Haima Therapeutics and has received grants from the National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, Department of Defense, Haemonetics, and Instrumentation Laboratories. He has received personal fees from Haemonetics, Takeda, CSL Behring, and Janssen Pharmaceuticals. JSH is the study chair for ACTIV-4a under a National Heart, Lung, and Blood Institute–University of Pittsburgh grant subaward. SLW, SB, JFL, ESL, ALK, MC, CC, and AA declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The American Heart Association (AHA), founded in 1924, is anchored in the core belief that scientific research can lead the way to better prevention, treatment, recovery, and ultimately a cure for cardiovascular disease. Historically, the association's involvement in international efforts centered on scientific cooperation. Activities mostly involved AHA leadership presenting at international scientific meetings and leaders from other countries sharing scientific and medical information at AHA meetings. Although the AHA's and American Stroke Association's international efforts have expanded substantially since those early days, global knowledge exchange remains the bedrock of its international endeavors. As the AHA turns 100, we reflect on the successful global efforts in prevention, resuscitation, global advocacy, quality improvement, and health equity that have guided the organization to a place of readiness for "advancing health and hope, for everyone, everywhere." Motivated by the enormous potential for population health gains in an aging world, the AHA is entering its second century with redoubled commitment to improving global cardiovascular and cerebrovascular health for all.

Background and Purpose: Walking and balance impairments after stroke are a global health concern, causing significant morbidity and mortality. However, effective strategies for achieving meaningful recovery in the chronic stages are limited. Backward locomotor treadmill training (BLTT) is a novel walking rehabilitation protocol that is safe, feasible, and likely beneficial in stroke survivors; however, its efficacy has not been tested. This single-center, randomized, assessor-blind clinical trial aims to test the preliminary efficacy of BLTT compared to forward locomotor treadmill training (FLTT) on walking speed, symmetry, and postural stability., Methods: Forty stroke survivors [BLTT (N=19), FLTT (N=21); mean age= 56.3 ± 8.6 years; 53% Female; 30% Non-Hispanic Black] with mild-moderate walking impairment were enrolled. Participants underwent nine 30-minute BLTT or FLTT sessions over three weeks. The primary outcome was the mean change in the 10-meter walk test (10 MWT) at 24 hours post-training (24 hr POST). Secondary outcome measures were changes in spatiotemporal walking symmetry and postural stability during quiet standing at 24 hr POST. Retention was explored at Days 30- and 90 POST., Results: We report clinically meaningful (≥ 0.16 m/s) improvements in overground walking speed at 24 hr POST, with retention up to Day 90 POST with BLTT and FLTT. However, contrary to our working hypothesis, no between-group differences in walking speed were observed. Nonetheless, we found that BLTT resulted in offline improvements in spatial symmetry and retention of subcomponents of the modified clinical test of sensory interaction on balance (mCTSIB), including the testing of proprio-vestibular integration up to Day 30 POST., Conclusion: Among chronic stroke patients with mild-moderate walking impairment, BLTT and FLTT both resulted in long-lasting and clinically meaningful improvement in walking speed. However, preliminary findings suggest that BLTT may better comprehensively target walking asymmetry and sensory systems processing and integration., Competing Interests: DISCLOSURES OOA reports grant support from the American Academy of Neurology Institute Career Development Award and National Institutes of Health under grant 121HD11576. CD reports no conflict of interest. AG reports no conflict of interest. PB reports support from the National Institutes of Health under grant R01HD093694. HJS reports no conflict of interest. EW reports no conflict of interest. AB reports no conflict of interest. KD reports no conflict of interest. PK reports no conflict of interest. BMK reports no conflict of interest.

Background: The rate of diagnosis of mast cell activation syndrome (MCAS) has increased since the disorder's original description as a mastocytosis-like phenotype. While a set of consortium MCAS criteria is well described and widely accepted, this increase occurs in the setting of a broader set of proposed alternative MCAS criteria., Objective: Effective diagnostic criteria must minimize the range of unrelated diagnoses that can be erroneously classified as the condition of interest. We sought to determine if the symptoms associated with alternative MCAS criteria result in less concise or consistent diagnostic alternatives, reducing diagnostic specificity., Methods: We used multiple large language models, including ChatGPT, Claude, and Gemini, to bootstrap the probabilities of diagnoses that are compatible with consortium or alternative MCAS criteria. We utilized diversity and network analyses to quantify diagnostic precision and specificity compared to control diagnostic criteria including systemic lupus erythematosus, Kawasaki disease, and migraines., Results: Compared to consortium MCAS criteria, alternative MCAS criteria are associated with more variable (Shannon diversity 5.8 vs 4.6, respectively; P = .004) and less precise (mean Bray-Curtis similarity 0.07 vs 0.19, respectively; P = .004) diagnoses. The diagnosis networks derived from consortium and alternative MCAS criteria had lower between-network similarity compared to the similarity between diagnosis networks derived from 2 distinct systemic lupus erythematosus criteria (cosine similarity 0.55 vs 0.86, respectively; P = .0022)., Conclusion: Alternative MCAS criteria are associated with a distinct set of diagnoses compared to consortium MCAS criteria and have lower diagnostic consistency. This lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses., Competing Interests: Disclosure statement Suported by the Bill and Melinda Gates Foundation (OPP1113682 to P.K.); the National Institute of Allergy and Infectious Diseases (NIAID) grants U19AI057229 and U19AI67903; NIAID contract 75N93022C00052; Department of Defense contracts W81XWH1910235 and W911NF2320019; and the National Institute of Child Health and Human Development (grant K12HD000850). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear., Methods: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization., Results: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%)., Conclusions: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Minor ischemic stroke, defined as National Institute of Health Stroke Scale score of 0-5 on admission, represents half of all acute ischemic strokes. The role of intravenous alteplase (IVA) among patients with minor stroke is inconclusive; therefore, we evaluated clinical outcomes of these patients treated with or without IVA., Materials and Methods: We searched Medline, Embase, Scopus, and the Cochrane library until August 1, 2023. Inclusion was restricted to the English literature of studies that reported on minor nondisabling stroke patients treated with or without IVA. Odds ratios (ORs) with their corresponding 95% CIs were utilized using a random-effects model. Efficacy outcomes included rates of excellent (modified Rankin scale [mRS] of 0-1) and good (mRS of 0-2) functional outcome at 90 days. The main safety outcome was symptomatic intracerebral hemorrhage (sICH)., Results: Five eligible studies, two RCTs and three observational studies, comprising 2764 patients (31.8% female) met inclusion criteria. IVA was administered to 1559 (56.4%) patients. Pooled analysis of the two RCTs revealed no difference between the two groups in terms of 90-days excellent functional outcomes (OR 0.76 [95% CI, 0.51-1.13]; I 2  = 0%) and sICH rates (OR 3.76 [95% CI, 0.61-23.20]). No significant differences were observed between the groups in terms of good functional outcomes, 90-day mortality, and 90-day stroke recurrence., Conclusion: This meta-analysis of minor nondisabling stroke suggests that IVA did not prove more beneficial compared to no-IVA., 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: Patients with suspected ischemic stroke and use of Direct Oral Anticoagulants (DOACs) within 48 h are excluded from thrombolysis. We aimed to determine practice patterns across institutions in the NIH StrokeNet, a network of hospitals to conduct NIH-funded stroke clinical trials, in the United States., Methods: A survey was sent electronically to all NIH StrokeNet regional coordinating centers. The survey questions were geared towards understanding practice patterns with intravenous thrombolysis use in patients on DOACs. We reported proportions and percentages answers to the questions. We compared the likelihood of thrombolysis use in patients with recent DOAC ingestion (never vs. all other responses) across characteristics of survey responder using Chi Square., Results: A total of 83 site principal investigators completed the survey; 78.3 % would never give thrombolysis to an otherwise eligible patients within 12-24 h from last DOAC ingestion and 54.2 % would never give thrombolysis to an otherwise eligible patient within 24-48 h from last DOAC ingestion. A higher proportion of vascular neurologists would never give thrombolysis in patients with DOAC ingestion within 12-48 h compared to other subspecialties (60.7 % vs. 36.4 %, p = 0.05). Nearly, 80 % would change their practice if a well-designed prospective study demonstrated that the symptomatic intracranial hemorrhage rate is not >5 %., Conclusions: A well-designed prospective study with a set safety threshold is likely to change practice patterns in giving thrombolysis in patients with recent DOAC ingestion, particularly among vascular neurologists who are more likely to never give thrombolysis in this setting., Competing Interests: Declaration of competing interest The authors have relevant disclosures or conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Dialysis adequacy is traditionally calculated from pre- and post-hemodialysis session serum urea concentrations and expressed as the urea reduction ratio, or Kt/Vurea. However, with increasing hemodiafiltration usage, we wished to determine whether there were any differences between standard Kt/Vurea equations and directly measured spent dialysate urea clearance., Methods: Urea clearance was measured from collected effluent dialysate and compared with various other methods of Kt/Vurea calculation, including change in total body urea from measuring pre- and post-total body water with bioimpedance and the Watson equation, by standard Kt/V equations, and online clearance measurements using effective ionic dialysance (OLC)., Results: We compared urea clearance in 41 patients, 56.1% male, mean age 69.3 ± 12.6 years with 87.8% treated by hemodiafiltration. Reduction in total body urea was greater when estimating changes in total body urea, compared to measured dialysate losses of 58.4% (48.5-67.6) vs 71.6% (62.1-78), p < 0.01. Sessional urea clearance (Kt/Vurea) was greater using the online Solute-Solver program compared to OLC, median 1.45(1.13-1.75) vs 1.2 (0.93-1.4), and 2nd generation Kt/V equations 1.3 (1.02-1.66), p < 0.01, but not different from estimated total body urea clearance 1.36 (1.15-1.73) and dialysate clearance 1.36 (1.07-1.76). The mean bias compared to the Solute-Solver program was greatest with OLC (-0.25), compared to second-generation equations (-0.02), estimated total body clearance (-0.02) and measured dialysate clearance (-0.01)., Conclusion: This study demonstrated that the result from equations estimating urea clearance indirectly from pre- and postblood samples from hemo- and hemodiafiltration treatments was highly correlated with direct measurements of dialysate urea clearance., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Long-term aerosol optical depth (AOD) datasets focused on the Pacific Ocean in the downwind area of China over a 19-year period from 2003 to 2021 were derived from satellite observations, reanalysis datasets, and numerical simulations. Considering the significant year-to-year changes in the amounts of aerosols transported from China to the Pacific Ocean during this period, we proposed a metric named R AOD . This is defined as the AOD over the ocean relative to that near the eastern coast of China within the same latitude band (25-30°N). R AOD was identified as a valuable metric for quantifying the long-term changes in transboundary air pollution pathways. Our analysis revealed a clear exponential decrease in R AOD values from China toward the Pacific Ocean; this was consistent with the prevailing meteorological conditions observed over the 19-year period. However, the possible long-term changes in R AOD due to climate change were found to be insignificant and were overshadowed by much larger year-to-year variations in the meteorological field. Additionally, significant seasonal variations in the absolute slope of the linear regression between R AOD and longitude were observed, and there correlated with wind patterns in the lower troposphere. Elevated slope values in the spring and winter suggested a west-to-east aerosol transport facilitated by strong winds, whereas the lower slope values in summer and autumn indicated a northward aerosol movement under weaker winds. In recent years, aerosols have become less likely to be transported far eastward from the coast of China. Based on these findings, to enhance the detectability of the climate change impacts on meteorological field affecting transboundary air pollution pathways, the R AOD metric derived using a continued long-term satellite observation of aerosols is proposed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Neutrophils accumulate early in tissue injury. However, the cellular and functional heterogeneity of neutrophils during homeostasis and in response to tissue damage remains unclear. In this study, we use larval zebrafish to understand neutrophil responses to thermal injury. Single-cell transcriptional mapping of myeloid cells during a 3-d time course in burn and control larvae revealed distinct neutrophil subsets and their cell-cell interactions with macrophages across time and conditions. The trajectory formed by three zebrafish neutrophil subsets resembles human neutrophil maturation, with varying transition patterns between conditions. Through ligand-receptor cell-cell interaction analysis, we found that neutrophils communicate more in burns in a pathway and temporal manner. Finally, we identified the correlation between zebrafish myeloid signatures and human burn severity, establishing GPR84+ neutrophils as a potential marker of early innate immune response in burns. This work builds a comparative single-cell transcriptomic framework to identify neutrophil markers of tissue damage using model organisms., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Background and Objectives: Few studies have examined trends and disparities in long-term outcome after stroke in a representative US population. We used a population-based stroke study in the Greater Cincinnati Northern Kentucky region to examine trends and racial disparities in poststroke 5-year mortality., Methods: All patients with acute ischemic strokes (AISs) and intracerebral hemorrhages (ICHs) among residents ≥20 years old were ascertained using ICD codes and physician-adjudicated using a consistent case definition during 5 periods: July 1993-June 1994 and calendar years 1999, 2005, 2010, and 2015. Race was obtained from the medical record; only those identified as White or Black were included. Premorbid functional status was assessed using the modified Rankin Scale, with a score of 0-1 being considered "good." Mortality was assessed with the National Death Index. Trends and racial disparities for each subtype were analyzed with logistic regression., Results: We identified 8,428 AIS cases (19.3% Black, 56.3% female, median age 72) and 1,501 ICH cases (23.5% Black, 54.8% female, median age 72). Among patients with AIS, 5-year mortality improved after adjustment for age, race, and sex (53% in 1993/94 to 48.3% in 2015, overall effect of study year p = 0.009). The absolute decline in 5-year mortality in patients with AIS was larger than what would be expected in the general population (5.1% vs 2.8%). Black individuals were at a higher risk of death after AIS (odds ratio [OR] 1.23, 95% CI 1.08-1.39) even after adjustment for age and sex, and this effect was consistent across study years. When premorbid functional status and comorbidities were included in the model, the primary effect of Black race was attenuated but race interacted with sex and premorbid functional status. Among male patients with a good baseline functional status, Black race remained associated with 5-year mortality (OR 1.4, 95% CI 1.1-1.7, p = 0.002). There were no changes in 5-year mortality after ICH over time (64.4% in 1993/94 to 69.2% in 2015, overall effect of study year p = 0.32)., Discussion: Long-term survival improved after AIS but not after ICH. Black individuals, particularly Black male patients with good premorbid function, have a higher mortality after AIS, and this disparity did not change over time.

The regulation of inflammation is a critical aspect of disease tolerance and naturally acquired clinical immunity to malaria. Here, we demonstrate using RNA sequencing and epigenetic landscape profiling by cytometry by time-of-flight, that the regulation of inflammatory pathways during asymptomatic parasitemia occurs downstream of pathogen sensing-at the epigenetic level. The abundance of certain epigenetic markers (methylation of H3K27 and dimethylation of arginine residues) and decreased prevalence of histone variant H3.3 correlated with suppressed cytokine responses among monocytes of Ugandan children. Such an epigenetic signature was observed across diverse immune cell populations and not only characterized active asymptomatic parasitemia but also correlated with future long-term disease tolerance and clinical immunity when observed in uninfected children. Pseudotime analyses revealed a potential trajectory of epigenetic change that correlated with a child's age and recent parasite exposure and paralleled the acquisition of clinical immunity. Thus, our data support a model whereby exposure to Plasmodium falciparum induces epigenetic changes that regulate excessive inflammation and contribute to naturally acquire clinical immunity to malaria., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Background: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States., Methods: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population., Results: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients., Conclusions: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke., Competing Interests: E.A. Mistry reports compensation from AbbVie for consultant services; compensation from RAPID AI for consultant services; compensation from the American Heart Association for consultant services; compensation from Translational Sciences for other services; grants from Patient-Centered Outcomes Research Institute; grants from the National Institutes of Health (NIH); and compensation from Silver Creek Pharmaceuticals, Inc, for other services. Dr Khoury reports grants from the NIH. Dr Kissela reports service as Board of Directors, Member for American Academy of Neurology, and employment by the University of Cincinnati. K.S. Alwell reports grants from the NIH. Dr Ferioli reports employment by the University of Cincinnati. Dr De Los Rios La Rosa reports employment by The Neurology Group; compensation from AstraZeneca for other services; and employment by Baptist Health South Florida. Dr Walsh reports grants from Jan Medical, Inc; grants from Sense Diagnostics LLC; grants from NIH Clinical Center; and grants from the American Heart Association. Dr Slavin reports grants from the NIH. M. Haverbusch reports employment by the University of Cincinnati. Dr Mackey reports grants from the NIH. Dr Woo reports grants from NIH. Dr Heldner reports grants from the Swiss Heart Foundation; grants from SITEM Research Funds; and grants from the Swiss National Science Foundation. Dr Fischer reports compensation from Biogen for expert witness services; employment by Universität Basel; and compensation from Boehringer Ingelheim for expert witness services. Dr Jadhav reports employment by Barrow Brain and Spine; stock options in Gravity Medical Technology; compensation from Basking Biosciences for consultant services; a patent issued for Novel Stent Retriever device licensed to Basking Biosciences; and travel support from Johnson and Johnson. Dr Jovin reports grants from Stryker Corporation; stock options in Basking; stock options in Kandu; grants from Medtronic USA, Inc; stock options in Anaconda; compensation from Contego Medical, Inc, for consultant services; stock options in StataDx; stock options in Freeox Biotech; stock options in Gravity; stock options in Route92; stock options in Methinks; compensation from Johnson & Johnson Cerenovus for data and safety monitoring services; stock options in viz-AI; and stock options in Galaxy. Dr Albers reports compensation from Genentech for consultant services; stock holdings in iSchemaView; and compensation from iSchemaView for consultant services. Dr Nogueira reports compensation from RapidPulse for consultant services; compensation from Cerebrotech for consultant services; compensation from Phenox for consultant services; compensation from Medtronic USA, Inc, for consultant services; compensation from Vesalio for consultant services; compensation from Corindus Vascular Robotics for consultant services; compensation from Anaconda for consultant services; compensation from Genentech for consultant services; stock options in Ceretrieve; stock options in Viseon, Inc; compensation from Biogen, Inc, for consultant services; stock options in Truvic; compensation from Brainomix for consultant services; compensation from Prolong Pharmaceuticals for consultant services; compensation from Ceretrieve for consultant services; compensation from Cerenovus for consultant services; stock holdings in Piraeus Medical; compensation from viz-AI for consultant services; stock options in Corindus, Inc; grants from Cerenovus; stock options in Perfuze; compensation from Genentech for consultant services; compensation from Philips for consultant services; compensation from Ceretrieve for consultant services; stock options in viz-AI; compensation from Stryker Corporation for consultant services; stock holdings in Brain4Care; compensation from Perfuze for consultant services; compensation from Brainomix for consultant services; compensation from Cerenovus for consultant services; compensation from viz-AI for consultant services; grants from Stryker; stock options in viz-AI; compensation from Phenox, Inc, for consultant services; compensation from Hybernia for consultant services; compensation from Perfuze for consultant services; compensation from Anaconda Biomed for consultant services; compensation from Imperative Care, Inc, for consultant services; compensation from NeuroVasc Technologies, Inc, for consultant services; compensation from Shanghai Wallaby for consultant services; stock options in Reist/Q’Apel Medical; stock holdings in Quantanosis AI; compensation from Prolong Pharmaceuticals for consultant services; stock options in Vesalio; compensation from Biogen, Inc, for consultant services; compensation from Synchron for data and safety monitoring services; compensation from Stryker for consultant services; compensation from Medtronic USA, Inc, for consultant services; compensation from Imperative Care for consultant services; compensation from RapidPulse for consultant services; stock options in Cerebrotech; compensation from Corindus, Inc, for consultant services; compensation from Astrocyte for consultant services; stock options in Brainomix; and stock options in Perfuze. Dr Khatri reports compensation from Translational Sciences for other services; compensation from Lumosa for consultant services; grants from Johnson & Johnson Health Care Systems, Inc; compensation from Basking Biosciences for consultant services; grants from NIH; compensation from Shionogi, Inc, for consultant services; and Online publication for Royalties from UptoDate, Inc, for online publication. The other authors report no conflicts.

Objectives: Hyperglycemia is associated with poor outcome in large vessel occlusion (LVO) stroke, with mechanism for this effect unknown., Materials and Methods: We used our prospective, multicenter, observational study, Blood Pressure After Endovascular Stroke Therapy (BEST), of anterior circulation LVO stroke undergoing endovascular therapy (EVT) from 11/2017-7/2018 to determine association between increasing blood glucose (BG) and intracerebral hemorrhage (ICH). Our primary outcome was degree of ICH, classified as none, asymptomatic ICH, or symptomatic ICH (≥4-point increase in National Institutes of Health Stroke Scale [NIHSS] at 24 h with any hemorrhage on imaging). Secondary outcomes included 24 h NIHSS, early neurologic recovery (ENR, NIHSS 0-1 or NIHSS reduction by ≥8 within 24 h), and 90-day modified Rankin Scale (mRS) using univariate and multivariable regression., Results: Of 485 enrolled patients, increasing BG was associated with increasing severity of ICH (adjusted OR, aOR 1.06, 95 % CI 1.02-1.1, p < 0.001), higher 24 h NIHSS (aOR 1.22, 95 % CI 1.11-1.34, p < 0.001), ENR (aOR 0.90, 95 % CI 0.82-1.00, p < 0.002), and 90-day mRS (aOR 1.06, 95 % CI 1.03-1.09, p < 0.001) when adjusted for age, presenting NIHSS, ASPECTS, 24-hour peak systolic blood pressure, time from last known well, and successful recanalization., Conclusions: In the BEST study, increasing BG was associated with greater odds of increasing ICH severity. Further study is warranted to determine whether treatment of will decrease ICH severity following EVT., Competing Interests: Declaration of competing interest There are no competing interests, and we have no disclosures to report., (Copyright © 2024. Published by Elsevier Inc.)

A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) that we refer to as 'resisters' (RSTR) show evidence of IFN-γ - T cell responses to Mtb-specific antigens despite serially negative results on clinical testing. Here we found that Mtb-specific T cells in RSTR were clonally expanded, confirming the priming of adaptive immune responses following Mtb exposure. RSTR CD4 + T cells showed enrichment of T H 17 and regulatory T cell-like functional programs compared to Mtb-specific T cells from individuals with latent Mtb infection. Using public datasets, we showed that these T H 17 cell-like functional programs were associated with lack of progression to active tuberculosis among South African adolescents with latent Mtb infection and with bacterial control in nonhuman primates. Our findings suggested that RSTR may successfully control Mtb following exposure and immune priming and established a set of T cell biomarkers to facilitate further study of this clinical phenotype., (© 2024. The Author(s).)

Background: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches., Methods: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme., Results: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes., Conclusions: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill., (© 2024. The Author(s).)

Background: Limited evidence is available for the treatment of acute symptomatic sub-occlusive lesions in ischemic stroke. We sought to identify current treatment patterns of stroke teams at academic health centers., Methods: We conducted an email survey of the National Institutes of Health (NIH) StrokeNet regional coordinating centers (RCCs). Each RCC principal investigator (PI) was asked to nominate a local stroke interventionalist, or neurologist if the RCC PI was an interventionalist, most aligned with the typical practice pattern of the RCC's lead hospital, to receive a survey. The survey consisted of a clinical vignette and displayed a sub-occlusive lesion in the left middle cerebral artery on CT angiogram followed by subsequent scenarios, revising only one historical, clinical, or radiographic variable at a time. Participants were asked to select initial management for each scenario. Results were reviewed and analyzed by stroke-trained physicians., Results: Responses were received from 42 (77.8%) of 54 surveyed individuals, representing 25 (92.6%) of 27 RCCs nationwide, including 25 (59.5%) interventionalists. The majority (76.2%) of respondents treated the patient in the primary clinical vignette with mechanical thrombectomy (MT). Among all six clinical scenarios, respondents chose MT with or without medical management as first-line treatment for four (67%) vignettes. Exceptions were low NIH Stroke Scale and known ipsilateral stenosis, where respondents chose medical management as first-line treatment., Conclusions: Despite limited evidence to support MT versus other treatment strategies, the majority of StrokeNet RCCs respondents would use MT with or without medical therapy to treat AIS due to intracranial sub-occlusive lesions.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Disclosures Dr Albers reports compensation from Genentech and iSchemaView for consultant services and stock holdings in iSchemaView. Dr Heit reports compensation from Medtronic, iSchemaView, and MicroVention Inc for consultant services. Dr Derdeyn reports grants from Siemens Healthineers and other from Penumbra, Silk Road, NoNo, and Euphrates Vascular outside the submitted work. Dr Inoue reports speaker fees from Bayer, Bristol Myers Squibb, Daichi Sankyo, and Nippon Boehringer Ingelheim. Dr Yedavalli reports consulting fees from MRIOnline and iSchemaView (RapidAI). Dr Seners reports consulting fees for Acticor Biotech. Dr Cereda reports compensation from iSchemaView for consultant services. Dr Mistry serves as a consultant for AbbVie, RAPID AI, and SilverCreek Pharmaceuticals and the American Heart Association. She reports a nonfinancial relationship with Translational Sciences Inc. She reports research funding from the NIH/NINDS and Patient Centered Outcomes Research Institute (PCORI). Dr Chattrerjee reports consulting fees from MDReview and Penumbra Inc. Dr Derdeyn reports Euphrates Vascular - stock options; Silk Road (NITE trial DSMB); Penumbra (MIND and THUNDER trial DSMBs); NoNO (ESCAPE NEXT and FRONTIER DSMBs). Dr Khatri has received a research grant from Cerenovus/Johnson & Johnson (ENDOLOW trial); consulting fees for scientific advisory roles from Lumosa, Basking Biosciences and Shionogi; drug and assays from Translation Sciences (for NIH-funded SISTER trial); royalties from UpToDate (online publication royalties); and funding from NIH STEP Grant (NINDS OT2NS129366). Dr Olivot reports grants from the French Minstry of Health; compensation from Abbvie, Acticor, and Boehringer Ingelheim; and speaker fees from Bristol Myers Squibb. Dr Hill reports grants from Medtronic, Boehringer Ingelheim, NoNO Inc, the Canadian Institutes of Health Research, and MicroVention Inc; compensation from Brainsgate Ltd, for consultant services; a patent issued for Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients licensed to Circle NVI; and employment by the University of Calgary. Dr Saver reports consulting fees for advising on rigorous and safe clinical trial design and conduct from Abbott, Acticor, Aeromics, Amgen, Argenica, Astrocyte, Bayer, Biogen, Boehringer Ingelheim, BrainsGate, BrainQ, CSL Behring, Filterlex, Genentech, Johnson&Johnson, MindRhythm, Medtronic, NeuroMerit, Neuronics, Novo Nordisk, Occlutech, Phenox, Phillips, QuantalX, Rapid Medical, Roche, and Stream Biomedical. Dr Fisher reports compensation from Simcere USA and Lumosa for consultant services; employment by Beth Israel Deaconess Medical Center and Beth Israel Deaconess Medical Center. The other authors report no conflicts.

Background: Publication of the research work done during the master's program is highly desirable. However, there is a paucity of data on the number of publications, especially from low-income countries. The objective was to find out the status of the publication of the theses of post-graduate students in Nursing from the Institute of Medicine, Tribhuvan University, Nepal from 2015-2019., Methods: Cross-sectional analytical design with a structured interview via telephone was done for data collection. Independent variables were age, marital status, current work status, current working organization, type of research, year of graduation, and facilitators and barriers to publication, whereas dependent was the publication status of the thesis., Results: Two hundred five (76.2%) out of 269 participated in the study. The age group ranged from 27 to 50 years (mean ± SD = 36.6±4.8). The majority 89.3% were married. Currently working in academic institutions was 51.7%. One hundred ninety-eight (96.6%) respondents performed a cross-sectional descriptive study. Only 2.9% of studies were cross-sectional analytical and 0.5% were qualitative. Seventy-five (36.6%) respondents published their theses. Twenty-seven (36.0%) were published in PubMed-indexed journals. The most common facilitator for publication was academic satisfaction [59 out of 75(78.7%)] followed by encouragement from supervisors 52.0% and peers 40.0%, whereas the commonest barrier to publication was lack of interest [80 out of 124 (64.5%)] followed by lack of confidence 51.6%., Conclusions: Based on the results, more than one-third of the participants published their theses in national and international journals including those indexed in PubMed. Provision of university research grants, development of publication culture among post-graduate students, and making a provision of academic publication before degree awards should be encouraged for more academic publication.

Background: In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI)., Methods: This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively., Results: Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT., Conclusions: About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes., Competing Interests: Disclosures Dr Caso reports consulting for Boehringer Ingelheim, a grant from Daichi Sankyo, and other funding from EVER Neuro Pharma. Dr Christensen reports being employed by the Capital Region of Denmark, and consulting for Alexion Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Daichi Sankyo, and Medtronic. Dr Connolly reports grants from AtriCure Inc and Pfizer and consulting for Bristol Myers Squibb, Daichi Sankyo, and Javelin Ventures. Dr Khatri reports grants from the National Institutes of Health; a grant from Johnson and Johnson Health Care Systems; royalties from UpToDate; consulting for Basking Biosciences, Lumosa, and Shinogi Inc; and other funding from Translational Sciences. Dr Chen reports no disclosures, or their institutions received financial support from Bayer for participation in the PACIFIC-Stroke trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke).

Background: Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist., Methods and Results: Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P <0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P <0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P <0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P <0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P <0.01) were also higher in Black patients., Conclusions: This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.

The number of patients aged > 75-years treated by dialysis continues to increase, particularly in developed countries. Haemodialysis is a well-established treatment with national and international clinical guidelines designed to provide patients with optimal treatment. However, these were developed when the dialysis population was younger, and less co-morbid. This change in patient demographics questions whether these guideline targets still apply to older patients. More patients now start dialysis with residual kidney function and could benefit from a less frequent dialysis schedule. Older patients have a lower thirst drive, so lower interdialytic gains, reduced appetite, muscle mass and physical activity would potentially allow starting dialysis with less frequent sessions a practical option. Similarly, patients with residual kidney function and lower metabolic activity may not need to meet current dialyser Kt/Vurea clearance targets to remain healthy. Instead, some elderly patients may be at risk of malnutrition and might need liberalisation of the low salt, potassium and phosphate dietary restrictions, or even additional supplements to ensure adequate protein intake. Although a fistula is the preferred vascular access, a forearm fistula may not be an option due to vascular disease, while a brachial fistula can potentially compromise cardiovascular reserve, so a dialysis catheter becomes the de facto access, especially in patients with limited life expectancy. Thus, clinical guideline targets designed for a younger less co-morbid dialysis population may not be equally applicable to the older patient initiating dialysis, and so a more individualised approach to dialysis prescription and vascular access is required., (© 2024. The Author(s).)

To accelerate medical breakthroughs, the All of Us Research Program aims to collect data from over one million participants. This report outlines processes used to construct the All of Us Social Determinants of Health (SDOH) survey and presents the psychometric characteristics of SDOH survey measures in All of Us. A consensus process was used to select SDOH measures, prioritizing concepts validated in diverse populations and other national cohort surveys. Survey item non-response was calculated, and Cronbach's alpha was used to analyze psychometric properties of scales. Multivariable logistic regression models were used to examine associations between demographic categories and item non-response. Twenty-nine percent (N = 117,783) of eligible All of Us participants submitted SDOH survey data for these analyses. Most scales had less than 5% incalculable scores due to item non-response. Patterns of item non-response were seen by racial identity, educational attainment, income level, survey language, and age. Internal consistency reliability was greater than 0.80 for almost all scales and most demographic groups. The SDOH survey demonstrated good to excellent reliability across several measures and within multiple populations underrepresented in biomedical research. Bias due to survey non-response and item non-response will be monitored and addressed as the survey is fielded more completely., (© 2024. The Author(s).)

Background and Objectives: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date., Methods: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073)., Results: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group ( p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group., Discussion: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

The global pharmaceutical industry portfolio is skewed towards cancer and rare diseases due to more predictable development pathways and financial incentives. In contrast, drug development for major chronic health conditions that are responsible for a large part of mortality and disability worldwide is stalled. To examine the processes of novel drug development for common chronic health conditions, a multistakeholder Think Tank meeting, including thought leaders from academia, clinical practice, non-profit healthcare organizations, the pharmaceutical industry, the Food and Drug Administration (FDA), payors as well as investors, was convened in July 2022. Herein, we summarize the proceedings of this meeting, including an overview of the current state of drug development for chronic health conditions and key barriers that were identified. Six major action items were formulated to accelerate drug development for chronic diseases, with a focus on improving the efficiency of clinical trials and rapid implementation of evidence into clinical practice., Competing Interests: Conflict of interest Konstantin A. Krychtiuk: advisory boards Novartis, Sanofi, Amgen; speaker fees Amgen, Daichii Sankyo, Zoll Medical Tomas LG Andersson: employed by AstraZeneca, owns stock in AstraZeneca, travel support by AstraZeneca Ulrike Bodesheim employed by Bayer AG; Javed Butler: Consulting fees: 3ivelabs, Abbott, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element, Faraday, G3 Pharmaceutical, Imbria, Impulse Dynamics, Innolife, Inventiva, Ionis, Janssen, LivaNova, Lexicon, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Occlutech, PharmaCosmos, Roche, Sanofi, Secretome, Sequana, Tricog, Vifor; Speaker Fees: Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Impulse Dynamics; Lesley H Curtis: Fees Boehringer Ingleheim, NIH, and Regeneron Pharmaceuticals Mitchell Elkind: Grants: Roche; Lecture Fees: Atria Academy of Science and Medicine; Travel Support: American Heart Association; Adrian F. Hernandez: Consulting fees Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CSL Behring, Cytokinetics, Eli Lilly, Intellia Therapeutics, Merck, Novartis, Novo Nordisk, Prolaio; Grants/Contracts: American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Intellia Therapeutics, Merck, Novartis, Novo Nordisk, Verily; Christoph Hornik: None declared; Gary H Lyman: Consulting Fees: Sandoz, Astra Zeneca, Beyond Spring, G1 Therapeutics, Merck, Partners Healthcare, ER Squibb, Samsung, Fresenius Kabi; Pooja Khatri: grants from Cerenovus; serving on the scientific advisory boards of Lumosa; Shionogi, Bayer, and Basking Biosciences; andreceiving online publication royalties from UpToDate; Michael Mbagwu: Stocks in Verana Health as employee Masahiro Murakami: employed by Eli Lilly; Gwen Nichols: None declared; Lothar Roessig: employed by Bayer; Anne Quinn Young: None declared; Richard L. Schilsky Consulting Fees: Cellworks, EQRx, Zephyr AI, Clarified Precision Medicine, Illumina, Member, DSMB, Baseline Study sponsored by Verily Chairman, Scientific Advisory Board, Ontario Institute for Cancer Research Member, Strategic External Advisory Committee for Canadian Cancer Trials Group Chairman, Board of Directors, Reagan-Udall Foundation for the FDA, Member, Board of Directors, Friends of Cancer Research, Member, Board of Directors, Leap Therapeutics; Neha Pagidipati: Research support from Alnylam, Amgen, Boehringer Ingelheim, Eggland's Best, Eli Lilly, Novartis, Novo Nordisk, Verily Life Sciences; Consultation/Advisory Panels for Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, Esperion, AstraZeneca, Merck, Novartis, and Novo Nordisk; Executive Committee member for trials sponsored by Novo Nordisk and by Amgen; DSMB for trials sponsored by J+J and Novartis; Medical advisory board for Miga Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Purpose: Recent endovascular trials have spurred a paradigm shift toward routine use of CT perfusion (CTP) for decision-making in acute ischemic stroke. CTP use in the late window, however, remains under evaluation. Our objective was to assess the accuracy of CTP-predicted core in the late window., Methods: In a retrospective review of our prospectively identified stroke registry at a single, comprehensive stroke center, we included patients with anterior large vessel occlusions presenting within the 6-24 h window who underwent baseline CTP evaluation and achieved TICI2b or TICI3 reperfusion on endovascular treatment. We recorded baseline CTP-predicted core volumes at relative cerebral blood flow (CBF) thresholds of <30% <34%, and <38% using RAPID software. Final infarct volumes (FIV) were calculated using follow up MRI and CT, obtained within 72 h after stroke onset., Results: Of the eligible patients, 134 met our inclusion criteria. Mean FIV was 39.5 (SD 49.6). Median CTP to reperfusion time was 93.5 min. Median absolute differences between CTP-predicted core and FIV were 14.7, 14.9, and 16.0 ml at <30%, <34%, and <38%, respectively. Correlation between CTP-predicted ischemic cores and FIV was moderate and statistically significant at all thresholds: r = 0.43 (p <0.001), r = 0.43 (p <0.001), and r = 0.42 (p <0.001) at the <30%, <34%, and <38% cutoffs, respectively., Conclusion: CTP cores in the 6-24 h period underestimate FIV, especially with larger infarcts. CTP-predicted core volumes in the late window show moderate positive correlation with FIV.

Infection, autoimmunity, and cancer are principal human health challenges of the 21 st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (T RM ) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A + immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A + CD8 + T cells correlate with reduced inflammation and increased humoral immunity and that they resemble T RM cells. Our results suggest NKG2A + biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer., Competing Interests: Declaration of interests J.R.H. is a consultant for Regeneron Pharmaceuticals. J.D.G. reports contracted research, a grant, and consulting fees from Gilead. K.M.C. reports being a shareholder in Geneoscopy LLC and has received consulting fees from Geneoscopy LLC, PACT Pharma, Tango Therapeutics, Flagship Labs 81 LLC, and the Rare Cancer Research Foundation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life., Methods: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE., Conclusion: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins., (S. Karger AG, Basel.)

Most patients with COVID-19 in the intensive care unit develop an acute respiratory distress syndrome characterized by severe hypoxemia, decreased lung compliance, and high vascular permeability. Activation of the complement system is a hallmark of moderate and severe COVID-19, with abundant deposition of complement proteins in inflamed tissue and on the endothelium during COVID-19. Using a transgenic mouse model of SARS-CoV-2 infection, we assessed the therapeutic utility of an inhibitory antibody (HG4) targeting MASP-2, a key enzyme in the lectin pathway. Treatment of infected mice with HG4 reduced the disease severity score and improved survival vs mice that received an isotype control antibody. Administration of HG4 significantly reduced the lung injury score, including alveolar inflammatory cell infiltration, alveolar edema, and alveolar hemorrhage. The ameliorating effect of MASP-2 inhibition on the severity of COVID-19 pathology is reflected by a significant reduction in the proinflammatory activation of brain microglia in HG4-treated mice., Competing Interests: Potential conflicts of interest. W. S., N. J. L., and Y. M. A. are consultants to Omeros Corporation, which is developing inhibitors of the LP. G. D. and M. Y. are employed by Omeros Corporation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial., Methods: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment., Results: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013)., Conclusion: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020., (© 2024. The Author(s).)

Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.

Introduction: The ongoing OPTIMISTmain study, an international, multicenter, stepped-wedge cluster randomized trial, aims to determine effectiveness and safety of low-intensity versus standard monitoring in thrombolysis-treated patients with mild-to-moderate acute ischemic stroke (AIS). An embedded process evaluation explored integration and impact of the intervention on care processes at participating US sites., Methods: A mixed-methods approach with quantitative and qualitative data were collected between September 2021 and November 2022. Implementer surveys were undertaken at pre- and post-intervention phases to understand the perceptions of low-intensity monitoring strategy. A sample of stroke care nurses were invited to participate in semi-structured interviews at an early stage of post-intervention. Qualitative data were analyzed deductively using the normalization process theory; quantitative data were tabulated., Results: Interviews with 21 nurses at 8 hospitals have shown low-intensity monitoring was well accepted, as there were less time constraints and reduced workload for each patient. There were initial safety concerns over missing deteriorating patients and difficulties in changing established routines. Proper training, education, and communication, and changing the habits and culture of care, were key elements to successfully adopting the new monitoring care into routine practice. Similar results were found in the post-intervention survey (42 nurses from 13 hospitals). Nurses reported time being freed up to provide patient education (56%), daily living care (50%), early mobilization (26%), mood/cognition assessment (44%), and other aspects (i.e. communication, family support)., Conclusions: Low-intensity monitoring for patients with mild-to-moderate acute ischemic stroke, facilitated by appropriate education and organizational support, appears feasible and acceptable at US hospitals., (S. Karger AG, Basel.)

Background: Data on systolic blood pressure (SBP) trajectories in the first 24 hours after endovascular thrombectomy (EVT) in acute ischemic stroke are limited. We sought to identify these trajectories and their relationship to outcomes., Methods: We combined individual-level data from 5 studies of patients with acute ischemic stroke who underwent EVT and had individual blood pressure values after the end of the procedure. We used group-based trajectory analysis to identify the number and shape of SBP trajectories post-EVT. We used mixed effects regression models to identify associations between trajectory groups and outcomes adjusting for potential confounders and reported the respective adjusted odds ratios (aORs) and common odds ratios., Results: There were 2640 total patients with acute ischemic stroke included in the analysis. The most parsimonious model identified 4 distinct SBP trajectories, that is, general directional patterns after repeated SBP measurements: high, moderate-high, moderate, and low. Patients in the higher blood pressure trajectory groups were older, had a higher prevalence of vascular risk factors, presented with more severe stroke syndromes, and were less likely to achieve successful recanalization after the EVT. In the adjusted analyses, only patients in the high-SBP trajectory were found to have significantly higher odds of early neurological deterioration (aOR, 1.84 [95% CI, 1.20-2.82]), intracranial hemorrhage (aOR, 1.84 [95% CI, 1.31-2.59]), mortality (aOR, 1.75 [95% CI, 1.21-2.53), death or disability (aOR, 1.63 [95% CI, 1.15-2.31]), and worse functional outcomes (adjusted common odds ratio,1.92 [95% CI, 1.47-2.50])., Conclusions: Patients follow distinct SBP trajectories in the first 24 hours after an EVT. Persistently elevated SBP after the procedure is associated with unfavorable short-term and long-term outcomes., Competing Interests: Disclosures A.H. Katsanos serves as the PI for the Blood Pressure Management in Stroke Following Endovascular Treatment trial. The other authors report no conflicts.