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Objective: Prevalence, susceptibility genes, and clinical and radiological features may differ across different ethnic groups of multiple sclerosis (MS). We aim to characterize brain lesions in Chinese patients with MS by use of 7-T MRI., Methods: MS participants were enrolled from the ongoing China National Registry of Neuro-Inflammatory Diseases (CNRID) cohort. 7-T MRI of the brain was performed. Each lesion was evaluated according to a standardized procedure. Central vein sign (CVS) and paramagnetic rim lesions were identified. The characteristics of lesions at patient-level and at lesion-level from previous 7-T MRI literature were also summarized., Results: We included 120 MS patients. Their mean (SD) age was 34.6 (9.4) years. The female-to-male ratio was 1.7:1 and mean disease duration of patients with MS was 5.5 ± 6.1 years. The median EDSS score was 2 (range, 0-8). A total of 8502 lesions were identified with a median lesion count of 45 (IQR, 18-90) (range, 2-370). The median (IQR) percentage for these special locations were as follows: cortical lesions (CLs) 2.7% (0%-5.7%), juxtacortical lesions 16.2% (7.8%-25.7%), periventricular lesions 30.2% (17.2%-38.7%), and infratentorial lesions 5.8% (0.4%-11.9%). CLs occurred in 70 (58%) patients, accounting for only 443 (5%) of the total lesions. Out of the 443 CLs, 309 (69.8%) were leukocortical lesions. CVS appeared in 5392 (63%) lesions from 117 (98%) patients. 1792 (21%) lesions and 104 (87%) patients exhibited a paramagnetic rim., Interpretation: Our study elaborated on the lesion features of Chinese patients with MS by use of 7-T MRI. Lesion burden is heavy in Chinese patients with MS. The median lesion count and proportion of PRL are high. The reported heavy lesion burden calls for ramping up regional and global efforts to care for MS patients. The management and research of Chinese population with MS needs to be further strengthened., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Grey matter (GM) atrophies are observed in multiple sclerosis, neuromyelitis optica spectrum disorders [NMOSD; both anti-aquaporin-4 antibody-positive (AQP4+) and -negative (AQP4-) subtypes] and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicentre cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD and 2169 healthy control subjects. First, interregional GM atrophy profiles across the cortical and subcortical regions were determined using Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD or MOGAD and healthy controls. The GM atrophy profiles were then spatially correlated with the gene expression levels extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical-feature relevant GM atrophy using a subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden and cognitive function. Multiple sclerosis showed a severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed an obvious widespread pattern of GM atrophy, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed a mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD, had spatial correlations with GM atrophy profile, while no atrophy profile-related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature-relevant GM atrophy pointed mainly to the shared neuronal and endothelial cells, among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings may help the differential diagnoses of these diseases and promote the use of optimal therapeutic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: To identify predictors for relapse in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to develop and validate a simple risk score for predicting relapse., Methods: In China National Registry of Neuro-Inflammatory Diseases (CNRID), we identified patients with MOGAD from March 2023 and followed up prospectively to September 2023. The primary endpoint was MOGAD relapse, confirmed by an independent panel. Patients were randomly divided into model development (75%) and internal validation (25%) cohorts. Prediction models were constructed and internally validated using Andersen-Gill models. Nomogram and relapse risk score were generated based on the final prediction models., Results: A total of 188 patients (comprising 612 treatment episodes) were included in cohorts. Female (HR: 0.687, 95% CI 0.524-0.899, p = 0.006), onset age 45 years or older (HR: 1.621, 95% CI 1.242-2.116, p < 0.001), immunosuppressive therapy (HR: 0.338, 95% CI 0.239-0.479, p < 0.001), oral corticosteroids >3 months (HR 0.449, 95% CI 0.326-0.620, p < 0.001), and onset phenotype ( p < 0.001) were identified as factors associated with MOGAD relapse. A predictive score, termed MOG-AR (Immunosuppressive therapy, oral Corticosteroids, Onset Age, Sex, Attack phenotype), derived in prediction model, demonstrated strong predictive ability for MOGAD relapse. MOG-AR score of 13-16 indicates a higher risk of relapse (HR: 3.285, 95% CI 1.473-7.327, p = 0.004)., Discussion: The risk of MOGAD relapse seems to be predictable. Further validation of MOG-AR score developed from this cohort to determine appropriate treatment and monitoring frequency is warranted., Trial Registration Information: CNRID, NCT05154370, registered December 13, 2021, first enrolled December 15, 2021.

Objectives: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS)., Methods: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3., Results: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups., Conclusions: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted., (© 2024 Wiley Periodicals LLC.)

Background: Liver transplantation (LT) is the most effective and radical treatment for hepatocellular carcinoma (HCC). Most LT criteria are based on the morphological characteristics of tumors, which are not enough to predict the risk of tumor recurrence. It is found that some serological biomarkers can predict tumor recurrence and may be a good indicator for selecting suitable HCC patients for LT. This article aims to evaluate the predictive effect of preoperative serological indicators on long-term overall survival (OS) and tumor recurrence-free survival (TFS) of patients with HCC after LT, and to explore its significance for expanding the Milan criteria., Methods: Clinical data of 253 patients after LT in HCC were collected retrospectively. The receiver operating characteristic curve was used to calculate the best cut-off value. χ 2 test was used to analyze the correlation between preoperative serological indicators and tumor pathological features. Univariate and multivariate analyses were used to analyze the risk factors affecting the OS and TFS rates and the predictive values of different LT criteria were compared. Nomogram model was used to predict the OS and TFS rates of patients exceeding Milan criteria., Results: Independent risk factors for poor OS and TFS rates were alpha-fetoprotein (AFP) >200 ng/mL, gamma-glutamyl transpeptidase (GGT) >80 IU/L, total tumor diameter (TTD) >8 cm and microsatellite lesions. Nomogram model showed patients beyond Milan criteria had better survival when AFP ≤200 ng/mL and GGT ≤80 IU/L or AFP >200 ng/mL, GGT ≤80 IU/L and TTD ≤8 cm. According to Milan criteria, AFP, GGT and TTD, Milan-AFP-GGT-TTD (M-AGT) criteria was established. There was no significant difference in OS and TFS rates among patients in M-AGT, Milan, Hangzhou, Malaya and the University of California at San Francisco (UCSF) criteria., Conclusions: Preoperative serological indicators AFP and GGT can effectively predict long-term OS and TFS in HCC patients after LT. Establishing M-AGT criteria based on serological indicators is helpful to supplement the Milan criteria., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-40/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The differential diagnosis of multiple sclerosis can present specific challenges in patients from Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific. In these areas, environmental factors, genetic background, and access to medical care can differ substantially from those in North America and western Europe, where multiple sclerosis is most common. Furthermore, multiple sclerosis diagnostic criteria have been developed primarily using data from North America and western Europe. Although some diagnoses mistaken for multiple sclerosis are common regardless of location, a comprehensive approach to the differential diagnosis of multiple sclerosis in Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific regions requires special consideration of diseases that are prevalent in those locations. A collaborative effort has therefore assessed global differences in multiple sclerosis differential diagnoses and proposed recommendations for evaluating patients with suspected multiple sclerosis in regions beyond North America and western Europe., Competing Interests: Declaration of interests JC declares receiving grants or research contracts from Biogen and Merck; personal compensation for consulting from Merck; payment or honoraria for lectures from Biogen, Merck, Bristol Myers Squibb, Novartis, and Roche; and support for attending meetings and travel from Merck. JC is a deputy chair International Medical and Scientific Board of Multiple sclerosis International Federation (MSIF), unpaid; and has received equipment, materials, drugs, medical writing, gifts, or other services from Novartis (Investigator initiated award). AJS declares receiving grant funding from National Institute of Neurological Disorders and Stroke, National Institutes of Health and Bristol Myers Squibb (investigator initiated award); has done contracted research with Sanofi, Biogen, Novartis, Actelion, and Genentech; has received personal compensation for consulting from Emmanuel Merck, Darmstadt, Serono and Octave Bioscience; has received payments or honoraria for lectures from Emmanuel Merck, Darmstadt, Serono; has received expert testimony from The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; is a participant on a Data Safety Monitoring Board for the Patient Centered Research Institute, and Yale University; declares participation on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics; and is a content Chair for the American Academy of Neurology (AAN) Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. JAC declares personal compensation for consulting from Astoria, Bristol-Myers Squibb, Convelo, EMD Serono, FiND Therapeutics, INMune, and Sandoz; and serving as an editor of Multiple Sclerosis Journal. BLB is funded by the National Multiple Sclerosis Society, and National Institute of Health; is a consultant for Roche, and Sanofi; and is a Board Director AAN (unpaid). TG has served as a consultant and received compensation from Genentech, Horizon, Sanofi, Alexion, and Greenwich Biosciences. BH declares grants from the European Union, Bundesministerium für Bildung und Forschung, and Deutsche Forschungsgemeinschaft; received personal compensation for consulting from Sandoz, Novartis, and GLG consulting; holds patents for antibodies against KIR4·1 in a subpopulation of patients with multiple sclerosis (2012) and genetic determinants of neutralising antibodies to interferon (filed 2010); and participated in a Data Safety and Monitoring Board for Novartis, Allergy Care DSMB, TG Therapeutics, and Polpharma, and Advisory Board for Novartis. HJK declares a research grant from the National Research Foundation of Korea and research support from Aprilbio, UCB, and Eisai; has received consultancy fees from Altos Biologics, AstraZeneca, Biogen, Daewoong, Kaigene, Kolon Life Science, MDimune, Merck Serono, and Roche; declares honoraria for lectures from Alexion, Eisai, GCPharma, Handok, Mitsubishi Tanabe Pharma, and Sanofi Genzyme; has received personal compensation for participation on a Data Safety Monitoring Board from Sanofi-Genzyme; has received compensation as Co-editor for the Multiple Sclerosis Journal and Associate Editor for the Journal of Clinical Neurology; and is a Vice President of Pan-Asian Committee on Treatment and Research in Multiple Sclerosis (unpaid). RAM declares grants or contracts from Biogen, Idec, and Roche. FM has received research funding to her institution from Sumaira Foundation, Genentech, Biogen, Horizon Therapeutics, US National Histitute Institute of Health, US Department of State, Foundation Pierre Fabre, and Novartis; has received consulting fees from Alexion, EMD Serono, Genentech, TG Therapeutics, and Horizon Therapeutics; and declares shares of the startup company Brain Capture (not related to the content of this manuscript). SDN declares grants or contracts (paid directly to institution) from Biogen, Roche, Genentech, National MS Society, Department of Defense, and Patient Centered Outcomes Research Institute; has received personal compensation for consulting from Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, Horizon Therapeutics, and TG Therapeutics; and is a study lead principal investigator for a Roche clinical trial programme. MAS declares personal honoraria for lectures from Roche, Biogen, Cinnagen, NanoAlvand, Merck, Novartis, and Abidi. DKS declares grants or research contracts from CNPq / Brazil 425331/2016–4 and 308636/2019–8, and Brazilian National Council for Scientific and Technological Development; has received investigator initiated awards from TEVA, Merck, and Biogen; has received personal compensation for consulting from Roche, and Alexion; declares personal honoraria for lectures from Roche, Alexion, Horizon, Merck, Americas Health Foundation; and is a member of International Society of Neuroimmunology, International Advisory Board (unpaid), and Academia Brasileira de Neurologia, Educational Committee (unpaid). DS declares a pilot research grant from the National MS Society paid to the Institution; declares receipt of personal honoraria for lecturing from Roche Pharmaceuticals; declares travel support from Roche Pharmaceutical; and is a Committee member and chair of Multiple Sclerosis International Federation (unpaid). AS has received grants or contracts from the Turkish MS Society, Istanbul University-Cerrahpasa Research Support Funds, and The Scientific and Technological Research Council of Türkiye Health Sciences Research Grants; has received consulting fees from Roche, Merck-Serono, Biogen Idec/Gen Pharma of Turkey , Sanofi-Genzyme, Novartis, and Alexion; has received honoraria for lectures from Sanofi-Genzyme, Novartis, TEVA, and Roche; and has received support for attending meetings from Sanofi-Genzyme, Roche, Merck-Serono, and Alexion. KT declares personal consulting fees from Merck and Eisai; declares payment for lectures from Merck, Eisai, Roche, and Terumo Blood and Cell Technology; and is a member of the Organizing Committee Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (unpaid). MW has received publication royalties from Springer and Elsevier; has received consultancy honoraria from Icometrix, Imcyse, Novartis, Sanofi, Merck, and Biologix; declares personal compensation for lectures or presentations from Alexion, Bayer Healthcare, Biogen, Biologix, Bristol Myers Squibb, Celgene, Genilac, Imcyse, Icometrix, Merck-Serono, Novartis, Roche, and Sanofi-Genzyme; and declares support for attending meetings from Merck-Serono. BGW declares royalties from RSR, Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR , and Oxford University; declares personal consulting fees from Roche, Horizon Therapeutics, Cambridge Pharmaceuticals, and Mitsubishi Tanabe; has received payments for lecture presentations from Roche and Horizon; has a patent planned for NMO-IgG for diagnosis of neuromyelitis optica; and declares participation on a Data Safety Monitoring Board and Advisory borads for Alexion MedImmune/VielaBio/Horizon, and UCB Biosciences. KF declares grants from Ministry of Education, Culture, Sports, Science and Technology of Japan and Ministry of Health, Welfare and Labor of Japan; has received personal compensation for consulting from Merck Biopharma, Japan Tobacco, and Abbvie; has received payment or honoraria forlectures and presentations from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, Teijin, Asahi Kasei Medical, Merck, and Takeda; declares participation in an Advisory Board for Biogen, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, and UCB; serves as President of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (unpaid), President of the Japanese Society of Neuroimmunology (unpaid), is a Board Member of the Japan Multiple Sclerosis Society (unpaid), is a board member of theEuropean Charcot Foundation (unpaid), and is a Member of the International Medical and Scientific Board, MSIF (unpaid). All other authors declared no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor-specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The objective is to characterize differentially expressed proteins (DEPs) in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) through high-throughput analysis. Sera from 11 healthy controls (HCs), 21 GBS and 19 CIDP patients were subjected to Olink Proteomics Analysis. In the comparison between CIDP and GBS groups, up-regulation of ITM2A and down-regulation of NTF4 were observed. Comparing GBS with HCs revealed 18 up-regulated and 4 down-regulated proteins. Comparing CIDP with the HCs identified 15 up-regulated and 4 down-regulated proteins. Additionally, the correlation between clinical characteristics and DEPs were uncovered. In conclusion, the DEPs have significant potential to advance our understanding of the pathogenesis in these debilitating neurological disorders., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood-brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS., (© 2024. The Author(s).)

Objective: The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON)., Methods: We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present., Results: According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%)., Interpretation: According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: We investigated the risk factors associated with severe or critical Coronavirus disease 2019 (COVID-19) infection due to the Omicron variant in patients with myasthenia gravis (MG) and determined the potential effect of COVID-19 on myasthenic exacerbation during the Omicron pandemic., Methods: This retrospective study included 287 patients with MG in Tianjin, China. Clinical data of the patients were collected using electronic questionnaires, databases, and clinical records., Results: The overall infection rate was 84.7%. Advanced age, comorbidities, generalized phenotype, and MG instability were drivers of COVID-19 severity, and post-COVID-19 myasthenic exacerbation. The concurrent use of a steroid-sparing agent did not affect COVID-19 susceptibility or severity. It did lower the risk of myasthenic exacerbation after COVID-19 infection. Patients with severe COVID-19 experienced myasthenic exacerbation earlier than patients with non-severe infection ( p  < 0.001). The severity of COVID-19 (Hazards Ratio = 3.04, 95% CI: 1.41-6.54, p  = 0.004) and the clinical phenotype (Hazards Ratio = 3.29, 95% CI: 1.63-6.63, p  < 0.001) emerged as independent risk factors for early MG exacerbation., Conclusion: Generally, patients with MG appear to be susceptible to the Omicron strains. Immunotherapy for MG did not increase COVID-19 susceptibility or severity. We do not advocate an immediate cessation of ongoing immunosuppressive treatments once a COVID-19 infection is diagnosed. Instead, a judicious evaluation of the risks and benefits, tailored to each individual, is recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Xu, Qin, Liu, Guo, Huang, Fan, Zhang, Qi, Zhang, Yang, Shi and Yang.)

Damage or microstructural alterations of the white matter can cause dysfunction of the intrinsic neural networks in a condition termed as white matter disease (WMD). Frequently detected on brain computed tomography and magnetic resonance imaging scans, WMD is commonly presented in inflammatory demyelinating diseases like multiple sclerosis (MS) and vascular diseases such as cerebral small vessel disease (CSVD). Prevention of MS and CSVD progression requires early treatments with drastically different medications and approaches, as such, early and accurate diagnosis of WMD, derived from vascular or demyelinating etiologies, is of paramount importance. However, the clinical and imaging similarities between MS, especially during the early stage, and CSVD, pose a significant dilemma in differentiating these two conditions. In this review, we attempt to summarize and contrast the distinguishing features of MS and CSVD for aiding accurate diagnosis to ensure timely corresponding management in the early stages of MS and CSVD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The diagnosis of tuberculous pleurisy (TP) presents a significant challenge due to the low bacterial load in pleural effusion (PE) samples. Cell-free Mycobacterium tuberculosis DNA (cf-TB) in PE samples is considered an optimal biomarker for diagnosing TP. This study aimed to evaluate the applicability of cf-TB testing across diverse research sites with a relatively large sample size., Methods: Patients suspected of TP and presenting with clinical symptoms and radiological evidence of PE were consecutively enrolled by treating physicians from 11 research sites across 6 provinces in China between April 2020 and August 2022. Following centrifugation, sediments obtained from PE were used for Xpert MTB/RIF (Xpert) and mycobacterial culture, while the supernatants were subjected to cf-TB testing. This study employed a composite reference standard to definite TP, which was characterized by any positive result for Mycobacterium tuberculosis (MTB) through either PE culture, PE Xpert, or pleural biopsy., Results: A total of 1412 participants underwent screening, and 1344 (95.2%) were subsequently enrolled in this study. Data from 1241 (92.3%) participants were included, comprising 284 with definite TP, 677 with clinically diagnosed TP, and 280 without TP. The sensitivity of cf-TB testing in definite TP was 73.6% (95% CI 68.2-78.4), significantly higher than both Xpert (40.8%, 95% CI 35.3-46.7, P < 0.001) and mycobacterial culture (54.2%, 95% CI 48.4-59.9, P < 0.001). When clinically diagnosed TP was incorporated into the composite reference standard for sensitivity analysis, cf-TB testing showed a sensitivity of 46.8% (450/961, 95% CI 43.7-50.0), significantly higher than both Xpert (116/961, 12.1%, 95% CI 10.2-14.3, P < 0.001) and mycobacterial culture (154/961, 16.0%, 95% CI 13.8-18.5, P < 0.001). The specificities of cf-TB testing, Xpert, and mycobacterial culture were all 100.0%., Conclusions: The performance of cf-TB testing is significantly superior to that of Xpert and mycobacterial culture methods, indicating that it can be considered as the primary diagnostic approach for improving TP detection. Trial registration The trial was registered on Chictr.org.cn (ChiCTR2000031680, https://www.chictr.org.cn/showproj.html?proj=49316 )., (© 2024. The Author(s).)

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.

Background: Although trigeminal nerve involvement is a characteristic of multiple sclerosis (MS), its prevalence across studies varies greatly due to MRI resolution and cohort selection bias. The mechanism behind the site specificity of trigeminal nerve injury is still unclear. We aim to determine the prevalence of trigeminal nerve involvement in patients with MS in a consecutive 7T brain MRI cohort., Methods: This observational cohort originates from an ongoing China National Registry of Neuro-Inflammatory Diseases. Inclusion criteria were the following: age 18 years or older, diagnosis of MS according to the 2017 McDonald criteria and no clinical relapse within the preceding 3 months. Each participant underwent 7T MAGNETOM Terra scanner (Siemens, Erlangen, Germany), using a 32-channel phased array coil at Beijing Tiantan Hospital. T1-weighted magnetisation-prepared rapid acquisition gradient echoes, fluid-attenuated inversion recovery (FLAIR) and fluid and white matter suppression images were used to identify lesions. FLAIR* and T2* weighted images were used to identify central vein sign (CVS) within the trigeminal lesions., Results: 120 patients underwent 7T MRI scans between December 2021 and May 2023. 19/120 (15.8%) patients had a total of 45 trigeminal lesions, of which 11/19 (57.9%) were bilateral. The linear lesions extended along the trigeminal nerve, from the root entry zone (REZ) (57.8%, 26/45) to the pontine-medullary nucleus (42.2%, 19/45). 26.9% (7/26) of the lesions in REZ showed a typical central venous sign., Conclusion: In this 7T MRI cohort, the prevalence of trigeminal nerve involvement was 15.8%. Characteristic CVS was detected in 26.9% of lesions in REZ. This suggests an inflammatory demyelination mechanism of trigeminal nerve involvement in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV-PACNS) using 7 T magnetic resonance imaging (MRI)., Methods: This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1-weighted magnetization-prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility-weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis., Results: We included 21 patients with SV-PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral-like sign." The onset age of patients with coral-like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral-like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV-PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral-like sign was not observed in patients with large vessel CNS vasculitis., Interpretation: The key characteristics of the coral-like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV-PACNS. ANN NEUROL 2024;96:194-203., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3)., Design: Multicentre, double blind, randomised, placebo controlled trial., Setting: 244 hospitals in China between 11 August 2022 and 13 April 2023., Participants: 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled., Interventions: Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days., Main Outcome Measures: The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat., Results: 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83)., Conclusions: The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L., Trial Registration: ClinicalTrials.gov, NCT05439356., Competing Interests: Declaration of interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from National Key R&D Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The parallel evolution of similar traits or species provides strong evidence for the role of natural selection in evolution. Traits or species that evolved repeatedly can be driven by separate de novo mutations or interspecific gene flow. Although parallel evolution has been reported in many studies, documented cases of parallel evolution caused by gene flow are scarce by comparison. Aquilegia ecalcarata and A. kansuensis belong to the genus of Aquilegia, and are the closest related sister species. Mutiple origins of A. ecalcarata have been reported in previous studies, but whether they have been driven by separate de novo mutations or gene flow remains unclear., Results: In this study, We conducted genomic analysis from 158 individuals of two repeatedly evolving pairs of A. ecalcarata and A. kansuensis. All samples were divided into two distinct clades with obvious geographical distribution based on phylogeny and population structure. Demographic modeling revealed that the origin of the A. ecalcarata in the Eastern of China was caused by gene flow, and the Eastern A. ecalcarata occurred following introgression from Western A. ecalcarata population. Analysis of Treemix and D-statistic also revealed that a strong signal of gene flow was detected from Western A. ecalcarata to Eastern A. ecalcarata. Genetic divergence and selective sweep analyses inferred parallel regions of genomic divergence and identified many candidate genes associated with ecologically adaptive divergence between species pair. Comparative analysis of parallel diverged regions and gene introgression confirms that gene flow contributed to the parallel evolution of A. ecalcarata., Conclusions: Our results further confirmed the multiple origins of A. ecalcarata and highlighted the roles of gene flow. These findings provide new evidence for parallel origin after hybridization as well as insights into the ecological adaptation mechanisms underlying the parallel origins of species., (© 2024. The Author(s).)

Competing Interests: We declare no competing interests. We thank the members of Beijing-Tianjin Center for Neuroinflammation for support and Elaine Shi and Samuel Shi for editorial assistance. The authors’ laboratories are funded in part by the National Natural Science Foundation of China (grant numbers 82171777 and 82320108007).

Background & Aims: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial., Patients and Methods: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs)., Results: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs., Conclusions: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine., Competing Interests: Declaration of competing interest The authors declare no competing interests, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Postoperative pneumonia (POP) is the most prevalent of all nosocomial infections in patients who underwent cardiac surgery. The aim of this study was to identify independent risk factors for pneumonia after cardiac surgery, from which we constructed a nomogram for prediction., Methods: The clinical data of patients admitted to the Department of Cardiothoracic Surgery of Nanjing Drum Tower Hospital from October 2020 to September 2021 who underwent cardiac surgery were retrospectively analyzed, and the patients were divided into two groups according to whether they had POP: POP group (n=105) and non-POP group (n=1083). Preoperative, intraoperative, and postoperative indicators were collected and analyzed. Logistic regression was used to identify independent risk factors for POP in patients who underwent cardiac surgery. We constructed a nomogram based on these independent risk factors. Model discrimination was assessed via area under the receiver operating characteristic curve (AUC), and calibration was assessed via calibration plot., Results: A total of 105 events occurred in the 1188 cases. Age (>55 years) (OR: 1.83, P=0.0225), preoperative malnutrition (OR: 3.71, P<0.0001), diabetes mellitus(OR: 2.33, P=0.0036), CPB time (Cardiopulmonary Bypass Time) > 135 min (OR: 2.80, P<0.0001), moderate to severe ARDS (Acute Respiratory Distress Syndrome )(OR: 1.79, P=0.0148), use of ECMO or IABP or CRRT (ECMO: Extra Corporeal Membrane Oxygenation; IABP: Intra-Aortic Balloon Pump; CRRT: Continuous Renal Replacement Therapy )(OR: 2.60, P=0.0057) and MV( Mechanical Ventilation )> 20 hours (OR: 3.11, P<0.0001) were independent risk factors for POP. Based on those independent risk factors, we constructed a simple nomogram with an AUC of 0.82. Calibration plots showed good agreement between predicted probabilities and actual probabilities., Conclusion: We constructed a facile nomogram for predicting pneumonia after cardiac surgery with good discrimination and calibration. The model has excellent clinical applicability and can be used to identify and adjust modifiable risk factors to reduce the incidence of POP as well as patient mortality., (© 2024. The Author(s).)

Background: Cardio-metabolic disorders (CMDs) are common in aging people and are pivotal risk factors for cardiovascular diseases (CVDs). Inflammation is involved in the pathogenesis of CVDs and aging, but the underlying inflammatory molecular phenotypes in CMDs and aging are still unknown., Method: We utilized multiple proteomics to detect 368 inflammatory proteins in the plasma of 30 subjects, including healthy young individuals, healthy elderly individuals, and elderly individuals with CMDs, by Proximity Extension Assay technology (PEA, O-link). Protein-protein interaction (PPI) network and functional modules were constructed to explore hub proteins in differentially expressed proteins (DEPs). The correlation between proteins and clinical traits of CMDs was analyzed and diagnostic value for CMDs of proteins was evaluated by ROC curve analysis., Result: Our results revealed that there were 161 DEPs (adjusted p < 0.05) in normal aging and EGF was the most differentially expressed hub protein in normal aging. Twenty-eight DEPs were found in elderly individuals with CMDs and MMP1 was the most differentially expressed hub protein in CMDs. After the intersection of DEPs in aging and CMDs, there were 10 overlapping proteins: SHMT1, MVK, EGLN1, SLC39A5, NCF2, CXCL6, IRAK4, REG4, PTPN6, and PRDX5. These proteins were significantly correlated with the level of HDL-C, TG, or FPG in plasma. They were verified to have good diagnostic value for CMDs in aging with an AUC > 0.7. Among these, EGLN1, NCF2, REG4, and SLC39A2 were prominently increased both in normal aging and aging with CMDs., Conclusion: Our results could reveal molecular markers for normal aging and CMDs, which need to be further expanded the sample size and to be further investigated to predict their significance for CVDs., (© 2024. The Author(s).)

Realizing ideal charge transport in field-effect transistors (FETs) of conjugated polymers is crucial for evaluating device performance, such as carrier mobility and practical applications of conjugated polymers. However, the current FETs using conjugated polymers as the active layers generally show certain non-ideal transport characteristics and poor stability. Here, ideal charge transport of n-type polymer FETs is achieved on flexible polyimide substrates by using an organic-inorganic hybrid double-layer dielectric. Deposited conjugated polymer films show highly ordered structures and low disorder, which are supported by grazing-incidence wide-angle X-ray scattering, near-edge X-ray absorption fine structure, and molecular dynamics simulations. Furthermore, the organic-inorganic hybrid double-layer dielectric provides low interfacial defects, leading to excellent charge transport in FETs with high electron mobility (1.49 ± 0.46 cm 2  V -1  s -1 ) and ideal reliability factors (102 ± 7%). Fabricated polymer FETs show a self-encapsulation effect, resulting in high stability of the FET charge transport. The polymer FETs still work with high mobility above 1 cm 2  V -1  s -1 after storage in air for more than 300 days. Compared with state-of-the-art conjugated polymer FETs, this work simultaneously achieves ideal charge transport and environmental stability in n-type polymer FETs, facilitating rapid device optimization of high-performance polymer electronics., (© 2023 Wiley‐VCH GmbH.)

Tocilizumab, a humanized IL-6R monoclonal antibody, has been used in autoimmune diseases closely related to humoral immunity. This report aims to evaluate the efficacy and safety in patients with anti-acetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG). We performed a prospective, open-label, single-arm study in patients with gMG in a 48-week follow-up. All patients were AChR+ and were given tocilizumab by intravenous infusion at a dose of 8 mg/kg at intervals of 4 weeks. The primary endpoint was mean change from baseline in quantitative MG (QMG) score at week 12. The secondary endpoints were mean changes from baseline in MG activities of daily living (MG-ADL) score, AChR-ab titers, and the dosage of oral prednisone at week 12. At week 48, QMG, MG-ADL, and the use of prednisone were also evaluated. Fourteen gMG patients were enrolled and all of them completed the study. Tocilizumab treatment started 8 (4-192) months after the onset of gMG. During tocilizumab treatment, the QMG score was significantly decreased from 15.5 (interqualile range, 9-26) at baseline to 4 (0-9) at week 12 (p < 0.001). The change of ADL was decreased from 14.5(11-19) at baseline to 4 (0-19) at week 12 (p < 0.001) and the change of AChR-ab titers from 15 (7.5-19) at baseline to 6.8 (11.6-4.3) at week 12 (p < 0.001). The dosage of prednisone decreased from baseline 60 (20-65) mg/d to 30 (30-50) mg/d at week 12 (p < 0.001). By the end of the study, the QMG score was 2 (0-7) and MG-ADL score was 1.5 (0-6). 12 (85.7%) patients achieved minimal manifestations. 4 (28.6%) patients were able to discontinue prednisone. No patients experienced exacerbation at the end of the study. No serious adverse events were observed during follow-up. Tocilizumab treatment was associated with a good clinical response and safety over a 48-week observation period, as evidenced by significant improvements in QMG and MG-ADL.

Background: Postoperative hyper-inflammation is a frequent event in patients with acute Stanford type A aortic dissection (ATAAD) after surgical repair. This study's objective was to determine which inflammatory biomarkers could be used to make a better formula for identifying postoperative hyper-inflammation, and which risk factors were associated with hyper-inflammation., Methods: A total of 405 patients were enrolled in this study from October 1, 2020 to April 1, 2023. Of these patients, 124 exhibited poor outcomes. In order to investigate the optimal cut-off values for poor outcomes, logistic and receiver operating characteristic analyses were performed on the following parameters on the first postoperative day: procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), and systemic immune-inflammation index (SII). These cut-off points were used to separate the patients into hyper-inflammatory (n = 52) and control (n = 353) groups. Finally, the logistic were used to find the risk factors of hyper-inflammatory., Results: PCT, CRP, IL-6, and SII were independent risk factors of poor outcomes in the multivariate logistic model. Cut-off points of these biomarkers were 2.18 ng/ml, 49.76 mg/L, 301.88 pg/ml, 2509.96 × 10 9 /L respectively. These points were used to define postoperative hyper-inflammation (OR 2.97, 95% CI 1.35-6.53, P < 0.01). Cardiopulmonary bypass (CPB) > 180 min, and deep hypothermia circulatory arrest (DHCA) > 40 min were the independent risk factors for hyper-inflammation., Conclusions: PCT > 2.18, CRP > 49.76, IL-6 > 301.88, and SII < 2509.96 could be used to define postoperative hyper-inflammation which increased mortality and morbidity in patients after ATAAD surgery. Based on these findings, we found that CPB > 180 min and DHCA > 40 min were separate risk factors for postoperative hyper-inflammation., (© 2024. The Author(s).)

Incorporating heteroatoms can effectively modulate the molecular optoelectronic properties. However, the fundamental understanding of BN doping effects in BN-embedded polycyclic aromatic hydrocarbons (PAHs) is underexplored, lacking rational guidelines to modulate the electronic structures through BN units for advanced materials. Herein, a concise synthesis of novel B 2 N 2 -perylenes with BN doped at the bay area is achieved to systematically explore the doping effect of BN position on the photophysical properties of PAHs. The shift of BN position in B 2 N 2 -perylenes alters the π electron conjugation, aromaticity and molecular rigidness significantly, achieving substantially higher electron transition abilities than those with BN doped in the nodal plane. It is further clarified that BN position dominates the photophysical properties over BN orientation. The revealed guideline here may apply generally to novel BN-PAHs, and aid the advancement of BN-PAHs with highly-emissive performance., (© 2024 Wiley‐VCH GmbH.)

This study aimed to evaluate the effectiveness and safety of an oral sequential triple combination therapy with selexipag after dual combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5I)/riociguat in pulmonary arterial hypertension (PAH) patients. A total of 192 PAH patients from 10 centers had received oral sequential selexipag therapy after being on dual-combination therapy with ERA and PDE5i/riociguat for a minimum of 3 months. Clinical data were collected at baseline and after 6 months of treatment. The study analyzed the event-free survival at 6 months and all-cause death over 2 years. At baseline, the distribution of patients among the risk groups was as follows: 22 in the low-risk group, 35 in the intermediate-low-risk group, 91 in the intermediate-high-risk group, and 44 in the high-risk group. After 6 months of treatment, the oral sequential triple combination therapy resulted in reduced NT-proBNP levels (media from 1604 to 678 pg/mL), a decline in the percentage of WHO-FC III/IV (from 79.2% to 60.4%), an increased in the 6MWD (from 325 ± 147 to 378 ± 143 m) and a rise in the percentage of patients with three low-risk criteria (from 5.7% to 13.5%). Among the low-risk group, there was an improvement in the right heart remodeling, marked by a decrease in right atrium area and eccentricity index. The intermediate-low-risk group exhibited significant enhancements in WHO-FC and tricuspid annular plane systolic excursion. For those in the intermediate-high and high-risk groups, there were marked improvements in activity tolerance, as reflected by WHO-FC and 6MWD. The event-free survival rate at 6 months stood at 88%. Over the long-term follow-up, the survival rates at 1 and 2 years were 86.5% and 86.0%, respectively. In conclusion, the oral sequential triple combination therapy enhanced both exercise capacity and cardiac remodeling across PAH patients of different risk stratifications., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence., Methods and Results: We conducted a nested case-control study using a hospital-based cohort from the Third China National Stroke Registry selecting 214 age- and sex-matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data-independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large-artery atherosclerosis (Causative Classification of Ischemic Stroke [CCS]1), 16 in small-artery occlusion (CCS3), and 25 in undetermined causes (CCS5) among patients with recurrent stroke. In the CCS1 and CCS3 subgroups, differentially expressed proteins were associated with platelet aggregation, neuronal death/cerebroprotection, and immune response, whereas differentially expressed proteins in the CCS5 subgroup were linked to altered metabolic functions. Validated recurrence predictors included proteins associated with neutrophil activity and vascular inflammation (TAGLN2 [transgelin 2], ITGAM [integrin subunit α M]/TAGLN2 ratio, ITGAM/MYL9 [myosin light chain 9] ratio, TAGLN2/RSU1 [Ras suppressor protein 1] ratio) in the CCS3 subgroup and proteins associated with endothelial plasticity and blood-brain barrier integrity (ITGAM/MYL9 ratio and COL1A2 [collagen type I α 2 chain]/MYL9 ratio) in the CCS3 and CCS5 subgroups, respectively., Conclusions: These findings provide a foundation for developing a blood-based biomarker panel, using causative classifications, which may be used in routine clinical practice to predict stroke recurrence.

Background and Aim: Chromoendoscopy with the use of indigo carmine (IC) dye is a crucial endoscopic technique to identify gastrointestinal neoplasms. However, its performance is limited by the endoscopist's skill, and no standards are available for lesion identification. Thus, we developed an artificial intelligence (AI) model to replace chromoendoscopy., Methods: This pilot study assessed the feasibility of our novel AI model in the conversion of white-light images (WLI) into virtual IC-dyed images based on a generative adversarial network. The predictions of our AI model were evaluated against the assessments of five endoscopic experts who were blinded to the purpose of this study with a staining quality rating from 1 (unacceptable) to 4 (excellent)., Results: The AI model successfully transformed the WLI of polyps with different morphologies and different types of lesions in the gastrointestinal tract into virtual IC-dyed images. The quality ratings of the real IC-dyed and AI images did not significantly differ concerning surface structure (AI vs IC: 3.08 vs 3.00), lesion border (3.04 vs 2.98), and overall contrast (3.14 vs 3.02) from 10 sets of images (10 AI images and 10 real IC-dyed images). Although the score depended significantly on the evaluator, the staining methods (AI or real IC) and evaluators had no significant interaction (P > 0.05) with each other., Conclusion: Our results demonstrated the feasibility of employing AI model's virtual IC staining, increasing the possibility of being employed in daily practice. This novel technology may facilitate gastrointestinal lesion identification in the future., (© 2023 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE 130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE 130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE -/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Objective: To characterize the susceptibility-weighted image (SWI) features including paramagnetic rim and nodular lesions with signal intensity changes and central vein sign (CVS) associated with aquaporin 4 (AQP4)-immunoglobulin G (IgG)-negative neuromyelitis optica spectrum disorder (NMOSD), and explore whether they can be used as potential imaging biomarkers for differentiating multiple sclerosis (MS) from this disorder., Methods: We prospectively recruited NMOSD with AQP4-IgG-negative (AQP4- NMOSD) and IgG-positive (AQP4+ NMOSD), and MS subjects from the Clinical and Imaging Patterns of Neuroinflammation Diseases in China (CLUE) project (NCT0410683) between 2019 and 2021. The SWI features including paramagnetic rim and nodular lesions with signal intensity changes and CVS were analyzed and compared among groups, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for distinguishing MS from AQP4- NMOSD., Results: We enrolled a total of 160 consecutive patients (22 AQP4- NMOSD, 65 AQP4+ NMOSD, and 73 MS). We observed paramagnetic rim lesion (0/120 lesions, 0 %) and nodular (1/120, 1 %) lesions with hypointense signals on SWI in the AQP4- NMOSD group. These characteristics were similar to those recorded from AQP4+ NMOSD patients (rim: 0/369 lesions, 0 %, P = 1.000; nodular: 10/369 lesions, 2.7 %, P = 1.000), but differed significantly from those observed in the MS group (rim: 162/1665 lesions, 9.7 %, P<0.001; nodular: 392/1665 lesions, 23.5 %, P < 0.001). AQP4- NMOSD patients had fewer average CVS+ rate (12 %) than MS patients (46 %, p<0.001), similar to AQP4+ NMOSD (13 %, p = 1.000). The SWI imaging features denoting lesions with paramagnetic rim or nodular hypointense SWI signals showed 90.4 % sensitivity, 95.5 % specificity, 98.5 % PPV, and 75 % NPV, and the criteria with≥3 CVS lesions showed sensitivity of 91.8 %, specificity of 90.9 %%, PPV of 97.1 %, and NPV of 76.9 % in distinguishing MS from AQP4- NMOSD., Discussion: The SWI imaging features including lesions with paramagnetic rim or nodular hypointense SWI signals and 3 CVS lesions carries useful information in distinguishing MS from AQP4- NMOSD., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023. Published by Elsevier B.V.)

Urease-producing bacteria (UPB) are widely present in soil and play an important role in soil ecosystems. In this study, 65 UPB strains were isolated from cadmium (Cd)-polluted soil around a lead-zinc mine in Yunnan Province, China. The Cd tolerance, removal of Cd from aqueous solution, production of indoleacetic acid (IAA) and plant growth-promoting effects of these materials were investigated. The results indicate that among the 65 UPB strains, four strains with IAA-producing ability were screened and identified as Bacillus thuringiensis W6-11, B. cereus C7-4, Serratia marcescens W11-10, and S. marcescens C5-6. Among the four strains, B. cereus C7-4 had the highest Cd tolerance, median effect concentration (EC 50 ) of 59.94 mg/L. Under Cd 5 mg/L, S. marcescens C5-6 had the highest Cd removal from aqueous solution, up to 69.83%. Under Cd 25 mg/kg, inoculation with B. cereus C7-4 significantly promoted maize growth in a sand pot by increasing the root volume, root surface area, and number of root branches by 22%, 29%, and 20%, respectively, and plant height and biomass by 16% and 36%, respectively, and significantly increasing Cd uptake in the maize roots. Therefore, UPB is a potential resource for enhancing plant adaptability to Cd stress in plants with Cd-polluted habitats.

Purpose: The explore the added value of peri-calcification regions on contrast-enhanced mammography (CEM) in the differential diagnosis of breast lesions presenting as only calcification on routine mammogram., Methods: Patients who underwent CEM because of suspicious calcification-only lesions were included. The test set included patients between March 2017 and March 2019, while the validation set was collected between April 2019 and October 2019. The calcifications were automatically detected and grouped by a machine learning-based computer-aided system. In addition to extracting radiomic features on both low-energy (LE) and recombined (RC) images from the calcification areas, the peri-calcification regions, which is generated by extending the annotation margin radially with gradients from 1 mm to 9 mm, were attempted. Machine learning (ML) models were built to classify calcifications into malignant and benign groups. The diagnostic matrices were also evaluated by combing ML models with subjective reading., Results: Models for LE (significant features: wavelet-LLL&#95;glcm&#95;Imc2&#95;MLO; wavelet-HLL&#95;firstorder&#95;Entropy&#95;MLO; wavelet-LHH&#95;glcm&#95;DifferenceVariance&#95;CC; wavelet-HLL&#95;glcm&#95;SumEntropy&#95;MLO;wavelet-HLH&#95;glrlm&#95;ShortRunLowGray LevelEmphasis&#95;MLO; original&#95;firstorder&#95;Entropy&#95;MLO; original&#95;shape&#95;Elongation&#95;MLO) and RC (significant features: wavelet-HLH&#95;glszm&#95;GrayLevelNonUniformityNormalized&#95;MLO; wavelet-LLH&#95;firstorder&#95;10Percentile&#95;CC; original&#95;firstorder&#95;Maximum&#95;MLO; wavelet-HHH&#95;glcm&#95;Autocorrelation&#95;MLO; original&#95;shape&#95;Elongation&#95;MLO; wavelet-LHL&#95;glszm&#95;GrayLevelNonUniformityNormalized&#95;MLO; wavelet-LLH&#95;firstorder&#95;RootMeanSquared&#95;MLO) images were set up with 7 features. Areas under the curve (AUCs) of RC models are significantly better than those of LE models with compact and expanded boundary (RC v.s. LE, compact: 0.81 v.s. 0.73, p < 0.05; expanded: 0.89 v.s. 0.81, p < 0.05) and RC models with 3 mm boundary extension yielded the best performance compared to those with other sizes (AUC = 0.89). Combining with radiologists' reading, the 3mm-boundary RC model achieved a sensitivity of 0.871 and negative predictive value of 0.937 with similar accuracy of 0.843 in predicting malignancy., Conclusions: The machine learning model integrating intra- and peri-calcification regions on CEM has the potential to aid radiologists' performance in predicting malignancy of suspicious breast calcifications.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions., Main Body: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes., Conclusions: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target., (© 2023. The Author(s).)

This article presents Holistically-Attracted Wireframe Parsing (HAWP), a method for geometric analysis of 2D images containing wireframes formed by line segments and junctions. HAWP utilizes a parsimonious Holistic Attraction (HAT) field representation that encodes line segments using a closed-form 4D geometric vector field. The proposed HAWP consists of three sequential components empowered by end-to-end and HAT-driven designs: 1) generating a dense set of line segments from HAT fields and endpoint proposals from heatmaps, 2) binding the dense line segments to sparse endpoint proposals to produce initial wireframes, and 3) filtering false positive proposals through a novel endpoint-decoupled line-of-interest aligning (EPD LOIAlign) module that captures the co-occurrence between endpoint proposals and HAT fields for better verification. Thanks to our novel designs, HAWPv2 shows strong performance in fully supervised learning, while HAWPv3 excels in self-supervised learning, achieving superior repeatability scores and efficient training (24 GPU hours on a single GPU). Furthermore, HAWPv3 exhibits a promising potential for wireframe parsing in out-of-distribution images without providing ground truth labels of wireframes.

Intraventricular hemorrhage (IVH) commonly occurs as an extension of intracerebral hemorrhage (ICH) into the brain ventricular system, leading to worse outcomes without effective management. Using a mouse model of IVH, we found that impaired neurogenesis is evident in the subventricular zone (SVZ), along with persistent microglia activation, leukocyte infiltration and cell death. Pharmacological depletion of microglia using PLX3397, an inhibitor of colony stimulating factor 1 receptor (CSF1R), promotes neurogenesis, and alleviated delayed functional impairments in IVH mice. Meanwhile, an elevated level of microglia-derived CC chemokine ligand 20 (CCL20) is observed in the SVZ following IVH, which can induce the upregulation of pro-inflammatory factors in microglia and impair the proliferation and survival of neural stem cells (NSCs) in vitro. Blocking CCL20 in microglia leads to downregulation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/the nuclear factor-κB (NF-κB) signaling pathway, which may contribute to CCL20-dependent pro-inflammatory responses and neural injury. These findings demonstrate a detrimental role of microglia in the neurogenesis and neurorepair after IVH in which CCL20 likely plays a role., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Eight previously undescribed indole-diterpenoids named penerpenes O-V (1-8), together with seven known analogues (9-14), were isolated from the marine soft coral-derived fungus Aspergillus sp. ZF-104. Their structures including the absolute configurations of these compounds were assigned on the basis of spectroscopic data and ECD analysis along with quantum ECD and NMR calculations. Compounds 4 and 5 bear rare indolin-2-one units in their structures and 6 bears a reconstructed novel skeleton in which the indole ring and the terpenoid substructure are cleaved before they are reconnected through the nitrogen atom. Compounds 1, 2, 7, and 10 showed protein tyrosine phosphatase 1B (PTP1B) inhibitory activities comparable to that of the positive control NaVO 3 ., 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: Brain injury triggers neuroaxonal injury and neural death, that leads to the development of secondary sequelae. Throughout this process, brain injury factors released into circulation via the injured neurovascular unit are important prognostic parameters. Plasma NfL, NfH, MCP-1, and MMP-9 have been identified as potential indicators in this regard., Methods: Using a microfluidic ELISA platform, we measured plasma from 273 healthy subjects that underwent quantifications of NfL, NfH, MCP-1, and MMP-9 levels. We investigated the possible associations between biomarkers and basic demographics., Results: The median concentration of plasma NfL was 10.40 (IQR = 6.73 - 16.60) pg/mL, NfH was 70.70 (IQR = 39.75 - 125.50) pg/mL, MCP-1 was 191.0 (IQR = 162.0 - 237.5) pg/mL, and MMP-9 was 169,255 (IQR = 107,657 - 231,276) pg/mL. Among all four biomarkers, plasma NfL and NfH levels were positively correlated with age (r = 0.557, p < 0.001, r = 0.364, p = 0.003). NfL was also correlated with NfH (r = 0.391, p = 0.002)., Conclusions: These data provide a basis for the potential application of a brain-injury biomarker panel in routine clinical practice. It lays a significant foundation in supporting circulating CNS-biomarkers as noninvasive biomarkers for neurological disorders.

Objective: This pilot study aimed to evaluate the efficacy and safety of domperidone for the treatment of Chinese patients with functional dyspepsia (FD) who were diagnosed according to the Rome IV criteria and to identify the FD subtypes that potentially responded better to domperidone., Methods: This multicenter prospective study was conducted in China from August 2018 to July 2020, consisting of a 1-week screening phase and a 2-week double-blind treatment phase. Participants were randomized to receive domperidone 10 mg or matching placebo tablets thrice daily for 14 days. The primary end-point was the overall treatment effect (OTE) response rate after 2-week therapy., Results: Altogether 160 patients were included, with 80 patients in each group. The OTE response rate after 2-week therapy was significantly higher for domperidone compared with placebo (60.7% vs 46.0%; relative risk [RR] 1.318, 95% confidence interval [CI] 0.972-1.787). Moreover, the OTE response rate after 2-week domperidone or placebo treatment was 60.3% versus 54.9% for postprandial distress syndrome (PDS) (RR 1.098, 95% CI 0.750-1.607) and 60.6% versus 35.2% for overlapping PDS-epigastric pain syndrome (EPS) (RR 1.722, 95% CI 0.995-2.980). Adverse events were reported by seven patients in the domperidone group and 12 patients in the placebo group. None of the adverse events in the domperidone group were serious., Conclusion: Domperidone showed a positive pattern regarding OTE response rates after 2-week therapy compared to placebo in patients with FD, as well as in subtypes of PDS and overlapping PDS-EPS. No new safety issue was observed., (© 2023 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1 high was enriched in interferon alpha (IFN-α) response and ITGA2 high was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy., (© 2023. The Author(s).)

Apiose is a natural pentose containing an unusual branched-chain structure. Apiosides are bioactive natural products widely present in the plant kingdom. However, little is known on the key apiosylation reaction in the biosynthetic pathways of apiosides. In this work, we discover an apiosyltransferase GuApiGT from Glycyrrhiza uralensis. GuApiGT could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, and exhibits strict selectivity towards UDP-apiose. We further solve the crystal structure of GuApiGT, determine a key sugar-binding motif (RLGSDH) through structural analysis and theoretical calculations, and obtain mutants with altered sugar selectivity through protein engineering. Moreover, we discover 121 candidate apiosyltransferase genes from Leguminosae plants, and identify the functions of 4 enzymes. Finally, we introduce GuApiGT and its upstream genes into Nicotiana benthamiana, and complete de novo biosynthesis of a series of flavonoid apiosides. This work reports an efficient phenolic apiosyltransferase, and reveals mechanisms for its sugar donor selectivity., (© 2023. Springer Nature Limited.)

Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Acute brain ischaemia elicits pronounced inflammation, which aggravates neural injury. However, the mechanisms governing the resolution of acute neuroinflammation remain poorly understood. In contrast to regulatory T and B cells, group 2 innate lymphoid cells (ILC2s) are immunoregulatory cells that can be swiftly mobilised without antigen presentation; whether and how these ILC2s participate in central nervous system inflammation following brain ischaemia is still unknown., Methods: Leveraging brain tissues from patients who had an ischaemic stroke and a mouse model of focal ischaemia, we characterised the presence and cytokine release of brain-infiltrating ILC2s. The impact of ILC2s on neural injury was evaluated through antibody depletion and ILC2 adoptive transfer experiments. Using Rag2 -/- γc -/- mice receiving passive transfer of IL-4 -/- ILC2s, we further assessed the contribution of interleukin (IL)-4, produced by ILC2s, in ischaemic brain injury., Results: We demonstrate that ILC2s accumulate in the areas surrounding the infarct in brain tissues of patients with cerebral ischaemia, as well as in mice subjected to focal cerebral ischaemia. Oligodendrocytes were a major source of IL-33, which contributed to ILC2s mobilisation. Adoptive transfer and expansion of ILC2s reduced brain infarction. Importantly, brain-infiltrating ILC2s reduced the magnitude of stroke injury severity through the production of IL-4., Conclusions: Our findings revealed that brain ischaemia mobilises ILC2s to curb neuroinflammation and brain injury, expanding the current understanding of inflammatory networks following stroke., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Intravenous thrombolysis via tPA (tissue-type plasminogen activator) is the only approved pharmacological treatment for acute ischemic stroke, but its benefits are limited by hemorrhagic transformation. Emerging evidence reveals that tPA swiftly mobilizes immune cells which extravasate into the brain parenchyma via the cerebral vasculature, augmenting neurovascular inflammation, and tissue injury. In this review, we summarize the pronounced alterations of immune cells induced by tPA in patients with stroke and experimental stroke models. We argue that neuroinflammation, triggered by ischemia-induced cell death and exacerbated by tPA, compromises neurovascular integrity and the microcirculation, leading to hemorrhagic transformation. Finally, we discuss current and future approaches to attenuate thrombolysis-associated hemorrhagic transformation via uncoupling immune cells from the neurovascular unit., Competing Interests: Disclosures None.

As the most promising candidates for the implementation of in-sensor computing, retinomorphic vision sensors can constitute built-in neural networks and directly implement multiply-and-accumulation operations using responsivities as the weights. However, existing retinomorphic vision sensors mainly use a sustained gate bias to maintain the responsivity due to its volatile nature. Here, we propose an ion-induced localized-field strategy to develop retinomorphic vision sensors with nonvolatile tunable responsivity in both positive and negative regimes and construct a broadband and reconfigurable sensory network with locally stored weights to implement in-sensor convolutional processing in spectral range of 400 to 1800 nanometers. In addition to in-sensor computing, this retinomorphic device can implement in-memory computing benefiting from the nonvolatile tunable conductance, and a complete neuromorphic visual system involving front-end in-sensor computing and back-end in-memory computing architectures has been constructed, executing supervised and unsupervised learning tasks as demonstrations. This work paves the way for the development of high-speed and low-power neuromorphic machine vision for time-critical and data-intensive applications.

Background: Early postoperative bacterial pneumonia and sepsis (ePOPS), which occurs within the first 48 hours after cardiovascular surgery, is a serious life-threatening complication. Diagnosis of ePOPS is extremely challenging, and the existing diagnostic tools are insufficient. The purpose of this study was to construct a novel diagnostic prediction model for ePOPS., Methods: Least Absolute Shrinkage and Selection Operator (LASSO) with logistic regression was used to construct a model to diagnose ePOPS based on patients' comorbidities, medical history, and laboratory findings. The area under the receiver operating characteristic curve (AUC) was used to evaluate the model discrimination., Results: A total of 1203 patients were recruited and randomly split into a training and validation set in a 7:3 ratio. By early morning on the 3rd postoperative day (POD3), 103 patients had experienced 133 episodes of bacterial pneumonia or sepsis (15 patients had both). LASSO logistic regression model showed that duration of mechanical ventilation (P=0.015), NYHA class ≥ III (P=0.001), diabetes (P<0.001), exudation on chest radiograph (P=0.011) and IL-6 on POD3 (P<0.001) were independent risk factors. Based on these factors, we created a nomogram named DICS-I with an AUC of 0.787 in the training set and 0.739 in the validation set., Conclusion: The DICS-I model may be used to predict the risk of ePOPS after cardiovascular surgery, and is also especially suitable for predicting the risk of IRAO. The DICS-I model could help clinicians to adjust antibiotics on the POD3., Competing Interests: 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., (© 2023 Zhang et al.)

Background: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease., Design: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD 2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat., Trial Registry Name: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number : NCT05439356.

NADPH oxidases 2 (NOX2) is the main source of ROS in macrophages, which plays a critical role in the formation of atherosclerosis. However, effects of NOX2 inhibition on established vulnerable plaques and the potential role involved remain unclear. The purpose of this study is to investigate the latent mechanism of NOX2-triggered vulnerable plaque development. We generated a vulnerable carotid plaque model induced by carotid branch ligation and renal artery constriction, combined with a high-fat diet in ApoE -/- mice. NOX2 specific inhibitor, GSK2795039 (10 mg/kg/day by intragastric administration for 8 weeks) significantly prevented vulnerable plaque, evaluated by micro-ultrasound imaging parameters. A profile of less intraplaque hemorrhage detection, increased collagen-lipid ratio, fibrous cap thickness and less necrotic core formation were also found in GSK2795039 treated group. Mechanistically, reduced 4-HNE, in situ lesional apoptosis and enhanced efferocytosis were involved in mice treated with NOX2 inhibitor. Further analysis in mouse macrophages confirmed the role of NOX2 inhibition in enhancing macrophage efferocytosis by regulating the MertK/PI3K/AKT pathway. In summary, our data defined previously few recognized roles of NOX2 in vulnerable plaque pathogenesis and an undescribed NOX2-ROS-MerTK axis acts involved in regulating macrophage efferocytosis in the formation of rupture-prone vulnerable plaques., Competing Interests: Declaration of competing interest Author declares no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Laboratory determination of autoantibodies against acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and other autoantigens have been integrated into the diagnosis of myasthenia gravis (MG). However, evidence supporting the selection of methodologies is lacking., Methods: In this prospective, multicentre cohort study, we recruited patients with suspected MG to evaluate the diagnostic accuracy of cell-based assay (CBA), radioimmunoprecipitation assay (RIPA) and enzyme-linked immunosorbent assay (ELISA) in detecting AChR and MuSK autoantibodies. This study is registered with www.clinicaltrials.gov, number NCT05219097., Findings: 2272 eligible participants were recruited, including 2043 MG, 229 non-MG subjects. AChR antibodies were detected in 1478, 1310, and 1280 out of a total of 2043 MG patients by CBA, RIPA, and ELISA, respectively; sensitivity, 72.3% (95% CI, 70.3-74.3), 64.1% (95% CI, 62.0-66.2), 62.7% (95% CI, 60.5-64.8); specificity, 97.8% (95% CI, 95.0-99.3), 97.8% (95% CI, 95.0-99.3), 94.8% (95% CI, 91.9-97.7). MuSK antibodies were found in 59, 50, and 54 from 2043 MG patients by CBA, RIPA and ELISA, respectively; sensitivity, 2.9% (95% CI, 2.2-3.7), 2.4% (95% CI, 1.8-3.2), 2.6% (95% CI, 2.0-3.4); specificity, 100% (95% CI, 98.4-100), 100% (95% CI, 98.4-100), and 99.1% (95% CI, 96.9-99.9). The area under the curve of AChR antibodies tested by CBA was 0.858, and there were statistical differences with RIPA (0.843; p = 0.03) and ELISA (0.809; p < 0.0001)., Interpretation: CBA has a higher diagnostic accuracy compared to RIPA or ELISA in detecting AChR and MuSK autoantibodies for MG diagnosis., Funding: New Terrain Biotechnology, Inc., Tianjin, China., Competing Interests: All authors declare no competing interests., (© 2023 The Author(s).)