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BackgroundDespite the efficacy of efgartigimod demonstrated in ADAPT phase 3 trial, data specifically derived from Chinese participants are not available. Therefore, we aimed to evaluate the efficacy and safety of efgartigimod in Chinese patients with generalized myasthenia gravis (gMG).MethodsThis is a prospective cohort study conducted in 8 hospitals across China. gMG patients received weekly intravenous infusions of efgartigimod (10 mg/kg) under a named patient program (NPP). The present study is an 8-week study, consisting of 4 consecutive doses of efgartigimod administered over 3 weeks (one cycle), followed by a 5-week follow-up period to assess the tolerability of efgartigimod’s therapeutic effects. The primary outcome was the mean change in MG activities of daily living (MG-ADL) total score from baseline to 4 weeks. MG-ADL responder was defined as a ≥ 2-point improvement that persisted for 4 weeks, starting by week 4. Safety evaluations encompassed the monitoring of adverse events (AE) and serious AE (SAE) throughout the study.ResultsBetween 5 July 2022 and 25 August 2023, a total of 14 gMG patients were included. The mean age was 57.7 years, with a mean MG-ADL score of 10.86 ± 3.32. At week 4, MG-ADL scores showed a mean reduction of 6 points, reaching a maximum decline of 13 points. Among the patients, 85.7% (12/14) achieved MG-ADL responder status after one cycle of treatment. The most significant reduction in quantitative MG (QMG) scores also occurred at week 4, with a mean decrease of 7 points. Notably, the improvements in MG-ADL and QMG scores persisted until week 8. During treatment and follow-up period, only two mild neck rashes occurred and resolved promptly. No infections or SAE were reported.DiscussionA single cycle of efgartigimod treatment demonstrates effectiveness and the tolerability through week 8, with no new safety signals observed in Chinese gMG patients.

Background: Multiple sclerosis (MS) is a heterogeneous autoimmune disease, with a rapidly evolving body of literature on disease-modifying therapy (DMT) that urgently needs to be synthesized and regularized. Methods: The original material used for the analysis was obtained from the Web of Science Core Collection (WoSCC) in the Science Citation Index Expanded Edition (SCI-E). The data material was accessed through VOSviewer, Citespace, R package “Bibliometrix”, and Scimago Graphica for data analysis and visualization. Among them, the clustering algorithm based on the Largest Likelihood Ratio (LLR) and the burst citation algorithm is the key. Results: As of November 6th, 2022, 4142 publications related to emerging disease-modifying therapies (e-DMT) for MS, 6521 publications related to traditional disease-modifying therapies (t-DMT) for MS, and 1793 publications in cross-cutting disease-modifying therapies (I-DMT) for MS were included in the analysis, respectively. Publications related to DMT in MS were analyzed descriptively (for three subjects: country, institution, and author) and predictively (for two subjects: keywords and references) separately according to three sections: e-DMT, t-DMT, and I-DMT. Topics that still have relevant reference output as of 2022 include the safety of Coronavirus disease 2019 (COVID-19) mRNA vaccination, therapeutic inertia (TI), cladribine tablets, autologous hematopoietic stem cell transplantation (aHSCT), progressive multiple sclerosis, and pediatric multiple sclerosis. Conclusion: The future research focus for MS DMT is the combination trial or cross-trial of various treatment methods to improve the development of individualized treatment plans for MS patients. The exact contents of the research frontiers are included but not limited to ocrelizumab, fingolimod and other monoclonal antibodies, fumaric acid ester, cladribine tablet, aHSCT, and other interventions of randomized controlled trials (RCTs); the impact of mRNA COVID-19 vaccination on MS patients; TI, patient adherence, and other medical management issues; and continued exploration of biomarkers for more accurate disease classification based on the existing clinical indication classification.

Abstract Here we show that striated muscle preferentially expressed protein kinase α (Spegα) maintains cardiac function in hearts with Spegβ deficiency. Speg is required for stability of excitation-contraction coupling (ECC) complexes and interacts with esterase D (Esd), Cardiomyopathy-Associated Protein 5 (Cmya5), and Fibronectin Type III and SPRY Domain Containing 2 (Fsd2) in cardiac and skeletal muscle. Mice with a sequence encoding a V5/HA tag inserted into the first exon of the Speg gene (HA-Speg mice) display a >90% decrease in Spegβ but Spegα is expressed at ~50% of normal levels. Mice deficient in both Spegα and Speg β (Speg KO mice) develop a severe dilated cardiomyopathy and muscle weakness and atrophy, but HA-Speg mice display mild muscle weakness with no cardiac involvement. Spegα in HA-Speg mice suppresses Ca2+ leak, proteolytic cleavage of Jph2, and disruption of transverse tubules. Despite it’s low levels, HA-Spegβ immunoprecipitation identified Esd, Cmya5 and Fsd2 as Spegβ binding partners that localize to triads and dyads to stabilize ECC complexes. This study suggests that Spegα and Spegβ display functional redundancy, identifies Esd, Cmya5 and Fsd2 as components of both cardiac dyads and skeletal muscle triads and lays the groundwork for the identification of new therapeutic targets for centronuclear myopathy.

BackgroundThymectomy is an efficient and standard treatment strategy for patients with myasthenia gravis (MG), postoperative myasthenic crisis (POMC) is the major complication related to thymectomy and has a strongly life-threatening effect. As a biomarker, whether the bilirubin level is a risk factor for MG progression remains unclear. This study aimed to investigate the association between the preoperative bilirubin level and postoperative myasthenic crisis (POMC).MethodsWe analyzed 375 patients with MG who underwent thymectomy at Tangdu Hospital between January 2012 and September 2021. The primary outcome measurement was POMC. The association between POMC and bilirubin level was analyzed by restricted cubic spline (RCS). Indirect bilirubin (IBIL) was divided into two subgroups based on the normal upper limit of IBIL, 14 μmol/L.ResultsCompared with non–POMC group, IBIL levels were significantly higher in patients with POMC. Elevated IBIL levels were closely associated with an increased risk of POMC (p for trend = 0.002). There was a dose-response curve relationship between IBIL levels and POMC incidence (p for non–linearity = 0.93). However, DBIL levels showed a U-shaped association with POMC incidence. High IBIL level (≥14 μmol/L) was an independent predictive factor for POMC [odds ratio = 3.47, 95% confidence interval (CI): 1.56–7.8, p = 0.002]. The addition of high IBIL levels improved the prediction model performance (net reclassification index = 0.186, 95% CI: 0.039–0.334; integrated discrimination improvement = 0.0345, 95% CI: 0.005–0.065).ConclusionHigh preoperative IBIL levels, especially those exceeding the normal upper limit, could independently predict the incidence of POMC.

Introduction: Risk of adverse effects and exacerbation in autoimmune neurological conditions (ANC)are frequently cited reasons for COVID-19 vaccine hesitancy. This study evaluates the ANC safety of COVID-19 vaccines in the real world. Methods: Electronic databases were searched to identify studies reporting the use of the COVID-19 vaccine in ANC. We selected studies that provided data on adverse effects and worsening conditions related to ANC after vaccination. The pooled incidence rates for various adverse effects, stratified for the disease category, dosage, and type of vaccine, were estimated. Results: Twenty-eight studies (31 vaccination cohorts) were included. The pooled incidence rate of general adverse events was 0.35 (95%CI, 0.27–0.43, I2 = 100 %). The pooled incidence rates of local injection reaction, fatigue, weakness, myalgia, fever, headache, and chills were 0.27 (0.18–0.36, I2 = 98 %), 0.16(0.11–0.21, I2 = 93 %), 0.15(0.00–0.31, I2 = 97 %), 0.13(0.08–0.19, I2 = 97 %), 0.11(0.07–0.15, I2 = 95 %), 0.11(0.07–0.16, I2 = 97 %), and 0.09 (0.03–0.16, I2 = 96 %), respectively. The pooled incidence rate of exacerbation adverse events was 0.05 (95%CI, 0.04–0.07, I2 = 84 %). Conclusion: According to available evidence, the administration of COVID-19 vaccines in individuals with autoimmune neurological disorders seems well-tolerated, with few reports of adverse events. Furthermore, exacerbation of autoimmune neurological conditions following vaccination appears to be infrequent.

Abstract Due to the problems that International Mobile Subscriber Identity is not encrypted during transmission, key disclosure, and high authentication overhead in Evolved Packet System‐Authentication and Key Agreement, the next generation of high‐speed railway Long‐Term Evolution for Railway train ground authentication protocol, this paper describes the improved Secure Remote Password algorithm and two‐way heterogeneous Long‐Term Evolution for Railway authentication key agreement scheme. First, the improved Secure Remote Password algorithm is used to encrypt the message transmission between User Equipment and Mobility Management Entity, solving the problem of International Mobile Subscriber Identity being not encrypted during transmission. Then, a two‐way heterogeneous digital signature method of Public Key Infrastructure and Identity‐Based Cryptosystem is proposed to authenticate and negotiate with the Mobility Management Entity and Home Subscriber Server, which improves the security of the root key and can effectively prevent man in the middle, replay and other attacks. Finally, in the research results, the random oracle model is used to verify, and the results show that our method is superior to the comparison method in security and authentication cost, and can meet the Long‐Term Evolution for Railway communication requirements.

This research delves into the impact of climate change on the wood traits of Cunninghamia lanceolata across various altitudinal gradients, aiming to understand the influence of altitude and climatic factors like temperature and precipitation on key wood characteristics. Employing a comprehensive approach, samples were collected from different altitudes for detailed phenotypic analysis. Methods included Pearson correlation, principal component analysis, cluster analysis, and random forest analysis. Results revealed significant variations in wood traits such as heartwood ratio, tracheid length, and width across altitudes. Notably, wood traits in lower- and middle-elevation populations exhibited higher variability compared to higher elevations, indicating greater environmental diversity and genetic adaptability at these altitudes. Climatic factors, particularly temperature and precipitation, were found to increasingly influence wood trait variation with altitude. The research concludes that the adaptation of Cunninghamia lanceolata to climate change is significantly influenced by both altitudinal and climatic factors, highlighting their importance in forest genetic breeding and conservation strategies amidst global climate change.

Abstract Objective This study aimed to develop and validate internally a clinical predictive model, for predicting myasthenic crisis within 30 days after thymectomy in patients with myasthenia gravis. Methods Eligible patients were enrolled between January 2015 and May 2019. The primary outcome measure was postoperative myasthenic crisis (POMC). A predictive model was constructed using logistic regression and presented in a nomogram. The area under the receiver operating characteristic curve (AUC) was calculated to examine the performance. The study population was divided into high‐ and low‐risk groups according to Youden index. Calibration curves with 1000 replications bootstrap resampling were plotted to visualize the calibration of the nomogram. Decision curve analyses (DCA) with 1000 replications bootstrap resampling were performed to evaluate the clinical usefulness of the model. Results A total of 445 patients were enrolled. Five variables were screened including thymus imaging, onset age, MGFA classification, preoperative treatment regimen, and surgical approach. The model exhibited moderate discriminative ability with AUC value 0.771. The threshold probability was 0.113, which was used to differentiate between high‐ and low‐risk groups. The sensitivity and specificity were 72.1% and 77.1%, respectively. The high‐risk group had an 8.70‐fold higher risk of POMC. The calibration plot showed that when the probability was between 0 and 0.5, the deviation calibration curve of the model was consistent with the ideal curve. Interpretation This nomogram could assist in identifying patients at higher risk of POMC and determining the optimal surgical time for these patients.

Abstract Background N6-methyladenosine (m6A) modification has been recognized to play fundamental roles in the development of autoimmune diseases. However, the implication of m6A modification in myasthenia gravis (MG) remains largely unknown. Thus, we aimed to systematically explore the potential functions and related immune characteristics of m6A regulators in MG. Methods The GSE85452 dataset with MG and healthy samples was downloaded from Gene Expression Omnibus (GEO) database. m6A modification regulators were manually curated. The targets of m6A regulators were obtained from m6A2Target database. The differential expressed m6A regulators in GSE85452 dataset were identified by “limma” package and were validated by RT-PCR. Function enrichment analysis of dysregulated m6A regulators was performed using “clusterProfiler” package. Correlation analysis was applied for analyzing the relationships between m6A regulators and immune characteristics. Unsupervised clustering analysis was used to identify distinct m6A modification subtypes. The differences between subtypes were analyzed, including the expression level of all genes and the enrichment degree of immune characteristics. Weighted gene co-expression network analysis (WGCNA) was conducted to obtain modules associated with m6A modification subtypes. Results We found that CBLL1, RBM15 and YTHDF1 were upregulated in MG samples of GSE85452 dataset, and the results were verified by RT-PCR in blood samples from19 MG patients and 19 controls. The targeted genes common modified by CBLL1, RBM15, and YTHDF1 were mainly enriched in histone modification and Wnt signaling pathway. Correlation analysis showed that three dysregulated m6A regulators were closely associated with immune characteristics. Among them, RBM15 possessed the strongest correlation with immune characteristics, including CD56dim natural killer cell (r = 0.77, P = 0.0023), T follicular helper cell (r = − 0.86, P = 0.0002), Interferon Receptor (r = 0.78, P = 0.0017), and HLA-DOA (r = 0.64, P = 0.0200). Further two distinct m6A modification patterns mediated by three dysregulated m6A regulators was identified. Bioinformatics analysis found that there were 3029 differentially expressed genes and different immune characteristics between two m6A modification patterns. Finally, WGCNA analysis obtained a total of 12 modules and yellow module was the most positively correlated to subtype-2. Conclusion Our findings suggested that m6A RNA modification had an important effect on immunity molecular mechanism of MG and provided a new perspective into understanding the pathogenesis of MG.

Objective: With the rising number of clinical trials conducted in China, the role of clinical research nurses (CRNs) within clinical trial organizations has become increasingly crucial. However, in the absence of industry guidelines, the management of CRNs lacks clarity. This study aims to address this gap by establishing a consensus on CRN management. Methods: The International Association of Clinical Research Nurses (IACRN)-Shanghai Chapter assembled a panel of experts to develop a consensus on the management of clinical research nurses. This consensus was formulated through an extensive literature review, expert evaluations, and collaborative conference discussions. Results: The consensus document offers a comprehensive professional definition of CRNs and provides detailed insights into their management. It covers aspects such as job settings, qualifications, responsibilities, training, assessment, workload management, staffing allocation, performance evaluation, and career progression. Conclusions: Establishing a professional definition for CRNs creates a standardized reference point for clinical trial institutions to effectively manage these professionals. Consistency in CRNs’ roles, training, staffing, and corresponding assessments is essential for promoting their sustainable and healthy development within the field of clinical research.

Summary: 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

BackgroundGlioma is the most common primary brain tumor. Traditional treatments for glioma include surgical resection, radiotherapy, chemotherapy, and bevacizumab therapy, but their efficacies are limited. Immunotherapy provides a new direction for glioma treatment. This study aimed to summarize the knowledge structure and research hotspots of glioma immunotherapy through a bibliometric analysis.MethodPublications pertaining to glioma immunotherapy published during the period from 1st January 1990 to 27th March 2023 were downloaded from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, Online Analysis Platform of Literature Metrology, and R software. The hotspots and prospects of glioma immunotherapy research were illustrated via analyzing the countries, institutions, journals, authors, citations and keywords of eligible publications.ResultsA total of 1,929 publications pertaining to glioma immunotherapy in 502 journals were identified as of 27th March 2023, involving 9,505 authors from 1,988 institutions in 62 countries. Among them were 1,285 articles and 644 reviews. Most of publications were produced by the United States. JOURNAL OF NEURO-ONCOLOGY published the majority of publications pertaining to glioma immunotherapy. Among the authors, Lim M contributed the largest number of publications. Through analyzing keyword bursts and co-cited references, immune-checkpoint inhibitors (ICIs) were identified as the research focus and hotspot.ConclusionUsing a bibliometric analysis, this study provided the knowledge structure and research hotspots in glioma immunotherapy research during the past 33 years, with ICIs staying in the current and future hotspot. Our findings may direct the research of glioma immunotherapy in the future.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a demyelinating syndrome of the central nervous system. A tremendous amount of literature on NMOSD has been published. This study aimed to perform a bibliometric analysis of the publications on NMOSD and show its hotspots and development trends.MethodsWe used the Web of Science Core Collection as a database and searched the literature published between 2002 and 2022. CiteSpace, VOSviewer, online bibliometric platform, and R-bibliometrix were used to conduct bibliometric analysis and network visualization, including the number of publications, citations, countries/regions, institutions, journals, authors, references, and keywords.ResultsA total of 3,057 publications on NMOSD were published in 198 journals by 200 authors at 200 institutions from 93 countries/regions. The United States published the most literature and made great contributions to this field. The Mayo Clinic was the institution with the largest number of publications. The journal with the most publications was Multiple Sclerosis and Related Disorders, and the most co-cited journal was Neurology. The author with the most publications was Fujihara, K., while the most frequently co-cited author was Wingerchuk, DM. The current research hotspots may be focused on “efficacy,” “multicenter,” “interleukin-6 receptor blockade,” “safety,” “azathioprine,” “tolerance,” and “adult”.ConclusionThis study was the first bibliometric analysis of publications on the NMOSD field, visualizing its bibliometric characteristics and gaining insight into the direction, hotspots, and development of global NMOSD research, which may provide helpful information for researchers. Future research hotspots might be conducting randomized controlled trials on targeted immunotherapy in the NMOSD field.

BackgroundThe safety of COVID-19 vaccines has been clarified in clinical trials; however, some immunocompromised patients, such as myasthenia gravis (MG) patients, are still hesitant to receive vaccines. Whether COVID-19 vaccination increases the risk of disease worsening in these patients remains unknown. This study aims to evaluate the risk of disease exacerbation in COVID-19-vaccinated MG patients.MethodsThe data in this study were collected from the MG database at Tangdu Hospital, the Fourth Military Medical University, and the Tertiary Referral Diagnostic Center at Huashan Hospital, Fudan University, from 1 April 2022 to 31 October 2022. A self-controlled case series method was applied, and the incidence rate ratios were calculated in the prespecified risk period using conditional Poisson regression.ResultsInactivated COVID-19 vaccines did not increase the risk of disease exacerbation in MG patients with stable disease status. A few patients experienced transient disease worsening, but the symptoms were mild. It is noted that more attention should be paid to thymoma-related MG, especially within 1 week after COVID-19 vaccination.ConclusionCOVID-19 vaccination has no long-term impact on MG relapse.

BackgroundMyasthenia gravis (MG) is an autoimmune disease with acquired neuromuscular junction transmission disorders. In the last two decades, various pathogenesis, application of immunosuppressive agents, and targeted immunotherapy have been significant events. However, extracting the most critical information from complex events is very difficult to guide clinical work. Therefore, we used bibliometrics to summarize and look forward.MethodsScience Citation Index Expanded (SCI-E) from the Web of Science Core Collection (WoSCC) database was identified as a source of material for obtaining MG-related articles. Scimago Graphica, CiteSpace, VOSviewer, and bibliometrix were utilized for bibliometric analysis. Knowledge network graphs were constructed and visualized; countries, institutions, authors, journals, references, and keywords were evaluated. In addition, GraphPad Prism and Microsoft Excel 365 were applied for statistical analysis.ResultsAs of October 25, 2022, 9,970 original MG-related articles were used for the bibliometric analysis; the cumulative number of citations to these articles was 236,987, with an H-index of 201. The United States ranked first in terms of the number of publications (2,877) and H-index (134). Oxford has the highest H-index (67), and Udice French Research University has the highest number of publications (319). The author with the highest average number of citations (66.19), publications (151), and H-index (53) was Vincent A. 28 articles have remained in an explosive period of citations. The final screening yielded predictive keywords related to clinical trials and COVID-19.ConclusionWe conducted a bibliometric analysis of 9,970 original MG-related articles published between 1966 and 2022. Ultimately, we found that future MG research hotspots include two major parts: (1) studies directly related to MG disease itself: clinical trials of various targeted biological agents; the relationship between biomarkers and therapeutic decisions, pathogenesis and outcome events, ultimately serving individualized management or precision therapy; (2) studies related to MG and COVID-19: different variants of COVID-19 (e.g., Omicron) on MG adverse outcome events; assessment of the safety of different COVID-19 vaccines for different subtypes of MG.

Background: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigability. The fluctuating nature of the disease course impedes the clinical management. Objective: The purpose of the study was to establish and validate a machine learning (ML)–based model for predicting the short-term clinical outcome in MG patients with different antibody types. Methods: We studied 890 MG patients who had regular follow-ups at 11 tertiary centers in China from 1 January 2015 to 31 July 2021 (653 patients for derivation and 237 for validation). The short-term outcome was the modified post-intervention status (PIS) at a 6-month visit. A two-step variable screening was used to determine the factors for model construction and 14 ML algorithms were used for model optimisation. Results: The derivation cohort included 653 patients from Huashan hospital [age 44.24 (17.22) years, female 57.6%, generalized MG 73.5%], and the validation cohort included 237 patients from 10 independent centers [age 44.24 (17.22) years, female 55.0%, generalized MG 81.2%]. The ML model identified patients who were improved with an area under the receiver operating characteristic curve (AUC) of 0.91 [0.89–0.93], ‘Unchanged’ 0.89 [0.87–0.91], and ‘Worse’ 0.89 [0.85–0.92] in the derivation cohort, whereas identified patients who were improved with an AUC of 0.84 [0.79–0.89], ‘Unchanged’ 0.74 [0.67–0.82], and ‘Worse’ 0.79 [0.70–0.88] in the validation cohort. Both datasets presented a good calibration ability by fitting the expectation slopes. The model is finally explained by 25 simple predictors and transferred to a feasible web tool for an initial assessment. Conclusion: The explainable, ML-based predictive model can aid in forecasting the short-term outcome for MG with good accuracy in clinical practice.

Abstract Evidences indicate that elevated levels of circulating ErbB2 are closely associated with increased incidence of diabetes. However, the relationship between ErbB2 concentration and glycemic variations (GV) in type 2 diabetic (T2D) patients remains elucidated. The aim of this study was to assess whether there is an association between serum ErbB2 concentration and GV in newly diagnosed T2D patients. This was a three-center, and observational study. Between April 2019 and July 2019, a total of 106 newly diagnosed T2D patients were recruited. All recruited subjects were admitted as inpatients and received anti-diabetes agents free during the study period. At baseline, fasting serum was collected for ErbB2 measurement and all recruited patients were subjected a prospective CGM for at least 3 days. The primary endpoint was the relationships between ErbB2 concentrations and GV in T2D patients. Data of a total of 95 subjects who met the inclusion criteria were analyzed at the endpoint. Subjects were divided into quartiles according to their serum ErbB2 concentrations. We observed that subjects with an elevated level of ErbB2 had a higher value of GV in terms of mean amplitude of glucose excursion (MAGE), standard deviation of mean glucose (SDMG), and the coefficient of variation (CV%) than those with lower levels (all P

Ischemic stroke (IS) is a common and grievous nervous system disease. Both autophagy activation and immune response after cerebral ischemia play important roles in the development of IS. Many studies have revealed a close interplay between autophagy and immunity. However, little is known about how autophagy influences the immune characteristics of IS. Hence, the study aims to systematically explore the role of autophagy and its impact on immune characteristics in IS. We first compared the expression differences of autophagy genes in a training set and identified 20 dysregulated autophagy genes between healthy and IS samples. An autophagy-related classifier composed of seven genes was further established and could well distinguish healthy and IS samples. Then, the association between autophagy and immune characteristics, including infiltrating immunocytes, activity of immune reactions, and HLA gene expression, was investigated. The results showed that autophagy closely correlated with immune characteristics, such as NAMPT and ARNT significantly related to infiltrating immunocytes; PPP1R15A and CASP3 significantly related to activity of immune reactions; and NAMPT and ATG16L2 significantly related to HLA genes. Next, two distinct autophagy expression patterns were identified by unsupervised clustering analysis, and diverse immune characteristics were discovered between them. A total of 5481 autophagy phenotype-related genes were obtained between two expression patterns, and their biological functions revealed that these genes were involved in immune-related biological pathways. Finally, five dysregulated autophagy genes (FOS, MAP1LC3B, ERO1L, ARNT, and PPP1R15A) were proved between IS and healthy samples using another two validation sets. Our results illustrated that autophagy had a dramatic effect on the immunity of IS and provided a novel sight into understanding the pathogenesis of IS.

BackgroundThe treatment of myasthenia gravis (MG) has advanced from steroids and traditional immunosuppressants to targeted immunotherapy. Targeted immunotherapy has been successfully employed in clinical practice in recent years. This study aimed to explore the emerging trend of targeted immunotherapy in MG and summarize the knowledge structure through bibliometric methods.MethodsThe Web of Science Core Collection database (WoSCC) was chosen to retrieve the literature on targeted immunotherapy for MG. Two bibliometric analysis software, VOSviewer and CiteSpace, and bibliometric online platform were mainly used to evaluate the contributions from countries/regions, institutions, journals, and authors through the construction and visualization of bibliometric networks. By systematically reviewing a knowledge domain, future research developments were determined. The R version 4.1.2 and Microsoft Excel 365 were used for statistical analysis.ResultsA total of 562 original articles and 262 reviews relevant to MG targeted immunotherapy were included. The number of publications on targeted immunotherapy for MG exhibited a two-phase advancement. The first stage showed a steady growth trend from 1998 to 2016, with an annual number of no more than 35 publications. The second stage revealed an explosive growth trend from 2017, reaching a peak number of publications in 2020. The United States ranked first in the number of publications, citations, and h-index. The author with the highest citation and h-index was Vincent A. And 28.03% of the articles were published in the top 10 journals. In addition to “myasthenia gravis”, the keyword with the highest consideration was “rituximab”, followed by “double-blind”, which indicate research hotspots gradually from basic research to clinical research over time, especially in the field of targeted immunotherapy. The MG treatment has entered a personalized precision treatment phase. Exploration into new target molecules and conducting high-quality randomized controlled trials on existing biological agents are the further research direction.ConclusionThe current study summarized the global research trends concerning targeted immunotherapy for MG. Research interests gradually advanced from basic research to clinical research. MG treatment has entered a personalized precision treatment phase. Further investigations into new target molecules and high-quality randomized controlled trials on existing biological agents are required urgently to direct future immunotherapy research.

Abstract Background An accurate prediction for prognosis can help in guiding the therapeutic options and optimizing the trial design for generalized myasthenia gravis (gMG). We aimed to develop and validate a predictive nomogram to assess the short-term outcome in patients with the anti-acetylcholine receptor (AChR) subtype gMG. Methods We retrospectively reviewed 165 patients with AChR subtype gMG who were immunotherapy naïve at the first visit from five tertiary centers in China. The short-term clinical outcome is defined as the achievement of minimal symptom expression (MSE) at 12 months. Of them, 120 gMG patients from Huashan Hospital were enrolled to form a derivation cohort (n = 96) and a temporal validation cohort (n = 24) for the nomogram. Then, this nomogram was externally validated using 45 immunotherapy naïve AChR subtype gMG from the other four hospitals. Multivariate logistic regression was used to screen independent factors and construct the nomogram. Results MSE was achieved in 70 (72.9%), 20 (83.3%), and 33 (73.3%) patients in the training, temporal validation, and external validation cohort, respectively. The duration ≤ 12 months (p = 0.021), ocular score ≤ 2 (p = 0.006), QMG score > 13 (p = 0.008), and gross motor score ≤ 9 (p = 0.006) were statistically associated with MSE in AChR subtype gMG. The nomogram has good performance in predicting MSE as the concordance indexes are 0.81 (95% CI, 0.72–0.90) in the development cohort, 0.944 (95% CI, 0.83–1.00) in the temporal validation cohort, and 0.773 (95% CI, 0.63–0.92) in the external validation cohort. Conclusion The nomogram achieved an optimal prediction of MSE in AChR subtype gMG patients using the baseline clinical characters.

BackgroundThis study aims to develop and validate a nomogram for predicting 1- and 2-year generalization probabilities in patients with ocular myasthenia gravis (OMG).MethodsIn total, 501 eligible patients with OMG treated at seven tertiary hospitals in China between January 2015 and May 2019 were included. The primary outcome measure was disease generalization. A nomogram for predicting 1- and 2-year generalization probabilities was constructed using a stepwise Cox regression model. Nomogram performance was quantified using C-indexes and calibration curves. Two-year cumulative generalization rates were analyzed using the Kaplan−Meier method for distinct nomogram-stratified risk groups. The clinical usefulness of the nomogram was evaluated using decision curve analysis (DCA).ResultThe eligible patients were randomly divided into a development cohort (n=351, 70%) and a validation cohort (n=150, 30%). The final model included five variables: sex, onset age, repetitive nerve stimulation findings, acetylcholine receptor antibody test results, and thymic status. The model demonstrated good discrimination (C-indexes of 0.733 and 0.788 in the development and validation cohorts, respectively) and calibration, with good agreement between actual and nomogram-estimated generalization probabilities. Kaplan−Meier curves revealed higher 2-year cumulative generalization rates in the high-risk group than that in the low-risk group. DCA demonstrated a higher net benefit of nomogram-assisted decisions compared to treatment of all patients or none.ConclusionThe nomogram model can predict 1- and 2-year generalization probabilities in patients with OMG and stratified these patients into distinct generalization risk groups. The nomogram has potential to aid neurologists in selecting suitable patients for initiating immunotherapy and for enrolment in clinical trials of risk-modifying treatments.

Myasthenia gravis (MG) is an autoimmune disease mediated by B cells secreting autoantibodies. Regulatory B (Breg) cells confirmed to have an immunosuppressive function play an important role in many autoimmune diseases. However, what about the changes in Breg cells in the thymus and peripheral blood of MG patients? The changes in the proportion of Breg cells in the peripheral blood of 41 MG patients without any drug treatment and 30 healthy controls were detected by flow cytometry. We found that the proportions of CD19+ IL-10+ cells and CD19+CD24hiCD38hi cell subsets in MG patients were significantly lower than those in healthy controls. Then, we detected the proportion of CD19+ IL-10+ cells in thymus tissues of 10 healthy children, 4 healthy adults, and 12 MG patients by flow cytometry. However, the percentage of CD19+ IL-10+ cells was highest in healthy children (~8%), followed by healthy adults (~3%), and was lowest in MG patients (~0.5%). CD19+CD24hiCD38hi B cells exerted immunosuppressive functions in healthy people but were refractory in MG patients. Moreover, p-STAT3 downstream of CD40 may be impaired in CD24hiCD38hi B cells from the peripheral blood of MG patients.

Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS

This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms.

Abstract Background Primary central nervous system (CNS) small lymphocytic lymphoma (SLL), as a type of low-grade lymphoma, is extremely rare. The diagnosis of CNS SLL is challenging due to its variable clinical and radiological features, which may overlap with those of diffuse large B-cell lymphoma (DLBCL). Primary CNS SLL differs from DLBCL in that it has an indolent clinical course and a good prognosis. Thus, it is important to distinguish SLL from DLBCL. By reviewing the literature, only two cases of low-grade SLL, primarily located in the CNS and involving the brain parenchyma and dura, have been reported. To our knowledge, primary CNS SLL in the bilateral ventricles has never been reported. Interestingly, the two cases in our report are identical in terms of the clinical presentations, magnetic resonance imaging (MRI) features, pathological results and prognoses. Case presentation Both patients presented with headaches. MRI suggested solid lesions located in the bilateral ventricles that were isointense on T1-weighted images and hypointense on T2-weighted images. After the injection of contrast agent (gadolinium, Gd), the intraventricular lesions were homogeneously enhanced and hyperperfused. CSF cytology revealed malignant cells. Brain biopsy revealed diffuse proliferation of small lymphocytes with positive labelling of B-cell immunomarkers. The primary origin in the CNS was confirmed with no evidence of systemic lymphoma. Two patients were given high doses of methotrexate-based chemotherapy and were free from symptoms and progression for more than 1-year of follow-up. Conclusions The presence of homogeneously enhanced intraventricular MRI lesions should raise the suspicion of primary CNS SLL.

Human adenylate kinase 1 (hAK1) plays a vital role in the energetic and metabolic regulation of cell life, and impaired functions of hAK1 are closely associated with many diseases. In the presence of Mg2+ ions, hAK1 in vivo can catalyze two ADP molecules into one ATP and one AMP molecule, activating the downstream AMP signaling. The ADP-binding also initiates AK1 transition from an open conformation to a closed conformation. However, how substrate binding triggers the conformational transition of hAK1 is still unclear, and the underlying molecular mechanisms remain elusive. Herein, we determined the solution structure of apo-hAK1 and its key residues for catalyzing ADP, and characterized backbone dynamics characteristics of apo-hAK1 and hAK1-Mg2+-ADP complex (holo-hAK1) using NMR relaxation experiments. We found that ADP was primarily bound to a cavity surrounded by the LID, NMP, and CORE domains of hAK1, and identified several critical residues for hAK1 catalyzing ADP including G16, G18, G20, G22, T39, G40, R44, V67, D93, G94, D140, and D141. Furthermore, we found that apo-hAK1 adopts an open conformation with significant ps-ns internal mobility, and Mg2+-ADP binding triggered conformational transition of hAK1 by suppressing the ps-ns internal motions of α3α4 in the NMP domain and α7α8 in the LID domain. Both α3α4 and α7α8 fragments became more rigid so as to fix the substrate, while the catalyzing center of hAK1 experiences promoted µs-ms conformational exchange, potentially facilitating catalysis reaction and conformational transition. Our results provide the structural basis of hAK1 catalyzing ADP into ATP and AMP, and disclose the driving force that triggers the conformational transition of hAK1, which will deepen understanding of the molecular mechanisms of hAK1 functions.

Al-5Cu-0.8Mn-0.1Zr strips produced during a twin-roll-casting process are investigated in this paper. Central segregation does occur in the alloy strip, and the segregation is a mixture of Al2Cu and Al20Cu2Mn3 eutectic phases. This mixture is difficult to be dissolved in solid solution heat treatment. In this paper, nano-sized TiC/TiB2 particles are introduced in the process of twin-roll-casting. It was found that after adding 0.3% nano-sized TiC-TiB2 particles, the composition distribution becomes more uniform, and the central segregation is eliminated, compared to the strip without nanoparticles. The tensile strength of T6-treated alloy increases from 350 MPa to 390 MPa when nanoparticles are added, and the goal of increasing the properties of twin-roll-cast Al-Cu-Mn-Zr alloy has been achieved.

Isocitrate dehydrogenase (IDH) mutations occur frequently in lower-grade gliomas, which result in genome-wide epigenetic alterations. The wild-type IDH1 is reported to participate in lipid biosynthesis and amino acid metabolism, but its role in tumorigenesis is still unclear. In this study, the expressions of IDH1 and podoplanin (Pdpn) were determined in IDH-mutated and IDH-wild-type gliomas, and their relationships in glioma were further analyzed. In addition, the regulation of wild-type IDH1 and mutant IDH1 on Pdpn expression was investigated by luciferase assays and promoter methylation analysis. Our study showed that Pdpn was almost undetectable in IDH-mutated glioma but strongly expressed in higher-grade IDH-wild-type glioma. Pdpn overexpression promoted the migration of glioma cells but had little effect on cell growth. Moreover, Pdpn expression was positively correlated with the increased wild-type IDH1 levels in IDH-wild-type glioma. Consistently, the wild-type IDH1 greatly promoted the transcription and expression of Pdpn, but the mutant IDH1 and D-2-hydroxyglutarate significantly suppressed Pdpn expression in glioma cells. Besides, our results revealed that the methylation of CpG islands in the Pdpn promoter was opposingly regulated by wild-type and mutant IDH1 in glioma. Collectively, our results indicated that wild-type and mutant IDH1 opposingly controlled the Pdpn expression in glioma by regulating its promoter methylation, which provides a basis for understanding the relationship between wild-type and mutant IDH1 in epigenetic regulation and tumorigenesis.

Background: The majority of ocular myasthenia gravis (OMG) patients will progress to generalized myasthenia gravis (GMG), usually within 2 years of disease onset. The aim of this meta-analysis was to evaluate the effect of early prednisolone and other immunosuppressants therapy on the generalization rate in OMG patients. Methods: We searched the CENTRAL, EMBASE, and MEDLINE databases via the Ovid SP database for all relevant publications on 16 July 2018. Results: Eight studies comprising a total of 547 participants were included in our meta-analysis. Compared with pyridostigmine treatment, prednisolone and other immunosuppressants therapy produced an odds ratio (OR) for the development of GMG of 0.19 [95% confidence interval (CI), 0.11–0.30; I 2 = 37%], indicating that early prednisolone and other immunosuppressants therapy reduced the generalization rate in OMG by 81%. Conclusions: Early prednisolone and other immunosuppressants therapy can significantly reduce the risk of generalization in OMG patients, and should be considered in newly diagnosed OMG patients. Due to the inclusion of retrospective studies, this noted effect might have been related to corticosteroids, especially when immunosuppressants used at low dosages and in mild disease. Additionally, the data derived from Western populations, thus a prospective randomized controlled trial (RCT) is warranted to confirm this effect of early prednisolone and other immunosuppressants therapy on OMG generalization both in Western and Asian populations.

In this study, we report the safety of coronavirus disease 2019 (COVID-19) vaccine in patients with myasthenia gravis (MG). Patients who were vaccinated against COVID-19 were included. Demographics, clinical characteristics, medications, and vaccination information were collected. The main observation outcome is the worsening of MG symptoms within 4 weeks following COVID-19 vaccination. A total of 22 patients with MG vaccinated for COVID-19 were included. Ten (45.5%) patients had ocular MG (OMG), and 12 (55.5%) patients had generalized MG (GMG). Six (27.3%) patients were female, and the mean (SD) onset age was 45.4 (11.8) years. Nineteen (86.4%) patients were seropositive for acetylcholine receptors (AChR) antibody. Seven (31.8%) patients underwent thymectomy, and four of them confirmed thymoma pathologically. Twenty-one patients were administrated with inactivated vaccines, and the remaining one was administrated with recombinant subunit vaccine. Twenty (90.9%) patients did not present MG symptom worsening within 4 weeks of COVID-19 vaccination, and two (9.1%) patients reported slight symptom worsening but resolved quickly within a few days. Our findings suggest inactivated COVID-19 vaccines might be safe in MG patients with Myasthenia Gravis Foundation of America (MGFA) classification I to II, supporting the recommendation to promote vaccination for MG patients during the still expanding COVID-19 pandemic.

Abstract There is a longstanding challenge to disperse metal nanoparticles uniformly in bulk polymers for widespread applications. Conventional scale-down techniques often are only able to shrink larger elements (such as microparticles and microfibers) into micro/nano-elements (i.e. nanoparticles and nanofibers) without much altering their relative spatial and size distributions. Here we show an unusual phenomenon that tin (Sn) microparticles with both poor size distribution and spatial dispersion were stretched into uniformly dispersed and sized Sn nanoparticles in polyethersulfone (PES) through a stack and draw technique in thermal drawing. It is believed that the capillary instability plays a crucial role during thermal drawing. This novel, inexpensive, and scalable method overcomes the longstanding challenge to produce bulk polymer-metal nanocomposites (PMNCs) with a uniform dispersion of metallic nano-elements.

Suramin was initially used to treat African sleeping sickness and has been clinically tested to treat human cancers and HIV infection in the recent years. However, the therapeutic index is low with numerous clinical side-effects, attributed to its diverse interactions with multiple biological macromolecules. Here, we report a novel binding target of suramin, human Raf1 kinase inhibitory protein (hRKIP), which is an important regulatory protein involved in the Ras/Raf1/MEK/ERK (MAPK) signal pathway. Biolayer interference technology showed that suramin had an intermediate affinity for binding hRKIP with a dissociation constant of 23.8 µM. Both nuclear magnetic resonance technology and molecular docking analysis revealed that suramin bound to the conserved ligand-binding pocket of hRKIP, and that residues K113, W173, and Y181 play crucial roles in hRKIP binding suramin. Furthermore, suramin treatment at 160 µM could profoundly increase the ERK phosphorylation level by around 3 times. Our results indicate that suramin binds to hRKIP and prevents hRKIP from binding with hRaf1, thus promoting the MAPK pathway. This work is beneficial to both mechanistically understanding the side-effects of suramin and efficiently improving the clinical applications of suramin.

Patients suffering from liver cirrhosis are often complicated with the formation of portosystemic collateral vessels, which is associated with the progression of a splanchnic hyperdynamic circulatory state. Alleviating pathological angiogenesis has thus been proposed to be a feasible treatment strategy. Indole-3-carbinol (C9H9NO, I3C) and 3,3′-diindolymethane (DIM), formed by the breakdown of glucosinolate glucobrassicin, are prevalent in cruciferous vegetables and have anti-angiogenesis properties. We aimed to evaluate their influences on portal hypertension, the severity of mesenteric angiogenesis, and portosystemic collaterals in cirrhosis. Sprague-Dawley rats with common bile duct ligation (CBDL)-induced liver cirrhosis or sham operation (surgical control) were randomly allocated to receive I3C (20 mg/kg/3 day), DIM (5 mg/kg/day) or vehicle for 28 days. The systemic and portal hemodynamics, severity of portosystemic shunting, mesenteric angiogenesis, and mesenteric proangiogenic factors protein expressions were evaluated. Compared to vehicle, both DIM and I3C significantly reduced portal pressure, ameliorated liver fibrosis, and down-regulated mesenteric protein expressions of vascular endothelial growth factor and phosphorylated Akt. DIM significantly down-regulated pErk, and I3C down-regulated NFκB, pIκBα protein expressions, and reduced portosystemic shunting degree. The cruciferous vegetable byproducts I3C and DIM not only exerted a portal hypotensive effect but also ameliorated abnormal angiogenesis and portosystemic collaterals in cirrhotic rats.

Strengthening high entropy alloys (HEAs) via second phases is a very effective approach. However, the design of intermetallic (IM) phases in HEAs is challenging, mainly because our understanding of IM phases in HEAs is still very limited. Here, a statistical approach is used to enhance our understanding towards IM phases in HEAs. A database consisting of 142 IM-containing HEAs was constructed. Our aim is twofold. The first is to reveal the most common IM phase types in published HEAs. The second is to understand whether HEAs inherit their IM structures from their binary/ternary subsystems, or whether they tend to form new structures irrelevant to their subsystems. The results show that the five most prevalent IM structures in the HEAs surveyed here are Laves, σ, B2, L12, and L21. This trend is evidently different from the overall trend among known binary/ternary IMs. As for structural inheritance, all the IM phases contained in the alloys are existing structures in the binary/ternary subsystems of the respective alloys. This suggests that the compositional complexity in HEAs does trigger additional complexity in IM structure formation. These findings have important implications in the future design and development of HEAs.

Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical.

YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we found that strong YAP expression was associated with poor ovarian cancer patient survival. Specifically, we showed for the first time that high YAP expression levels were positively correlated with TEAD4 gene expression, and their co-expression was a prognostic marker for poor ovarian cancer survival. Hyperactivation of YAP by mutating its five inhibitory phosphorylation sites (YAP-5SA) increased ovarian cancer cell proliferation, resistance to chemotherapeutic drugs, cell migration, and anchorage-independent growth. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes in ovarian cancer cells both in vitro and in vivo. Our results suggested that YAP caused these effects by promoting an epithelial-to-mesenchymal transition. Thus, YAP promotes ovarian cancer cell growth and tumorigenesis both in vitro and in vivo. Further, high YAP and TEAD4 expression is a prognostic marker for ovarian cancer progression and a potential target for ovarian cancer treatment.

This study presents a comprehensive investigation of the impact of the deposition temperature on the HfxZr1−xO2 (HZO) ferroelectric layer of ferroelectric random access memory with TaN electrodes. This investigation mainly focuses on its electrical characteristics and compares the differences. It is revealed that the deposition temperature plays a crucial role in determining the crystal structure of HZO, which can exhibit a combination of tetragonal and orthorhombic phases or exist solely in one of the two phases. Furthermore, the grain size of HZO varies with the deposition temperature. These findings correspond well to the electrical measurement results, including leakage current, polarization, capacitance, and reliability tests. The study tracks the phase transition process during the operation of switching cycles when the phase transition process can be monitored as well. To better understand the observed differences, physical models that shed light on the underlying mechanisms affected by deposition temperature are proposed at the end of the article. [ABSTRACT FROM AUTHOR]