Clinical outcome and peripheral immune profile of myasthenic crisis with omicron infections: A prospective cohort study.

The impact of Omicron infections on the clinical outcome and immune responses of myasthenia gravis (MG) remained largely unknown. From a prospective multicenter MG cohort (n = 189) with 197 myasthenic crisis (MC), we finally included 41 independent MG patients to classify into two groups: the Omicron Group (n = 13) and the Control Group (n = 28). In this matched cohort study, all-cause mortality was 7.69% (1/13) in Omicron Group and 14.29% (4/28) in Control Group. A higher proportion of elevated serum IL-6 was identified in the Omicron Group (88.89% vs 52.38%, P = 0.049). In addition, the proportions of CD3+CD8+T in lymphocytes and Tregs in CD3+CD4+ T cells were significantly elevated in the Omicron Group (both P = 0.0101). After treatment, the Omicron Group exhibited a marked improvement in MG-ADL score (P = 0.026) and MG-QoL-15 (P = 0.0357). MCs with Omicron infections were associated with elevated serum IL-6 and CD3+CD8+T response. These patients tended to present a better therapeutic response after fast-acting therapies and anti-IL-6 treatment.

Peripheral immune landscape for hypercytokinemia in myasthenic crisis utilizing single-cell transcriptomics.

BACKGROUND: Myasthenia gravis (MG) is the most prevalent autoimmune disorder affecting the neuromuscular junction. A rapid deterioration in respiratory muscle can lead to a myasthenic crisis (MC), which represents a life-threatening condition with high mortality in MG. Multiple CD4+ T subsets and hypercytokinemia have been identified in the peripheral pro-inflammatory milieu during the crisis. However, the pathogenesis is complicated due to the many types of cells involved, leaving the underlying mechanism largely unexplored. METHODS: We conducted single-cell transcriptomic and immune repertoire sequencing on 33,577 peripheral blood mononuclear cells (PBMCs) from two acetylcholine receptor antibody-positive (AChR +) MG patients during MC and again three months post-MC. We followed the Scanpy workflow for quality control, dimension reduction, and clustering of the single-cell data. Subsequently, we annotated high-resolution cell types utilizing transfer-learning models derived from publicly available single-cell immune datasets. RNA velocity calculations from unspliced and spliced mRNAs were applied to infer cellular state progression. We analyzed cell communication and MG-relevant cytokines and chemokines to identify potential inflammation initiators. RESULTS: We identified a unique subset of monocytes, termed monocytes 3 (FCGR3B+ monocytes), which exhibited significant differential expression of pro-inflammatory signaling pathways during and after the crisis. In line with the activated innate immune state indicated by MC, a high neutrophil-lymphocyte ratio (NLR) was confirmed in an additional 22 AChR + MC patients in subsequent hemogram analysis and was associated with MG-relevant clinical scores. Furthermore, oligoclonal expansions were identified in age-associated B cells exhibiting high autoimmune activity, and in CD4+ and CD8+ T cells demonstrating persistent T exhaustion. CONCLUSIONS: In summary, our integrated analysis of single-cell transcriptomics and TCR/BCR sequencing has underscored the role of innate immune activation which is associated with hypercytokinemia in MC. The identification of a specific monocyte cluster that dominates the peripheral immune profile may provide some hints into the etiology and pathology of MC. However, future functional studies are required to explore causality.

Increased serum IL-2, IL-4, IL-5 and IL-12p70 levels in AChR subtype generalized myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular junctions. Cytokines play important roles in facilitating the immune response and augmenting the pathogenic antibody production. The current study aims to sensitively characterize the serum levels of cytokines with very low concentration in generalized MG (gMG). METHODS: Using ultrasensitive single-molecule arrays (SIMOA), we measured serum IL-2, IL-4, IL-5 and IL-12p70 in 228 participants including 152 immunotherapy-naïve anti-acetylcholine receptor (AChR) subtype gMG from Huashan MG registry and 76 age-matched healthy controls. Subgroup analysis was then performed by stratifying patients according to the onset ages, MGFA classification, disease duration at baseline. RESULTS: Serum IL-2, IL-4, IL-5 and IL-12p70 levels were significantly elevated in gMG compared to controls (0.179 pg/mL versus 0.011 pg/mL, P < 0.0001; 0.029 pg/mL versus 0.018 pg/mL, P = 0.0259; 0.215 pg/mL versus 0.143 pg/mL, P = 0.0007; 0.132 pg/mL versus 0.118 pg/mL, P = 0.0401). Subgroup analysis revealed that IL-2 levels were slightly elevated in gMG with MGFA II compared to MGFA III/IV (0.195 pg/mL versus 0.160 pg/mL, P = 0.022), as well as elevated levels of IL-2 (0.220 pg/mL versus 0.159 pg/mL, P = 0.0002) and IL-5 (0.251 pg/mL versus 0.181 pg/mL, P = 0.004) in late-onset gMG compared with the early-onset gMG. gMG patients with a long duration had a significant increased serum IL-12p70 than those with a short duration (0.163 pg/mL versus 0.120 pg/mL, P = 0.011). CONCLUSION: Serum IL-2, IL-4, IL-5 and IL-12p70 levels were increased in AChR subtype gMG using ultrasensitive measurement. Serum cytokines with very low concentrations may provide as potential biomarkers in stratifying gMG patients in future prospective cohort studies.

Global identification and integrated analysis of heat-responsive long non-coding RNAs in contrasting rice cultivars.

KEY MESSAGE: Identified 2743 rice lncRNAs LncRNAs in response to heat stress Function prediction of HRLs Network among HRLs, genes and miRNAs co-localization of HRLs with QTLs Significant motifs in HRL sequences Long non-coding RNAs (lncRNAs) play vital roles in plant responses to environmental challenges. A better understanding of the gene regulation mediated by lncRNAs and their systematic identification would provide great benefits for modern agriculture. In this study, we performed strand-specific RNA sequencing for two rice varieties, heat-tolerant ZS97B and heat-susceptible SYD2 under heat stress. In total, 2743 putative lncRNAs were identified, and their expression profiles in response to heat treatments were established. We identified 231 differentially expressed lncRNAs (DELs) under heat stress, including 31 DELs common to both varieties and 103 and 97 specific to ZS97B and SYD2, respectively, all defined as heat-responsive lncRNAs (HRLs). The target-coding genes of HRLs were predicted, and GO and KEGG annotations of HRL targets revealed functions in which HRLs might be involved. The interaction network between HRLs, target genes and relevant miRNAs was constructed. The HRLs and their targets were compared with publicly available QTLs for rice seedling growth under heat stimulus. Ten HRLs and twelve target genes were linked with five heat stress-relevant QTLs. Sequence analysis revealed several motifs significantly enriched within the 231 HRL sequences. Our findings provide a valuable resource for further characterization of lncRNAs in terms of heat response and plant heat tolerance improvement.

Molecular landscape of CAPN3 mutations in limb-girdle muscular dystrophy type R1: from a Chinese multicentre analysis to a worldwide perspective.

BACKGROUND: Limb-girdle muscular dystrophy type R1 (LGMDR1) can be caused by recessive CAPN3 mutations accounting for the majority of LGMD. To date, no systemic evaluation has been performed to analyse the detrimental and normal mutations on CAPN3 and its hotspots. METHODS: CAPN3 variants (n=112) from a total of 124 patients with LGMDR1 recruited in four centres in China were retrospectively analysed. Then external CAPN3 variants (n=2031) from online databases were integrated with our Chinese cohort data to achieve a worldwide perspective on CAPN3 mutations. According to their related phenotypes (LGMDR1 or normal), we analysed consequence, distribution, ethnicity and severity scores of CAPN3 mutations. RESULTS: Two hotspot mutations were identified including c.2120A>G in Chinese population and c.550del in Europe. According to the integrated dataset, 521 mutations were classified as LGMDR1-related and converged on exons 1, 10, 5, 22 and 13 of CAPN3. The remaining 1585 variants were classified as normal-population related. The deleterious ratio of LGMDR1-relevant variants to total variants in each population was 0.26 on average with a maximum of 0.35 in Finns and a minimum of 0.21 in South Asians. Severity evaluation showed that Chinese LGMDR1-related variants exhibited a higher risk (Combined Annotation Dependent Depletion score +1.10) than that from database patients (p<0.001). CONCLUSIONS: This study confirmed two hotspots and LGMDR1-related CAPN3 variants, highlighting the advantages in using a data-based comprehensive analysis to achieve a genetic landscape for patients with LGMDR1.

Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective.

Dysferlinopathy is one of the most common subgroup of autosomal recessive limb-girdle muscular dystrophies that is caused by mutations in DYSF gene. However, there is currently no worldwide comprehensive genetic analysis of DYSF variants. Through a national multicenter collaborative effort in China, we identified 222 DYSF variants with 40 novel variants from 245 patients. We then integrated DYSF variants from disease-related genetic databases including LOVD (n = 1020) and Clinvar (n = 1179), to depict the global landscape of disease-related DYSF variants. Normal-population-derived DSYF variants from gnomAD (n = 4318) and ChinaMAP (n = 13,330) were also analyzed in comparison. In Chinese patients, gender instead of genotype showed influence on the onset age of dysferlinopathy, with males showing an earlier age of onset. After integrative analysis, we identified two hotspot DYSF mutations, c.2997G>T in world patients and c.1375dup in Chinese patients, respectively. Both the pathogenic and likely pathogenic variants scattered on the whole gene length of DYSF. However, three specific domains (C2F-C2G-TM, DysF, and C2B-Ferl-C2C) contained variants at higher frequencies than reported in both the databases and Chinese patients. This study comprehensively collected available DYSF variant data, which may pave way for genetic counselling and future clinical trial design for gene therapies in dysferlinopathy.

Nomogram for short-term outcome assessment in AChR subtype generalized myasthenia gravis.

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.

Short-term effect of low-dose rituximab on myasthenia gravis with muscle-specific tyrosine kinase antibody.

INTRODUCTION/AIMS: The study aims to investigate the short-term efficacy of low-dose rituximab and its effect on immunological biomarker levels in myasthenia gravis (MG) patients with antibodies against muscle-specific tyrosine kinase (MuSK-MG). METHODS: Twelve MuSK-MG patients were enrolled in this prospective, open-label, self-controlled pilot study. Clinical severity was evaluated at baseline and 6 mo after a single rituximab treatment (600 mg). B lymphocyte subtypes, MuSK antibody titers, together with levels of immunoglobulins, serum B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), soluble CD40L, and four exosomal microRNAs were evaluated. A correlation matrix to reveal pairwise relationships among above variables was also generated. RESULTS: The single rituximab treatment significantly lowered the clinical severity scores and reduced daily dosage of prednisone (P = .032) at 6 mo. MuSK antibody titers decreased (P = .035) without significant changes in immunoglobulin levels. Serum BAFF level increased (P = .010), which negatively correlated with the percentages of B cells in lymphocytes as well as clinical severity. Additionally, serum exosomal miR-151a-3p showed a reduction of 28.1% (P = .031). DISCUSSION: We confirmed the clinical efficacy of low-dose rituximab in MuSK-MG, accompanied by a decrease in MuSK antibody titers and an increase in serum BAFF. Serum BAFF levels negatively correlated with B-cell counts as well as clinical severity.

Low-dose rituximab every 6 months for the treatment of acetylcholine receptor-positive refractory generalized myasthenia gravis.

INTRODUCTION: In this prospective, open-label study we explore the effectiveness of low-dose rituximab every 6 months in treating refractory generalized myasthenia gravis (GMG). METHODS: Twelve patients with acetylcholine receptor (AChR)-positive refractory GMG were enrolled for the study. The primary endpoint was the change in quantitative myasthenia gravis (QMG) score from baseline to the study end. Secondary endpoints included changes in manual muscle testing (MMT), MG-Related Activities of Daily Living (MG-ADL), and 15-item Quality-of-Life (MGQOL-15) scores, as well as prednisolone reduction. RESULTS: MG decreased from 18.25 ± 4.03 to 8.42 ± 3.99 (P = .0001), MMT from 27.50 ± 17.78 to 4.58 ± 4.34 (P = .0001), ADL from 8.50 ± 2.84 to 1.17 ± 1.27 (P < .0001), MGQOL-15 from 37.25 ± 13.78 to 17.50 ± 9.73 (P = .0015), and prednisolone dose from 29.38 ± 11.92 mg/day to 8.86 ± 1.88 mg/day (P ≤ .01). DISCUSSION: Low-dose rituximab every 6 months is effective in treating refractory GMG patients.

Predictive Score for In-Hospital Mortality of Myasthenic Crisis: A Retrospective Chinese Cohort Study.

INTRODUCTION: Myasthenic crisis (MC) is a life-threatening condition usually occurred in patients with myasthenia gravis (MG). OBJECTIVE: On the basis of a retrospective case series review, we try to develop a scoring system to evaluate the probability for in-hospital death in MC patients. METHODS: We retrospectively reviewed 78 MC patients who were hospitalized from January 2014 to December 2018. Clinical and laboratory data including 17 variables were analyzed univariately. The main clinical outcome was defined as the in-hospital death. Then eligible variables were evaluated by a stepwise multivariate regression and a scoring system was then generated. Calibration and discrimination methods were used to evaluate and validate the model performance. RESULTS: The overall in-hospital mortality was 11.5% (9/78) in the MC cohort. Five clinical variables including Myasthenia Gravis Foundation of America (MGFA) classification at onset, septic shock, thymoma classification, cardiac arrest, and the lowest serum albumin were found to be associated with in-hospital mortality. Further 3 variables entered the final regression, and internal validation showed that the area under the curve was 0.919 (95% CI 0.788-1.000). A scoring system with a full credit of 7 points was generated to predict the in-hospital mortality (MGFA at onset, 2 points; septic shock, 4 points; and cardiac arrest, 3 points). CONCLUSIONS: A 7-point scoring model was established on the basis of a retrospective review of MC patients to predict the in-hospital mortality.

Revealing myopathy spectrum: integrating transcriptional and clinical features of human skeletal muscles with varying health conditions.

Myopathy refers to a large group of heterogeneous, rare muscle diseases. Bulk RNA-sequencing has been utilized for the diagnosis and research of these diseases for many years. However, the existing valuable sequencing data often lack integration and clinical interpretation. In this study, we integrated bulk RNA-sequencing data from 1221 human skeletal muscles (292 with myopathies, 929 controls) from both databases and our local samples. By applying a method similar to single-cell analysis, we revealed a general spectrum of muscle diseases, ranging from healthy to mild disease, moderate muscle wasting, and severe muscle disease. This spectrum was further partly validated in three specific myopathies (97 muscles) through clinical features including trinucleotide repeat expansion, magnetic resonance imaging fat fraction, pathology, and clinical severity scores. This spectrum helped us identify 234 genuinely healthy muscles as unprecedented controls, providing a new perspective for deciphering the hallmark genes and pathways among different myopathies. The newly identified featured genes of general myopathy, inclusion body myositis, and titinopathy were highly expressed in our local muscles, as validated by quantitative polymerase chain reaction.

Serum cytokines profile changes in amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by progressive limb weakness, dysphagia, dysphonia, and respiratory failure due to degeneration of upper and lower motor neurons. The pathogenesis of ALS is still unclear. Neuroinflammation has been found to be involved in its development and progression. Cytokines play a significant role in the inflammatory process. This study aims to identify novel biomarkers that may assist in the diagnosis of ALS. Methods: In Fujian Medical University Union Hospital and Huashan Hospital Fudan University, two independent centers, we prospectively recruited 50 ALS patients, and 41 healthy controls (25 ALS and 26 controls in the first stage and 25 ALS and 15 controls in the validation stage). An 18-plex Luminex kit was used to screen the serum cytokines levels in the first stage. Commercial ELISA kits were used to measure the levels of target cytokines in the validation stage. A single-molecule array HD-X platform was applied to assess the levels of serum neurofilament light chain (NFL). Results: The levels of serum IL-18 were markedly increased in patients with ALS in the first stage (p = 0.016). The ROC curve showed an area under the curve at 0.695 (95% CI 0.50-0.84) in distinguishing ALS patients from healthy controls. The IL-21 was decreased in elderly patients when grouped by 55 years old (the medium age). Furthermore, the IL-5, IL-13, IL-18, and NFL had a positive relationship with the disease progression of ALS. We also found that serum IL-18 was markedly increased in ALS patients in the validation stage (167.67 [148.25-175.59] vs 116.44 [102.43-122.19]pg/ml, p < 0.0015). Conclusion: In this study, we identified systemic cytokine profile changes in the serum of ALS patients, especially the elevated IL-18, as well as the decreased IL-21 in elder patients. These changes in serum cytokine profiles may shed new light on an in-depth understanding of the immunopathogenic characteristics of ALS.

Eomesodermin expression in CD4+T-cells associated with disease progression in amyotrophic lateral sclerosis.

AIM: To clarify the role of Eomesodermin (EOMES) to serve as a disease-relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4+T subsets in amyotrophic lateral sclerosis (ALS). METHODS: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T-cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1-year longitudinal follow-ups, the ALSFRS-R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort. RESULTS: In the derivation cohort, the CD4+EOMES+T-cell subsets were significantly increased (p < 0.001). EOMES+ subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4+EOMES+T-cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003). CONCLUSIONS: We demonstrated that increased CD4+EOMES+T-cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.

Clinical features and genetic spectrum of a multicenter Chinese cohort with myotonic dystrophy type 1.

BACKGROUND: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. METHODS: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. RESULTS: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12-74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92-1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. CONCLUSION: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients.

Machine learning-based radiomics to differentiate immune-mediated necrotizing myopathy from limb-girdle muscular dystrophy R2 using MRI.

Objectives: This study aimed to assess the feasibility of a machine learning-based radiomics tools to discriminate between Limb-girdle muscular dystrophy R2 (LGMDR2) and immune-mediated necrotizing myopathy (IMNM) using lower-limb muscle magnetic resonance imaging (MRI) examination. Methods: After institutional review board approval, 30 patients with genetically proven LGMDR2 (12 females; age, 34.0 ± 11.3) and 45 patients with IMNM (28 females; age, 49.2 ± 16.6) who underwent lower-limb MRI examination including T1-weighted and interactive decomposition water and fat with echos asymmetric and least-squares estimation (IDEAL) sequences between July 2014 and August 2022 were included. Radiomics features of muscles were obtained, and four machine learning algorithms were conducted to select the optimal radiomics classifier for differential diagnosis. This selected algorithm was performed to construct the T1-weighted (TM), water-only (WM), or the combined model (CM) for calf-only, thigh-only, or the calf and thigh MR images, respectively. And their diagnostic performance was studied using area under the curve (AUC) and compared to the semi-quantitative model constructed by the modified Mercuri scale of calf and thigh muscles scored by two radiologists specialized in musculoskeletal imaging. Results: The logistic regression (LR) model was the optimal radiomics model. The performance of the WM and CM for thigh-only images (AUC 0.893, 0.913) was better than those for calf-only images (AUC 0.846, 0.880) except the TM. For "calf + thigh" images, the TM, WM, and CM models always performed best (AUC 0.953, 0.907, 0.953) with excellent accuracy (92.0, 84.0, 88.0%). The AUCs of the Mercuri model of the calf, thigh, and "calf + thigh" images were 0.847, 0.900, and 0.953 with accuracy (84.0, 84.0, 88.0%). Conclusion: Machine learning-based radiomics models can differentiate LGMDR2 from IMNM, performing better than visual assessment. The model built by combining calf and thigh images presents excellent diagnostic efficiency.

Gender differences and left-behind experiences in the relationship between gaming disorder, rumination and sleep quality among a sample of Chinese university students during the late stage of the COVID-19 pandemic.

Background and aims: Studies have shown that gaming disorder (GD) is associated with rumination and poor sleep quality. However, the reciprocal relationship between GD, rumination and sleep quality is unclear. Moreover, the differences between gender and between left-behind experiences in the aforementioned relationship remain unknown. Therefore, the present study examined gender differences and left-behind experiences in the relationship between GD, rumination, and sleep quality among a sample of Chinese university students during the late stage of COVID-19 pandemic using a network analysis approach. Methods: A cross-sectional online survey of 1,872 Chinese university students was conducted comprising demographic information (age, gender, and left-behind experience), gaming experience, gaming frequency, Gaming Disorder Test (GDT), Short Version of Rumination Response Scale (RRS), and Pittsburgh Sleep Quality Index (PSQI). Results: Among Chinese university students, the prevalence of (i) GD was 3.5% and (ii) sleep disturbance was 14%. GD had positive and weak connection with rumination and sleep quality in the domain-level relational network. The network structures and global strengths both showed no significant differences between gender and between left-behind experiences. The nodes gd3 ("continuation or escalation of gaming") and gd4 ("gaming problems") had the strongest edge in the network. Conclusion: The results suggest reciprocal relationships between GD, rumination, and sleep quality. Gender and left-behind experiences did not influence the reciprocal relationship between GD, rumination, and sleep quality during the late stage of COVID-19 pandemic. Using network analysis, the findings provide novel insights that rumination and sleep quality may have interacted with GD among Chinese students during the late stage of COVID-19 pandemic. Reducing or eliminating negative rumination may decrease GD and improve sleep quality. Moreover, good sleep quality contributes to positive rumination which may decrease the risk of GD among Chinese university students.

Causal relationships between mood instability and autoimmune diseases: A mendelian randomization analysis.

OBJECTIVES: The interrelationship between mental health and autoimmunity gains more and more attention in recent years. However, the causality between personality traits and autoimmune diseases remained largely unknown. METHODS: We first conducted two-sample mendelian randomization (MR) analysis on the relationships between mood instability, which is a common personality trait in the general population, and 10 autoimmune diseases. The results were further validated in secondary analyses of sensitivity where different MR methods, ethnicities, genders, and ascertainment methods were compared. RESULTS: In the primary analyses, three autoimmune diseases showed genetical predisposition to mood instability: asthma (OR [95%CI] = 3.45 [2.48, 4.78], P = 1.33E- 13), hypothyroidism (OR [95%CI] = 1.02 [1.00, 1.03], P = 1.71E-02), and systemic lupus erythematosus (OR [95%CI] = 5.25 [1.21, 22.76], P = 2.67E-02). The results were consistent in subsequent secondary analyses. Three diseases remained significantly correlated with mood instability by different MR methods with asthma remaining significant in Finnish and mixed populations, and in females from the UK biobank, while hypothyroidism remained significant in both genders from the UK biobank. CONCLUSION: Mood instability is a modifiable risk factor for three autoimmune diseases including asthma, hypothyroidism and systemic lupus erythematosus.

Short-term outcome prediction for myasthenia gravis: an explainable machine learning model.

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.

Herpesvirus entry mediator on T cells as a protective factor for myasthenia gravis: A Mendelian randomization study.

Background and objectives: Myasthenia gravis (MG) is a T cell-driven, autoantibody-mediated disorder affecting transmission in neuromuscular junctions. The associations between the peripheral T cells and MG have been extensively studied. However, they are mainly of observational nature, thus limiting our understanding of the effect of inflammatory biomarkers on MG risk. With large data sets now available, we used Mendelian randomization (MR) analysis to investigate whether the biomarkers on T cells are causally associated with MG and further validate the relationships. Methods: We performed a two-sample MR analysis using genetic data from one genome-wide association study (GWAS) for 210 extensive T-cell traits in 3,757 general population individuals and the largest GWAS for MG currently available (1,873 patients versus 36,370 age/gender-matched controls) from US and Italy. Then the biomarkers of interest were validated separately in two GWASs for MG in FIN biobank (232 patients versus 217,056 controls) and UK biobank (152 patients versus 386,631 controls). Results: In the first analysis, three T-cell traits were identified to be causally protective for MG risk: 1) CD8 on terminally differentiated CD8+ T cells (OR [95% CI] = 0.71 [0.59, 0.86], P = 5.62e-04, adjusted P =2.81e-02); 2) CD4+ regulatory T proportion in T cells (OR [95% CI] = 0.44 [0.26, 0.72], P = 1.30e-03, adjusted P =2.81e-02); 3) HVEM expression on total T cells (OR [95% CI] = 0.67 [0.52, 0.86], P = 1.61e-03, adjusted P =2.81e-02) and other eight T-cell subtypes (e.g., naïve CD4+ T cells). In particular, HVEM is a novel immune checkpoint on T cells that has never been linked to MG before. The SNPs on the TNFRSF14 per se further support a more direct link between the HVEM and MG. The validation analysis replicated these results in both FIN and UK biobanks. Both datasets showed a concordant protective trend supporting the findings, albeit not significant. Conclusion: This study highlighted the role of HVEM on T cells as a novel molecular-modified factor for MG risk and validated the causality between T cells and MG. These findings may advance our understanding of MG's immunopathology and facilitate the future development of predictive disease-relevant biomarkers.

Pneumonia and systemic inflammatory response syndrome as predictors for difficult-/prolonged-weaning after invasive ventilation in myasthenic crisis: A retrospective analysis of a Chinese cohort.

Weaning from invasive mechanical ventilation (MV) represents a pivotal step for myasthenic crisis (MC) patients. The aim was to evaluate the association between the weaning process and clinical outcomes, as well as to determine the independent predictors for difficult-/prolonged-weaning in MC. MC patients requiring invasive MV were recruited from Jan 2014 through Sep 2020. Among 124 consecutive MC patients, we finally included 66 patients (age 48.4 ±â€¯18.7 years, female 45.5%). According to the WIND (Weaning according to a New Definition) classification, these patients were classified into no-weaning (n = 5, 7.6%), short-weaning (n = 13, 19.7%), difficult-weaning (n = 26, 39.4%), and prolonged-weaning group (n = 22, 33.3%). Four-week functional assessment in short-weaning group was more favorable than that in difficult-/prolonged-weaning group (p<0.001). Length of hospital stay (23.0 (15.0-28.0) vs. 37.5 (27.0-54.8), p<0.001), length of ICU stay (17.0 (8.5-22.5) vs. 34.0 (20.3-45.0), p<0.001), duration on ventilation (6.0 (6.0-8.5) vs. 18.0 (13.3-30.0), p<0.001), and time interval from MV to first weaning (6.0 (6.0-8.0) vs. 11.0 (8.0-20.8), p<0.001) in short-weaning group were significantly shorter than those in difficult-/prolonged-weaning group. Short-weaning group had a lower prevalence of pneumonia (23.1% vs. 75.0%) and systemic inflammatory response syndrome (SIRS) (38.5% vs. 85.4%), and a higher value in the lowest hemoglobin level (123.0 ±â€¯12.9 g/L vs. 108.3 ±â€¯18.1 g/L) and the lowest serum albumin level (33.2 ±â€¯3.4 g/L vs. 29.9 ±â€¯4.2 g/L) than difficult-/prolonged-weaning group. Multivariate logistic regression analysis identified pneumonia and the presence of SIRS within one week of MC as independent predictors for difficult-/prolonged-weaning. The weaning process is associated with clinical outcomes in MC patients requiring ventilation. Pneumonia concurrence and the presence of SIRS within one week of MC were identified as independent predictors for difficult-/prolonged-weaning after invasive MV.