A multicenter, randomized, open-label, phase 2 clinical study of telitacicept in adult patients with generalized myasthenia gravis.

BACKGROUND AND PURPOSE: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS: Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

Landscape analysis of m6A modification regulators related biological functions and immune characteristics in myasthenia gravis.

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.

Association of immunosuppression treatment with generalization among patients with ocular myasthenia gravis: A propensity score analysis.

BACKGROUND: To analyze disease generalization in patients with ocular myasthenia gravis (OMG) treated with immunosuppression compared with patients without immunosuppression treatment. METHODS: In this retrospective cohort study, we analyzed data from patients with OMG at seven medical centers in China from January 1, 2015 to May 1, 2019 and compared disease generalization in patients (treated with immunosuppression vs. not treated) within 2 years of disease onset using raw and inverse probability of treatment weighting (IPTW) analyses. RESULTS: In the study population of 813 patients with OMG, 425 (52.3%) with immunosuppression had a mean (SD) onset age of 50.0 (15.1) years, and 188 (44.2%) were women. The remaining 388 (47.7%) patients were not immunosuppressed (mean age, 48.4 [15.0] years; 185 [47.7%] women). Disease generalization developed in 122 (31.4%) and 37 (8.7%) patients in the non-immunosuppression and immunosuppression groups, respectively. Relative to non-immunosuppression, immunosuppression was associated with a lower risk of generalization in a multivariable-adjusted Cox model (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.18-0.40; p < 0.001) and IPTW-weighted Cox model (HR 0.28; 95% CI 0.19-0.42; p < 0.001). In sensitivity analyses, longer duration of immunosuppression was associated with a lower risk of generalization (HR 0.90 for every 1-month increase; 95% CI 0.87-0.92; p < 0.001; IPTW-adjusted). Combination therapy with steroids and non-steroidal immunosuppressants showed superior efficacy in reducing the risk of generalization (HR 0.14; 95% CI 0.07-0.26; p < 0.001). CONCLUSION: Immunosuppression significantly reduced the 2-year risk of generalization in patients with OMG.

Clinical features, treatment and prognosis of MuSK antibody-associated myasthenia gravis in Northwest China: a single-centre retrospective cohort study.

BACKGROUND AND PURPOSE: To summarize the clinical characteristics of patients with muscle-specific kinase antibody-associated myasthenia gravis (MuSK-MG) and to evaluate the therapeutic responses to different treatment regimes. METHODS: Eighteen MuSK-MG patients admitted in our department between October 2017 and September 2020 were included. Clinical parameters were collected and the responses to different immunosuppressive drugs were assessed by MGFA Postintervention Status (MGFA-PIS). Meanwhile, the correlation between QMG scores and MuSK antibody titers were analyzed and MuSK antibody (MuSK-ab) titers were compared before and after therapy based on different immunosuppressive treatment regimes. RESULTS: Female predominance (ratio of females to males, 15:3) was evident in the study population, with the average onset age of (40.28 ± 18.57) years and the median disease course of 30.50 months (interquartile range [IQR], 17.50-44.75 months). Ocular manifestation was the most common onset symptom (11/18; 61.11%), and mild symmetrical ptosis was most frequent. Bulbar symptoms had the highest incidence of 88.89% over the entire disease course. Abnormal responses to RNS test were recorded most frequently on the musculus deltoideus (83.33%). All patients were treated with prednisone (Pred) alone or plus azathioprine (AZA), tacrolimus (TAC) or low-dose rituximab (RTX), and 17 (94.44%) of them achieved a favorable outcome defined as minimal manifestation (MM) or better. In general, an obvious positive correlation between QMG score and MuSK-ab titer (r = 0.710, P < 0.001) were found in all patients. A more significant reduction of MuSK-ab titers was observed in patients receiving TAC or RTX plus Pred than those receiving AZA plus Pred. CONCLUSIONS: The prominent clinical manifestations of ocular and bulbar muscles involvements, together with abnormal RNS response mostly recorded on the musculus deltoideus and better efficacy associated with TAC or low-dose RTX plus Pred, provide a more exhaustive picture of MuSK-MG, particularly in Northwest China.

Prediction of generalization of ocular myasthenia gravis under immunosuppressive therapy in Northwest China.

BACKGROUND: It is well demonstrated that immunosuppressants can reduce, but not eliminate the risk of generalized development in ocular myasthenia gravis (OMG). In this study, we aimed to explore the predictive factors of generalized conversion of OMG patients who received immunosuppressive treatments. METHODS: OMG patients under immunosuppressive treatments in Tangdu Hospital from June 2008 to June 2012 were retrospectively reviewed. Baseline clinical characteristics were documented. Patients were followed up regularly by face-to-face interview and the main outcome measure was generalized conversion. The logistic regression analysis was performed to determine the predictive factors of generalization of OMG. RESULTS: Two hundred twenty-three eligible OMG patients completed the final follow-up visit and 38 (17.0%) progressed to generalized MG (GMG) at a median time to generalization of 0.9 year. Patients with adult onset and positive repetitive nerve stimulation (RNS) of facial or axillary nerve had higher conversion rate than those with juvenile onset and negative RNS (p = 0.001; p = 0.019; p = 0.015, respectively). Adult-onset patients converted earlier than juvenile-onset OMG patients (p = 0.014). Upon multivariate logistic regression analysis, age of onset (Odds ratio [OR] 1.023, 95% confidence interval [CI] 1.006-1.041, p = 0.007) and positive facial nerve RNS (OR 2.826, 95%CI 1.045-5.460, p = 0.038) were found to be positively associated with generalized development. Moreover, an obviously negative association was found for disease duration (OR 0.603, 95%CI 0.365-0.850, p = 0.019). CONCLUSIONS: Age of onset, disease duration and facial nerve RNS test can predict generalized conversion of OMG under immunosuppressive therapy. Adult-onset, shorter disease duration and facial nerve RNS-positive OMG patients have a higher risk of generalized development.

Isocitrate dehydrogenase1 mutation reduces the pericyte coverage of microvessels in astrocytic tumours.

INTRODUCTION: Tumour-associated angiogenesis is associated with the malignancy and poor prognosis of glioma. Isocitrate dehydrogenase (IDH) mutations are present in the majority of lower-grade (WHO grade II and III) and secondary glioblastomas, but their roles in tumour angiogenesis remain unclear. METHODS: Using magnetic resonance imaging (MRI), the cerebral blood flow (CBF) of IDH-mutated glioma was measured and compared with the IDH-wildtype glioma. The densities of microvessels in IDH-mutated and wildtype astrocytoma and glioblastoma were assessed by immunohistochemical (IHC) staining with CD34, and the pericytes were labelled with α-smooth muscle antigen (α-SMA), neural-glial antigen 2 (NG2) and PDGF receptor-ß (PDGFR-ß), respectively. Furthermore, glia-specific mutant IDH1 knock-in mice were generated to evaluate the roles of mutant IDH1 on brain vascular architectures. The transcriptions of the angiogenesis-related genes were assessed in TCGA datasets, including ANGPT1, PDGFB and VEGFA. The expressions of these genes were further determined by western blot in U87-MG cells expressing a mutant IDH1 or treated with 2-HG. RESULTS: The MRI results indicated that CBF was reduced in the IDH-mutated gliomas. The IHC staining showed that the pericyte coverages of microvessels were significantly decreased, but the microvessel densities (MVDs) were only slightly decreased in IDH-mutated glioma. The mutant IDH1 knock-in also impeded the pericyte coverage of brain microvessels in mice. Moreover, the TCGA database showed the mRNA levels of angiogenesis factors, including ANGPT1, PDGFB and VEGFA, were downregulated, and their promoters were also highly hyper-methylated in IDH-mutated gliomas. In addition, both mutant IDH1 and D-2-HG could downregulate the expression of these genes in U87-MG cells. CONCLUSIONS: Our results suggested that IDH mutations could reduce the pericyte coverage of microvessels in astrocytic tumours by inhibiting the expression of angiogenesis factors. As vascular pericytes play an essential role in maintaining functional blood vessels to support tumour growth, our findings imply a potential avenue of therapeutic strategy for IDH-mutated gliomas.

Efficacy and safety of autologous hematopoietic stem-cell transplantation in multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: Autologous hematopoietic stem-cell transplantation (AHSCT) has been utilized as a treatment option for multiple sclerosis (MS) since 1995. However, this procedure has not been widely implemented in clinical practice owing to its mortality risk. Here, we conduct a meta-analysis to evaluate the long-term efficacy and safety of AHSCT in MS treatment, aiming to optimize the benefit/risk ratio of this therapeutic strategy. METHODS: We searched the PubMed Web site and clinicaltrials.gov databases. The efficacy endpoints were progression-free survival (PFS) and disease activity-free survival. The safety outcomes were transplant-related mortality (TRM) and overall deaths. RESULTS: Eighteen eligible studies with a total of 732 participants were enrolled. The PFS was 75% (95% CI, 0.69-0.81), and the estimate of disease activity-free survival was 61% with 48-month follow-up. Subgroups analysis showed that low- and intermediate-intensity regimens were associated with higher PFS 80%. Relapsing remitting MS (RRMS) benefited more from AHSCT than other MS subtypes with PFS 85%. Patients with Gd+ lesions at baseline MRI responded better to AHSCT with PFS 77%. The estimate of TRM was 1.34% (95% CI, 0.39-2.30), and the overall mortality was 3.58%. TRM was significantly higher in high-intensity regimen studies (3.13%) and in older studies (1.93%) performed before 2006. CONCLUSIONS: This meta-analysis provides evidences that AHSCT can induce long-term remissions for MS patients with a high degree of safety. We indicate low- and intermediate-intensity regimens and RRMS patients with the presence of Gd+ lesions at baseline MRI can obtain the optimal benefit/risk ratio from AHSCT.

Intracranial lesion as onset symptom in a patient with early undifferentiated connective tissue disease: a case report.

BACKGROUND: Undifferentiated connective tissue disease (UCTD) is widely considered to be a distinct clinical entity, and now divided into two subgroups: stable UCTD and early UCTD. The most frequent onset symptoms of UCTD include arthralgias, arthritis, Raynaud's phenomenon, mucocutaneous involvement, and sicca symptoms. However, Neurologic involvement is rare, and intracranial lesion as onset symptom in a patient with early UCTD has not yet been reported. CASE PRESENTATION: A 51-year-old Chinese female experienced progressive left leg weakness for 14 days before hospitalizing in our department. The lesion on right parietal lobe was initially detected by brain magnetic resonance imaging. Although the patient declined a cerebral biopsy, the possibility of stroke, cerebral venous sinus thrombosis, NMOSD, MS, autoimmune encephalitis, intracranial infections, and malignant tumors as cause of the lesion was excluded by intracranial angiogram, CSF study, MRI enhancement and MRS examination. Moreover, immunologic studies showed high titer of antinuclear antibody, increased erythrocyte sedimentation rate and C-reactive protein. These results led to a diagnosis of early UCTD with central nerve system (CNS) involvement. After low dose corticosteroid and azathioprine therapy, the patient's symptoms, abnormalities in immunologic tests and cerebral radiologic examinations were all greatly improved within a short duration. CONCLUSIONS: This is the first report of intracranial lesion as onset symptom in a patient with early UCTD. Our case suggested that central nerve system (CNS) involvement could be the onset symptom in early UCTD, and should be recognized quickly with exclusion of other causative factors in the differential diagnosis. Prompt and adequate treatment with low-dose steroid and immunosuppressive drugs could improve the prognosis of both early UCTD and CNS involvement.

High frequencies of circulating Tfh-Th17 cells in myasthenia gravis patients.

Recent studies show that the frequencies of circulating follicullar helper T (cTfh) cells are significantly higher in myasthenia gravis (MG) patients compared with healthy controls (HC). And, they are positively correlated with levels of serum anti-acetylcholine receptor antibody (anti-AchR Ab). It is unclear whether cTfh cell subset frequencies are altered and what role they play in MG patients. In order to clarify this, we examined the frequencies of cTfh cell counterparts, their subsets, and circulating plasmablasts in MG patients by flow cytometry. We determined the concentrations of serum anti-AChR Ab by enzyme-linked immunosorbent assay (ELISA). We assayed the function of cTfh cell subsets by flow cytometry and real-time polymerase chain reaction (RT-PCR). We found higher frequencies of cTfh cell counterparts, cTfh-Th17 cells, and plasmablasts in MG patients compared with HC. The frequencies of cTfh cell counterparts and cTfh-Th17 cells were positively correlated with the frequencies of plasmablasts and the concentrations of anti-AChR Ab in MG patients. Functional assays showed that activated cTfh-Th17 cells highly expressed key molecular features of Tfh cells including ICOS, PD-1, and IL-21. Results indicate that, just like cTfh cell counterparts, cTfh-Th17 cells may play a role in the immunopathogenesis and the production of anti-AChR Ab of MG.

Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice.

OBJECTIVE: Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. METHODS: Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. RESULTS: Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, ß-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. INTERPRETATION: Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD.

Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.

Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Aß levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Aß production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3ß signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.

Quality of life in 188 patients with myasthenia gravis in China.

Myasthenia gravis (MG) is a kind of chronic autoimmune disease which can weaken patients' motor function and, furthermore, produce negative impact on the health-related quality of life (HRQoL). The primary purpose of this research was to evaluate factors that might affect the HRQoL of MG patients. A cross-sectional clinical research was carried out including 188 successive patients with MG. Myasthenia Gravis Foundation of America (MGFA) classification and Quantitative Myasthenia Gravis (QMG) score were applied to assess the severity of the disease. The Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36) was used to estimate the HRQoL. Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS) were utilized to measure the depression and anxiety symptom. Factors may influence the HRQoL of MG patients include age, educational level, occupation, the situation of the thymus, the type of MG and generalized myasthenia gravis (GMG), the severity of the disease and the psychological disorder. Higher QMG and HARS scores were two significant factors that can prognosticate lower Physical Composite Score (PCS) and Mental Composite Score (MCS), while older age was just a significant factor which has prognostic value for lower PCS. The results of this research may have a potential guiding significance for the clinical treatment strategy and improve the quality of life in patients with MG consequently. In addition to the treatment of physical symptoms, the psychological symptoms such as anxiety and depression should be concerned as well.

Expression and refolding of bioactive α-bungarotoxin V31 in E. coli.

In order to obtain bioactive α-bungarotoxin (αBtx) using recombinant protein technique, a codon-optimized synthetic gene was expressed in fusion with the N-terminal 10-His-tag and C-terminal Strep-tag in Escherichia coli. Further optimization through site-directed mutagenesis enabled moderate expression of the protein without the N-terminal His-tag or the C-terminal Strep-tag. Two such recombinant αBtx (rαBtx) were obtained, both with an additional methionine and a glycine at the N-terminal and one with (G4S1)2-Strep-tag at the C-terminal. The rαBtx proteins were refolded using a novel protocol, which efficiently produced final products with activity similar to its natural counterpart. The protocol could easily be scale up, which produced 0.3-1mg of pure and highly active rαBtx per liter of E. coli culture.

Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion has been identified to be a risk factor for cognitive decline in aging, vascular dementia, and Alzheimer's disease. Substantial evidence has shown that chronic cerebral hypoperfusion may cause cognitive impairment, but the underlying neurobiological mechanism is poorly understood so far. In this study, we used a rat model of chronic cerebral hypoperfusion by permanent bilateral common carotid artery occlusion (BCCAO) to investigate the alterations of neuronal damage, glial activation oxidative stress and central cholinergic dysfunction, and their causal relationship with the cognitive deficits induced by chronic cerebral hypoperfusion. We found that BCCAO rats exhibited spatial learning and memory impairments and working memory dysfunction 12 weeks after BCCAO compared with sham-operated rats, simultaneously accompanied by significantly increased neuronal damage and glial cell activation in the cerebral cortex and hippocampus. Twelve weeks of BCCAO treatment in rats resulted in central cholinergic dysfunction and increased oxidative damage compared with sham-operated rats. Correlational analyses revealed that spatial learning and memory impairments and working memory dysfunction were significantly correlated with the measures of neuronal damage, central cholinergic dysfunction and oxidative damage in the cerebral cortex and hippocampus of rats with BCCAO. Moreover, the measures of neuronal damage and central cholinergic dysfunction were significantly correlated with the indexes of oxidative damage in rats with BCCAO. Collectively, this study provides novel evidence that neuronal damage and central cholinergic dysfunction is likely due to increased oxidative stress under the condition of chronic cerebral hypoperfusion. Furthermore, the results of the present study suggest that neuronal damage, central cholinergic dysfunction and oxidative damage in the brain following the reduction of cerebral blood flow could be involved in cognitive deficits induced by chronic cerebral hypoperfusion.

Callous-unemotional behaviors and conduct problems in Chinese preschoolers: the moderating roles of surgency and gender.

Introduction: Conduct problems in children are related to callous-unemotional (CU) behaviors. However, results of the relationships between CU behaviors and conduct problems among preschoolers mainly focused on Western countries, no studies have examined whether CU behaviors predict conduct problem in Chinese preschoolers. The primary objective of the current study therefore was to examine the associations between CU behaviors and conduct problems as well as the moderating effects of surgency and child gender in Chinese preschool children. Methods: The present study randomly selected 2,154 children (1,043 boys, Mage = 56 months, SD = 10.47) from six kindergartens in Shanghai, People's Republic of China. Mothers rated children's surgency and teachers reported children's CU behaviors and conduct problems. Results: Results demonstrated that CU behaviors were positively associated with conduct problems. Surgency and child gender significantly moderated these associations. Specifically, CU behaviors were positively associated with conduct problems, with a stronger effect found for high levels of surgency. CU behaviors had a positive association with conduct problems, with a stronger effect found for boys. Discussion: This study indicate that temperament and gender characteristics influence conduct problems in preschoolers who exhibit high levels of CU behaviors. As well, the findings emphasize the significance of considering the meaning and implication of CU behaviors in Chinese culture.

Effect of Freeze-Thaw Cycles on the Freshness of Prepackaged Penaeus vannamei.

The effect of temperature fluctuations on the freshness of shrimp in simulated trays was investigated by setting a freeze-thaw (F-T) cycle of 12 h after freezing at -20 °C and thawing at 1 °C under refrigeration. The results showed that the shrimp's physicochemical properties deteriorated to different extents with the increase in F-T cycles. The total colony count of shrimp was 6.07 lg CFU/g after 21 cycles, and the volatile saline nitrogen content reached 30.36 mg/100 g, which exceeded the edible standard. In addition, the sensory quality and textural properties (hardness, elasticity, chewiness, and adhesion) declined to different degrees with increased F-T cycles. LF-NMR and protein property measurements showed that F-T cycles resulted in reduced water holding capacity and protein denaturation, which were the main factors leading to the deterioration of shrimp quality. Furthermore, flavor changes were analyzed using an electronic nose sensor to establish a freshness model. The W1W, W1S, W2S, and W5S sensors were correlated with the quality changes in shrimp and used as the main sensors for detecting the freshness of Penaeus vannamei. As a result, to better maintain the overall freshness, temperature fluctuations should be minimized in sales and storage, and fewer than 8 F-T cycles should be performed.

Safety of SARS-CoV-2 vaccine in patients with autoimmune neurological conditions: A systematic review and meta-analysis.

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.

GC-MS, GC-IMS, and E-Nose Analysis of Volatile Aroma Compounds in Wet-Marinated Fermented Golden Pomfret Prepared Using Different Cooking Methods.

The cooking method is extremely important for the production of low-salt, wet-marinated, fermented golden pomfret because it strongly influences its flavor components and organoleptic quality. There are also significant differences in flavor preferences in different populations. The present study analyzed differences in the aroma characteristics of wet-marinated fermented golden pomfret after boiling, steaming, microwaving, air-frying, and baking using a combination of an electronic nose, GC-IMS, and SPME-GC-MS. Electronic nose PCA showed that the flavors of the boiled (A), steamed (B), and microwaved (C) treatment groups were similar, and the flavors of the baking (D) and air-frying (E) groups were similar. A total of 72 flavor compounds were detected in the GC-IMS analysis, and the comparative analysis of the cooked wet-marinated and fermented golden pomfret yielded a greater abundance of flavor compounds. SPME-GC-MS analysis detected 108 flavor compounds, and the results were similar for baking and air-frying. Twelve key flavor substances, including hexanal, isovaleraldehyde, and (E)-2-dodecenal, were identified by orthogonal partial least-squares discriminant analysis (OPLS-DA) and VIP analysis. These results showed that the cooking method could be a key factor in the flavor distribution of wet-marinated fermented golden pomfret, and consumers can choose the appropriate cooking method accordingly. The results can provide theoretical guidance for the more effective processing of fish products and the development of subsequent food products.

Efficacy and safety of tocilizumab in patients with refractory generalized myasthenia gravis.

BACKGROUND: We aimed to compare the efficacy of tocilizumab with conventional immunotherapy in refractory patients with acetylcholine receptor antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG). METHODS: This single-center prospective cohort study was based on patients from an MG registry study in China and conducted from February 10, 2021 to March 31, 2022. Adult refractory patients with AChR-Ab+ gMG were assigned to tocilizumab or conventional immunotherapy groups. The primary efficacy outcome was the mean difference of MG activities of daily living (MG-ADL) change at weeks 4, 8, 12, 16, 20, 24 corresponding to that at the baseline between the two groups. A generalized estimating equation model was used for the primary outcome analysis. Safety was assessed based on adverse events. RESULTS: Of 34 eligible patients, 20 (mean [standard deviation] age, 53.8 [21.9] years; 12 [60.0%] female) received tocilizumab and 14 received conventional immunotherapy (45.8 [18.0] years; 8 [57.1%] female). The tocilizumab group had greater reduction in MG-ADL score at week 4 (adjusted mean difference, -3.4; 95% CI, -4.7 to -2.0; p < 0.001) than the conventional immunotherapy group, with significant differences sustained through week 24 (adjusted mean difference, -4.5; 95% CI, -6.4 to -2.6; p < 0.001). At week 24, the proportion of patients achieving higher levels of MG-ADL (up to 7-point reduction) and QMG (up to 11-point reduction) scores improvement was significantly greater with tocilizumab. Tocilizumab had acceptable safety profiles without severe or unexpected safety issues. CONCLUSION: Tocilizumab is safe and effective in improving the MG-ADL score and reducing prednisone dose in refractory AChR-Ab+ gMG, suggesting tocilizumab has the potential to be a valuable therapeutic option for such patients.

The Cryoprotective Effect of an Antifreeze Collagen Peptide Complex Obtained by Enzymatic Glycosylation on Tilapia.

Antifreeze peptides have become effective antifreeze agents for frozen products, but their low quantity of active ingredients and high cost limit large-scale application. This study used the glycosylation of fish collagen peptides with glucosamine hydrochloride catalyzed by transglutaminase to obtain a transglutaminase-catalyzed glycosylation product (TGP) and investigate its antifreeze effect on tilapia. Compared with the blank group, the freshness (pH value of 6.31, TVB-N value of 21.7 mg/100 g, whiteness of 46.28), textural properties (especially hardness and elasticity), and rheological properties of the TGP groups were significantly improved. In addition, the protein structures of the samples were investigated using UV absorption and fluorescence spectroscopy. The results showed that the tertiary structure of the TGP groups changed to form a dense polymer. Therefore, this approach can reduce the denaturation and decomposition of muscle fibers and proteins in fish meat more effectively and has a better protective effect on muscle structure and protein aggregation, improving the stability of fish meat. This study reveals an innovative method for generating antifreeze peptides by enzymatic glycosylation, and glycosylated fish collagen peptide products can be used as new and effective green antifreeze agents in frozen foods.