Integrated gut microbiota and serum pharmacochemistry reveal the mechanisms of wine steaming in alleviating rhubarb diarrhea.

BACKGROUND: Long-term use of rhubarb (RH) can cause adverse gastrointestinal reactions (such as diarrhea), whereas RH steaming with wine (PRH) can alleviate RH-induced diarrhea. However, the potential material basis and mechanisms by which wine steaming alleviates diarrhea caused by RH remain unclear. PURPOSE: To reveal the potential material basis and underlying mechanisms of wine steaming in alleviating diarrhea caused by RH from the perspective of small intestinal flora and immune function. METHODS: The major anthraquinone/anthrone components were detected using high-performance liquid chromatography (HPLC). Constipation model mice were replicated using loperamide hydrochloride and were administered RH and PRH for six consecutive weeks. Histopathological observation (duodenum, jejunum, and ileum) was performed using hematoxylin-eosin (HE) staining, and the serum levels of inflammatory cytokines, immunoglobulin G (IgG), and immunoglobulin A (IgA) were examined. CD4+, CD8+, and Treg cells counts in peripheral blood were determined using flow cytometry; The protein expression of Toll-like receptor 4 (TLR4) and nuclear factor kappa-B (NF-κB) was determined using immunohistochemistry (IHC) and western blot (WB). The small intestine contents and feces were analyzed by 16 S rRNA sequencing and the contents of short chain fatty acids (SCFAs) in feces were determined using gas chromatography-mass spectrometry (GC-MS). Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the blood absorption compounds and endogenous metabolites. RESULTS: The levels of the major anthraquinone/anthrone components were decreased in PRH. RH and PRH both increased the wet fecal weight at 12 h (WFW-12) and fecal water rate (FWR), alleviated the dry and black fecal morphology, and relieved small intestine injuries in the second week. In the fourth week, although RH and PRH alleviated the abnormal levels of indicators in the model mice (fecal water rate, immune cells percentage, and TLR4/NF-κB expression), minor small intestinal damage was observed. Compared to that at the fourth week, RH and PRH increased the levels of WFW-12, FWR, inflammatory cytokines, and TLR4/NF-κB expression, and decreased the levels of IgG/IgA and immune cells with extended administration (sixth week). Further, damage to the small intestine worsened (severe ileal damage) and different degrees of loose stools were observed in RH- and PRH-administered mice in the sixth week. Compared with those in the control group, the levels of WFW-12, FWR, inflammatory cytokines, TLR4/NF-κB expression, IgG/IgA, and immune cell percentage were significantly different in the RH-H and PRH-H mice at the sixth week (except for CD8+in PRH-H). Further, RH and PRH disturbed the gut microbiota (GM) (Lactobacillus and Dubosiella decreased, Aerococcus and Corynebacterium increased) and obviously reduced the content of SCFAs (acetic acid, butyric acid, and isobutyric acid). However, almost all the results indicated a lower impact of PRH than that of RH. Metabolic pathways mainly involved in glycerophospholipid metabolism were identified along with a total of 21 blood absorption components, including anthraquinones, anthrones, flavanols, and tannins. The correlation analysis showed a positive correlation of pathogenic bacteria (Aerococcus and Corynebacterium) with inflammatory cytokines, TLR4/NF-κB, LysoPC(20:0/0:0), and PE (16:0/20:4(8Z,11Z,14Z,17Z)) and a negative correlation with immune cells and SCFAs (acetic acid and isobutyric acid); however, the opposite results were observed for beneficial bacteria (Lactobacillus and Dubosiella). CONCLUSION: Overall, PRH can alleviate RH-induced diarrhea by recovering the GM imbalance and abnormal levels of GM-mediated SCFAs, alleviating the decrease in cellular immune function and abnormal expression of TLR4/NF-κB, thereby suppressing the release of inflammatory factors, possibly, through its lower content of anthraquinones. This study explored for the first time the processing mechanism of wine steaming in alleviating RH-induced diarrhea from the aspects of small intestinal flora and small intestinal immune function.

High-risk screening for late-onset Pompe disease in China: An expanded multicenter study.

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

Therapeutic potentials of adoptive cell therapy in immune-mediated neuropathy.

Immune-mediated neuropathy (IMN) is a group of heterogenous neuropathies caused by intricate autoimmune responses. For now, known mechanisms of different IMN subtypes involve the production of autoantibodies, complement activation, enhanced inflammation and subsequent axonal/demyelinating nerve damages. Recent therapeutic studies mainly focus on specific antibodies and small molecule inhibitors previously approved in rheumatoid diseases. Initial strategies based on the pathophysiologic features of IMN should be explored. Adoptive cell therapy (ACT) refers to the emerging immunotherapies in which circulating immunocytes are collected from peripheral blood and modified with killing and immunomodulatory capacities. It consists of chimeric antigen receptor-T cell therapy, T cell receptor-engineered T cell, CAR-Natural killer cell therapy, and others. In the last decade, ACT has demonstrated extraordinary potentials in treating cancers, infectious diseases and autoimmune diseases. Versatile combinations of targets, chimeric domains and effector cells greatly empower ACT to treat complicated immune disorders. In this review, we summarized the advances of ACT and envisioned suitable strategies for different IMN subtypes.

Ferulic Acid Methyl Ester Attenuates Cerebral Ischemia-Reperfusion Injury in Rats by Modulating PI3K/HIF-1α/VEGF Signaling Pathway.

Background: Cerebral ischaemia-reperfusion injury (CIRI) could worsen the inflammatory response and oxidative stress in brain tissue. According to previous studies, ferulic acid methyl ester (FAME), as the extract with the strongest comprehensive activity in the traditional Chinese medicine Huang Hua oil dot herb, has significant anti-oxidative stress and neuroprotective functions, and can effectively alleviate CIRI, but its mechanism of action is still unclear. Methods: Firstly, the pharmacological effects of FAME were investigated by in vitro oxidative stress and inflammatory experiments. Secondly, evaluate the therapeutic effects of FAME in the treatment of CIRI by brain histopathological staining and cerebral infarct area by replicating the in vivo MACO model. Thirdly, RNA-Seq and network pharmacology were utilized to predict the possible targets and mechanisms of FAME for CIRI at the molecular level. Finally, the expression of key target proteins, as well as the key regulatory relationships were verified by molecular docking visualization, Western Blotting and immunohistochemistry. Results: The results of in vitro experiments concluded that FAME could significantly reduce the content of TNF-α, IL-1ß and ROS, inhibiting COX-2 and iNOS protein expression in cells(p<0.01). FAME was demonstrated to have anti-oxidative stress and anti-inflammatory effects. The results of in vivo experiments showed that after the administration of FAME, the area of cerebral infarction in rats with CIRI was reduced, the content of Bcl-2 and VEGF was increased(p<0.05). Network pharmacology and RNA-Seq showed that the alleviation of CIRI by FAME may be through PI3K-AKT and HIF-1 signaling pathway. Enhanced expression of HIF-1α, VEGF, p-PI3K, p-AKT proteins in the brain tissues of rats in the FAME group was verified by molecular docking and Western Blotting. Conclusion: FAME possesses significant anti-inflammatory and anti-oxidative stress activities and alleviates CIRI through the PI3K/HIF-1α/VEGF signaling pathway.

Efficacy and safety of patisiran for ATTRv-PN: a systematic review and meta-analysis.

Background: Hereditary transthyretin amyloidosis (ATTRv; v for variant) with polyneuropathy is a rare, progressive, and fatal autosomal dominant disorder. Therapies such as liver transplantation and TTR stabilizations have limitations. Patisiran is a small interfering RNA (siRNA), offering potential as a genetic-level therapy for hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). However, evidence on patisiran's efficacy and safety for ATTRv-PN remains limited. Objectives: This study aimed to further clarify patisiran's efficacy and safety for ATTRv-PN by meta-analysis. Design: Systematic review and meta-analysis. Methods: After literature searches in PubMed, Ovid MEDLINE, Embase, JBI EBP, Cochrane, and ClinicalTrials.gov databases on 7 June 2024, 11 studies with 503 patients were included and clinical data were extracted. Results: Results showed an 88% (95% confidence interval (CI): 81%-94%) pooled responsiveness rate. The standardized mean difference of modified Neuropathy Impairment Score plus 7 nerve tests (mNIS + 7) scores was -0.18 (95% CI: -0.32 to -0.03, p-value 0.018) and Norfolk Quality of Life-Diabetic Neuropathy was -0.21 (95% CI: -0.35 to -0.08, p-value 0.002). In total, 413 adverse events (AEs) (84.8%), 158 serious AEs (32.4%), and 37 deaths (7.6%) were recorded. Most of AEs were mild to moderate. No deaths were attributed to patisiran. However, there is no statistically significant improvement in Neuropathy Impairment Scores. Conclusion: In conclusion, patisiran was effective and safe for patients with ATTRv-PN. More large-scale clinical trials and long-term studies are necessary to further validate patisiran's efficacy and safety. Trial registration: PROSPERO registration ID: CRD42023428838.

Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China.

BACKGROUND: GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. OBJECTIVE: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations. METHODS: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity. RESULTS: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients. CONCLUSIONS: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

Human induced pluripotent stem cell line (FDHSi005-A) derived from a patient with a deep intronic variant in the GNE gene.

GlcNAc2-epimerase myopathy is a rare autosomal recessive myopathy characterized by distal involvement in the lower extremities. Our study reprogrammed human-induced pluripotent stem cells from peripheral blood mononuclear cells of a patient with GNE gene deep intronic variant c.862 + 870C>T and c.478C>T compound heterozygous mutations that co-segregated with the disease. The generated iPSCs express pluripotent cell markers with no mycoplasma contamination. Additionally, these iPSCs demonstrated pluripotency, the capacity to differentiate into the three germ layers, and maintained normal karyotypes. Importantly, we identified that these iPSCs possess the same specific mutations as the patient, making them a robust model for studying GNE myopathy and developing potential therapeutic interventions.

Long-term and low-dose rituximab treatment for chronic inflammatory demyelinating polyneuropathy.

OBJECTIVE: To evaluate the efficacy and safety of a low-dose, long-term rituximab regimen in the treatment of idiopathic CIDP. METHODS: This study included 15 CIDP patients treated with rituximab. Patients were administered 600 mg of rituximab intravenously every 6 months. Baseline evaluation was conducted before the initiation of rituximab treatment and subsequent evaluations were conducted 6 months after each rituximab infusion at on-site visits. Clinical improvement was objectively determined by improvement of scale score at least decrease ≥1 INCAT or mRS or increase ≥4 MRC or ≥8 cI-RODS after each infusion compared to baseline evaluation. RESULTS: Fifteen CIDP patients were included and 10 of them were typical CIDP and five were distal CIDP. Nine in 15 (60%) patients after first infusion and three in six (50%) patients after second infusion exhibited significant clinical improvement compared to baseline evaluation. Additionally, rituximab facilitated a reduction or cessation of other medications in 73% of patients at last visit. The safety profile was favorable, with no reported adverse events. CONCLUSION: Rituximab presents a promising therapeutic option for idiopathic CIDP, offering both efficacy and safety with a low-dose, long-term regimen.

Isolation, structures, bioactivities, and utilizations of polysaccharides from Dictyophora species: A review.

Dictyophora species is an edible and medicinal fungus belonging to the Basidiomycotina, Gasteromycetes, Phallales, family Phallaceae, and genus Dictyophora, which is popular with consumers in China and across various Asian regions. Polysaccharides from Dictyophora species (DPs) are important bioactive macromolecules with multiple health benefits, according to published studies, including anti-tumor, antioxidative, anti-obesity, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory, regulation of gut microbiota, antibacterial, renoprotective, and other pharmacological effects. Based on their rich pharmacological activities, the preparation techniques, structural characteristics and pharmacological activities of DPs have been extensively studied. However, to the best of our knowledge, there is no dedicated review to shed light on recent advances in DPs. Therefore, in order to fill this gap, this review provides a comprehensive overview of the research on DPs, including the latest advances in extraction, isolation and purification, structural characteristics, pharmacological properties, safety assessment and potential utilizations, which will provide a theoretical basis for the research and development of subsequent DPs-related products.

The protective effects of aqueous extract of Schisandra sphenanthera against alcoholic liver disease partly through the PI3K-AKT-IKK signaling pathway.

Purpose: This study aimed to investigated the key chemical components and the effect of the aqueous extract of Schisandra sphenanthera (SSAE) on alcoholic liver disease (ALD) and the related molecular mechanism. Methods: This study employed UPLC-Q-TOF-MS/MS to identify the chemical compositions in SSAE. ALD rat model was established through oral administration of white spirit. Transcriptome sequencing, weighted gene co-expression network construction analysis (WGCNA), and network pharmacology were used to predict key compositions and pathways targeted by SSAE for the treatment of ALD. Enzyme-linked immunosorbent assay (ELISA), biochemical kits, hematoxylin-eosin (HE) staining, Western blotting (WB) analysis, and immunohistochemical analysis were used to validate the mechanism of action of SSAE in treating ALD. Results: Active ingredients such as schisandrin A, schisandrol A, and schisandrol B were found to regulate the PI3K/AKT/IKK signaling pathway. Compared to the model group, the SSAE group demonstrated significant improvements in cellular solidification and tissue inflammation in the liver tissues of ALD model rats. Additionally, SSAE regulated the levels of a spartate aminotransferase (AST), alanine aminotransferase (ALT), alcohol dehydrogenase (ADH), and aldehyde Dehydrogenase (ALDH) in serum (P < 0.05); Western blotting and immunohistochemical analyses showed that the expression levels of phosphorylated PI3K, AKT, IKK, NFκB, and FOXO1 proteins were significantly reduced in liver tissues (P < 0.05), whereas the expression level of Bcl-2 proteins was significantly increased (P < 0.05). Conclusion: The active components of SSAE were schisandrin A, schisandrol A, and schisandrol B, which regulated the phosphorylation levels of PI3K, AKT, IKK, and NFκB and the expression of FOXO1 protein and upregulated the expression of Bcl-2 protein in the liver tissues of ALD rats. These findings indicate that SSAE acts against ALD partly through the PI3K-AKT-IKK signaling pathway. This study provided a reference for future research and treatment of ALD and the development of novel natural hepatoprotective drugs.

Efgartigimod as a promising add-on therapy for myasthenic crisis: a prospective case series.

Introduction: Efgartigimod is effective and well-tolerated in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (MG). However, the therapeutic potential and the safety profile of efgartigimod in myasthenic crisis (MC) remained largely unknown. Methods: This is an observational, prospective, multicenter, real-world study to follow 2 MC patients who initiated efgartigimod as a first-line rescue therapy and 8 cases who used it as an add-on therapy. Baseline demographic features and immunotherapies were collected, and the MG-activities of daily living (MG-ADL) scale was evaluated every week since efgartigimod treatment for 8 weeks. Additionally, serum IgG and anti-AChR antibody levels and the peripheral CD4+ T lymphocytes were measured before and after one cycle of treatment. Results: Ten patients with MC were enrolled in the study, including 9 anti-AChR antibody positive and 1 anti-muscle-specific kinase (MuSK) positive. All patients were successfully weaned from the ventilation after receiving efgartigimod treatment, with a length of 10.44 ± 4.30 days. After one cycle of infusions, the MG-ADL score reduced from 15.6 ± 4.4 at the baseline to 3.4 ± 2.2, while the corticosteroid dose was tapered from 55.0 ± 20.7 mg to 26.0 ± 14.1 mg. The proportions of regulatory T cells and naïve T cells (% in CD4+ T) significantly decreased post-efgartigimod treatment (5.48 ± 1.23 vs. 6.90 ± 1.80, P=0.0313, and 34.98 ± 6.47 vs. 43.68 ± 6.54, P=0.0313, respectively). Conclusion: These findings validated the rapid action of efgartigimod in facilitating the weaning process with a good safety profile in patients with MC.

Revealing the optimal traditional processing methods and its protective effects against febrile seizures of Arisaema cum bile.

Arisaema cum bile (known as Dan Nanxing in Chinese, DNX) is a herbal medicine used for treating febrile seizure (FS), which commonly prepared by using Arisaematis Rhizoma and animal bile. This study was designed to explore the optimal processing time of DNX and its potential mechanism on the anti-FS effect. A total of 17 volatile organic compounds (VOCs) were the characteristic ones to distinguish different fermentation stages of DNX by using gas chromatography-ion mobility spectrometry (GC-IMS), such as 2-heptanone monomer, and heptanal monomer. DNX with fermentation for 3 months had an obvious pattern of VOCs with others, which could be regarded as the optimal fermentation time. The Enterococcus and Staphylococcus might be the core bacteria on the production of VOCs. Additionally, DNX (2.8 g/kg, p.o.) reversed hot water bath-induced FSs of rats, as indicated by increased seizure latency and decreased seizure duration time. It also prevented hippocampal neuronal loss, increased GABAAR, and decreased GRIA1 expression. At the genus level, relative abundance of Enterococcus and Akkermansia were enriched after DNX treatment. These findings suggested that fermentation for 3 months might be the optimal process time for DNX, and DNX possess an anti-FS effect through regulating neurotransmitter disorder and gut microbiota.

The safety and efficacy profile of eculizumab in myasthenic crisis: a prospective small case series.

Eculizumab has improved recovery from ventilatory support in myasthenic crisis (MC) cases. However, the safety and efficacy profiles from prospective studies are still lacking. This study aimed to explore eculizumab's safety and efficacy in a prospective case series of patients with refractory MC. We followed a series of anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG) patients who received eculizumab as an add-on therapy for 12 weeks during MC to facilitate the weaning process and reduced disease activity. Serum anti-AChR antibodies and peripheral immune molecules associated with the complement pathway were evaluated before and after eculizumab administration. Compared to the baseline Myasthenia Gravis Foundation of America (MGFA)-quantitative MG test (QMG) scores (22.25 ± 4.92) and MG-activities of daily living (MG-ADL; 18.25 ± 2.5) scores at crisis, improvements were observed from 4 weeks (14.5 ± 10.47 and 7.5 ± 7.59, respectively) through 12 weeks (7.5 ± 5.74 and 2.25 ± 3.86, respectively) post-treatment. Muscle strength consistently improved across ocular, bulbar, respiratory, and limb/gross domain groups. One patient died of cardiac failure at 16 weeks. Three cases remained in remission at 24 weeks, with a mean QMG score of 2.67 ± 2.89 and ADL score of 0.33 ± 0.58. No significant side effects were reported. Serum CH50 and soluble C5b-9 levels significantly declined, while there were no significant changes in serum anti-AChR antibody levels, C1q, C5a levels, or peripheral lymphocyte proportions. Eculizumab was well tolerated and showed efficacy in this case series. Large prospective cohort studies with extended follow-up periods are needed to further explore the safety and efficacy profile in real-world practice.

Prospective cohort study evaluating efficacy and safety of efgartigimod in Chinese generalized myasthenia gravis patients.

Background: Despite 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). Methods: This 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. Results: Between 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. Discussion: A single cycle of efgartigimod treatment demonstrates effectiveness and the tolerability through week 8, with no new safety signals observed in Chinese gMG patients.

Efgartigimod for generalized myasthenia gravis: A multicenter real-world cohort study in China.

OBJECTIVE: Efgartigimod, a neonatal Fc receptor antagonist, facilitates antibody degradation including pathogenic IgGs. The ADAPT study demonstrated the tolerability and efficacy of efgartigimod in the treatment of generalized myasthenia gravis (gMG). However, very limited evidence is available for the Chinese population, and it remains inconclusive about which kind of patients are selected to preferentially receive efgartigimod in real-world settings. METHODS: This multicenter cohort study included gMG patients treated at 14 neuromuscular reference centers in China. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, immunosuppressants, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected. RESULTS: Of the 1640 gMG admitted between September and December 2023, 61 (3.7%) received efgartigimod for at least one treatment cycle. Among them, 56 cases (92%) were anti-AChR antibody-positive, 4 were anti-MuSK antibody-positive, and 1 was seronegative. Thymoma-associated myasthenia gravis accounted for most cases (44%, 27 out of 61). The principal causes of efgartigimod initiation included MG acute exacerbation (MGAE) (48%, 29 out of 61) and myasthenic crisis (MC) (15%, 9 out of 61). Clinically meaningful improvement was rapidly achieved in 97% (58 out of 61) of patients at 1.3 ± 0.7 weeks. By week 12, the MG-ADL score reduced to 3.8 ± 4.1 (baseline:10.5 ± 5.2) for all participants, while it reduced to 4.0 ± 4.7 for MGAE and 3.8 ± 4.2 for MC, respectively. All but one TMG patient required no additional rescue therapies after efgartigimod initiation. 11.5% (7 out of 61) reported ≥1 TEAEs. INTERPRETATION: This multicenter cohort study demonstrated the efficacy of efgartigimod in rapid control of gMG. Patients with MGAE or MC would benefit from efgartigimod treatment.

Long-term impact of nusinersen on motor and electrophysiological outcomes in adolescent and adult spinal muscular atrophy: insights from a multicenter retrospective study.

BACKGROUND: 5q spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease. OBJECTIVE: We aimed to assess the effects of nusinersen on motor function and electrophysiological parameters in adolescent and adult patients with 5q SMA. METHODS: Patients with genetically confirmed 5q SMA were eligible for inclusion, and clinical data were collected at baseline (V1), 63 days (V4), 180 days (V5), and 300 days (V6). The efficacy of nusinersen was monitored by encompassing clinical assessments, including the Revised Upper Limb Module (RULM), Hammersmith Functional Motor Scale Expanded (HFMSE), 6-Minute Walk Test (6MWT), and percent-predicted Forced Vital Capacity in sitting position (FVC%) and Compound Muscle Action Potential (CMAP) amplitude. The patients were divided into "sitter" and "walker" subgroups according to motor function status. RESULTS: 54 patients were screened, divided into "sitter" (N = 22) and "walker" (N = 32), with the mean age at baseline of 27.03 years (range 13-53 years). The HFMSE in the walker subgroup increased significantly from baseline to V4 (mean change +2.32-point, P = 0.004), V5 (+3.09, P = 0.004) and V6 (+4.21, P = 0.005). The patients in both the sitter and walker subgroup had no significant changes in mean RULM between V1 and the following time points. Significant increases in CMAP amplitudes were observed in both upper and lower limbs after treatment. Also, patients with RULM ≥ 36 points showed significant CMAP improvements. Our analysis predicted that patients with CMAP amplitudes of trapezius ≥ 1.76 mV were more likely to achieve significant motor function improvements. CONCLUSIONS: Nusinersen effectively improves motor function and electrophysiological data in adolescent and adult patients with SMA. This is the first report on the CMAP amplitude changes in the trapezius after treatment in patients with SMA. The CMAP values effectively compensate for the ceiling effect observed in the RULM, suggesting that CMAP could serve as an additional biomarker for evaluating treatment efficacy.

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.

Da-Jian-Zhong decoction alleviates diarrhea-predominant irritable bowel syndrome via modulation of gut microbiota and Th17/Treg balance.

ETHNOPHARMACOLOGICAL RELEVANCE: Da-Jian-Zhong decoction (DJZD) is a herbal formula clinically used for abdominal pain and diarrhea induced by spleen-Yang deficiency syndrome. Recently, treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) with DJZD has received increasing attention, but the underlying mechanism of action remains elusive. AIM OF THE STUDY: We aimed to evaluate the therapeutic effect of DJZD on IBS-D rats and to elucidate the underlying mechanisms. MATERIALS AND METHODS: An IBS-D rats model was constructed using a two-factor superposition method of neonatal maternal separation and Senna folium aqueous extract lavage. Moreover, the effect of DJZD was evaluated based on the body weight, rectal temperature, abdominal withdrawal reflex (AWR), and Bristol stool scale score (BSS). The factors that regulate the DJZD effects on IBS-D were estimated using whole microbial genome, transcriptome sequencing (RNA-Seq), flow cytometry, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analyses. RESULTS: We found that DJZD alleviated the symptoms of IBS-D rats, with the low-dose (2.4 g/kg) as the better ones, as shown by the higher body weight and lower AWR score and BSS. At the phylum level, the relative abundance of Bacteroidetes was obviously increased, and at the genus level, Lactobacillus and Parabacteroides were increased, while that of Firmicutes_bacterium_424 and Ruminococcus gnavus was decreased in DJZD group. Furthermore, the significantly enriched GO terms after treatment with DJZD mainly included the immune response, positive regulation of activated T cell proliferation, and positive regulation of interleukin-17 (IL-17) production. Importantly, flow cytometry analysis further revealed that the T helper cell type 17/regulatory T cell (Th17/Treg) balance contributed to the DJZD-induced alleviation of IBS-D symptoms, as DJZD downregulated Th17/Treg ratio and Th17 cell-related cytokines IL-17 and IL-6 levels in the colon. CONCLUSIONS: These results demonstrated that DJZD has a good therapeutic effect on IBS-D rats, probably by maintaining the homeostasis of gut microbiota and regulating Th17/Treg balance and its related inflammatory factors.

A predictive nomogram for short-term outcomes of myasthenia gravis patients treated with low-dose rituximab.

BACKGROUND: This study aims to establish and validate a predictive nomogram for the short-term clinical outcomes of myasthenia gravis (MG) patients treated with low-dose rituximab. METHODS: We retrospectively reviewed 108 patients who received rituximab of 600 mg every 6 months in Huashan Hospital and Tangdu Hospital. Of them, 76 patients from Huashan Hospital were included in the derivation cohort to develop the predictive nomogram, which was externally validated using 32 patients from Tangdu Hospital. The clinical response is defined as a ≥ 3 points decrease in QMG score within 6 months. Both clinical and genetic characteristics were included to screen predictors via multivariate logistic regression. Discrimination and calibration were measured by the area under the receiver operating characteristic curve (AUC-ROC) and Hosmer-Lemeshow test, respectively. RESULTS: Disease duration (OR = 0.987, p = 0.032), positive anti-muscle-specific tyrosine kinase antibodies (OR = 19.8, p = 0.007), and genotypes in FCGR2A rs1801274 (AG: OR = 0.131, p = 0.024;GG:OR = 0.037, p = 0.010) were independently associated with clinical response of post-rituximab patients. The nomogram identified MG patients with clinical response with an AUC-ROC (95% CI) of 0.875 (0.798-0.952) in the derivation cohort and 0.741(0.501-0.982) in the validation cohort. Hosmer-Lemeshow test showed a good calibration (derivation: Chi-square = 3.181, p = 0.923; validation: Chi-square = 8.098, p = 0.424). CONCLUSIONS: The nomogram achieved an optimal prediction of short-term outcomes in patients treated with low-dose rituximab.