OBJECTIVE: To elucidate the mechanism of Banxia Houpo Decoction (BHD) in treating gastroesophageal reflux disease (GERD) by integrating and utilizing the compound analysis, network pharmacology, and empirical verification. METHODS: Ultra-high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) was utilized to identify the primary compounds in BHD. Network pharmacology was employed to retrieve target genes. A GERD rat model was developed and 32 SD rats were randomly divided into model, BHD-L (3 g/kg), BHD-H (6 g/kg), and mosapride (0.75 mg/kg) groups using a random number table, 8 rats in each group. Eight rats without the construction of a GERD model were selected as the blank group. Esophageal damage was evaluated through visualization and histopathology evaluation. 5-hydroxytryptamine (5-HT) levels in serum and lower esophageal sphincter (LES) were determined by ELISA. LES contractility was measured with a force transducer, and serotonin transporter (SERT) and 5-HT4R expressions in LES were assessed by RT-PCR, Western blot, and immunofluorescence staining, respectively. RESULTS: UPLC-HRMS analysis identified 37 absorption peaks and 157 compounds in BHD. Functional enrichment identified SERT as a significant target for LES contractility. Histopathological findings indicated less severe esophageal mucosal damage in the BHD-H group compared with the model group. Although serum 5-HT levels showed no significant difference, 5-HT concentration in LES tissue was notably higher in the BHD-H group (P<0.05). Within the range from 10^-10 to 10^-7 mmol/L, LES contractility in the BHD-H and mosapride groups was significantly increased (P<0.05). Within the range from 3 × 10^-7 to 3 × 10^-6 mmol/L 5-HT, LES contractility in the BHD-H group was increased (P<0.05). No significant difference was detected within the range from 10^-5 to 10^-4 mmol/L 5-HT. Notably, SERT expression in the BHD-H group assessed by RT-PCR, Western blot, and immunofluorescence staining were significantly lower than that in the model group (all P<0.01); while 5-HT4R expression remained unchanged. CONCLUSION BHD may increase LES contractility by inhibiting SERT expression in LES tissue.
Animals ; Gastroesophageal Reflux/physiopathology* ; Drugs, Chinese Herbal/chemistry* ; Rats, Sprague-Dawley ; Network Pharmacology ; Male ; Serotonin/metabolism* ; Rats ; Disease Models, Animal ; Serotonin Plasma Membrane Transport Proteins/metabolism* ; Esophagus/drug effects*

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Objective To investigate the correlation between muscle mass and gait parameters in patients with cerebral small vessel disease(CSVD),as well as the impact of reduced muscle mass on the occurrence of falls in CSVD patients.Methods This study was employed a cross-sectional design.Ninety-five inpatients with CSVD confirmed by the Department of Neurology of the Seventh Medical Center of Chinese People's Liberation Army General Hospital from January 1,2022 to June 1,2023 were included consecutively.The 95 patients with CSVD were divided into two groups,namely the reduced muscle mass group and the normal muscle mass group,based on the criteria of appendicular skeletal muscle mass(ASM)≤7.0 kg/m2 for males and ASM ≤5.7 kg/m2 for females as reduced muscle mass.Baseline data(sex,age,years of schooling,number of accompanying diseases[hypertension,hyperlipidemia,diabetes,angina pectoris,myocardial infarction,and migraines]),cognitive function assessment results(mini-mental status examination[MMSE],verbal fluency test[VFT],clock drawing test[CDT],and trail-making test part-B[TMT-B]),gait characteristics(basic gait parameters[gait speed,stride time,stride length,stride frequency]and reanalysis gait parameters[variation coefficient of gait speed,stride time,stride length,stride frequency,and time-phase coordination index,gait asymmetry index]),CSVD imaging findings(cerebral microbleeds,lacunar infarcts,and white matter hyperintensities),and history of falls.The differences in baseline data,cognitive function assessment results,and gait characteristics between the reduced muscle mass group and the normal muscle mass group were compared and analyzed.Linear regression was used to analyze the correlation between muscle mass and gait parameters.The 95 CSVD patients were divided into fall group and non-fall group,and the differences in baseline data,cognitive function assessment results,gait characteristics,CSVD imaging findings,and muscle mass between the two groups were compared.Binary Logistic regression analysis was used to evaluate the impact of reduced muscle mass on falls.Results(1)The majority of patients in the reduced muscle mass group were females(67.7％[21/31]).There was a statistically significant difference in the sex distribution between the reduced muscle mass group and the normal muscle mass group(x2=6.143,P=0.013).There were no statistically significant differences in the other baseline characteristics and cognitive function between the two groups(all P＞0.05).(2)Compared to the normal muscle mass group,patients in the reduced muscle mass group had slower gait speed([0.72±0.16]m/s vs.[0.94±0.15]m/s),longer stride time([1.22±0.12]s vs.[1.08±0.08]s),shorter stride length([0.84±0.19]m vs.[1.00±0.14]m),and lower step frequency([100±9]steps/min vs.[112±8]steps/min).The coefficients of variation for gait speed(11.579[8.163,15.870]％vs.7.304[5.873,9.959]％),stride time(3.876[2.778,5.769]％vs.2.480[1.874,3.001]％),stride length(7.800[5.400,10.700]％vs.5.600[4.100,7.950]％),step frequency(5.313[3.568,7.272]％vs.3.674[3.099,5.082]％),and time-phase coordination index(5.894[4.392,9.080]％vs.3.828[3.031,5.972]％)were all increased,and the differences were statistically significant(all P＜0.05).There was no statistically significant difference in gait asymmetry index between the two groups(P＞0.05).Further analysis with sex and lacunar infarction as potential confounding factors showed that there were statistically significant differences in baseline gait parameters between the normal muscle mass group and the reduced muscle mass group(all P＜0.01).In the reanalysis of gait parameters,only the differences in the coefficients of variation for gait speed and stride time were statistically significant(both P＜0.05).(3)When analyzing ASM as a continuous variable,age and CDT as potential confounders,and stratifying by sex,the results showed that in male patients,baseline gait parameters(gait speed,stride time,stride length,and step frequency with 95％CI ranging from 0.057 to 0.152,-0.105 to-0.023,0.013 to 0.097,and 1.686 to 8.854,respectively),as well as coefficients of variation for stride time(95％CI-0.016 to-0.003)and stride length(95％CI-0.026 to-0.006),were correlated with muscle mass reduction(all P＜0.05).In female patients,gait speed(95％CI0.034 to 0.166)and coefficient of variation for gait speed(95％CI-0.059 to-0.010),stride time(95％CI-0.110 to-0.011),coefficient of variation for stride time(95％CI-0.025 to-0.001),and stride length(95％CI 0.018 to 0.163)were correlated with muscle mass reduction(all P＜0.05).(4)Muscle mass reduction was an independent risk factor for falls(OR,5.044,95％CI 1.840 to 13.827,P=0.002).Conclusions The preliminary analysis of this study suggests that there is a certain correlation between muscle mass and gait parameters in patients with CSVD.Additionally,the study indicates that a decrease in muscle mass among CSVD patients may increase the risk of falls.Therefore,it is important to prioritize the management of muscle mass in CSVD patients.

Liver is the main organ of glucose and lipid metabolism, and persistent hyperglycemia is a common cause of liver injury. Panax notoginsenosides (PNS) is the main active ingredient in Panax notoginseng, which have anti-inflammatory and antioxidant effects. In this study, quantitative proteomics combined with experimental verification was used to explore the protective effect of PNS on liver injury in type 2 diabetes mellitus (T2DM) mice and its potential mechanism. All experiments were approved by the Ethical Committee Experimental Animal Center of North Sichuan Medical College (NSMC2022023). Hematoxylin-eosin (H&E) staining and transmission electron microscopy were used to observe the effect of PNS on the histopathological changes of liver in T2DM mice. TdT-mediated dUTP Nick-end labeling (TUNEL) staining was used to analyze the effect of PNS on hepatocyte apoptosis in T2DM mice. Reactive oxygen species (ROS) and malonaldehyde (MDA) kits were used to detect the effect of PNS on oxidative damage of liver in T2DM mice. Subsequently, proteomics profiling of mice in T2DM and T2DM+PNS groups were investigated based on quantitative proteomics. Differentially expressed proteins were screened out according to fold change and significance level in T2DM and T2DM+PNS groups, respectively. Pathway enrichment analysis of these differential proteins was done using GeneAnalytics database. Gene ontology analysis was conducted by Metascape database. Protein-protein interaction networks were constructed based on STRING database. Western blot was used to detect protein expression. These results showed that PNS could improve liver abnormalities, inhibit hepatocyte apoptosis, and improve the morphology of mitochondria and endoplasmic reticulum in T2DM mice. Proteome data demonstrated that 489 genes expression changed significantly in liver of T2DM mice compared with normal, and 42 ones were significantly reversed after PNS treatment and returned to normal levels. Pathway analysis showed that sterol hormone biosynthesis, adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway, oxidative stress, insulin signaling, phosphatidylinositol pathway, tumor necrosis factor-α (TNF-α) mediated inflammation, insulin resistance, and mTOR signaling pathway exhibited notable changes based on pathway enrichment ratio and significance level. It is worth noting that PNS could improve the abnormal changes of AMPK, TNF-α, apoptosis and insulin pathways. Western blot manifested that PNS inhibit the expression of Bax, Grp78 and Chop, reduce ratio of cleaved casp6/casp6, increase the levels of pAMPKα, HO-1 and Nu-Nrf2 in the liver of T2DM mice. These results suggested that PNS may play protective roles in the liver of T2DM mice by inhibiting apoptosis via activating AMPK/Nrf2/HO-1 signaling pathway, alleviating oxidative stress and endoplasmic reticulum stress.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in healthcare facilities in major regions of China in 2023.Methods Clinical isolates collected from 73 hospitals across China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2023 Clinical & Laboratory Standards Institute (CLSI) breakpoints.Results A total of 445199 clinical isolates were collected in 2023,of which 29.0％ were gram-positive and 71.0％ were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species (excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi) (MRSA,MRSE and MRCNS) was 29.6％,81.9％ and 78.5％,respectively.Methicillin-resistant strains showed significantly higher resistance rates to most antimicrobial agents than methicillin-susceptible strains (MSSA,MSSE and MSCNS).Overall,92.9％ of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 91.4％ of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis had significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 93.1％ in the isolates from children and and 95.9％ in the isolates from adults.The resistance rate to carbapenems was lower than 15.0％ for most Enterobacterales species except for Klebsiella,22.5％ and 23.6％ of which were resistant to imipenem and meropenem,respectively .Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.6％ to 10.0％.The resistance rate to imipenem and meropenem was 21.9％ and 17.4％ for Pseudomonas aeruginosa,respectively,and 67.5％ and 68.1％ for Acinetobacter baumannii,respectively.Conclusions Increasing resistance to the commonly used antimicrobial agents is still observed in clinical bacterial isolates.However,the prevalence of important crabapenem-resistant organisms such as crabapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a slightly decreasing trend.This finding suggests that strengthening bacterial resistance surveillance and multidisciplinary linkage are important for preventing the occurrence and development of bacterial resistance.

Zilucoplan is a novel subcutaneous self-administered macrocyclic peptide inhibitor of complement component 5.It was approved by the FDA in October 2023 for the treatment of adults with generalized myasthenia gravis(gMG)who are positive for acetylcholine receptor(AChR)antibodies.This article reviews its pharmacological action,pharmacokinetics,clinical evaluation and safety.

The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1β/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1, and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.

AIM:To evaluate the bioequivalence of the two rivaroxaban tablets in Chinese healthy subjects.METHODS:Twenty-eight subjects under fasting status and twenty-eight subjects under fed status were enrolled in the study.This study was designed as a four period,fully repetitive,cross-over study.All subjects were administered test(T)and reference(R)rivaroxaban tablets(10 mg)un-der fasting and fed condition respectively.Liquid chromatography-tandem mass spectrometry was used to detect the concentrations of rivaroxaban in plasma.WinNonlin 7.0 was used to calculate the main pharmacokinetic parameters(PK)and to eval-uate the bioequivalence.RESULTS:In fasting group,the main pharmacokinetic parameters of T and R preparation were as follows:Cmax were(186.57±56.41)and(187.61±50.89)ng/mL;AUC0-t were(1 156.21±335.85)and(1 177.59±343.72)h·ng·mL-1;AUC0-∞ were(1 235.77±384.03)and(1223.53±392.10)ng·h·mL-1.The 90％confidential interval(CI)of the three main parameters were 90.81％-105.67％,92.83％-103.85％and 95.04％-107.13％.The upper limit of the 90％CI for the test-to-reference ratio of the within-subject of Cmax,AUC0-t and AUC0-∞ were 1.56,1.41 and 1.73.In fed group,the main pharmacokinetic parameters of T and R preparation were as follows:Cmax were(207.81±45.26)and(211.04±36.62)ng/mL;AUC0-t were(1 271.26±260.92)and(1 233.23±201.85)h·ng·mL-1;AUC0-∞ were(1 290.76±264.90)and(1251.68±203.73)ng·h·mL-1.The 90％CI of the three main parameters were 92.82％-102.28％,97.68％-106.68％and 97.71％-106.68％.The upper limit of the 90％CI for the test-to-reference ratio of the within-subject of Cmax,AUC0t and AUC0-∞were 1.76,1.47 and 1.47.CONCLUSION:The two preparations of rivaroxaban tablets were bioequiva-lent.