Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

Background/Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a significant risk factor for gallstone formation, but mechanisms underlying MASH-related gallstone formation remain unclear. Golgi membrane protein 1 (GOLM1) participates in hepatic cholesterol metabolism and is upregulated in MASH. Here, we aimed to explore the role of GOLM1 in MASH-related gallstone formation. Methods: The UK Biobank cohort was used for etiological analysis. GOLM1 knockout (GOLM1-/-) and wild-type (WT) mice were fed with a high-fat diet (HFD). Livers were excised for histology and immunohistochemistry analysis. Gallbladders were collected to calculate incidence of cholesterol gallstones (CGSs). Biles were collected for biliary lipid analysis. HepG2 cells were used to explore underlying mechanisms. Human liver samples were used for clinical validation. Results: MASH patients had a greater risk of cholelithiasis. All HFD-fed mice developed MASH, and the incidence of gallstones was 16.7% and 75.0% in GOLM1-/- and WT mice, respectively. GOLM1-/- decreased biliary cholesterol concentration and output. In vivo and in vitro assays confirmed that GOLM1 facilitated cholesterol efflux through upregulating ATP binding cassette transporter subfamily G member 5 (ABCG5). Mechanistically, GOLM1 translocated into nucleus to promote osteopontin (OPN) transcription, thus stimulating ABCG5-mediated cholesterol efflux. Moreover, GOLM1 was upregulated by interleukin-1β (IL-1β) in a dose-dependent manner. Finally, we confirmed that IL-1β, GOLM1, OPN, and ABCG5 were enhanced in livers of MASH patients with CGSs. Conclusions In MASH livers, upregulation of GOLM1 by IL-1β increases ABCG5-mediated cholesterol efflux in an OPN-dependent manner, promoting CGS formation. GOLM1 has the potential to be a molecular hub interconnecting MASH and CGSs.

ObjectiveThis study aims to observe the clinical effect of Danggui Liuhuang Tang （DGLHT） on patients with type 2 diabetes mellitus （T2DM） complicated by atherosclerotic cardiovascular disease （ASCVD） at high risk， focus on evaluating the influence of DGLHT on cardiovascular risk indicators such as flow-mediated dilation （FMD）， atherogenic index of plasma （AIP）， and triglyceride-glucose index （TyG）， and explore the regulatory effect of DGLHT on the myeloid differentiation factor 88/nuclear factor-kappa B （MyD88/NF-κB） signaling pathway. MethodsThe clinical study was a single-center， double-blind， and randomized controlled trial. A total of 68 patients with T2DM-ASCVD at high risk for cardiovascular events with Yin deficiency and fire excess syndrome were enrolled and randomly assigned to a treatment group and a control group. The treatment group was given atorvastatin calcium tablets and DGLHT， while the control group was given atorvastatin calcium tablets and placebos. The treatment course was 12 weeks， with a final study completion of 30 patients in the treatment group and 29 in the control group. Changes in cardiovascular risk indicators such as FMD， AIP， TyG， and small dense low-density lipoprotein cholesterol （sdLDL-C） index were compared. Human umbilical vein endothelial cells （HUVECs） were used to establish a vascular endothelial injury and inflammation model. The protective effect of DGLHT on endothelial injury was verified by reverse transcription polymerase chain reaction （Real-time PCR） and Western blot . ResultsAfter 12 weeks of treatment， the AIP in the treatment group significantly decreased compared with that before the treatment （P<0.05）. Compared with the control group， the treatment group showed significant improvements in FMD and TyG （P<0.05）. Additionally， the treatment group demonstrated significant reductions in two-hour postprandial glucose （2 hPG）， glycated albumin （GA）， triglycerides （TG）， apolipoprotein E （Apo E）， and sdLDL-C （P<0.05）. Analysis of traditional Chinese medicine （TCM） syndrome efficacy indicated that in the treatment group， Yin deficiency and fire excess syndromes， including dry throat and mouth （P<0.05）， excessive thirst （P<0.01）， tidal fever and night sweats （P<0.05）， and dry stools （P<0.05）， improved. Compared with the control group， the treatment group showed significant improvements in symptoms of dry throat and mouth （P<0.05） and excessive thirst （P<0.01）. TCM syndrome scores significantly decreased （P<0.01）， and the overall efficacy rate was 56.67%， significantly higher than the 10.34% observed in the control group （P<0.01）. At the cellular level， increasing concentrations of DGLHT led to decreased messenger ribonucleic acid （mRNA） levels of pro-inflammatory cytokines interleukin-6 （IL-6）， tumor necrosis factor-alpha （TNF-α）， and interleukin-1-beta （IL-1β） in lipopolysaccharide （LPS）-stimulated HUVECs （P<0.01）， with significant reductions in the high-concentration group （P<0.01）. DGLHT may inhibit the expressions of MyD88 and phosphorylated （p）-NF-κB p65 proteins in a concentration-dependent manner. ConclusionDGLHT shows significant effects in reducing cardiovascular risks and may exert an anti-inflammatory effect by inhibiting the MyD88/NF-κB signaling pathway. This finding provides a new perspective for the prevention and treatment of cardiovascular diseases in high-risk individuals with T2DM-ASCVD.

Objective To investigate the factors influencing international normalized ratio (INR)>3.0 in patients undergoing warfarin anticoagulation therapy after mechanical heart valve replacement. Methods A retrospective analysis was performed on the clinical data of patients who underwent mechanical heart valve replacement surgery and received warfarin anticoagulation therapy at West China Hospital of Sichuan University from January 1, 2011 to June 30, 2022. Based on the discharge INR values, patients were divided into two groups: an INR≤3.0 group and an INR>3.0 group. The factors associated with INR>3.0 at the time of discharge were analyzed. Results A total of 8901 patients were enrolled, including 3409 males and 5492 females, with a median age of 49.3 (43.5, 55.6) years. The gender, body mass index (BMI), New York Heart Association (NYHA) cardiac function grading, INR, glutamic oxaloacetic transaminase, and preoperative prothrombin time (PT) were statistically different between the two groups (P<0.05). Multivariate logistic regression analysis revealed that lower BMI, preoperative PT>15 s, and mitral valve replacement were independent risk factors for INR>3.0 at discharge (P<0.05). Conclusion BMI, preoperative PT, and surgical site are factors influencing INR>3.0 at discharge in patients undergoing warfarin anticoagulation therapy after mechanical heart valve replacement. Special attention should be given to patients with lower BMI, longer preoperative PT, and mitral valve replacement to avoid excessive anticoagulation therapy.

OBJECTIVE To evaluate the effectiveness and safety of warfarin anticoagulation therapy guided by gene test in patients undergoing left ventricular assist device （LVAD） implantation， and to analyze the influencing factors of warfarin anticoagulation efficacy. METHODS Patients who underwent LVAD implantation at the Heart and Vascular Center of Northern Jiangsu People’s Hospital from January 2023 to October 2024 and required warfarin anticoagulant therapy were selected as the study subjects. They were divided into genetic testing group （n＝51） and empirical treatment group （n＝17） based on whether they underwent CYP2C9 and VKORC1 gene test. The gene test group was given warfarin based on the predicted dose calculated by gene test， while the empirical treatment group was given warfarin by clinical doctors based on international normalized ratio （INR） experience， all patients were given warfarin once a day. Follow-up observation was conducted for 6 months to compare the effectiveness [time in therapeutic range（TTR）， the time required to reach INR for the first time， the incidence of embolic events， the incidence of INR＜1.5 events] and safety （the incidence of major and minor bleeding events，the incidence of INR＞3.5 events） of warfarin treatment between two groups of patients. According to whether the patient’s TTR was ≥60%， they were divided into TTR≥60% group （n＝20） and TTR＜60% group （n＝48）. Univariate and multivariate binary Logistic regression analysis were used to determine the factors affecting the anticoagulant effect of warfarin in patients. RESULTS The TTR of patients in the gene test group was significantly higher than that in the empirical treatment group （P＜0.05）. The incidence of INR＜1.5 events in the gene test group was significantly lower than in the empirical treatment group （P＜0.05）. The incidence of minor bleeding events and INR＞3.5 events in the gene test group were lower than in the empirical treatment group， but the difference was not statistically significant （P＞0.05）. The results of multivariate binary Logistic regression analysis showed that gene test was an independent protective factor for warfarin anticoagulant therapy [odds ratio （OR）＝10.842， 95% confidence interval （CI）： 1.211-27.037， P＝0.033]， and the combination of statins was an independent risk factor for warfarin anticoagulant therapy [OR＝0.196， 95%CI： 0.045-0.861， P＝0.031]. CONCLUSIONS Under the guidance of gene test， warfarin anticoagulation therapy for LVAD patients after implantation can improve TTR， shorten the anticoagulation target time， and has good safety； meanwhile， it should be noted that the combination of statins may enhance the anticoagulant effect of warfarin， thereby increasing the risk of bleeding in patients.

Objective To evaluate the bioequivalence and safety of two pyrazinamide tablets in healthy Chinese subjects.Methods An open,randomized,single-dose,two-sequence,two-cycle,double-cross trial design was used.All 48 healthy subjects(24 in fasting and 24 in fed trial)were randomized to receive a single oral dose of a 0.5 g pyrazinamide tablet(test or reference)per cycle.The plasma concentration of the drug was determined by liquid chromatography coupled to tandem mass spectrometry method.The pharmacokinetic parameters were calculated by WinNonlin v8.2,and the bioequivalence was evaluated by SAS 9.4.Results In the fasting group,the Cmax of the test and reference preparation of pyrazinamide tablets were(13.28±2.82)and(12.88±4.49)μg·mL-1,the AUC0-t were(139.17±26.58)and(138.63±28.92)h·μg·mL-1,the AUC0-∞ were(148.96±33.65)and(148.71±36.97)h·μg·mL-1 respectively.In the fed group,the Cmax of the test and reference preparation of pyrazinamide tablets were(11.89±1.96)and(11.99±1.92)μg·mL-1,the AUC0-t were(138.22±37.21)and(141.68±25.80)h·μg·mL-1,the AUC0-∞ were(152.20±32.41)and(151.04±28.05)h·μg·mL-,respectively.The 90％confidence intervals of Cmax,AUC0-t and AUC0-∞ geometric mean ratios of the test and reference preparation were all within 80.00％to 125.00％.The incidence of adverse events was 16.70％for both the test and reference preparation in the fasting group and 8.30％for both the test and reference preparation in the fed group,all of which were mild in severity.Conclusion The test and reference preparation of pyrazinamide tablets were bioequivalent,safe and well tolerated in healthy Chinese subjects under fasting and fed conditions.

Objective To observe the application effect of N-acetylcysteine in children with respiratory tract infection.Methods According to random number table method,children with respiratory tract infection were divided into control group and treatment group.The control group was given intravenous injection of ceftazidime(30-100 mg·kg-1,q12 h)on basis of routine symptomatic treatment,while treatment group was given aerosol inhalation of N-acetylcysteine solution(0.3 g∶3 mL,qd)on basis of control group.All patients were treated for 7 d.The clinical curative effect,remission time of symptoms,changes of chest X-ray,lung function[forced expiratory volume in 1 second(FEV1),tidal volume(VT),peak expiratory flow(PEF)],serum inflammatory factors,immune function and adverse drug reactions in the two groups were compared.Results In the trial,there were 28 cases excluded due to shedding and loss of follow-up,and there were 40 cases in treatment group and 52 cases in control group,respectively.After treatment,total clinical response rates in treatment group and control group were 92.50％(37 cases/40 cases)and 76.92％(40 cases/52 cases),the difference was statistically significant(P＜0.05).After treatment,disappearance time of fever in treatment group and control group were(2.96±0.65)and(4.83±0.81)d;remission time of cough were(5.58±1.08)and(7.45±1.24)d;remission time of asthma were(3.23±0.54)and(4.72±0.75)d;disappearance time of lung rales were(4.66±0.72)and(5.94±0.87)d;FEV1 were(2.26±0.25)and(1.79±0.21)L;VT were(13.76±1.32)and(10.27±1.17)mL·kg-1;PEF were(5.78±0.68)％and(4.92±0.62)％;levels of serum C-reactive protein(CRP)were(7.68±1.18)and(9.41±1.29)mg·L-1;levels of interleukin-6(IL-6)were(18.76±3.24)and(22.75±3.85)ng·mL-1;levels of tumor necrosis factor α(TNF-α)were(8.93±1.51)and(15.46±2.24)ng·mL-1;CD4+/CD8+were 1.35±0.29 and 1.20±0.30.There were statistically significant differences in the above indexes between the treatment group and the control group(all P＜0.05).In treatment group,there were 3 cases with nausea,1 case with vomiting and 1 case with diarrhea.In control group,there were 3 cases with vomiting and 2 cases with diarrhea.There was no significant difference in incidence of adverse drug reactions between treatment group and control group[12.50％(5 cases/40 cases)vs 9.62％(5 cases/52 cases),P＞0.05].Conclusion Curative effect of N-acetylcysteine combined with ceftazidime is significant in children with respiratory tract infection,which can effectively improve lung function,relieve airway inflammation and enhance immune function,with good safety.

Objective:The purpose of this study was to investigate the characteristics of distortion product otoacoustic emissions (DPOAE) in patients with auditory neuropathy (AN). The factors affecting DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate of first and last diagnosis in the natural course were analyzed.Methods:The sample was obtained from the Multicenter Study on Clinical Diagnosis and Intervention of AN (registration number: ChiCTR2100050125), and the diagnostic criteria for AN were based on the Chinese Clinical Practice Guidelines of Auditory Neuropathy (version 2022). Patients with bilateral AN who underwent 2 or more DPOAE tests were screened and divided into infant groups (≤3 years old) and non-infant groups (>3 years old) according to the age of detection, and the trend of DPOAE elicitation rate of each frequency, elicitation rate of each ear and change rate in the natural course of disease were analyzed, in order to explore the relevant influencing factors.Results:A total of 165 patients (330 ears) with AN were included in the study. The overall DPOAE elicitation rate per ear was 77.0%±29.4% at the initial diagnosis and 65.1%±35.2% at the final diagnosis, with a reduction observed in the elicitation rate of 171 ears (51.82%). In the infant group, there were 49 cases (98 ears), including 28 males and 21 females, whose found age ranged from 0 to 3 years old, with a median age of 0.7 years. DPOAE elicitation rate per ear was 57.9%±35.5% in the initial diagnosis, and 32.4%±32.1% in the final diagnosis, with a reduction observed in the elicitation rate of 69 ears (70.41%). In the non-infant group, there were 116 cases (232 ears), including 59 males and 57 females, ranging in found age from 3.9 to 40 years old, with a median age of 14 years old. DPOAE elicitation rate per ear was 84.6%±23.4% in the initial diagnosis, and 78.3%±27.1% in the final diagnosis, with a reduction observed in the elicitation rate of 102 ears (43.97%). Age was found to be correlated with DPOAE changes by multicategorical unordered logistic regression analysis ( B=-0.224, OR=0.799, P<0.001). Conclusions:The elicitation rate of DPOAE in AN patients decreases or even disappears with increasing disease duration; The rate of DPOAE extraction is found to be lower in infant patients with auditory neuropathy (AN) compared to non-infant AN patients. Additionally, it is observed that the decrease in DPOAE extraction rate is more pronounced in infant AN patients as the disease progressed, as compared to non-infant AN patients. DPOAE and cochlear microphonic potentials should be fully combined for accurate diagnosis, and regular follow-up should be conducted to understand the natural course of the disease and give personalized guidance and assistance.

Objective:To assess the association between short-term ambient air pollution exposure and arterial stiffness and whether obesity modifies these associations.Methods:A cross-sectional study was conducted based on Fangshan family cohort in Beijing. The 24 hours average air pollutant levels on the day cohort participants took baseline survey were calculated as short-term air pollution. A generalized additive model (GAM) with Gaussian links was used to estimate changes in typical carotid artery intima-media thickness (CIMT), brachial-ankle pulse wave velocity (BAPWV), pulse pressure (PP) and ankle-branchial index (ABI) after short-term exposure to each air pollution (PM 2.5, PM 10, SO 2, NO 2, CO). The cross-product terms of each air pollution, body mass index (BMI), and waist-to-hip ratio were included in the GAM model to test the interaction. Further, they conducted a stratified analysis to test their effects on the relationship between short-term exposure to each air pollution and the arterial stiffness indicators. Results:A total of 4 211 individuals were included in the analysis. Individuals' age was (58.9±8.7) years, of which 2 268 (53.9%) were female. Several covariates, including sociodemographic factors, lifestyle behaviors, and history of drugs, were included in the analysis. The results of the GAM analysis showed that an increase in PM 2.5 ( β=2.912×10 -4, 95% CI: 1.424×10 -4-4.400×10 -4, P<0.001), CO ( β=0.027, 95% CI: 0.011-0.043, P<0.001), SO 2 ( β=2.070×10 -3, 95% CI: 7.060×10 -4-3.430×10 -3, P=0.003), and NO 2 ( β=3.650×10 -4, 95% CI: 2.340×10 -5-7.060×10 -4, P=0.036) were associated with an increase in CIMT, while an increase in PM 10 ( β=0.018, 95% CI: 0.002-0.033, P=0.028) was associated with an increase in PP in the study population. Besides, the waist-to-hip ratio had an effect-modification on the correlation of short-term exposure of PM 2.5 (interaction P=0.015), NO 2 (interaction P=0.008), and CO (interaction P=0.044) with CIMT, and the correlation between short-term exposure of PM 2.5 (interaction P=0.002), NO 2 (interaction P=0.010), CO (interaction P=0.029), PM 10 (interaction P<0.001) with PP. The significant association between CIMT, PP, and air pollution concentrations was more visible in people with lower waist-to-hip ratios. Conclusions:Short-term ambient air pollution exposure was associated with arterial stiffness indicators, and there was an effect modification of waist-to-hip ratio on these associations, and lower waist-to-hip ratios may enhance the association between air pollution exposure and indicators.