The continuous emergence of SARS-CoV-2 variants as well as other potential future coronavirus has challenged the effectiveness of current COVID-19 vaccines. Therefore, there remains a need for alternative antivirals that target processes less susceptible to mutations, such as the formation of six-helix bundle (6-HB) during the viral fusion step of host cell entry. In this study, a novel high-throughput screening (HTS) assay employing a yeast-two-hybrid (Y2H) system was established to identify inhibitors of HR1/HR2 interaction. The compound IMB-9C, which achieved single-digit micromolar inhibition of SARS-CoV-2 and its Omicron variants with low cytotoxicity, was selected. IMB-9C effectively blocks the HR1/HR2 interaction in vitro and inhibits SARS-CoV-2-S-mediated cell-cell fusion. It binds to both HR1 and HR2 through non-covalent interaction and influences the secondary structure of HR1/HR2 complex. In addition, virtual docking and site-mutagenesis results suggest that amino acid residues A930, I931, K933, T941, and L945 are critical for IMB-9C binding to HR1. Collectively, in this study, we have developed a novel screening method for HR1/HR2 interaction inhibitors and identified IMB-9C as a potential antiviral small molecule against COVID-19 and its variants.

Objective:To investigate the effect and mechanism of ginkgo acid(GA)on hepatic fibrosis in rats.Methods:CCl4 and TAA were used to construct rat liver fibrosis model,and GA or combined ferroptosis inhibitor(Fer-1)was given to intervene.The liver tissue and serum of rats were obtained and histopathologically evaluated by HE,Masson and Sirius red staining,respecively.The expression of HA,LN,Ⅳ-C and PC-Ⅲ in serum were detected by Elisa and the expression of GPX4 and FTH1 were detected by Western blot.Results:HE staining showed that,com-pared with TAA and CCl4 groups,the fibrosis level of GA group was significantly decreased.The results of Masoon and Sirius red staining showed that compared with TAA and CCl4 groups,the rate of collagen fibers in liver of GA group was significantly decreased(P＜0.05).Elisa results showed that compared with TAA and CCl4 groups,the levels of HA,LN,Ⅳ-C and PC-Ⅲ in serum of rats in GA group were significantly decreased(P＜0.05).After the intervention of GA com-bined with Fer-1,Western blot results showed that compared with TAA and CCl4 groups,the expression of GPX4 and FTH1 in liver of rats in GA group were significantly increased(P＜0.05).Compared with GA group,GPX4 and FTH1 levels in Fer group were significantly decreased(P＜0.05);The histopathological results showed that compared with GA group,the rate of liver collagen fibers in Fer group was significantly increased(P＜0.05).Conclusion:GA has anti-hepatic fi-brosis effect,which is associated with inducing ferroptosis.

Objective:To investigate the effect and mechanism of ginkgo acid(GA)on hepatic fibrosis in rats.Methods:CCl4 and TAA were used to construct rat liver fibrosis model,and GA or combined ferroptosis inhibitor(Fer-1)was given to intervene.The liver tissue and serum of rats were obtained and histopathologically evaluated by HE,Masson and Sirius red staining,respecively.The expression of HA,LN,Ⅳ-C and PC-Ⅲ in serum were detected by Elisa and the expression of GPX4 and FTH1 were detected by Western blot.Results:HE staining showed that,com-pared with TAA and CCl4 groups,the fibrosis level of GA group was significantly decreased.The results of Masoon and Sirius red staining showed that compared with TAA and CCl4 groups,the rate of collagen fibers in liver of GA group was significantly decreased(P＜0.05).Elisa results showed that compared with TAA and CCl4 groups,the levels of HA,LN,Ⅳ-C and PC-Ⅲ in serum of rats in GA group were significantly decreased(P＜0.05).After the intervention of GA com-bined with Fer-1,Western blot results showed that compared with TAA and CCl4 groups,the expression of GPX4 and FTH1 in liver of rats in GA group were significantly increased(P＜0.05).Compared with GA group,GPX4 and FTH1 levels in Fer group were significantly decreased(P＜0.05);The histopathological results showed that compared with GA group,the rate of liver collagen fibers in Fer group was significantly increased(P＜0.05).Conclusion:GA has anti-hepatic fi-brosis effect,which is associated with inducing ferroptosis.

Objective To investigate the clinical effect of anterior cervical discectomy and fusion(ACDF)in the treatment of cervical spondylosis of vertebral artery type(CSA).Methods The clinical data of 42 patients with CSA from January 2020 to January 2022 were retrospectively analyzed.There were 25 males and 17 females,aged from 30 to 74 years old with an average of(53.9±11.0)years old.There were 18 cases with single-segment lesions,17 cases with two-segment lesions,and 7 cases with three-segment lesions.The American Academy of Otolaryngology-Head and Neck Surgery's Hearing and Balance Committee score(CHE),the Neck Disability Index(NDI)and the cervical curvature Cobb angle were recorded before surgery and after surgery at 6 months.Results All 42 ACDF patients were followed up for 6 to 30 months with an average of(14.0±5.2)months.The operative time ranged from 95 to 220 min with an average of(160.38±36.77)min,the intraoperative blood loss ranged from 30 to 85 ml with an average of(53.60±18.98)ml.Tow patients had mild postoperative dysphagia,which improved with symptomatic treatment such as nebulized inhalation.CHE score decreased from(4.05±0.96)preoperatively to(2.40±0.70)at 6 months postoperatively(t=12.97,P＜0.05).The number of improved vertigo at 6 months postoperatively was 38,with an im-provement rate of 90.5％.NDI score was reduced from(34.43±8.04)preoperatively to(20.76±3.91)at 6 months postopera-tively(t=1 1.83,P＜0.05).The cervical curvature Cobb angle improved from(8.04±6.70)° preoperatively to(12.42±5.23)° at 6 months postoperatively(t=-15.96,P＜0.05).Conclusion The ACDF procedure has outstanding clinical efficacy in treating CSA.The operation can rapidly relieve patients'episodic vertigo symptoms by relieving bony compression and reconstructing cervical curvature.However,it is necessary to strictly grasp the indications for surgery and clarify the causes of vertigo in pa-tients,and ACDF surgery is recommended for CSA patients for whom conservative treatment is ineffective.

Background::Breast cancer (BC) risk-stratification tools for Asian women that are highly accurate and can provide improved interpretation ability are lacking. We aimed to develop risk-stratification models to predict long- and short-term BC risk among Chinese women and to simultaneously rank potential non-experimental risk factors.Methods::The Breast Cancer Cohort Study in Chinese Women, a large ongoing prospective dynamic cohort study, includes 122,058 women aged 25-70 years old from the eastern part of China. We developed multiple machine-learning risk prediction models using parametric models (penalized logistic regression, bootstrap, and ensemble learning), which were the short-term ensemble penalized logistic regression (EPLR) risk prediction model and the ensemble penalized long-term (EPLT) risk prediction model to estimate BC risk. The models were assessed based on calibration and discrimination, and following this assessment, they were externally validated in new study participants from 2017 to 2020.Results::The AUC values of the short-term EPLR risk prediction model were 0.800 for the internal validation and 0.751 for the external validation set. For the long-term EPLT risk prediction model, the area under the receiver operating characteristic curve was 0.692 and 0.760 in internal and external validations, respectively. The net reclassification improvement index of the EPLT relative to the Gail and the Han Chinese Breast Cancer Prediction Model (HCBCP) models for external validation was 0.193 and 0.233, respectively, indicating that the EPLT model has higher classification accuracy.Conclusions::We developed the EPLR and EPLT models to screen populations with a high risk of developing BC. These can serve as useful tools to aid in risk-stratified screening and BC prevention.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Background/Aims: Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. Methods: We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan’s cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray’s cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Results: Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Conclusions Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

Traditional Chinese medicine Scrophulariae Radix, which is also called Yuan Shen, black Shen, is the dried root of Scrophularia ningpoensis of the Scrophulariaceae family. Research has indicated that the chemical constituents of Scrophulariae Radix mainly include terpenoids, phenylpropanoids, organic acids, volatile oils, steroids, sugars, flavonoids, alkaloids and phenols, among which iridoids and phenylpropanoids were the main active constituents. It has been reported that extracts of Scrophulariae Radix or its active substances have anti-inflammatory, antioxidant, hepatoprotective, anti-tumor, anti-fatigue, uric acid-lowering, anti-depression, myocardial cell-protective and other pharmacological activities, and can regulate cardiovascular system, central nervous system and immune system. This paper reviewed the present research achievements of Scrophulariae Radix in chemical constituents, pharmacological activities, processing methods, toxicity and other aspects, and the clinical application of Scrophulariae Radix in ancient and modern times was illustrated. This paper aimed to provide reference for further research of Scrophulariae Radix and facilitated its clinical application.
Medicine, Chinese Traditional ; Drugs, Chinese Herbal/chemistry* ; Chromatography, High Pressure Liquid ; Plant Roots/chemistry* ; Scrophularia/chemistry*

Acute hepatitis C virus (HCV) infection is a global health concern with substantial geographical variation in the incidence rate. People who have received unsafe medical procedures, used injection drugs, and lived with human immunodeficiency virus are reported to be most susceptible to acute HCV infection. The diagnosis of acute HCV infection is particularly challenging in immunocompromised, reinfected, and superinfected patients due to difficulty in detecting anti-HCV antibody seroconversion and HCV ribonucleic acid from a previously negative antibody response. With an excellent treatment effect on chronic HCV infection, recently, clinical trials investigating the benefit of direct-acting antivirals (DAAs) treatment for acute HCV infection have been conducted. Based on the results of cost-effectiveness analysis, DAAs should be initiated early in acute HCV infection prior to spontaneous viral clearance. Compared to the standard 8–12 week-course of DAAs for chronic HCV infection, DAAs treatment duration may be shortened to 6–8 weeks in acute HCV infection without compromising the efficacy. Standard DAA regimens provide comparable efficacy in treating HCV-reinfected patients and DAA-naïve ones. For cases contracting acute HCV infection from HCV-viremic liver transplant, a 12-week course of pangenotypic DAAs is suggested. While for cases contracting acute HCV infection from HCV-viremic non-liver solid organ transplants, a short course of prophylactic or pre-emptive DAAs is suggested. Currently, prophylactic HCV vaccines are unavailable. In addition to treatment scale-up for acute HCV infection, practice of universal precaution, harm reduction, safe sex, and vigilant surveillance after viral clearance remain critical in reducing HCV transmission.