Background/Aims: Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed. Methods: We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models. Results: ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis. Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.

OBJECTIVE To evaluate the long-term cost-effectiveness of canagliflozin or semaglutide in patients with type 2 diabetes mellitus（T2DM）poorly controlled with metformin. METHODS Based on the perspective of China’s health system， a Markov model was used to calculate the long-term costs and utilities of canagliflozin or semaglutide combined with metformin for T2DM patients in China for 30 years based on the data from SUSTAIN 8 study. The incremental cost-effectiveness ratio（ICER） and incremental net monetary benefit （INMB） were calculated using one time the 2024 per capita gross domestic product（GDP） as the willingness-to-pay（WTP） threshold. One-way sensitivity analysis， probability sensitivity analysis and scenario analysis were conducted to confirm the stability of the conclusions. RESULTS Compared with canagliflozin + metformin， ICER of semaglutide combined with metformin was 260 485.67 yuan/quality-adjusted life year （QALY），which was higher than the WTP threshold set in this study （95 749 yuan/QALY），and the corresponding INMB was －61 576.24 yuan，indicating that the canagliflozin + metformin regimen was more cost-effective. The cost of diabetes without complications treatment in the semaglutide + metformin group had the greatest influence on INMB，but changes in parameters within the selected range did not drive decision reversal. With the increasing of WTP threshold，the economic acceptability of semaglutide + metformin regimen increased. Under the current WTP threshold，the annual cost of semaglutide should be reduced by 42.95% to make the semaglutide + metformin regimen more cost- effective. CONCLUSIONS From the perspective of China’s health system， canagliflozin + metformin is more cost-effective than semaglutide + metformin for T2DM patients yueru. with poor glycemic control with metformin alone.

Objective: To evaluate the application of blood conservation measures in obstetric patients with different red blood cell transfusion volumes and to assess the impact of different transfusion volumes on postpartum outcomes. Methods: A retrospective investigation was conducted on 448 obstetric patients who received blood transfusions at the Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2016 to December 2022. Patients were divided into four groups (1-2 units group, 3-4 units group, 5-6 units group, and >6 units group) based on the volumes of red blood cells (RBCs) transfused during and within 7 days after delivery. The maternal physiological indicators, pre- and postpartum laboratory test indicators, obstetric complications, application of blood conservation measures, use of blood products, and postpartum outcomes were reviewed. The clinical characteristics, application of blood conservation measures, and their impact on postpartum outcomes were compared among different transfusion groups. Results: There were statistically significant differences in the multivariate logistic analysis of history of previous cesarean section (OR=1.781), eclampsia/pre-eclampsia/(OR=1.972) and postpartum blood loss>1 000 mL（OR=1.699）(P<0.05) among different transfusion groups. In terms of blood conservation measures, the more RBCs transfused, the higher the rate of mothers receiving blood conservation measures such as balloon occlusion, arterial ligation, autologous blood transfusion with a cell saver, and hysterectomy. With the increase in the volume of RBCs transfusion, the demand for fresh frozen plasma（FFP）, cryoprecipitate, and platelet transfusions also increased. The hospitalization days for the four groups of parturients were 6.0 (4.0-9.0), 7.5 (5.0-14.8), 7.0 (4.5-13.0) and 11.0 (9.0-20.5), respectively (P<0.05) and the rates of ICU transfer were 2.0% (5/250), 9.4% (12/128),18.2% (6/33) and 51.4% (19/37), respectively (P<0.05). Both increased significantly with the increase in the volume of RBCs transfusion, and the differences between groups were statistically significant. Conclusion: Parturients who received higher volume of RBCs had multiple risks factors for bleeding before childbirth, had higher postpartum blood loss, and had a higher rate of application of various blood conservation measures. In addition, an increase in the volume of RBCs transfusion may have adverse effects on postpartum recovery.

BACKGROUND:Surface electromyography has been extensively utilized for monitoring muscle fatigue. However,traditional electromyographic metrics typically focus on individual muscles and fail to assess the variations in a muscle group during the fatigue process. OBJECTIVE:To establish a muscle functional network to extract complex network parameters and investigate the topological property changes of the muscle functional network under different levels of fatigue,aiming to provide theoretical and methodological foundations for fatigue monitoring and prevention. METHODS:Eleven participants performed single-leg leg press exercise at 50％ of one-repetition maximum until exhaustion. Simultaneously,electromyographic signals of seven muscles (rectus femoris,vastus lateralis,vastus medialis,biceps femoris,tibialis anterior,lateral gastrocnemius,and medial gastrocnemius),electrocardiographic signals,and Borg CR-10 scale scores were collected. The Borg CR-10 scale was used to categorize three fatigue stages:mild,moderate,and severe. Heart rate and heart rate variability were calculated to validate the effective division of fatigue stages. Using the coherence of muscle signals,a muscle functional network was constructed with the seven muscles as nodes,and four complex network parameters (clustering coefficient,average weighted degree,global efficiency,and eigenvector centrality) were extracted. Additionally,four electromyographic indices (root mean square,median frequency,instantaneous mean frequency,and co-activation ratio) were extracted and compared under the three levels of fatigue. RESULTS AND CONCLUSION:(1) Differences in heart rate and heart rate variability were observed across three fatigue stages,indicating the effectiveness of fatigue stage delineation. (2) Electromyographic indicators for different muscles under three levels of fatigue:root mean square and co-activation ratio showed no differences;however,median frequency exhibited robust fatigue trends in vastus lateralis,vastus medialis,and biceps femoris,while instantaneous mean frequency demonstrated robust fatigue trends in rectus femoris,vastus lateralis,vastus medialis,and biceps femoris. Instantaneous mean frequency outperformed median frequency and root mean square,yet all three indicators showed robust trends only for the major working muscle groups,unaffected by fatigue factors,unlike the co-activation ratio. (3) The connectivity strength between vastus lateralis and vastus medialis,vastus lateralis and biceps femoris,vastus lateralis and gastrocnemius medialis,and vastus medialis and biceps femoris gradually increased,showing significant differences in average weighted degree,clustering coefficient,and global efficiency post-fatigue,significantly correlated with fatigue levels. To conclude,changes in connectivity strength reflect the synergy and complementarity among muscles during fatigue. Clustering coefficient,average weighted degree,and global efficiency serve as fatigue markers reflecting overall muscle changes.

Objective To establish a flow cytometry method for detecting C1s protein on platelet surface and preliminarily explore its potential application value in the auxiliary diagnosis of primary immune thrombocytopenia(ITP).Methods C1s-conjugated 2 μm car-boxylated magnetic beads(C1s beads)were prepared and used as quality control particles.Fluorescein isothiocyanate(FITC)-labeled anti-C1s antibody was employed as the detection antibody to develop a flow cytometric assay for detecting C1s protein expression on platelets.The intra-assay and inter-assay precision,as well as the dilution linearity of the method,were evaluated.Subsequently,the expression levels of C1 s protein on the surface of platelets were compared among the ITP group,the non-ITP thrombocytopenia group,and the healthy control group.Results Light microscopy showed that both unconjugated carboxylated magnetic beads(blank beads)and C1s-conjugated beads were uniformly dispersed without aggregation.Under fluorescence microscopy,C1s beads exhibited strong yellow-green fluorescence,whereas the blank beads showed no fluorescence signal.The established flow cytometry assay exhibited ac-ceptable precision,with intra-assay coefficient of variation(CV)values of 7.02％,7.12％,and 3.91％for low,medium,and high con-centrations of C1s beads,respectively,and inter-assay CV values of 13.49％,6.15％,and 0.78％,respectively.The dilution linearity was satisfactory,coefficient of determination(R2)=0.998 8.Clinical sample testing revealed that the proportion of C1s-positive plate-lets in ITP group(2.56±0.79)％was significantly higher than that in healthy control group(0.23±0.18)％and the non-ITP thrombo-cytopenia control group(0.22±0.10)％,with statistically significant differences(both P＜0.05).Conclusion This study successfully established a stable and reliable flow-cytometry method for quantifying C1s expression on platelet surface and preliminarily demonstrated that C1s expression is significantly elevated on platelets of ITP patients,suggesting that C1s could serve as a potential auxiliary diag-nostic marker for ITP.

Objective This study aimed to investigate the antimicrobial resistance profiles of bacterial strains isolated from pediatric intensive care units(PICU)in China for better antimicrobial therapy.Methods Clinical isolates were collected from 17 institutions,including tertiary care children's hospitals and pediatric department of tertiary general hospitals in China from January 1,2020 to December 31,2022.Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems.Results were interpreted according to the breakpoints released by the Clinical and Laboratory Standards Institute(CLSI)in 2020.Results A total of 10 688 isolates were collected,including gram-positive organisms(39.2％)and gram-negative organisms(60.8％).The top three organisms were S.aureus(13.6％,1 453/10 688),A.baumannii(10.0％,1 067/10 688),and coagulase-negative Staphylococcus(9.9％,1 058/10 688).Multi-drug resistant organisms(MDROs)were very common in children.The prevalence of methicillin-resistant Staphylococcus aureus(MRSA),carbapenem-resistant Enterobacterales(CRE),carbapenem-resistant E.coli,carbapenem-resistant K.pneumoniae(CRKP),carbapenem-resistant A.baumannii(CRAB),and carbapenem-resistant P.aeruginosa(CRPA)was 41.1％,19.4％,8.8％,30.9％,67.4％,and 28.8％,respectively.Overall,more than 50％of Enterobacteriales isolates were resistant to cephalosporins,while nearly 25％of Enterobacteriales isolates were resistant to carbapenems.MDROs were highly resistant to commonly used antibiotics.More than 80％of CRE and CRAB strains were resistant to all beta-lactam antibiotics.CRE and CRAB showed low resistance rates to tigecycline and polymyxin.CRPA showed lower resistance rates to piperacillin,beta-lactamase inhibitor combinations than the resistance rates to third and fourth generation cephalosporins.All of the Staphylococcus and Enterococcus isolates were susceptible to vancomycin and tigecycline.None of PRSP strains isolated from meningitis and nonmeningitis samples were resistant to rifampicin,vancomycin,or linezolid.The prevalence of β-lactamase-negative ampicillin-resistant(BLNAR)strains was 43.3％in Haemophilus influenzae.Conclusions MDROs were prevalent in PICU.It is necessary to establish an effective multidisciplinary team(MDT)to control the antimicrobial resistance.

Objective To investigate the protective effects of Ligilactobacillus salivarius Li01(L.salivarius Li01)against DNA damage induced by Helicobacter pylori(Hp),Benzo(a)pyrene(BaP),and Hp+BaP,and to evaluate the probiotic properties of L.salivarius Li01.Methods After 1 week of adaptive feeding,specific pathogen-free male Mongolian gerbils were randomly assigned to groups and subjected to intragastric administration of Hp,BaP,and Hp+BaP for model induction.At week 32 post model establishment,therapeutic L.salivarius Li01 was administered intragastrically.At week 36,peripheral blood samples were collected from each group for the comet assay,while liver tissues were collected and tested for Cyp1a1 gene expression levels.Results Compared with those in the control group,the comet tail length,％tail DNA,and hepatic Cyp1a1 expression levels were significantly increased in the Hp,BaP,and Hp+BaP groups(P＜0.0001).Among these,the comet tail length,olive tail moment,％tail DNA,and hepatic Cyp1a1 expression levels were significantly higher in the Hp+BaP group than in the Hp and BaP groups(P＜0.05).Following intervention with L.salivarius Li01,the comet tail length,olive tail moment,％tail DNA,and hepatic Cyp1a1 expression levels were significantly reduced in each group(P＜0.001).Conclusions Hp infection,BaP exposure,and the Hp+BaP combination induced DNA damage in the peripheral lymphocytes of Mongolian gerbils,with the Hp+BaP combination showing synergistic damage.L.salivarius Li01 had a protective effect against DNA damage caused by Hp,BaP,and Hp+BaP.

Objective The purpose of the study is to breed homozygous interferon-γ knockout(IFN-γ-/-)mice and optimize the breeding strategies to achieve continuous and stable reproduction of IFN-γ-/-mice,which could be used as an ideal animal model for fundamental research.Methods Initially,heterozygous IFN-γ knockout(IFN-γ+/-)C57BL/6J mice were used as the parental generation for breeding.Subsequently,3 breeding strategies were employed using the offspring:(1)female heterozygotes mated with male heterozygotes;(2)male homozygotes mated with female heterozygotes;(3)female homozygotes mated with male homozygotes.The number and survival rate of IFN-γ-/-mice were compared across the three breeding strategies to determine the optimal breeding strategy.Under the optimal strategy,the effects of female mating age and diet type on the reproductive performance of IFN-γ-/-mice were further evaluated.Data from the first three litters of 60 IFN-γ-/-female mice,including litter size,number of weaning survivors,and weaning survival rate,were recorded and analyzed.In addition,the effects of dietary supplementation of pregnant mice and environmental optimization measures,such as the provision of shelters,were evaluated.Results Under conditions where the nutritional needs of pregnant mice were adequately met by supplementation with egg yolk and sunflower seeds,mating of female and male IFN-γ-/-mice result ed in a litter size of five to eight IFN-γ-/-mice,demonstrating higher efficiency compared to other breeding strategies.In addition,diet type and mating age significantly influenced female reproductive performance.When 7～9 weeks old female IFN-γ-/-mice were mated to male IFN-γ-/-mice and fed a high-protein breeding diet,litter size(6.9±1.7),weaning survival number(6.5％±2.0％)and weaning survival rate(93.2％±17.8％)were higher than those under other conditions.In addition,providing shelters to prevent fighting between breeding pairs further improved reproductive outcomes.Conclusions By adopting an optimized breeding strategy,combined with a high-protein diet,nutritional supplementation,and standardized mating age management,the breeding efficiency and stability of IFN-γ-/-mice can be significantly improved.This provides a reliable animal model for related research.

Objective:To propose a functional method for locating the shoulder joint center of rotation aimed at rapid estimation of the upper limb reachable domain envelope, thereby informing ergonomic design and task optimization.Methods:In March 2024, shoulder kinematics during gait were recorded from ten adults using a three-dimensional motion-capture system. Assuming the existence of a point near the glenohumeral joint that maintains a fixed spatial relationship to the humerus and the acromion, we estimated both static and dynamic centers of rotation. Localization accuracy was quantified by the standard deviation of distance residuals to upper-arm markers. Upper-limb joint angles and anthropometric parameters were modeled via regression; combined with maximal joint ranges of motion, these were used to infer the reachable domain envelope.Results:The static center of rotation was located approximately twenty-two millimeters medial to the acromial landmark in the coronal plane and thirty-seven millimeters inferior to it. The standard deviation of the residuals for the distances from the dynamic shoulder joint center of rotation to upper-arm markers averaged 1.02 mm, which was 47.42% lower than that of the static center of rotation and 66.56% lower than that of the acromion. Moreover, the trajectory of this dynamic center showed a strong correlation with upper-limb joint angles ( R2>0.7) . Conclusion:The proposed method enables rapid and accurate estimation of the upper limb reachable domain envelope to support ergonomic design and may help reduce the risk of work-related musculoskeletal disorders.

Objective:To compare the diagnostic value of semi-quantitative parameters of fluorine 18-labelled prostate-specific membrane antigen( 18F-PSMA)positron emission tomography /computed tomography(PET/CT)and the Prostate-specific Membrane Antigen Reporting and Data System(PSMA-RADS)score for identifying benign and malignant oligo-PSMA-avid bone lesions(1-5 lesions)in elderly patients with prostate cancer. Methods:A retrospective analysis was conducted on 157 prostate cancer patients who underwent 18F-PSMA PET/CT examinations at Beijing Hospital from October 2022 to August 2024.According to the inclusion and exclusion criteria, a total of 63 patients were selected.All patients underwent 18F-PSMA PET/CT examination for the purpose of initial staging or detecting lesions with biochemical recurrence.PSMA-avid bone lesions were evaluated using the PSMA-RADS version 2.0 scoring system and the semi-quantitative parameters were measured on PSMA PET/CT images.According to the comprehensive diagnostic criteria, PSMA-avid bone lesions were divided into metastatic group and non-metastatic group.The differences in PSMA-RADS scores, semi-quantitative parameters, bone density abnormalities, and lesion distribution were compared between the two groups.Multivariate logistic regression analysis was performed to determine the factors related to the bone metastasis in prostate cancer.By plotting the receiver operating characteristic(ROC)curves and calculating the area under the curve(AUC), factors with better diagnostic performance were evaluated and screened, and the optimal diagnostic threshold for each factor in diagnosing bone metastasis was determined. Results:There were a total of 129 PSMA-avid bone lesions for 63 patients(aged 60-84 years, median age 69 years), including 35 lesions(27.1%)in the metastatic group and 94 lesions(72.9%)in the non-metastatic group.The differences between metastatic group and non-metastatic group in PSMA-RADS scores[5(4, 5) vs.3(3, 3)], maximum standardized uptake value(SUV max)[12.6(7.0, 18.4) vs.4.7(3.5, 5.9)], lesion SUV max/mediastinal blood pool SUV max ratio(lesion-to-blood pool ratio, LBR)[5.4(3.0, 8.3) vs.1.7(1.4, 2.2)], lesion SUV max/liver SUV max ratio(lesion-to-liver ratio, LLR)[2.6(1.6, 4.1) vs.0.8(0.7, 1.1)], PSMA receptor expressing tumor volume(PSMA-TV)[0.6(0.3, 1.0) vs.1.0(0.7, 1.5)], total lesion of PSMA(TL-PSMA)[4.4(2.4, 7.0) vs.2.4(1.7, 3.9)], proportion of changes in osteogenic bone density[77.1%(27/35) vs.2.1%(2/94)], proportion of lesions located in the ribs[14.3%(5/35) vs.46.8%(44/94)], and proportion of lesions located in the pelvis[54.3%(19/35) vs.20.2%(19/94)]were all statistically significant(all P<0.05). Multivariate logistic regression analysis indicated that none of the variables with statistically significant differences between groups above were independent risk factors for osseous metastasis in prostate cancer(all P>0.05). Among them, The PSMA-RADS score, LLR, LBR, and SUV max all had good diagnostic efficacy for osseous metastasis, with 0.995(95% CI: 0.987-1.000), 0.923(95% CI: 0.869-0.977), 0.898(95% CI: 0.828-0.967), and 0.890(95% CI: 0.820-0.961), respectively.The cut-off values for diagnosing osseous metastasis were 4 score for PSMA-RADS score, 0.934 for LLR, 1.990 for LBR, and 5.47 for SUV max, respectively.According to Delong's test, there were statistically significant differences in AUC between PSMA-RADS score and 18F-PSMA PET/CT semi-quantitative parameters(LLR, LBR, and SUV max)( Z-values were 2.677, 2.776, and 2.929, respectively, and P-values were 0.007, 0.006, and 0.003, respectively). Conclusions:The PSMA-RADS score(Version 2.0)and 18F-PSMA PET/CT semi-quantitative parameters(LLR, LBR, and SUV max)both have good diagnostic value in differentiating benign and malignant PSMA-avid bone lesions in elderly patients with prostate cancer, among which the PSMA-RADS score has the best diagnostic efficacy.