Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Electromagnetic fields can regulate the fundamental biological processes involved in bone remodeling. As a non-invasive physical therapy, electromagnetic fields with specific parameters have demonstrated therapeutic effects on bone remodeling diseases, such as fractures and osteoporosis. Electromagnetic fields can be generated by the movement of charged particles or induced by varying currents. Based on whether the strength and direction of the electric field change over time, electromagnetic fields can be classified into static and time-varying fields. The treatment of bone remodeling diseases with static magnetic fields primarily focuses on fractures, often using magnetic splints to immobilize the fracture site while studying the effects of static magnetic fields on bone healing. However, there has been relatively little research on the prevention and treatment of osteoporosis using static magnetic fields. Pulsed electromagnetic fields, a type of time-varying field, have been widely used in clinical studies for treating fractures, osteoporosis, and non-union. However, current clinical applications are limited to low-frequency, and research on the relationship between frequency and biological effects remains insufficient. We believe that different types of electromagnetic fields acting on bone can induce various “secondary physical quantities”, such as magnetism, force, electricity, acoustics, and thermal energy, which can stimulate bone cells either individually or simultaneously. Bone cells possess specific electromagnetic properties, and in a static magnetic field, the presence of a magnetic field gradient can exert a certain magnetism on the bone tissue, leading to observable effects. In a time-varying magnetic field, the charged particles within the bone experience varying Lorentz forces, causing vibrations and generating acoustic effects. Additionally, as the frequency of the time-varying field increases, induced currents or potentials can be generated within the bone, leading to electrical effects. When the frequency and power exceed a certain threshold, electromagnetic energy can be converted into thermal energy, producing thermal effects. In summary, external electromagnetic fields with different characteristics can generate multiple physical quantities within biological tissues, such as magnetic, electric, mechanical, acoustic, and thermal effects. These physical quantities may also interact and couple with each other, stimulating the biological tissues in a combined or composite manner, thereby producing biological effects. This understanding is key to elucidating the electromagnetic mechanisms of how electromagnetic fields influence biological tissues. In the study of electromagnetic fields for bone remodeling diseases, attention should be paid to the biological effects of bone remodeling under different electromagnetic wave characteristics. This includes exploring innovative electromagnetic source technologies applicable to bone remodeling, identifying safe and effective electromagnetic field parameters, and combining basic research with technological invention to develop scientifically grounded, advanced key technologies for innovative electromagnetic treatment devices targeting bone remodeling diseases. In conclusion, electromagnetic fields and multiple physical factors have the potential to prevent and treat bone remodeling diseases, and have significant application prospects.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

OBJECTIVE To investigate the potential mechanism of berberine improving diabetes mellitus type 2 （T2DM） combined with metabolic-associated fatty liver disease （MAFLD） by regulating ceramide. METHODS Thirty-two db/db mice with blood glucose levels＞11.1 mmol/L （T2DM model） were divided into four groups： model group， berberine low- and high-dose groups [100， 200 mg/（kg·d）] and metformin group [300 mg/（kg·d）]， with 8 mice in each group. Additionally， 8 wt/wt mice were selected as the normal control group. Mice in each group were administered the corresponding drug solution or water by gavage once daily for a continuous period of 6 weeks. During the experiment， the body weight of the mice was monitored， and the differences in final body weight were analyzed. After the last administration， the body shape of the mice in each group was observed， and their fasting blood glucose （FBG） and the lipid indicators [total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）] were measured. Fasting serum insulin （FINS） levels were also measured， and the insulin resistance index HOMA-IR） and insulin sensitivity index （ISI） were calculated. Liver weight， liver index and serum liver function indicators [alanine transaminase （ALT）， aspartate transaminase（AST）] were assessed， and hepatic histopathological changes were observed. Additionally， the expression of fatty acid synthesis-related proteins [sterol regulatory element-binding protein 1 （SREBP1）， fatty acid synthase （FASN）， acetyl-CoA carboxylase 1 （ACC1）] in liver tissue was examined. Serum samples from the normal control group， model group， and berberine high-dose group were collected for non-targeted lipidomics analysis and validation. RESULTS Compared with the model group， the pathological changes， including disordered liver tissue cell arrangement and lipid vacuoles， were significantly improved in the berberine low- and high-dose groups. The significant decreases or down-regulations were observed in body weight in the last week， as well as FBG， TC， TG， and LDL-C levels， HOMA-IR （except for the berberine low-dose group）， liver weight， liver index， AST and ALT levels， and protein expressions of SREBP1， FASN and ACC1. Additionally， HDL-C levels， FINS （except for the berberine high-dose group）， and ISI （except for the berberine low-dose group） were significantly increased （P＜0.05）. A total of 21 potential differential metabolites， including multiple types of ceramides， were identified； these metabolites were primarily enriched in sphingolipid metabolism and glycerophospholipid metabolism pathways. Verification experiments confirmed that high-dose berberine significantly reduced the serum content of ceramide in model mice （P＜0.05）. CONCLUSIONS Berberine reduces insulin resistance， improves liver damage and lipid accumulation in the T2DM combined with MAFLD mice， and these effects may be related to the reduction of ceramide content.

Objective: To investigate the epidemic characteristics and trends in incidence of pulmonary tuberculosis (PTB) in Wenzhou City, Zhejiang Province from 2010 to 2024, so as to provide the basis for improving PTB prevention and control strategies. Methods: The PTB data in Wenzhou City from 2010 to 2024 were captured from the Surveillance System of China Information System for Disease Control and Prevention. Descriptive epidemiological methods were applied to analyze the characteristics across different genders, age, and regions. The average annual percent change (AAPC) was used to evaluate the trend in PTB incidence. Results: A total of 73 706 PTB cases were reported in Wenzhou City from 2010 to 2024, with an average annual reported incidence of 52.92/100 000. The reported incidence of PTB decreased from 75.33/100 000 in 2010 to 35.47/100 000 in 2024, showing a significant overall downward trend (AAPC=-5 .287%, P<0.05). The average annual reported incidence of PTB was higher in males than in females (70.45/100 000vs. 33.41/100 000, P<0.05). The trends in reported incidence for both males and females were generally consistent with the overall population, showing declining trends (AAPC=-4.992% and -6.112%, both P<0.05). The group aged ≥65 years had the highest average annual reported incidence of PTB at 91.73/100 000. From 2010 to 2024, significant declining trends were observed in the groups aged 15-<25, 25-<35, 35-<45, and 45-<55 years (AAPC=-8.599%, -7.975%, -9.007%, and -5.104%, all P<0.05). The average annual reported incidences of PTB in Taishun County, Longwan District, and Yongjia County were higher, at 81.08/100 000, 75.31/100 000, and 64.68/100 000, respectively. Except for Dongtou District, Pingyang County, and Taishun County, the reported incidences in all other counties (cities, districts) showed declining trends from 2010 to 2024, with AAPC values ranging from -9.056% to -3.791% (all P<0.05). Conclusions The reported incidence of PTB in Wenzhou City from 2010 to 2024 showed an overall declining trend, varying in genders, age, and regions. Males and individuals aged ≥65 years were the key populations for prevention and control. Taishun County, Longwan District, and Yongjia County were high-incidence areas.

Pseudorabies virus(PRV)is the etiological agent of pseudorabies in pigs,which is char-acterized by dyspnea,reproductive disorders,and neurological diseases,and it spreads widely a-round the world.Since 2011,the newly emerged PRV variants have resulted in poor immunity pro-tection of traditional vaccine strains,and the original method of vaccine strain preparation is time-consuming and labor-intensive.Therefore,it is urgently needed to develop an efficient screening method of the vaccine strain at present.Using CRISPR/Cas9 gene editing technology in this study,two single guide RNAs(sgRNA)were designed targeting the virulence gene TK of PRV variant strain CH/JX/2016,and then the enhanced green fluorescent protein the reporter(EGFP)gene was inserted at the TK locus by a homologous repair plasmid.After multiple rounds of plaque puri-fication,the rPRV-ΔTK/EGFP strain was obtained.The results showed the cleavage efficiency of the two sgRNAs was extremely high.The preparation of rPRV-ΔTK/EGFP strain was succeed af-ter only three rounds of purification,and the EGFP expressed normally.The CRISPR/Cas9 system can edit the PRV gene simply,rapidly,and efficiently,and exhibits great potential in the construction of vaccine candidate strains.Meanwhile,the rescued rPRV-ΔTK/EGFP strain not only could be used as a tracer strain in PRV variant infection progresses,but also for subsequent antivi-ral drug screening.

Objective:To systematically evaluate the methodological quality and reporting quality of randomized controlled tri-als(RCT)on the treatment of BPH with traditional Chinese medicine(TCM),in order to provide some methodological reference for clinical practice and research.Methods:We searched CNKI,VIP,Wanfang Data and PubMed for RCTs on the treatment of BPH with TCM published in China from January 2013 to November 2023.Two researchers screened the literature separately,and evaluated the methodological and reporting quality of the RCTs based on the Cochrane bias risk assessment tool and CONSORT TCM compound.Results:Totally,88 RCTs were included in this study.In terms of methodological quality,according to the Cochrane bias risk assess-ment tool,27 biases in the process of randomization were identified as of low-risk and the other 61 of a certain risk.Among the alloca-tion-related biases deviating from the established interventions,76 were of low risk,10 of a certain risk and 2 of high risk;among the compliance-related biases deviating from the established interventions,76 were of low risk and 12 of a certain risk;among the biases due to missing outcome data,86 were of low risk and 2 of a certain risk,while all the biases due to outcome measurement were of low risk;and among the biases from selective reporting,65 were of low-risk,2 of a certain risk and 21 of high-risk.In terms of reporting quality,according to the evaluation criteria of consort TCM compound,appropriate key words were used in 1 RCT(0.01％),the ran-dom assignment sequence method described in 27(30.68％),the details of assignment limitation given in 5(5.68％),assignment concealment mentioned in 3(3.41％),the blind method and assignment concealment employed in 3(3.41％),fall-offs recorded in 10(11.36％),adverse events reported in 38(43.18％),and limitations of the trials analyzed in 18(20.45％).All the RCTs lacked complete intervention measures,subject flow chart,clinical trial registration and research schemes.Conclusion:At present,the methodological quality and reporting quality of RCTs on the treatment of BPH with TCM are generally low,with the main problems of incomplete experimental designs,lack of detailed description of randomized and blind methods,and insufficient TCM symptom eval-uation of outcome indicators.Researchers should be cautious in adopting and applying the results reported,follow the CONSORT state-ment in design,registration,implement and reporting of the scheme,fully consider the clinical characteristics of TCM in the treatment of BPH,and reasonably design and report the evaluation indicators.

Objective:To evaluate the potential causal relationship between inflammatory factors and PCa using the two-sample Mendelian randomization(MR)method.Methods:We selected summary statistics of genome-wide association studies(GWAS)(n=14 824)on 91 inflammatory factors,with PCa as the outcome in the latest 9th edition of FinnGen database for MR analysis.We evaluated the causal relationship between inflammatory factors and PCa using the odds ratio(OR)and 95%confidence interval(CI)of such regression models as inverse variance weighting(IVW),MR-Egger regression,simple mode(SM),weighted mode(WM)and weighted median estimator(WME),with IVW as the main statistical method for this study.We further verified the results of MR by Bayesian analysis,and evaluated the heterogeneity of genetic instrumental variables,pleiotropic effects and sensitivity of single nu-cleotide polymorphisms(SNP)as instrumental variables to the exposure-outcome relationship by Cochran's Q test,MR-Egger intercept test and leave-one-out cross validation.Results:IVW showed that among the 91 inflammatory factors,interleukin-22 receptor A1(IL-22RA1)and sulfotransferase 1A1(ST1A1)were correlated positively with the risk of PCa;IL-22RA1:IVW(OR[95%CI]:1.12[1.00-1.25],P=0.04);ST1A1:IVW(OR[95%CI]:1.08(1.00-1.16),P=0.03),while Chemokine ligand 11(CXCL11)and interleukin 17 A(IL-17 A)negatively with the risk of PCa;CXCL11:IVW(OR[95%CI]:0.88[0.81-0.95],P=0.00);IL-17A:IVW(OR[95%CI]:0.91[0.84-0.98],P=0.02).No potential horizontal pleiotropy was detected by MR-Egger intercept analysis(P>0.05,IL-22RA1=0.885,ST1A1=0.949,CXCL11=0.391,IL-17A=0.884),nor biased SNPs in the MR pleiotropy residual sum and outlier(MR-PRESSO)test(P>0.05,IL-22RA1=0.479,ST1A1=0.629,CXCL11=0.326,IL-17A=0.444),or heterogeneity P>0.05,IL-22RA1=0.543,ST1A1=0.677,CXCL11=0.336,IL-17A=0.494).Leave-one-out sensitivity analysis indicated no significant impact of individual SNP sites on the overall causal rela-tionship prediction,suggesting the reliable results of analysis.Conclusion:Among the 91 inflammatory factors,IL-22RA1 and ST1A1 have a positive causal relationship,while CXCL11 and IL-17A have a negative causal relationship with PCa.

Objective:To study the mechanism of icariin inhibiting the proliferation of human PCa PC-3 cells based on cell metabolomics technology.Methods:We determined the proliferation activity of human PC-3 cells by methyl thiazolyl tetrazolium(MTT)assay,and compared the proliferation of the PC-3 cells among the control,5-fluorouracil and icariin intervention groups.Using the Bligh Dyer method,we extracted endogenous metabolites from the cells,analyzed the metabolic profile by ultra-high pressure liquid chromatography tandem quadrupole time-of-flight mass spectrometry,identified the differential metabolites by principal component anal-ysis and orthogonal partial least-squares discrimination analysis,and enriched the metabolic pathways based on the MetaboAnalyst data-base.Results:Icariin significantly inhibited the proliferation of human PCa PC-3 cells.A total of 89 differential metabolites were i-dentified,mainly including amino acids,phosphatidylcholine,phosphatidylethanolamine,lysophosphatidylcholine,and lysophosphati-dylethanolamine,all with the tendency to return to the normal level after icariin intervention.Icariin significantly downregulated the metabolic levels of the glycerophospholipid metabolites phosphatidylcholine,phosphatidylethanolamine,lysophosphatidylcholine and ly-sophosphatidylethanolamine,and upregulated those of amino acid metabolites tryptophan,leucine,and proline in the PC-3 cells.Conclusion:Icariin inhibits the proliferation of human PCa PC-3 cells,which may be closely related to its regulatory effect on lipid metabolism(glycerophospholipid metabolism)and amino acid metabolism.