BACKGROUND:Studies have shown that rheumatoid arthritis and osteoporosis are positively correlated,but the causal relationship and related mechanisms have not yet been confirmed.With the cross-fertilization of computer science and life sciences,Mendelian randomization and bioinformatics analyses based on genome-wide association study(GWAS)and transcriptome sequencing data can assess the causal relationship between two diseases,explore the related mechanisms,and mine the therapeutic targets,which will be beneficial to the precision treatment of rheumatoid arthritis combined with osteoporosis.OBJECTIVE:To explore the causal relationship between rheumatoid arthritis and osteoporosis using two-sample Mendelian randomization and to mine potential co-morbid targets and potential targeted drugs through summary-data-based Mendelian randomization and bioinformatics analyses,aiming to provide theoretical basis for mechanism exploration and precision treatment in the field of rheumatoid arthritis combined with osteoporosis.METHODS:(1)Firstly,GWAS data of rheumatoid arthritis,osteoporosis,and cis-expression quantitative trait locus(cis-eQTL)in Asian and European populations were downloaded from the GWAS Catalog,IEU Open GWAS,FinnGen,and eQTLGen databases,and were used for two-sample Mendelian randomization analysis and summary-data-based Mendelian randomization analysis.(2)Transcriptome sequencing data of rheumatoid arthritis(GSE93272 and GSE15573)were downloaded from the GEO database for bioinformatics analysis.(3)Subsequently,forward and inverse Mendelian randomization analyses between rheumatoid arthritis and osteoporosis were performed,and inverse variance weighted was used as the main metric for the analyses,and the results were corroborated with MR Egger,simple mode,weighted median and weighted mode.(4)Then,the genes closely related to rheumatoid arthritis and osteoporosis were identified based on the summary-data-based Mendelian randomization analysis,and the co-disease targets of rheumatoid arthritis and osteoporosis were mined based on cross-analysis.Meanwhile,the biological functions of the co-morbid targets were verified based on bioinformatics analysis and cellular experiments.(5)In addition,a rheumatoid arthritis risk prediction nomogram was constructed based on DYRK2,and its prediction performance was verified by receiver operating characteristic curve,correction curve and decision curve.Finally,the target potential drugs were mined based on Enrichr database and molecular docking was performed.RESULTS AND CONCLUSION:(1)Forward Mendelian randomization analysis of rheumatoid arthritis and osteoporosis showed statistically significant results except for GCST90044540 and GCST90086118,and all other results indicated a significant causal relationship and positive correlation between rheumatoid arthritis and osteoporosis.(2)Inverse Mendelian randomization analysis suggested that no significant causal relationship was seen between osteoporosis and rheumatoid arthritis.(3)Summary-data-based Mendelian randomization analysis identified a total of 412 and 344 genes positively associated with rheumatoid arthritis and osteoporosis,and 421 and 347 genes negatively associated.Based on the cross-analysis,26 co-morbid genes were subsequently obtained.Among them,DYRK2 was a potential therapeutic target,and subsequent bioinformatics analysis and cellular experiments confirmed its important role in the progression of rheumatoid arthritis and osteoporosis.(4)Furthermore,the constructed nomogram has excellent predictive performance.Finally,four potential DYRK2-targeting drugs(undecanoic acid,metyrapone,JNJ-38877605,and ACA)were discovered and molecular docking also demonstrated reliable targeting ability.(5)In conclusion,based on GWAS data from Asian and European populations,we successfully demonstrated that rheumatoid arthritis and osteoporosis are causally related at the genetic level,DYRK2 is a potential therapeutic target,and four small molecules are potential target drugs.

BACKGROUND:Studies have shown that rheumatoid arthritis and osteoporosis are positively correlated,but the causal relationship and related mechanisms have not yet been confirmed.With the cross-fertilization of computer science and life sciences,Mendelian randomization and bioinformatics analyses based on genome-wide association study(GWAS)and transcriptome sequencing data can assess the causal relationship between two diseases,explore the related mechanisms,and mine the therapeutic targets,which will be beneficial to the precision treatment of rheumatoid arthritis combined with osteoporosis.OBJECTIVE:To explore the causal relationship between rheumatoid arthritis and osteoporosis using two-sample Mendelian randomization and to mine potential co-morbid targets and potential targeted drugs through summary-data-based Mendelian randomization and bioinformatics analyses,aiming to provide theoretical basis for mechanism exploration and precision treatment in the field of rheumatoid arthritis combined with osteoporosis.METHODS:(1)Firstly,GWAS data of rheumatoid arthritis,osteoporosis,and cis-expression quantitative trait locus(cis-eQTL)in Asian and European populations were downloaded from the GWAS Catalog,IEU Open GWAS,FinnGen,and eQTLGen databases,and were used for two-sample Mendelian randomization analysis and summary-data-based Mendelian randomization analysis.(2)Transcriptome sequencing data of rheumatoid arthritis(GSE93272 and GSE15573)were downloaded from the GEO database for bioinformatics analysis.(3)Subsequently,forward and inverse Mendelian randomization analyses between rheumatoid arthritis and osteoporosis were performed,and inverse variance weighted was used as the main metric for the analyses,and the results were corroborated with MR Egger,simple mode,weighted median and weighted mode.(4)Then,the genes closely related to rheumatoid arthritis and osteoporosis were identified based on the summary-data-based Mendelian randomization analysis,and the co-disease targets of rheumatoid arthritis and osteoporosis were mined based on cross-analysis.Meanwhile,the biological functions of the co-morbid targets were verified based on bioinformatics analysis and cellular experiments.(5)In addition,a rheumatoid arthritis risk prediction nomogram was constructed based on DYRK2,and its prediction performance was verified by receiver operating characteristic curve,correction curve and decision curve.Finally,the target potential drugs were mined based on Enrichr database and molecular docking was performed.RESULTS AND CONCLUSION:(1)Forward Mendelian randomization analysis of rheumatoid arthritis and osteoporosis showed statistically significant results except for GCST90044540 and GCST90086118,and all other results indicated a significant causal relationship and positive correlation between rheumatoid arthritis and osteoporosis.(2)Inverse Mendelian randomization analysis suggested that no significant causal relationship was seen between osteoporosis and rheumatoid arthritis.(3)Summary-data-based Mendelian randomization analysis identified a total of 412 and 344 genes positively associated with rheumatoid arthritis and osteoporosis,and 421 and 347 genes negatively associated.Based on the cross-analysis,26 co-morbid genes were subsequently obtained.Among them,DYRK2 was a potential therapeutic target,and subsequent bioinformatics analysis and cellular experiments confirmed its important role in the progression of rheumatoid arthritis and osteoporosis.(4)Furthermore,the constructed nomogram has excellent predictive performance.Finally,four potential DYRK2-targeting drugs(undecanoic acid,metyrapone,JNJ-38877605,and ACA)were discovered and molecular docking also demonstrated reliable targeting ability.(5)In conclusion,based on GWAS data from Asian and European populations,we successfully demonstrated that rheumatoid arthritis and osteoporosis are causally related at the genetic level,DYRK2 is a potential therapeutic target,and four small molecules are potential target drugs.

OBJECTIVE To investigate the mechanism of Xibining Ⅱ formula in alleviating synovial inflammation and fibrosis in knee osteoarthritis （KOA） rats based on Janus kinase 2 （JAK2）/signal transducer and activator of transcription 3 （STAT3） pathway. METHODS Seventy-five male SD rats were randomly divided into sham operation group （Sham group）， KOA group， Xibining Ⅱ low-dose group （XBNⅡ-L group， 4 g/kg）， Xibining Ⅱ high-dose group （XBNⅡ-H group， 8 g/kg）， and Xibining Ⅱ high-dose combined with STAT3 activator Colivelin trifluoroacetate （C-TFA） group [C-TFA group， 8 g/kg Xibining Ⅱ+ 1.0 mg/（kg·d） C-TFA]， with 15 rats in each group. Except for the Sham group， the KOA model was established by anterior cruciate ligament transection in the other groups. After successful modeling， each group was given corresponding drugs by intragastric administration and （or） intraperitoneal injection once daily for 28 consecutive days. After the last medication， the pathological changes of synovial tissue of knee joint in each group were evaluated and the indicators were calculated. The levels of serum inflammatory factors were detected. The positive expressions of phosphorylated JAK2 （p-JAK2） and phosphorylated STAT3 （p-STAT3） in synovial tissue of the knee joint were detected. The expressions of JAK2/STAT3 pathway-related proteins and mRNAs in synovial tissue were detected. RESULTS Compared with the Sham group， the synovial lining cells in the KOA group showed significant proliferation and disordered arrangement； the Krenn score， fibrosis ratio， positive area percentage of p-JAK2 and p-STAT3， p-JAK2/JAK2 and p-STAT3/STAT3， protein expression of Collagen-Ⅰ and α -smooth muscle actin， the mRNA expression of JAK2， STAT3， Collagen-Ⅰ and α -smooth muscle actin， as well as serum levels of interleukin-1β and interleukin-18 were significantly increased （ P ＜0.05）. Compared with the KOA group， the above pathological changes were significantly improved in each dose group of Xibining Ⅱ formula， and all indicators were significantly decreased （ P ＜0.05）， with the XBNⅡ-H group showing better effects than the XBNⅡ-L group （ P ＜0.05）. Compared with the XBNⅡ-H group， the above pathological damages were aggravated in the C-TFA group， and all indicators were significantly worsened （ P ＜0.05）. CONCLUSIONS Xibining Ⅱ formula can alleviate synovial inflammation and fibrosis in KOA rats， and its mechanism may be related to inhibiting the activation of JAK2/STAT3 pathway.

A mounting body of research suggests that circRNAs significantly contribute to the develop-ment of myocardial fibrosis.The microarray results of human circular RNA expression profile indicated that circHERC4_041 expression increased in the myocardium of patients with heart failure,RT-qPCR a-nalysis confirmed that the myocardial expression level of circHERC4_041 in individuals with heart failure were considerably elevated compared to that in healthy organ donors.Fluorescence in situ hybridization(FISH)confirmed that circHERC4_041 was abundant in the cytoplasm of human cardiomyocyte AC16.Overexpression of circHERC4_041 in mouse myocardial fibroblasts(mCFs)mediated by adenovirus in-hibited the expression of fibrosis-related proteins in mCFs.Experiments involving cell proliferation,wound healing,and Transwell assays demonstrated that overexpression of circHERC4_041 suppressed the growth and mobility of mCFs(P＜0.001).Sequence analysis results suggested that circHERC4_041 con-tains potential ribosome entry sequence(IRES)and open reading frame(ORF).Western blot confirmed that circHERC4_041 could translate the 516 amino acid HERC4-516aa protein,which was mainly located in the cytoplasm of the cell.Cell functional experiments confirmed that circHERC4_041 inhibited the fi-brotic phenotype of mCFs by specifically translating HERC4-516aa(P＜0.05).The specific interaction between HERC4-516aa and transglutaminase 2(TGM2)was confirmed by IP-MS screening and Co-IP i-dentification.Further results found that the degradation of TGM2 was promoted through proteasome path-way.The overexpression of TGM2 in mCFs facilitated by adenoviral vectors could counteract the suppres-sive effects of HERC4-516aa on the fibrotic phenotype of mCFs.Therefore,this study confirmed that the HERC4-516aa protein translated by circHERC4_041 can specifically bind to TGM2 to inhibit the fibrotic phenotype of myocardial fibroblasts.

Aim To establish and evaluate an alternative meth-od for detecting skin sensitization of cosmetics based on local lymph node assay using bromodeoxyuridine(BrdU)with flow cytometry(FCM).Methods(1)25％hexyl cinnamic alde-hyde(HCA)was chosen as a positive control with an acetone:olive oil(4∶1,V/V,AOO)mixture as a vehicle control for the experiment.The dorsal sides of both ears of mice were treated with test solutions on day 1,day 2,and day 3.Brdu solution was injected inter-peritoneally on day 5.On day 6,the bilateral ears and mandibular lymph nodes were excised,and the number of Brdu positive cells was measured by flow cytometry.The stim-ulation index(SI)was calculated to identify whether it was ≥3,in order to establish the method of LLNA:Brdu-FCM.(2)BrdU-FCM test was conducted using a blind method with the fif-teen reference substances listed in OECD TG429 whose skin sensitization potentials were known.The test substances were dissolved in AOO,N,N-dimethylformamide(DMF)or dimeth-yl sulfoxide(DMSO)at three different concentrations.Tests were performed the same as above.SI and EC2.7 were calculat-ed to evaluate whether the test substance was categorized as a skin sensitizer.The reliability and accuracy of the method were validated by comparing the classification of test substances with that in OECD TG429.Results The SI for 25％HCA was 3.9,showing positive in the skin sensitization test.It demonstrated that the LLNA:Brdu-FCM test method was properly implemen-ted.Nine test substances(2,4-dinitrochlorobenzene,4-pheny-lenediamine,cobalt chloride,2-mercaptobenzothiazole,hexyl-cinnamaldehyde,eugenol,phenyl benzoate,cinnamic alcohol,imidazolidinyl urea)were positive,and six test substances(methyl methacrylate,chlorobenzene,isopropanol,lactic acid,methyl salicylate,salicylic acid)were negative.The method was evaluated with sensitivity of 90％,specificity of 100％,positive prediction rate of 100％,negative prediction rate of 83％,false positive rate of 0％,false negative rate of 17％and accuracy of 93％.The LLNA:BrdU-FCM assay could correctly categorize the test substances that were skin sensitizers or non-sensitizers.Conclusion The LLNA:BrdU-FCM assay appears to be a relia-ble predictor of skin sensitization protential of chemicals,and it is expected to an alternative method for identifying skin sensitization as a supplementary in safety evaluation of cosmetic ingredient.

This consensus was developed by the Orthodontic Society of the Chinese Stomatological Association to provide a systematic, scientific, and practical guideline for informed consent in orthodontic care. Orthodontic treatment is typically lengthy, highly individualized, and involves multiple factors such as growth and development, occlusal function, and facial esthetics. Rapid technological advances and diverse risk profiles make the traditional reliance on orthodontist experience or institutional templates insufficient to ensure patients′ full understanding and autonomous decision-making. To address this, the expert panel conducted extensive reviews of domestic and international guidelines, analyzed representative dispute cases, and performed multicenter patient-clinician surveys. Using a multi-round Delphi method, the group established a standardized informed consent framework covering the initial consultation, treatment, and retention phases. The consensus emphasizes that informed consent is not only a fundamental legal and ethical requirement but also a key step in building trust, improving patient compliance, and enhancing treatment satisfaction. Orthodontists should clearly and comprehensively explain treatment plans, potential risks, uncertainties, and associated costs, while respecting the autonomy of patients or guardians, and maintain continuous communication and dynamic evaluation throughout the treatment process. The release of this consensus provides unified and authoritative guidance for clinical orthodontics, helping to standardize informed consent, enhance its transparency, safeguard patient rights, reduce medical risks, and promote high-quality, sustainable development of orthodontic practice.

Objective To investigate the association between triglyceride-glucose(TyG)index and the prevalence of gallstones in women,and to assess whether it can be used as a convenient indicator for the epidemiological survey of gallstones in women.Methods A total of 22 979 adult women who underwent physical examination in Subei People's Hospital of Jiangsu from January 2021 to June 2023 were enrolled,and according to the results of abdominal color Doppler ultrasound,they were divided into gallstone group with 1 763 women and non-gallstone group with 21 216 women.The independent samples t-test was used for comparison of normally distributed continuous data between groups,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups;the chi-square test was used for comparison of categorical data between groups.The multivariate logistic regression analysis,the restricted cubic spline analysis,the subgroup analysis,and mediating effect were used to investigate the association between TyG index and the risk of gallstones in women.Results The overall prevalence rate of gallstones was 7.7％in women.Compared with the non-gallstone group,the gallstone group had significantly higher age,BMI,FPG,TG,TyG index,TC,Hb,BUN,UA,SCr,TC,and LDL-C(all P<0.05),and the women with diabetes,fatty liver,hypertension,and hyperuricemia were more likely to have gallstones(all P<0.05).The multivariate logistic regression analysis showed that based on the quartiles of TyG index,the risk of gallstones in the Q3(8.97-9.38)group was 1.38(95％confidence interval[CI]:1.15-1.62,P<0.001)times that in the Q1(<8.63)group,and the risk of gallstones in the Q4(≥9.38)group was 1.39(95％CI:1.16-1.68,P<0.001)times that in the Q1 group.After adjustment for all covariates,TyG index,as a continuous variable,showed an independent positive correlation with the risk of gallstones(odds ratio[OR]=1.24,95％CI:1.11-1.39,P=0.004).The restricted cubic spline curve revealed a significant nonlinear association between TyG index and the risk of gallstones(P for non linear=0.008),and the threshold analysis showed statistical significance in the effect of TyG index below the inflection point of 8.95(OR=1.34,95％CI:1.15-1.97,P=0.042).The subgroup analysis showed that TyG index was significantly positively correlated with gallstones in women with a BMI of<25 kg/m2,an age of<50 years,an age of≥50 years,the absence of diabetes or fatty liver,total cholesterol<5.72 mmol/L,total bilirubin<21 μmol/L,a hemoglobin level of 110-150 g/L,and blood urea nitrogen<7.5 μmol/L(all P<0.05).A mediating analysis was performed for the subgroups with a statistically significant P value for interaction,and the results showed that BMI accounted for 23.0％of the mediating effect in the influence of TyG index on gallstones,and fatty liver and diabetes accounted for 15.7％and 21.0％,respectively.Conclusion In women,a higher TyG index indicates a higher risk of gallstones.Lowering TyG index may reduce the risk of gallstones by improving insulin sensitivity.

Objective To evaluate the recognition capability of AI-enabled Cellsee CS-BM1 automatic cell morphology analyzer for pe-ripheral blood smears and its roles in assisting manual classification,and explore the application value of AI system in the diagnosis network of tiered primary medical units.Methods The blood samples which triggered the re-examination rules were collected from six primary medical units,including the Laboratory Department of Shanghai Jiahui International Hospital,and so on,from March to No-vember 2023.The smears of peripheral blood were prepared and AI analyzer was used for pre-classification to evaluate its recognition performance in identifying the samples with abnormal WBC and RBC.The sensitivity,specificity,and accuracy of WBC classification by six junior and intermediate technicians,both with and without AI assistance,were analyzed.Additionally,the roles of the AI system in tiered diagnosis of primary medical units were also evaluated.Results The sensitivity,specificity,and accuracy of AI system in recognizing malignant primitive cells were 92.86％,95.16％,and 95.10％,respectively.The sensitivities of AI system in recognizing immature granulocytes,reactive lymphocytes,and nucleated RBCs were all greater than 90％.The sensitivity of AI system in identif-ying abnormal morphology of RBCs reached 99.59％,along with rapid quantitative analysis for various anomalous types of RBCs.In AI-assisted mode,the sensitivity of recognition for all cell types was improved to varying degrees by junior and intermediate technicians,and the sensitivity for recognizing malignant primitive cells,reactive lymphocytes,and immature granulocytes increased to 58.24％,53.39％,and 62.37％for junior technicians,and to 92.06％,83.24％,and 83.12％for intermediate technicians,respectively.The improvements for junior technicians were particularly significant,with increases of 12.46％,10.61％,and 3.71％for each cell type,respectively.Both groups achieved higher specificity and accuracy.Through AI pre-classification and manual review,a variety of pe-ripheral blood cell-related diseases were accurately diagnosed in the tiered healthcare practice of primary medical units,including 339 cases(11.13％)of red blood cell diseases,5 cases(0.16％)of platelet diseases,2 343 cases(76.90％)of infection-related disea-ses,and 28 cases(0.92％)of malignant hematological diseases.In addition,332 cases(10.90％)which lacked an obvious related cause or required further examinations were identified as well.Conclusion AI pre-classification has demonstrated strong cell recogni-tion capabilities and may assist technicians in improving the sensitivity,specificity,and accuracy of blood cell classification.AI could en-hance the disease-screening capabilities in the tiered diagnosis network of primary medical units,presenting a broad application prospect.

Objective:To investigate and analyze basic status of radiotherapy units in Hebei Province in 2024.Methods:Led by the Fourth Hospital of Hebei Medical University, the Radiation Oncology Branch of the Hebei Medical Association, and the Radiation Oncology Expert Committee of the Hebei Society of Clinical Oncology, a province-wide survey was conducted using structured questionnaires. The survey covered key aspects such as basic information of radiotherapy institutions, personnel allocation, equipment configuration, and implementation of radiotherapy techniques. Collected data were summarized and descriptively analyzed comparing with a 2013 survey of radiotherapy in Hebei Province.Results:All 158 radiotherapy institutions across Hebei Province participated in the survey. A total of 2273 radiotherapy professionals were reported, including 1317 radiation oncologists (57.94%), 332 medical physicists (14.61%), 71 radiotherapy engineers (3.12%), and 553 radiotherapy technologists (24.33%). The number of radiotherapy devices significantly increased from 121 in 2013 to 237 in 2024, including 68 domestic radiotherapy equipment. The current inventory includes 195 medical linear accelerators (2.61 units per million population), 2 cobalt-60 units, 27 afterloading machines, 9 tomotherapy (TOMO) systems, 3 CyberKnife units, and 1 proton therapy system. Three-dimensional conformal radiotherapy and stati intensity-modulated radiotherapy have been widely adopted across the province, while advanced techniques such as volumetric-modulated arc therapy, stereotactic body radiotherapy, and respiration-gated technology, and respiratory gating are gradually being implemented.Conclusions:In recent years, the configuration of radiotherapy personnel in Hebei Province has become more balanced, and the availability of precision radiotherapy equipment has significantly improved. There is a growing trend in the adoption of domestically manufactured radiotherapy equipment, marking substantial progress in the development of radiation oncology services in the region.

Objective:To explore the prognostic value of the age-adjusted Charlson comorbidity index (ACCI) in patients with stage IIB cervical squamous cell carcinoma (CSCC) who received radical concurrent chemoradiotherapy (rCCRT).Methods:Clinical data of 115 patients with stage IIB CSCC who underwent rCCRT at the First Affiliated Hospital of Xinxiang Medical University from January 2017 to January 2023 were retrospectively analyzed. Fourteen clinical factors, including ACCI, were assessed. Univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factors for progression-free survival (PFS) and overall survival (OS). The optimal cut-off value for ACCI was determined using the receiver operating characteristic (ROC) curve analysis, and patients were divided into the high ACCI (ACCI > 3) and low ACCI (ACCI ≤ 3) groups. Survival differences between two groups were evaluated using Kaplan-Meier curves and compared by log-rank tests.Results:Multivariate Cox regression analysis revealed that ACCI was an independent prognostic factor for both PFS and OS ( HR=3.405, 95% CI: 1.108-10.467, P=0.032; HR=4.732, 95% CI: 1.363-16.425, P=0.014). Significant differences were observed in PFS and OS between the high and low ACCI groups ( P=0.023 and 0.003, respectively). The median PFS was 44 months in the high ACCI group and 56 months in the low ACCI group. The 2-year and 3-year PFS rates were 81.9% and 80.1% in the high ACCI group, and 94.4% and 94.4% in the low ACCI group, respectively. The median OS was 46 months in the high ACCI group and 56 months in the low ACCI group. The 2-year and 3-year OS rates were 88.3% and 84.7% in the high ACCI group, and 94.4% and 94.4% in the low ACCI group, respectively. Conclusions:For patients with stage IIB CSCC receiving rCCRT, ACCI is an independent and significant prognostic factor, with patients in the high ACCI group exhibiting worse prognosis.