BACKGROUND:Duhuo Jisheng Decoction is a classic prescription for the treatment of rheumatoid arthritis,but its specific mechanism is not clear.Extracellular vesicles have the powerful function of inter-cell communication and signal transmission,and may be the signal carrier for the Decoction.OBJECTIVE:To explore the effects of serum extracellular vesicles treated with Duhuo Jisheng Decoction on the proliferation,migration,invasion,and apoptosis of rheumatoid arthritis fibroblast-like synovial cells.METHODS:The rheumatoid arthritis fibroblast-like synovial cell model was established by co-culturing with tumor necrosis factor-α in vitro.The experiment was divided into five groups:normal group,model group,serum treated with Duhuo Jisheng Decoction group,extracellular vesicles treated with Duhuo Jisheng Decoction group,and extracellular vesicles treated with normal saline group.The optimal concentration and time of drug-containing serum and extracellular vesicles were screened by CCK-8 assay.Expression of inflammatory cytokines in the supernatants of cells in each group was detected by ELISA.The migration ability of rheumatoid arthritis fibroblast-like synovial cells was detected by scratch assay.The invasive ability of cells was measured by Transwell Invasion assay.Hoechst staining was adoped to detect cell apoptosis.The expression levels of apoptosis-related genes and proteins were detected by qRT-PCR and western blot assay.RESULTS AND CONCLUSION:(1)The optimal volume fraction of serum treated with Duhuo Jisheng Decoction was 10%and optimal mass concentration of extracellular vesicles treated with Duhuo Jisheng Decoction was 10 ng/mL;the optimal time for the interaction between the two was 24 hours.(2)Compared with the model group,serum treated with Duhuo Jisheng Decoction,extracellular vesicles treated with Duhuo Jisheng Decoction,and extracellular vesicles treated with normal saline could suppress the expression of inflammatory factors of rheumatoid arthritis fibroblast-like synovial cells(P<0.05),scratch healing(P<0.05),migration and invasion(P<0.05).Moreover,the inhibition of extracellular vesicles treated with Duhuo Jisheng Decoction was more significant(P<0.05).(3)Drug-containing serum and extracellular vesicles treated with Duhuo Jisheng Decoction promoted the apoptosis of rheumatoid arthritis fibroblast-like synovial cells.(4)Compared with the model group,serum treated with Duhuo Jisheng Decoction,extracellular vesicles treated with Duhuo Jisheng Decoction,and extracellular vesicles treated with normal saline could increase the expression of proapoptotic factors Caspase-3,Caspase-9,and Bax(P<0.05)and decrease the expression of antiapoptotic factor Bcl-2(P<0.05).Moreover,extracellular vesicles treated with Duhuo Jisheng Decoction had a more significant regulatory effect on apoptosis-related factors.Above findings indicate that extracellular vesicles treated with Duhuo Jisheng Decoction can inhibit the excessive proliferation,migration,and invasion of rheumatoid arthritis fibroblast-like synovial cells and promote their apoptosis.

Objective:To explore the association between the use of tetracyclines during pregnancy and congenital malformations, with the aim of providing evidence-based guidance for the rational use of antibiotics during pregnancy.Methods:Data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction (CVAR) database from January 2015 to September 2024 were collected. Five methods including Tree-based scan statistic (TreeScan), proportional reporting ratio (PRR), reporting odds ratio (ROR), the UK Medicines and Healthcare Products Regulatory Agency (MHRA) comprehensive standard, and the Bayesian confidence propagation neural network (BCPNN) were used to detect signals of risk for congenital malformations in offspring following maternal use of tetracyclines during pregnancy. A signal that met the threshold criteria of all above 5 methods was considered as a risk signal. Based on population-based cohort of the drug exposures and adverse pregnancy outcomes (DEEP) data from January 2013 to December 2021 in Xiamen City, propensity score matching (PSM)-based Poisson regression was applied to evaluate the association between the first-trimester tetracyclines exposure and congenital malformations in offspring. Adjusted relative risk (a RR) and its 95% confidence interval ( CI) were calculated. Sensitivity analysis was conducted to validate the reliability of the results. Results:A total of 304 098 reports of adverse events during pregnancy were obtained from the FAERS and CVAR databases. Among them, 5 028 reports were related to tetracyclines, including 1 026 reports of congenital malformations in offspring, involving congenital malformations of musculoskeletal system, other digestive system, and other congenital malformations. Signal detection results suggested that tetracyclines may be a risk signal for above congenital malformations in offspring. The DEEP data included 411 936 pregnant women. After PSM, 240 pregnant women exposed to tetracyclines were included. The results showed no significant association between the first-trimester tetracyclines exposure and congenital malformations in offspring (a RR=0.75, 95% CI: 0.26-2.17), sensitivity analysis also showed no correlation. Conclusions:Data mining from the FAERS and CVAR databases suggests a potential association between tetracyclines use during pregnancy and congenital malformations in offspring. However, the DEEP data study shows no significant correlation.

BACKGROUND:Duhuo Jisheng Decoction is a classic prescription for the treatment of rheumatoid arthritis,but its specific mechanism is not clear.Extracellular vesicles have the powerful function of inter-cell communication and signal transmission,and may be the signal carrier for the Decoction.OBJECTIVE:To explore the effects of serum extracellular vesicles treated with Duhuo Jisheng Decoction on the proliferation,migration,invasion,and apoptosis of rheumatoid arthritis fibroblast-like synovial cells.METHODS:The rheumatoid arthritis fibroblast-like synovial cell model was established by co-culturing with tumor necrosis factor-α in vitro.The experiment was divided into five groups:normal group,model group,serum treated with Duhuo Jisheng Decoction group,extracellular vesicles treated with Duhuo Jisheng Decoction group,and extracellular vesicles treated with normal saline group.The optimal concentration and time of drug-containing serum and extracellular vesicles were screened by CCK-8 assay.Expression of inflammatory cytokines in the supernatants of cells in each group was detected by ELISA.The migration ability of rheumatoid arthritis fibroblast-like synovial cells was detected by scratch assay.The invasive ability of cells was measured by Transwell Invasion assay.Hoechst staining was adoped to detect cell apoptosis.The expression levels of apoptosis-related genes and proteins were detected by qRT-PCR and western blot assay.RESULTS AND CONCLUSION:(1)The optimal volume fraction of serum treated with Duhuo Jisheng Decoction was 10%and optimal mass concentration of extracellular vesicles treated with Duhuo Jisheng Decoction was 10 ng/mL;the optimal time for the interaction between the two was 24 hours.(2)Compared with the model group,serum treated with Duhuo Jisheng Decoction,extracellular vesicles treated with Duhuo Jisheng Decoction,and extracellular vesicles treated with normal saline could suppress the expression of inflammatory factors of rheumatoid arthritis fibroblast-like synovial cells(P<0.05),scratch healing(P<0.05),migration and invasion(P<0.05).Moreover,the inhibition of extracellular vesicles treated with Duhuo Jisheng Decoction was more significant(P<0.05).(3)Drug-containing serum and extracellular vesicles treated with Duhuo Jisheng Decoction promoted the apoptosis of rheumatoid arthritis fibroblast-like synovial cells.(4)Compared with the model group,serum treated with Duhuo Jisheng Decoction,extracellular vesicles treated with Duhuo Jisheng Decoction,and extracellular vesicles treated with normal saline could increase the expression of proapoptotic factors Caspase-3,Caspase-9,and Bax(P<0.05)and decrease the expression of antiapoptotic factor Bcl-2(P<0.05).Moreover,extracellular vesicles treated with Duhuo Jisheng Decoction had a more significant regulatory effect on apoptosis-related factors.Above findings indicate that extracellular vesicles treated with Duhuo Jisheng Decoction can inhibit the excessive proliferation,migration,and invasion of rheumatoid arthritis fibroblast-like synovial cells and promote their apoptosis.

Objective:To explore the association between the use of tetracyclines during pregnancy and congenital malformations, with the aim of providing evidence-based guidance for the rational use of antibiotics during pregnancy.Methods:Data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction (CVAR) database from January 2015 to September 2024 were collected. Five methods including Tree-based scan statistic (TreeScan), proportional reporting ratio (PRR), reporting odds ratio (ROR), the UK Medicines and Healthcare Products Regulatory Agency (MHRA) comprehensive standard, and the Bayesian confidence propagation neural network (BCPNN) were used to detect signals of risk for congenital malformations in offspring following maternal use of tetracyclines during pregnancy. A signal that met the threshold criteria of all above 5 methods was considered as a risk signal. Based on population-based cohort of the drug exposures and adverse pregnancy outcomes (DEEP) data from January 2013 to December 2021 in Xiamen City, propensity score matching (PSM)-based Poisson regression was applied to evaluate the association between the first-trimester tetracyclines exposure and congenital malformations in offspring. Adjusted relative risk (a RR) and its 95% confidence interval ( CI) were calculated. Sensitivity analysis was conducted to validate the reliability of the results. Results:A total of 304 098 reports of adverse events during pregnancy were obtained from the FAERS and CVAR databases. Among them, 5 028 reports were related to tetracyclines, including 1 026 reports of congenital malformations in offspring, involving congenital malformations of musculoskeletal system, other digestive system, and other congenital malformations. Signal detection results suggested that tetracyclines may be a risk signal for above congenital malformations in offspring. The DEEP data included 411 936 pregnant women. After PSM, 240 pregnant women exposed to tetracyclines were included. The results showed no significant association between the first-trimester tetracyclines exposure and congenital malformations in offspring (a RR=0.75, 95% CI: 0.26-2.17), sensitivity analysis also showed no correlation. Conclusions:Data mining from the FAERS and CVAR databases suggests a potential association between tetracyclines use during pregnancy and congenital malformations in offspring. However, the DEEP data study shows no significant correlation.

Objective To explore the application status and development trend of machine learning in the field of pharmacovigilance worldwide,and to provide reference for the research on the application of machine learning in the field of pharmacovigilance.Methods Relevant literature was searched in the Web of Science with the key words of"machine learning"and"pharmacovigilance"from the inception to March 1,2023.R language and other software were used to quantitatively analyze the literature data in this field.The clustering,co-occurrence and emergence visual analysis were carried out on the characteristics of annual published papers,institutions,countries,keywords and other aspects.Results A total of 904 literature were included.The number of literature published showed a fluctuating upward trend since 1994.There was cross-regional,cross-regional and cross-agency cooperation among the cooperative network institutions.The top 5 countries in the number of publications were the United States,China,Japan,South Korea and India,China and the United States had relatively close cooperation in this field.Signal detection,social media and electronic health records were high-frequency keywords in this field.Clustering and association rule analysis showed that this field focused on three aspects signal recognition,unstructured text mining and analysis,and processing and analysis of electronic medical information.At present,machine learning has made significant progress in signal recognition,social media information mining,and unstructured text processing of electronic medical information,which broaden the data sources of pharmacovigilance,improve the real-time monitoring ability of adverse drug reactions,bringing innovation impetus to the field of pharmacovigilance.Conclusion The rapid development of big data and artificial intelligence technologies has led to an increasing integration of machine learning into the field of pharmacovigilance,which promotes technical exchanges and cooperation and cross-disciplinary integration.It is necessary to optimize each machine learning algorithm to improve its accuracy and stability in pharmacovigilance,strengthen the protection measures of data privacy and security to ensure the safety of patient information.Integrating expertise in the fields of science,medicine,and data statistics with a view to promoting technological progress in the field of pharmacovigilance.

Objective To explore the current status,research hotspots and development trends of safe medication in the global elderly with multimorbidity,and to provide theoretical reference for research in this field.Methods CNKI,Yiigle and Web of Science were searched for studies on medication safety in the elderly with multimorbidity.The search time was from the establishment of the database to May 1,2024.R language and other software were used to visually analyze the annual number of publications,institutions,and the clustering,refinement,and hotspots and trends of keywords.Results A total of 20 Chinese articles and 654 English articles were included.There is little global attention to this field,and cooperation between institutions needs to be further strengthened.General practice,general practitioners,Beers criteria,polypharmacy,primary care,inappropriate prescribing,medication adherence,deprescribing are the key directions of concern in this field globally.At present,most of the Chinese literature is from the perspective of clinical practice,such as medication management and intervention measures.The English literature mainly focuses on the safety of chronic disease medication,quality of life,medication adherence,and risk of chronic disease medication from the patients'perspective.With the increasing popularity of deprescribing,future research in this area of medication management will place greater emphasis on personalized and precision medicine.Conclusions The study of drug safety in the elderly with multimorbidity needs to establish and improve the primary care mechanism,improve the adherence of patients,and use relevant standards to effectively evaluate the safety and potential risks of polypharmacy in the elderly with multimorbidity,identify potentially inappropriate drugs and deprescribing,to reduce the risk of adverse drug reactions,and to further improve the quality of life and reduce medical costs in the elderly with multimorbidity.

Vitiligo is an immune memory skin disease. T-cell factor 1 (TCF1) is essential for maintaining the memory T-cell pool. There is an urgent need to investigate the characteristics of peripheral memory T-cell profile and TCF1⁺ T-cell frequencies in patients with vitiligo. In this study, 31 patients with active vitiligo (AV), 22 with stable vitiligo (SV), and 30 healthy controls (HCs) were included. We measured circulating memory and TCF1⁺ T-cell frequencies using flow cytometry. The Spearman's rank test was used to evaluate the correlation between cell frequencies and disease characteristics. Receiver operating characteristic curves (ROC) were constructed to investigate the discriminative power of the cell subpopulations. Circulating CD4⁺ and CD8⁺ terminally differentiated effector memory T-cell (T_EMRA) frequencies were significantly higher in the AV group than in HCs (P < 0.05). TCF1⁺ T-cell subpopulations were widespread increased in patients with vitiligo (P < 0.05). After adjusting for potential confounders, CD8⁺ and CD4⁺ central memory (T_CM) cells, and CD8⁺ T_EMRA were correlated with disease activity (P < 0.05). The combined diagnostic value of the four (naïve, effector memory, T_CM, and T_EMRA) CD8⁺TCF1⁺ T-cell subsets was relatively high (area under the ROC curve (AUC) = 0.804, sensitivity = 71.70%, specificity = 83.34%), and the CD8⁺ T-cell subsets combination performed well in discriminating disease activity (AUC = 0.849, sensitivity = 70.97%, specificity = 90.91%). We demonstrated an altered circulating memory T-cell profile and increased TCF1⁺ T-cell percentage in patients with vitiligo. T-cell subpopulations had a strong value for vitiligo diagnosis and activity evaluation. This evidence presents a potential new pharmacological target for inhibiting autoimmunity that leads to vitiligo.

Vitiligo is an immune memory skin disease.T-cell factor 1(TCF1)is essential for maintaining the memory T-cell pool.There is an urgent need to investigate the characteristics of peripheral memory T-cell profile and TCF1+T-cell frequencies in patients with vitiligo.In this study,31 patients with active vitiligo(AV),22 with stable vitiligo(SV),and 30 healthy controls(HCs)were included.We measured circulating memory and TCF1+T-cell frequencies using flow cytometry.The Spearman's rank test was used to evaluate the correlation between cell frequencies and disease characteristics.Receiver operating characteristic curves(ROC)were constructed to investigate the discriminative power of the cell subpopulations.Circulating CD4+and CD8+terminally differentiated effector memory T-cell(TEMRA)frequencies were significantly higher in the AV group than in HCs(P＜0.05).TCF1+T-cell subpopulations were widespread increased in patients with vitiligo(P＜0.05).After adjusting for potential confounders,CD8+and CD4+central memory(TcM)cells,and CD8+TEMRA were correlated with disease activity(P＜0.05).The combined diagnostic value of the four(naive,effector memory,TcM,and TEMRA)CD8+TCF1+T-cell subsets was relatively high(area under the ROC curve(AUC)=0.804,sensitivity=71.70％,specificity=8334％),and the CD8+T-cell subsets combination per-formed well in discriminating disease activity(AUC=0.849,sensitivity=70.97％,specificity=90.91％).We demonstrated an altered circulating memory T-cell profile and increased TCF1+T-cell percentage in patients with vitiligo.T-cell subpopulations had a strong value for vitiligo diagnosis and activity evaluation.This evidence presents a potential new pharmacological target for inhibiting autoimmunity that leads to vitiligo.

Objective To explore the current status,research hotspots and development trends of safe medication in the global elderly with multimorbidity,and to provide theoretical reference for research in this field.Methods CNKI,Yiigle and Web of Science were searched for studies on medication safety in the elderly with multimorbidity.The search time was from the establishment of the database to May 1,2024.R language and other software were used to visually analyze the annual number of publications,institutions,and the clustering,refinement,and hotspots and trends of keywords.Results A total of 20 Chinese articles and 654 English articles were included.There is little global attention to this field,and cooperation between institutions needs to be further strengthened.General practice,general practitioners,Beers criteria,polypharmacy,primary care,inappropriate prescribing,medication adherence,deprescribing are the key directions of concern in this field globally.At present,most of the Chinese literature is from the perspective of clinical practice,such as medication management and intervention measures.The English literature mainly focuses on the safety of chronic disease medication,quality of life,medication adherence,and risk of chronic disease medication from the patients'perspective.With the increasing popularity of deprescribing,future research in this area of medication management will place greater emphasis on personalized and precision medicine.Conclusions The study of drug safety in the elderly with multimorbidity needs to establish and improve the primary care mechanism,improve the adherence of patients,and use relevant standards to effectively evaluate the safety and potential risks of polypharmacy in the elderly with multimorbidity,identify potentially inappropriate drugs and deprescribing,to reduce the risk of adverse drug reactions,and to further improve the quality of life and reduce medical costs in the elderly with multimorbidity.

Background The influencing factors of noise hazards in the automotive manufacturing industry are complex, diverse, and mutually correlated, resulting in significant health impacts on workers. Objective To explore the application of generalized estimating equations (GEE) to analyze the factors affecting high-frequency hearing loss among noise-exposed workers in an automotive manufacturing company, guiding enterprises to scientifically carry out employee hearing protection programs. Methods The data of occupational health field evaluation and occupational health surveillance of an automobile manufacturing company for five consecutive years from 2018 to 2022 were collected, and 806 noise-exposed workers with pure tone hearing test results for all five consecutive years were selected as study participants. The retrieved indicators were gender, physical examination year, noise intensity, blood pressure, white blood cell counts, red blood cell counts, platelet counts, concentrations of hemoglobin, alanine transaminase, aspartate aminotransferase, smoking, drinking, etc. Gender, noise intensity, blood pressure, white blood cell counts, red blood cell counts, concentrations of hemoglobin, platelet counts, glutamate aminotransferase, glutamate aminotransferase, smoking, and drinking were set as independent variables, and occurrence of high-frequency hearing loss was set as a dependent variable, and GEE were constructed by using the statistical software of SPSS 20.0 to analyze the influencing factors of high-frequency hearing loss. Results Of the 806 workers, 698 were male (86.6%) and 108 were female (13.4%). The detection rates of high-frequency hearing loss in each year from 2018 to 2022 were 66.4% (535/806), 69.8% (563/806), 70.0% (564/806), 68.9% (555/806), and 68.2% (550/806), respectively. The detection rate of high-frequency hearing loss in the company was varied significantly by gender, lowered white blood cell counts, lowered red blood cell counts, lowered platelet counts, smoking, and drinking (P<0.05). The results of GEE analysis showed that after adjusting for selected confounding factors and excluding interaction effects, the risk of high-frequency hearing loss was higher in men than in women (P=0.001; OR=1.907, 95%CI: 1.286, 2.829); it was higher in workplace with disqualified noise intensity than in those without (P=0.043; OR=1.289, 95%CI: 1.009, 1.648); it was also higher in smokers than in non-smokers (P=0.004; OR=1.507, 95%CI: 1.137, 1.999). Conclusion Gender, noise intensity, and smoking are the main influencing factors of high-frequency hearing loss in noise-exposed workers in this automobile manufacturing company. Controlling smoking and reducing noise exposure intensity may reduce the occurrence of high-frequency hearing loss in workers.