Osteoarthritis (OA), the most prevalent joint disease of late life, is closely linked to cellular senescence. Previously, we found that the senescence of fibroblast-like synoviocytes (FLS) played an essential role in the degradation of cartilage. In this work, single-cell sequencing data further demonstrated that cartilage acidic protein 1 (CRTAC1) is a critical secreted factor of senescent FLS, which suppresses mitophagy and induces mitochondrial dysfunction by regulating SIRT3 expression. In vivo, deletion of SIRT3 in chondrocytes accelerated cartilage degradation and aggravated the progression of OA. Oppositely, intra-articular injection of adeno-associated virus expressing SIRT3 effectively alleviated OA progression in mice. Mechanistically, we demonstrated that elevated CRTAC1 could bind with NRF2 in chondrocytes, which subsequently suppresses the transcription of SIRT3 in vitro. In addition, SIRT3 reduction could promote the acetylation of FOXO3a and result in mitochondrial dysfunction, which finally contributes to the degradation of chondrocytes. To conclude, this work revealed the critical role and underlying mechanism of senescent FLSs-derived CRTAC1 in OA progression, which provided a potential strategy for the OA therapy.

AIM:To analyze the reasons for screening failure and explore the influencing fac-tors in clinical trial in healthy volunteers,guidance was provided to improve the success rate of screen-ing in the future.clarify the reasons for the failure in healthy subjects(HS)screening,and to provide guidance for screening in phase Ⅰ clinical trials.METHODS:We performed a retrospective study that described the process of HS screening in phase Ⅰ clinical trials carried out in department of clinical pharmacology lab,Nanjing First Hospital be-tween 2019 and 2022.We analyzed the reasons for screening failure and their impact on the failure rate.A retrospective analysis was conducted on the data of subjects who participated in drug clinical trial screening 2019 to 2022.The reasons for screening failure were analyzed,and statistical methods were used to explore the independent factors that led to screening failure.RESULTS:A to-tal of 11 clinical trials were included in this study,and 502 out of 1 582 participants(31.7％)passed the screening.The analysis of the remaining 1 080 subjects showed that the items that did not pass the screening were laboratory examinations(631 cases,58.4％),abnormal vital signs results(228 cas-es,21.1％),intolerance to blood drawn(86 cases,8.0％),sufficient subjects(62 cases,5.7％),with-drawal at the screening(54 cases,5.0％),demogra-phy(54 cases,5.0％),urinary cotinine examination(42 cases,3.9％),imaging examination(31 cases,2.9％),electrocardiogram(24 cases,2.2％),inquiry(medical inquiry 19 cases,1.8％,smoking inquiry 2 cases,0.2％,alcohol inquiry 2 cases,0.2％)and identity verification(17 cases,1.8％).In the popula-tion with a body mass index(BMI)of 19.0 to 26.0,an increase in BMI is an independent factor signifi-cantly associated with screening failure(P＜0.000 1,OR=0.890 4,95％CI 0.841 9-0.941 3).The impact of different examination items on the screening fail-ure rate varies.CONCLUSION:In clinical trials of healthy subjects,laboratory tests,vital signs and in-tolerance to blood drawn are the main reasons for screening failure.Lowering the upper limit of BMI when recruiting subjects may increase the success rate of screening.Laboratory examinations,vital signs,intolerance to blood drawn are the most im-portant three reasons for screening failure,and im-provements can be made to reduce the screening failure rate of phase Ⅰ clinical trials in response to the main screening failure reasons.

AIM:To analyze the reasons for screening failure and explore the influencing fac-tors in clinical trial in healthy volunteers,guidance was provided to improve the success rate of screen-ing in the future.clarify the reasons for the failure in healthy subjects(HS)screening,and to provide guidance for screening in phase Ⅰ clinical trials.METHODS:We performed a retrospective study that described the process of HS screening in phase Ⅰ clinical trials carried out in department of clinical pharmacology lab,Nanjing First Hospital be-tween 2019 and 2022.We analyzed the reasons for screening failure and their impact on the failure rate.A retrospective analysis was conducted on the data of subjects who participated in drug clinical trial screening 2019 to 2022.The reasons for screening failure were analyzed,and statistical methods were used to explore the independent factors that led to screening failure.RESULTS:A to-tal of 11 clinical trials were included in this study,and 502 out of 1 582 participants(31.7％)passed the screening.The analysis of the remaining 1 080 subjects showed that the items that did not pass the screening were laboratory examinations(631 cases,58.4％),abnormal vital signs results(228 cas-es,21.1％),intolerance to blood drawn(86 cases,8.0％),sufficient subjects(62 cases,5.7％),with-drawal at the screening(54 cases,5.0％),demogra-phy(54 cases,5.0％),urinary cotinine examination(42 cases,3.9％),imaging examination(31 cases,2.9％),electrocardiogram(24 cases,2.2％),inquiry(medical inquiry 19 cases,1.8％,smoking inquiry 2 cases,0.2％,alcohol inquiry 2 cases,0.2％)and identity verification(17 cases,1.8％).In the popula-tion with a body mass index(BMI)of 19.0 to 26.0,an increase in BMI is an independent factor signifi-cantly associated with screening failure(P＜0.000 1,OR=0.890 4,95％CI 0.841 9-0.941 3).The impact of different examination items on the screening fail-ure rate varies.CONCLUSION:In clinical trials of healthy subjects,laboratory tests,vital signs and in-tolerance to blood drawn are the main reasons for screening failure.Lowering the upper limit of BMI when recruiting subjects may increase the success rate of screening.Laboratory examinations,vital signs,intolerance to blood drawn are the most im-portant three reasons for screening failure,and im-provements can be made to reduce the screening failure rate of phase Ⅰ clinical trials in response to the main screening failure reasons.

Background The complex and diverse occupational disease hazards in automobile manufacturing industry pose high occupational health risks to workers. Objective To explore the methods that can accurately reflect the workplace health risk grade of automobile manufacturing enterprises, and to guide enterprises to practice risk classification management. Methods Comprehensive index method, International Commission on Mining and Metals occupational health risk assessment method (ICMM method), and risk index method were used toassess health risks of occupational disease hazards in major workstations such as welding, polishing, and painting in three automobile manufacturing enterprises in Hunan Province. Kappa consistency test was used to test the grading results of the three assessment methods. The re-examine results and detection rate of contraindications of occupational health examinations in the past three years were used to verify the assessment results. Results The results of comprehensive index method showed that the hazards of each selected workstation in enterprises A and B were evaluated as grade 2-3, among which NO₂ in enterprise A was grade 3, and welding fume, NO₂, and formaldehyde in enterprise B were all grade 3. The hazards of each selected workstation in enterprise C were grade 3-4, among which NO₂ and benzene in were grade 4, and welding fume, manganese and its compounds, grinding wheel dust, and xylene were grade 3. The hazards evaluated by ICMM quantitative method were grade 2 and grade 5, among which manganese and its compounds in enterprise A and welding fume, grinding wheel dust, and benzene series in enterprise C were graded as grade 5. The hazards evaluated by risk index method were grade 1-4, among which manganese and its compounds in enterprises A and B were grade 3, and manganese and its compounds and benzene in enterprise C were grade 4. The Kappa value between comprehensive index method and ICMM method was 0.084 (P>0.05), that between comprehensive index method and risk index method was −0.046 (P>0.05), and that between ICMM method and risk index method was 0.014 (P>0.05), indicating poor consistency. By comparing the results of occupational health surveillance with the results of occupational health risk assessment, one worker was found to have occupational contraindication of manganese exposure and 1 worker was found to have excessive manganese in hair in enterprise A. However, the comprehensive index method graded low risk for manganese and its compounds in enterprise A and the result is conservative. The key workstations identified by ICMM method were consistent with the occupational health examination results, but the assessment grades were all extremely high risk, and the results were too strict. One worker was found to be contraindicated to welding fumes, and 2 polishers were found to have severe mixed pulmonary ventilation dysfunction in enterprise C. Mild and moderate pulmonary ventilation dysfunction was found to be common in welding and polishing workstations in each enterprise. The assessment results of welding fumes and grinding wheel dust by the risk index method were negligible risks, which were inconsistent with the occupational health examination results. Conclusion The comprehensive index method, ICMM method, and risk index method can basically identify workstations with serious occupational hazards, but they have certain limitations and applicability. In general, the evaluation results of the comprehensive index method were generates more consistent with the results with occupational health surveillance than the other two methods, is more comprehensive and objective in consideration, and is more suitable for health risk assessment of automobile manufacturing enterprises.

Background The mining of non-coal underground mines may come into contact with various types of dust, such as lead, zinc, copper, and non-metallic minerals. Dust of various kinds commonly exists in all aspects of mining and selection, and is one of the main occupational hazard groups in non-coal underground mines. Objective To compare the application of two risk assessment methods in the occupational health risk assessment of productive dust in non-coal underground mines, and to provide a reference for the selection of dust hazard health risk assessment methods and the management of dust hazards in non-coal mines. Methods A field investigation of the dust hazards of three typical non-coal underground mining enterprises (lead-zinc mines, copper mines, and fluorite mines) was carried out, and the comprehensive index method and the occupational health risk assessment method from the International Council on Mining and Metals (ICMM) were used to perform risk assessments. The comprehensiveindex method considers the following factors: dust monitoring data, the aerodynamic diameter of dust, hazard control measures, occupational health management, daily usage, and daily exposure time to determine exposure levels. The ICMM method determines the risk level based on the consequences caused by dust, exposure probability, exposure time, and uncertainty coefficient. Kendall consistency test was used to compare agreement between the results generated by the two methods. Results The results generated by the comprehensive index method were as follows: level 3 (medium risk) or level 4 (high risk) for silica dust or lead dust; level 1 (negligible risk) or level 2 (low risk) for other dust (dust with free SiO₂ content<10% and containing lead, zinc, and copper, using other dust limit values for comparison), fluorspar mixed dust, fluorine and its compounds, zinc oxide, and copper dust. The risk levels graded by the ICMM method were as follows: level 4 (very high risk) and level 3 (high risk) for exposure to silica dust and lead dust, respectively, and level 1 (tolerable risk) or level 2 (potential risk) for exposure to other dust (dust with free SiO₂ content <10% and containing lead, zinc, and copper, using other dust limit values for comparison), fluorspar mixed dust, fluorine and its compounds, zinc oxide, and copper dust. The consistency level between the results graded by the two methods was very high (Kendall W coefficient=0.974, P < 0.05). Conclusion For the occupational health risk assessment of productive dust in non-coal underground mines, the consistency level of risk assessment results between the ICMM method and the comprehensive index method is very high. The ICMM method is more convenient to operate and should be preferred in assessing health risks of dust hazard in non-coal underground mines.

Traditionally, Tripterygium hypoglaucum (Levl.) Hutch (THH) are widely used in Chinese folk to treat rheumatoid arthritis (RA). This study aimed to investigate whether the anti-RA effect of THH is related with the gut microbiota. The main components of prepared THH extract were identified by HPLC-MS. C57BL/6 mice with adjuvant-induced arthritis (AIA) were treated with THH extract by gavage for one month. THH extract significantly alleviated swollen ankle, joint cavity exudation, and articular cartilage destruction in AIA mice. The mRNA and protein levels of inflammatory mediators in muscles and plasma indicated that THH extract attenuated inflammatory responses in the joint by blocking TLR4/MyD88/MAPK signaling pathways. THH extract remarkably restored the dysbiosis of the gut microbiota in AIA mice, featuring the increases of Bifidobacterium, Akkermansia, and Lactobacillus and the decreases of Butyricimonas, Parabacteroides, and Anaeroplasma. Furthermore, the altered bacteria were closely correlated with physiological indices and drove metabolic changes of the intestinal microbiota. In addition, antibiotic-induced pseudo germ-free mice were employed to verify the role of the intestinal flora. Strikingly, THH treatment failed to ameliorate the arthritis symptoms and signaling pathways in pseudo germ-free mice, which validates the indispensable role of the intestinal flora. For the first time, we demonstrated that THH extract protects joint inflammation by manipulating the intestinal flora and regulating the TLR4/MyD88/MAPK signaling pathway. Therefore, THH extract may serve as a microbial modulator to recover RA in clincial practice.ver RA in clincial practice.
Mice ; Animals ; Gastrointestinal Microbiome ; Tripterygium ; Myeloid Differentiation Factor 88/genetics* ; Toll-Like Receptor 4/genetics* ; Mice, Inbred C57BL ; Arthritis, Experimental/drug therapy*

Objective:To investigate the topological properties of whole-brain functional networks in first-episode drug-na?ve adolescents with major depressive disorder (MDD).Methods:Seventy-six first-episode drug-na?ve adolescents with MDD admitted to Department of Neurology, Xiangyang No.1 Hospital Affilated to Hubei University of Medicince from January 2022 to January 2023 were selected as study subjects; 66 gender- and age-matched healthy controls (HCs) were recruited via advertisement. All subjects underwent resting-state functional MRI. The whole-brain functional networks were constructed for each subject; and then, the global topological metrics (global efficiency, local efficiency, clustering coefficient, characteristic path length, normalized clustering coefficient, normalized characteristic path length, and small-worldness properties) and local topological metrics (nodal degree centrality, nodal efficiency and nodal betweenness centrality) of the functional brain networks were analyzed between the two groups using graph-theory methods. Network-based statistics were used to examine between-group differences in functional connectivity strength of whole brain networks. Results:Small-worldness properties were demonstrated in both MDD group and HC group. MDD patients showed significantly higher global efficiency (0.129[0.124, 0.132] vs. 0.131[0.128, 0.133]), significantly lower clustering coefficient and characteristic path length (0.143[0.139, 0.146] vs. 0.139[0.135, 0.144]; 0.457[0.446, 0.734] vs. 0.451[0.440, 0.463]), and significantly increased nodal centralities in the right inferior parietal lobule, bilateral caudate nucleus and bilateral thalamus of brain functional networks compared with HCs ( P<0.05, FDR-corrected). Compared with HCs, MDD patients exhibited obviously lower functional connectivity strength in the orbitofrontal-temporal and anterior cingulate-limbic-temporal circuits. Conclusion:Abnormal alterations of topological properties of the brain functional networks are found in adolescents with MDD, which may be the underlying neuropathologic basis for MDD.

Objective    To explore the application value of machine learning models in predicting postoperative survival of patients with thoracic squamous esophageal cancer. Methods    The clinical data of 369 patients with thoracic esophageal squamous carcinoma who underwent radical esophageal cancer surgery at the Department of Thoracic Surgery of Northern Jiangsu People's Hospital from January 2014 to September 2015 were retrospectively analyzed. There were 279 (75.6%) males and 90 (24.4%) females aged 41-78 years. The patients were randomly divided into a training set (259 patients) and a test set (110 patients) with a ratio of 7 : 3. Variable screening was performed by selecting the best subset of features. Six machine learning models were constructed on this basis and validated in an independent test set. The  performance of the models' predictions was evaluated by area under the curve (AUC), accuracy and logarithmic loss, and the fit of the models was reflected by calibration curves. The best model was selected as the final model. Risk stratification was performed using X-tile, and survival analysis was performed using the Kaplan-Meier method with log-rank test. Results    The 5-year postoperative survival rate of the patients was 67.5%. All clinicopathological characteristics of patients between the two groups in the training and test sets were not statistically different (P>0.05). A total of seven variables, including hypertension, history of smoking, history of alcohol consumption, degree of tissue differentiation, pN stage, vascular invasion and nerve invasion, were included for modelling. The AUC values for each model in the independent test set were: decision tree (AUC=0.796), support vector machine (AUC=0.829), random forest (AUC=0.831), logistic regression (AUC=0.838), gradient boosting machine (AUC=0.846), and XGBoost (AUC=0.853). The XGBoost model was finally selected as the best model, and risk stratification was performed on the training and test sets. Patients in the training and test sets were divided into a low risk group, an intermediate risk group and a high risk group, respectively. In both data sets, the differences in surgical prognosis among three groups were statistically significant (P<0.001). Conclusion    Machine learning models have high value in predicting postoperative prognosis of thoracic squamous esophageal cancer. The XGBoost model outperforms common machine learning methods in predicting 5-year survival of patients with thoracic squamous esophageal cancer, and it has high utility and reliability.

Obsessive-compulsive disorder (OCD), which has the main clinical features of intrusive obsessions and compulsive behaviors, is listed as one of the top ten disabling diseases by the World Health Organization.Error related negativity(ERN) is a neurocognitive alarm signal in the case of errors.The individual differences in the ERN reflect the variability in reactivity to errors and to an internally generated threat.More and more studies have reported that ERN amplitudes in OCD have significantly increased.As a result, overactive error-monitoring is a core dysfunction disorder in OCD, which is closely related to the key symptoms of OCD including worry, doubt, repeating check behaviors.In addition, the increased ERN amplitudes are expected to serve as a diagnostic or predictive marker of OCD as well as a potential intervention target of this disease.Therefore, further understanding about the relationship between ERN and pathophysiology of OCD plays an important role in the effective diagnosis and treatment of OCD.The current paper aims to review the research results of ERN in patients with OCD and explore the following issues: the common experiment paradigms of ERN in OCD, the brain region sources of ERN in OCD, the characteristic manifestations of ERN in OCD, influencing factors of ERN and clinical value and application of ERN in OCD.In a word, it will provide reference for clinical practice and scientific research in the future.

Objective:To test whether the constructed intervention model of advance care planning (ACP) for patients with advanced cancer can be successfully implemented and the preliminary intervention effect, which provides reference for empirical research.Methods:32 cases of advanced cancer patients and 25 cases of their families at the Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai were selected. The patients were subdivided into the experimental group and the control group by random number table method. The control group received routine nursing, while the experimental group adopted the intervention model of "VIP for future care" on the basis of customary nursing. We measured the main outcome indicators: enrollment rate, consent rate, completion rate and loss of follow-up rate and secondary outcome indicators: decision-making certainty, end-of-life care preference and post-intervention satisfaction of patients and their families, within 1 week and 1 month after intervention.Results:The enrollment rate, consent rate and loss of follow-up rate were 74.6% (206/276), 36.9% (76/151)and 15.6% (5/32), respectively. After intervention, the completion rates of the experimental group and the control group were 16/16 and 15/16 within one week, and 14/16 and 13/16 within one month. All of the family members were conducted during the follow-up period. The intervention mode of "VIP for future care" had a statistically significant difference in decision-making certainty between the two groups of patients ( β=0.63, 95% CI 0.08-1.18, P<0.05), no statistically significant difference in end-of-life care preference between the two groups of patients and their families ( P>0.05), and had a statistically significant difference in "whether to recommend this project to others" between the two groups ( χ2 value was 4.167 , P<0.05). Conclusions:On the premise of sufficient preparation, the "VIP for future care" intervention mode can be successfully implemented in advanced cancer patients in mainland China, can improve the decision-making certainty of patients and the satisfaction of patients and their families, and it is recommended. And should be applied to ACP intervention for patients with advanced cancer.