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Weiwei Du, Wentao Ji, Tian Luo, Yinying Zhang, Weihong Guo, Jianping Liang, Yanhua Lv Department of Respiratory and Critical Care Medicine, Zhongshan City People’s Hospital, Zhongshan, Guangdong Province, People’s Republic of ChinaCorrespondence: Yanhua Lv, Department of Respiratory and Critical Care Medicine, Zhongshan City People’s Hospital, No. 2 Sunwen East Road, Zhongshan, 528400, Guangdong Province, People’s Republic of China, Tel/Fax +86-760-89880256, Email lyh009001@163.comBackground: The incidence of invasive pulmonary aspergillosis (IPA) is progressively rising in the nonneutropenic population, but studies investigating relevant prognostic factors remain scarce.Methods: Participants who were hospitalized at Zhongshan City People’s Hospital from January 2018 to May 2023 and diagnosed with nonneutropenic deficient IPA were included in this study. The least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression methods were used to select variables for constructing the predictive model. The performance of the predictive model was evaluated using the concordance index (C-index), calibration curve, time-dependent receiver operating characteristic (T-ROC) curve, area under the curve (AUC), and decision curve analysis (DCA). Finally, prognostic risk stratification was performed for nonneutropenic IPA patients, transforming the nomogram into a risk-stratified prognostic model.Results: A total of 210 participants were included in this study, divided into training and validation cohorts at a ratio of 7.5:2.5. Lasso regression identified seven potential predictive factors, including age, comorbid bacterial pneumonia, pleural effusion, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), invasive mechanical ventilation and ICU treatment. Multivariate Cox regression analysis showed age (HR=1.02), comorbid bacterial pneumonia (HR=3.36), NLR (HR=1.02), LDH (HR=1.001), and invasive mechanical ventilation (HR=4.86) as independent predictive factors and constructed nomogram. The calibration curves show that the nomogram performs well in terms of consistency between predictions and actual observations. The T-ROC curves and DCA of the nomogram model show that the recognition ability of the nomogram model was outstanding. Participants could be classified into high and low-risk groups based on the final score of this nomogram, demonstrating the excellent risk stratification performance of our model.Conclusion: The nomogram model developed in this study is an effective tool for predicting mortality risk in nonneutropenic IPA patients, aiding clinicians in identifying high-risk patients and optimizing early treatment strategies.Keywords: invasive pulmonary aspergillosis, pulmonary fungal infections, overall survival, risk stratification, nomogram, model

Yingli Wang,1,2,* Yalin Jiang,2,* Meiling Xie,1,2,* Bin Qi,2 Kunpeng Pu,2 Wenjie Du,2 Qingqing Zhang,2 Mengmeng Ma,2 Ziyong Chen,2 Yongxia Guo,2 Hui Qian,2 Kaiqin Wang,2 Tulei Tian,2 Lin Fu,3 Xiaofei Zhang2 1Bengbu Medical University Graduate School, Bengbu, Anhui, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin Fu, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of China, Tel +86 551 6516 7923, Email fulindev@126.com Xiaofei Zhang, Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, 236800, People’s Republic of China, Email zhangxiaofeibz@163.comBackground: Leucine-rich α-2 glycoprotein 1 (LRG1) is associated with various inflammatory lung diseases. Nevertheless, the connection between LRG1 and adult community-acquired pneumonia (CAP) individuals was still not well understood. Through a prospective cohort study, the correlations of serum LRG1 with severity and prognosis were evaluated in CAP patients.Methods: The study encompassed 327 patients who received the diagnosis of CAP. We collected fasting venous blood and clinical features. Serum LRG1 was detected by ELISA. CAP severity was assessed using various scoring systems. The prognostic outcomes were observed through follow-up visits.Results: The level of serum LRG1 at admission was gradually increased with CAP severity scores. Serum LRG1 level shown positive associations with inflammatory indices, including C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6). Linear and logistic regression analyses suggested that serum LRG1 at admission was positively associated with severity scores and the risk of death in CAP patients. Serum LRG1 in combination with CAP severity scores significantly increased the predictive powers for severity and death compared with single serum LRG1 or severity scores.Conclusion: The study revealed positive connections of serum LRG1 levels with severity and poor prognosis in CAP patients, suggesting LRG1 partakes into the physiological processes of CAP. Serum LRG1 may be regarded as a potential biomarker in predicting the severity and death among CAP patients.Keywords: community-acquired pneumonia, LRG1, severity, outcomes, cohort study

Shuoshuo Li,1 Zhongtao Zhou,1 Ling Cheng,1 Weina Du,1 Zhengqun Pan,2 Jing Zhang3 1School of Nursing, Bengbu Medical University, Bengbu, People’s Republic of China; 2Forest Heights LTC, Kitchener, Ontario, Canada; 3School of Mental Health, Bengbu Medical University, Bengbu, People’s Republic of ChinaCorrespondence: Jing Zhang, School of Mental Health, Bengbu Medical University, Bengbu, 233030, People’s Republic of China, Email mini0217@126.comObjective: Fear of recurrence and reproductive concerns are great public health concerns among breast cancer patients in childbearing age. The purpose of this study was to explore whether psychological resilience and coping styles play mediating roles in fear of recurrence and reproductive concerns among Chinese breast cancer patients in childbearing age.Methods: A total of 1267 breast cancer patients of childbearing age completed the questionnaires, including a brief demographic questionnaire survey. The Chinese version of the Fear of Cancer Recurrence Scale and the Chinese version of the Reproductive Concerns Scale were used to assess the fear of recurrence and reproductive concerns, respectively. And the psychological resilience scale and the simple coping style questionnaire were used to evaluate breast cancer patients’ psychological resilience and coping style during childbearing age. Mediation analyses were conducted by using PROCESS macro in the SPSS software.Results: Fear of recurrence had both direct and indirect effects on Reproductive Concerns. psychological resilience and coping style were not only independent mediators in the relationship between fear of recurrence and Reproductive Concerns but also chain mediators.Conclusion: The results of the current study highlight the crucial role of early intervention for Reproductive Concerns with a focus on fear of recurrence of breast cancer patients of childbearing age, more especially, on those with poorer psychological resilience and coping style.Keywords: childbearing age, breast cancer, fear of recurrence, reproductive concerns, psychological resilience, coping style

Yuan Liu,1,2,* Xingchen Shang,1,* Wenyi Du,1,* Wei Shen,1 Yanfei Zhu1 1Department of General Surgery, Wuxi Medical Center of Nanjing Medical University, Wuxi, People’s Republic of China; 2Department of General Surgery, Tengzhou Central People’s Hospital, Jining Medical College, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Shen; Yanfei Zhu, Department of General Surgery, Wuxi Medical Center of Nanjing Medical University, Wuxi, People’s Republic of China, Tel +8613385110723 ; +8617852061572, Email shenweiijs@outlook.com; wxsrmyy@outlook.comPurpose: The reappearance of gastric cancer, a frequent postoperative complication following radical gastric cancer surgery, substantially impacts the near-term and far-reaching medical outlook of patients. The objective of this research was to create a machine learning algorithm that could recognize high-risk factors for gastric cancer recurrence and anticipate the correlation between gastric cancer recurrence and Helicobacter pylori (H. pylori) infection.Patients and Methods: This investigation comprised 1234 patients diagnosed with gastric cancer, and 37 characteristic variables were obtained. Four machine learning algorithms, namely, extreme gradient boosting (XGBoost), random forest (RF), k-nearest neighbor algorithm (KNN), and multilayer perceptron (MLP), were implemented to develop the models. The k-fold cross-validation technique was utilized to perform internal validation of the four models, while independent datasets were employed for external validation of the models.Results: In contrast to the other machine learning models, the XGBoost algorithm demonstrated superior predictive ability regarding high-risk factors for gastric cancer recurrence. The outcomes of Shapley additive explanation (SHAP) analysis revealed that tumor invasion depth, tumor lymph node metastasis, H. pylori infection, postoperative carcinoembryonic antigen (CEA), tumor size, and tumor number were risk elements for gastric cancer recurrence in patients, with H. pylori infection being the primary high-risk factor.Conclusion: Out of the four machine learning models, the XGBoost algorithm exhibited superior performance in predicting the recurrence of gastric cancer. In addition, machine learning models can help clinicians identify key prognostic factors that are clinically meaningful for the application of personalized patient monitoring and immunotherapy.Keywords: gastric tumor, gastrectomy, helicobacter pylori, immunotherapy, risk factor, machine learning

Yingying Tu,1 Wenwen Du,2 Yuanyuan Pan,2 Xiaozhen Zhang,1 Yunchang Mo,2 Caixia Sun,1 Junlu Wang2 1Nursing Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Junlu Wang, Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, South Baixiang Street, Ouhai District, Wenzhou City, Zhejiang, 325000, People’s Republic of China, Email wangjunlu973@163.comBackground: Postoperative high-activity delirium (PDHA) manifests as a high alertness, restlessness, hallucinations, and delusions. Occurrence of PDHA represents an increased risk of poor prognosis for patients.Objective: To establish and validate a nomogram prediction model for high-activity delirium after non-cardiac surgery in a post-anesthesia care unit (PACU).Methods: This study retrospectively enrolled adult patients who underwent non-cardiac surgery and were observed in the PACU as training data. Patients were divided into PDHA (199 patients) and non-PDHA (396 patients) groups. Patients’ general data, preoperative indicators, intraoperative conditions, and postoperative PACU conditions were collected. The risk factors for PDHA were identified using univariate and multivariate logistic regression analyses. A predictive column chart was created using R language. Adult patients who underwent non-cardiac surgery and entered the PACU for observation were randomly selected as the validation set data (198 cases) for model performance validation.Results: The incidence rate of adult PDHA in the PACU was 0.275%. Sex, age, smoking history, low preoperative albumin level, Society of Anesthesiologists (ASA) classification, anesthesia duration, and postoperative PACU pain score were independent risk factors for hyperactive delirium in PACU adults. In this study, an adult PACU PDHA nomogram prediction model was developed. The training dataset verified that the ROC curve (area under the curve) and 95% confidence interval (95% CI) were 0.936 (0.917– 0.955). The ROC curve of the validation data row showed that the area under the curve and 95% CI were 0.926 (0.885– 0.967).Conclusion: The nomogram predictive model for PACU adult high-activity delirium constructed in this study showed good predictive performance. This model could enable the visualization and graphical prediction of adult high-activity delirium occurrence after PACU, which has clinical value.Keywords: post anesthesia care unit, PACU, delirium, risk factor, nomograms

Jiangping Zhang,* Xinran Liu,* Xiaorong Zhou, Yumei Li, Ke Chen, Tingting Kang, Wenting Du, Rongfei Suo The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai City, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaorong Zhou, The Fifth Affiliated Hospital of Sun Yat-sen University, Meihua Road, Xiangzhou District, Zhuhai City, Guangdong Province, People’s Republic of China, Tel +86-756-15916286566, Email joxiaoro@163.comObjective: To explore the relationships among benefit finding (BF), self-management, and quality of life (QOL) among patients with COPD.Methods: A total of 205 patients with COPD were selected via a convenient sampling method. BF refers to the ability to find meaning or benefit from difficult situations. The Benefit Finding Scale (BFS), self-management scale, and 36-item Short-Form Health Survey (MOS SF-36) were used to investigate BF, self-management and QOL (including a physical component summary (PCS) and a psychological component summary (MCS)). Structural equation modeling was used to examine the relationships among BF, self-management and QOL in patients with COPD and to analyze the effects of BF and self-management on QOL.Results: The total QOL score of patients with COPD was 61.38± 21.15, and the PCS and MCS scores were 57.67± 23.60 and 65.09± 21.24, respectively. BF and self-management had positive predictive effects on both the PCS (βBF = 0.519, PBF = 0.012; βself-management = 0.473, Pself-management = 0.012) and MCS (βBF = 0.425, PBF = 0.013; βself-management = 0.535, Pself-management = 0.016) of patients with COPD, and self-management mediated the relationships of BF with the PCS (β = 0.144, P = 0.008) and MCS (β = 0.162, P = 0.007).Conclusion: The QOL of patients with COPD needs to be improved, especially in terms of physical aspects. Helping COPD patients obtain better BF not only helps them improve their PCS and MCS directly but also indirectly through enhancing self-management to improve their PCS and MCS.Keywords: COPD, benefit finding, self-management, quality of life

Xuan Ma,1,2,&ast; Baolan Ji,2,&ast; Wenhua Du,2 Shuwei Shi,1,2 Hongyan Zhao,1,2 Jie Sheng,1,2 Xinghe Jiang,1,2 Bo Ban,3 Guanqi Gao2 1School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, 261000, People’s Republic of China; 2Department of Endocrinology, Linyi People’s Hospital Affiliated to Shandong Second Medical University, Linyi, Shandong, 276034, People’s Republic of China; 3Department of Endocrinology, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanqi Gao, Department of Endocrinology, Linyi People’s Hospital, North Side of the Intersection of Wohushan Road and Wuhan Road in Lanshan District, Linyi, Shandong, 276034, People’s Republic of China, Email guanqi_gao@yeah.net Bo Ban, Department of Endocrinology, Affiliated Hospital of Jining Medical University, 89 Guhuai Road, Jining, Shandong, 272029, People’s Republic of China, Email banbo2011@163.comPurpose: Substantial evidence has established a strong association between non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and insulin resistance (IR). Insulin resistance metabolic score (METS-IR) is a new and more effective comprehensive indicator for measuring IR. Our aim was to investigate the relationship between METS-IR and NAFLD in T2DM population.Patients and methods: This cross-sectional study included 1097 adult patients with T2DM. Anthropometric measurements and biochemical indicators were collected, and the NAFLD was diagnosed by ultrasound. The METS-IR was calculated. Based on the presence of NAFLD, the population was divided into non-NAFLD and NAFLD groups. The relationship between METS-IR and NAFLD was evaluated.Results: Compared with the non-NAFLD group, the METS-IR was higher in the NAFLD group (P < 0.001). The incidence rate of NAFLD increased across the quartiles of the METS-IR (P < 0.001). Spearman correlation analysis showed that METS-IR was positively correlated with NAFLD (Correlation Coefficient: 0.441, P < 0.001). The binary logistic regression analysis indicated that METS-IR was independently associated with NAFLD (OR: 1.120, 95% CI 1.080– 1.161). Furthermore, the area under the receiver operating characteristic curve of the METS-IR was 0.781 (95% CI 0.746– 0.817) and relatively higher than other evaluation variables.Conclusion: In patients with T2DM, METS-IR is closely associated with NAFLD, and might be a valuable predictor of NAFLD. Further research is needed to verify this association.Keywords: Type 2 diabetes mellitus, NAFLD, insulin resistance, METS-IR

Jiaqing Zhou,1 Huan Xu,2 Wen Du,1 Lijun Peng1 1Department of Respiratory Medicine, West China Fourth Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Scientific Affairs, Vision Medicals for Infectious Diseases, Guangzhou, People’s Republic of ChinaCorrespondence: Lijun Peng, Department of Respiratory Medicine, West China Fourth Hospital, Sichuan University, No. 17, Section 3, Renmin South Road, Wuhou District, Chengdu, 610041, People’s Republic of China, Tel +86 13208119408, Email penglijun711@163.comAbstract: We reported a 51-year-old male electric welder with stage I pneumoconiosis, who had no significant cough, sputum, fever, chest pain, or other discomfort. However, regular physical examination at our hospital revealed bilateral pulmonary nodules with cavity formation. Blood routine, liver or kidney function, and infection-related biomarkers, including interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and procalcitonin (PCT), were normal. Sputum and alveolar lavage fluid (BALF) acid-fast bacilli (AFB) smears, BALF Mycobacterium tuberculosis (TB) PCR, and T-SPOT.TB were negative. The nucleic acid sequence of Mycobacterium europaeum was detected by BALF metagenomic next-generation sequencing (mNGS), which was confirmed by the subsequent positive culture for NTM. Considering stable conditions, no significant discomfort, and no significant changes in the lung lesion, the patient was diagnosed with inactive nontuberculous mycobacterial pulmonary disease (NTM-PD).Keywords: pneumoconiosis, nontuberculous mycobacterial pulmonary disease, NTM-PD, Mycobacterium europaeum, metagenomic next-generation sequencing, mNGS

Jing Wang,1,&ast; Yanxiang Sang,2,&ast; Weijian Chen,3 Liang Cheng,2 Wenxiang Du,2 Hongjie Zhang,2 Benyan Zheng,2 Lei Song,2 Yuan Hu,2 Xiaopeng Ma1 1Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2State Key Laboratory of Fire Science, University of Science and Technology of China, Hefei, Anhui, 230006, People’s Republic of China; 3Technology Center, China Tobacco Anhui Industrial Co, Ltd, Hefei, Anhui, 230088, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuan Hu; Xiaopeng Ma, Email yuanhu@ustc.edu.cn; XiaopengMa@fsyy.ustc.edu.cnIntroduction: As an effective alternative choice to traditional mono-therapy, multifunctional nanoplatforms hold great promise for cancer therapy. Based on the strategies of Fenton-like reactions and reactive oxygen species (ROS)-mediated therapy, black phosphorus (BP) nanoplatform BP@Cu2O@L-Arg (BCL) co-assembly of cuprous oxide (Cu2O) and L-Arginine (L-Arg) nanoparticles was developed and evaluated for synergistic cascade breast cancer therapy.Methods: Cu2O particles were generated in situ on the surface of the BP nanosheets, followed by L-Arg incorporation through electrostatic interactions. In vitro ROS/nitric oxide (NO) generation and glutathione (GSH) depletion were evaluated. In vitro and in vivo anti-cancer activity were also assessed. Finally, immune response of BCL under ultrasound was investigated.Results: Cu2O was incorporated into BP to exhaust the overexpressed intracellular GSH in cancer cells via the Fenton reaction, thereby decreasing ROS consumption. Apart from being used as biocompatible carriers, BP nanoparticles served as sonosensitizers to produce excessive ROS under ultrasound irradiation. The enhanced ROS accumulation accelerated the oxidation of L-Arg, which further promoted NO generation for gas therapy. In vitro experiments revealed the outstanding therapeutic killing effects of BCL under ultrasound via mechanisms involving GSH deletion and excessive ROS and NO generation. In vivo studies have illustrated that the nanocomplex modified the immune response by promoting macrophage and CD8+ cell infiltration and inhibiting MDSC infiltration.Discussion: BCL nanoparticles exhibited multifunctional characteristics for GSH depletion-induced ROS/NO generation, making a new multitherapy strategy for cascade breast cancer therapy.Keywords: black phosphorus, combination cancer therapy, sonodynamic therapy, chemodynamic therapy, nitric oxide gas therapy

Weiquan Du,1 Zhaoyuan Fan,1 Diankun Li,2 Mingshuang Wu1 1School of Sociology and Population Studies, Nanjing University of Posts and Telecommunications, Nanjing, People’s Republic of China; 2School of Economics, Nanjing University of Posts and Telecommunications, Nanjing, People’s Republic of ChinaCorrespondence: Weiquan Du, School of Sociology and Population Studies, Nanjing University of Posts and Telecommunications, No. 9, Wenyuan Road, Nanjing City, 210023, People’s Republic of China, Tel +86 13451870628, Email duwq@njupt.edu.cnPurpose: This study focuses on how Internet use behavior affects adolescents’ mental health and whether self-education expectations and parental support mediate the relationship between Internet use behavior and adolescents’ mental health.Methods: The data for this paper came from the results of the student questionnaire of the 2018 Programme for International Student Assessment (PISA 2018), which was a structured questionnaire that asked students about their family situation, school life, studies, internet use, and mental health, among other things. A sample of 336,600 children in grades 7– 13 was selected for this study. The data were analyzed using STATA version 16 and the theoretical framework was tested using a mediated effects model.Results: The results of the study showed that Internet use behavior made a positive contribution to mental health and the mediating effects of self-education expectations and parental support on the relationship between Internet use behavior and adolescent mental health were all significant.Conclusion: It is recommended that appropriate policies should be formulated to help adolescents use the Internet rationally, and the positive effects of parental support and self-education expectations should be utilized.Keywords: adolescent, mental health, internet use, self-education expectations, parental support

Wenyi Du,1,&ast; Yixuan Wang,2,&ast; Chen Song,1 Zhiqiang Tian,1 Yuan Liu,1 Wei Shen1 1Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 2Medical Integration and Practice Center, Reproductive Hospital Affiliated to Shandong University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuan Liu; Wei Shen, Department of General Surgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China, Tel +86 17852061572 ; +86 13385110723, Email liuyuanjs@outlook.com; shenweijs@outlook.comPurpose: Previous studies have shown a correlation between diabetes mellitus and gallstone formation. The atherogenic index of plasma (AIP) is associated with many metabolic diseases. However, insufficient evidence still exists to elucidate the association between AIP and gallstones. The primary objective of this study was to investigate the correlation between AIP and gallstones in US adults, and the secondary objective was to analyze whether diabetes plays a mediating role in the association.Patients and Methods: Using data from the National Health and Nutrition Survey (NHANES) conducted between 2017 and March 2020, this study investigated the association between AIP and gallstone incidence in US adults. A variety of statistical methods were used to analyze the data in this study, including multivariate logistic regression, subgroup analyses, restricted cubic spline curves (RCS), and mediation effects analysis. In addition, two-stage linear regression was used to detect possible threshold and saturation effects.Results: A total of 6952 subjects were enrolled in the trial, of which 748 patients were diagnosed with gallstones. A significant positive association between AIP and gallstones was observed by fully adjusted multivariate logistic regression analysis, with an odds ratio (OR) of 1.45 and a 95% confidence interval (CI) of (1.09, 1.93). In addition, a non-linear positive association and saturation effect between AIP and gallstones were found, with an inflection point of 0.2246. Mediation analysis showed that diabetes had a mediating effect of 16.9% in the association between AIP and gallstones.Conclusion: This study suggests that elevated levels of AIP are linked to an augmented vulnerability to gallstone development, with diabetes serving as a mediating factor. These findings present a novel perspective on clinical approaches to prevent and manage gallstones.Keywords: gallstones, atherogenic index of plasma, diabetes mellitus, National Health and Nutrition Examination Survey, cross-sectional studies

Yue Cao, Yue-Yue Feng, Wei Du, Jing Li, Ya-Lan Fei, Hao Yang, Meng Wang, Shi-Jie Li, Xian-Jin Li, Bing Han Division of Cardiology, Xuzhou Central Hospital, Xuzhou, People’s Republic of ChinaCorrespondence: Bing Han, Division of Cardiology, Xuzhou Central Hospital, 199 South Jiefang Road, Xuzhou, 221009, People’s Republic of China, Tel +86-516-83985069, Fax +86-516-83956012, Email hbing777@hotmail.comPurpose: To investigate the reasons for elderly atrial fibrillation (AF) patients not continuing their oral anticoagulation (OAC) treatment and the factors that influence this behavior.Methods: Elderly AF patients (aged≥ 75 years) hospitalized from December 2019 to May 2022 were consecutively enrolled. Clinical, demographic, and concomitant medication data were collected. The endpoint was defined as OAC discontinuation for more than 30 days or a switch to an alternative therapy. Predictors of OAC non-persistence were investigated using a multivariable Cox regression model.Results: This study included 560 participants (51.1% men, mean age 80.9± 0.2 years). During a median follow-up of 20 months, medication persistence was observed in 322 patients (57.5%). Non-persistence was found to be significantly higher with warfarin than with NOAC (48.8% vs 33.6%, p = 0.006). In the multivariate analysis, OAC non-persistence was independently predicted by a history of permanent pacemaker implantation, the use of antiplatelet drugs, employee Medicare, living with children, college degree or above, and persistent AF (HR = 1.580, 1.586, 0.604, 0.668, 0.028, 0.769, p < 0.05, respectively). Treatment discontinuation within 3 months of discharge was observed in a large number of patients (81.8%). Medication discontinuation due to bleeding was more frequently observed in patients who continued for longer than 3 months (p < 0.001), while discontinuation due to patient preference was more frequent in those with shorter durations (≤ 3 months) (p = 0.049). Patient preference was the second leading cause of non-persistence in patients, regardless of whether they were taking warfarin or NOAC.Conclusion: OAC non-persistence remains high among elderly AF patients during long-term follow-up, with a significant proportion discontinuing shortly after discharge. This pattern of non-persistence is heavily influenced by demographic factors and patient preference. Further interventions should be developed based on the reasons and risk factors to improve persistence and initiated early in the treatment process.Keywords: atrial fibrillation, the elderly, oral anticoagulants, non-persistence

Zhiqiang He,1 Huan Yang,1 Yufan Gu,1 Yuhan Xie,1 Jianan Wu,1 Chen Wu,1 Jiawei Song,1 Maofang Zhao,2,3 Da Zong,1 Wenlong Du,1 Jiaju Qiao,1 Yipeng Pang,1– 3 Yi Liu1– 3 1Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 2School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of ChinaCorrespondence: Yi Liu; Yipeng Pang, Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China, Tel/Fax +86-0516-83262084, Email cbpeliuyinew@163.com; pangyipeng.xzmu@foxmail.comPurpose: Herein, an emerging drug delivery system was constructed based on zeolite imidazole backbone (ZIF-8) to improve antibacterial defects of nanosilver (AgNPs), such as easily precipitated and highly cytotoxic.Methods: The homogeneous dispersion of AgNPs on ZIF-8 was confirmed by UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM. The appropriate AgNPs loading ratio on ZIF-8 was screened through the cell and antibacterial experiments based on biosafety and antibacterial performance. The optimal environment for AgNPs@ZIF-8 to exert antibacterial performance was probed in the context of bacterial communities under different acid-base conditions. The potential mechanism of AgNPs@ZIF-8 to inhibit the common clinical strains was investigated by observing the biofilm metabolic activity and the level of reactive oxygen species (ROS) in bacteria.Results: The successful piggybacking of AgNPs by ZIF-8 was confirmed using UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM characterization methods. Based on the bacterial growth curve (0– 24 hours), the antibacterial ability of AgNPs@ZIF-8 was found to be superior to AgNPs. When the mass ratio of ZIF-8 and AgNPs was 1:0.25, the selection of AgNPs@ZIF-8 was based on its superior antimicrobial efficacy and enhanced biocompatibility. Notably, under weakly acidic bacterial microenvironments (pH=6.4), AgNPs@ZIF-8 demonstrated a more satisfactory antibacterial effect. In addition, experiments on biofilms showed that concentrations of AgNPs@ZIF-8 exceeding 1×MIC resulted in more than 50% biofilm removal. The nanomedicine was found to increase ROS levels upon detecting the ROS concentration in bacteria.Conclusion: Novel nanocomposites consisting of low cytotoxicity drug carrier ZIF-8 loaded with AgNPs exhibited enhanced antimicrobial effects compared to AgNPs alone. The pH-responsive nano drug delivery system, AgNPs@ZIF-8, exhibited superior antimicrobial activity in a mildly acidic environment. Moreover, AgNPs@ZIF-8 effectively eradicated pathogenic bacterial biofilms and elevated the intracellular level of ROS.Graphical Abstract: Keywords: MOF, ZIF-8, AgNPs, nanocomplex, ROS, pathogenic biofilm

Jing Wang,1,&ast; Weijian Chen,1,2,&ast; Wenxiang Du,2 Hongjie Zhang,2 Matthias Ilmer,3 Lei Song,2 Yuan Hu,2 Xiaopeng Ma1 1Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2State Key Laboratory of Fire Science, University of Science and Technology of China, Hefei, Anhui, 230026, People’s Republic of China; 3Department of General, Visceral, and Transplantation Surgery, Ludwig-Maximilians-University (LMU), Campus Grosshadern, Munich, 81377, Germany&ast;These authors contributed equally to this workCorrespondence: Yuan Hu; Xiaopeng Ma, Email yuanhu@ustc.edu.cn; XiaopengMa@fsyy.ustc.edu.cnIntroduction: Tamoxifen (TAM) has proven to be a therapeutic breakthrough to reduce mortality and recurrence in estrogen receptor-positive (ER+) breast cancer patients. However, the application of TAM exhibits low bioavailability, off-target toxicity, instinct and acquired TAM resistance.Methods: We utilized black phosphorus (BP) as a drug carrier and sonosensitizer, integrated with TAM and tumor-targeting ligand folic acid (FA) to construct TAM@BP-FA for synergistic endocrine and sonodynamic therapy (SDT) of breast cancer. The exfoliated BP nanosheets were modified through in situ polymerization of dopamine, followed by electrostatic adsorption of TAM and FA. The anticancer effect of TAM@BP-FA was evaluated through in vitro cytotoxicity and in vivo antitumor model. RNA-sequencing (RNA-seq), quantitative real-time PCR, Western blot analysis, flow cytometry analysis and peripheral blood mononuclear cells (PBMCs) analysis were performed for mechanism investigation.Results: TAM@BP-FA had satisfactory drug loading capacity, the TAM release behavior can be controlled through pH microenvironment and ultrasonic stimulation. An amount of hydroxyl radical (∙OH) and singlet oxygen (1O2) were as expected generated under ultrasound stimulation. TAM@BP-FA nanoplatform showed excellent internalization in both TAM-sensitive MCF7 and TAM-resistant (TMR) cells. Using TMR cells, TAM@BP-FA displayed significantly enhanced antitumor ability in comparison with TAM (7.7% vs 69.6% viability at 5μg/mL), the additional SDT further caused 15% more cell death. RNA-seq unraveled the TAM@BP-FA antitumor mechanisms including effects on cell cycle, apoptosis and cell proliferation. Further analysis showed additional SDT successfully triggering reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) reduction. Moreover, PBMCs exposed to TAM@BP-FA induced an antitumor immune response by natural killer (NK) cell upregulation and immunosuppression macrophage reduction.Conclusion: The novel BP-based strategy not only delivers TAM specifically to tumor cells but also exhibits satisfactory antitumor effects through targeted therapy, SDT, and immune cell modulation. The nanoplatform may provide a superior synergistic strategy for breast cancer therapy.Keywords: black phosphorus, breast cancer, sonodynamic therapy, tamoxifen, PBMC, combination therapy

Wenbo Du,1 Zhihua Li,2 Yanan Xu,1 Chaoyang Chen1 1Department and Institute of Psychology, Ningbo University, Ningbo, Zhejiang Province, 315211, People’s Republic of China; 2Institute of Education, Hunan University of Science & Technology, Xiangtan, Hunan Province, 411201, People’s Republic of ChinaCorrespondence: Chaoyang Chen, Department and Institute of Psychology, Ningbo University, Ningbo, 315211, Zhejiang Province, People’s Republic of China, Email ccy6409@sina.comPurpose: Grit plays a critical role in the academic achievement and future career success of college students. The family environment has an important influence on the development of individual grit, but the mechanisms linking family and grit are not well known. To further understand these relationships, this study sought to explore the mediating role of basic psychological needs between parental autonomy support and grit, and the moderating role of achievement motivation.Methods: The present study model was developed according to the proposed hypotheses and was analyzed using structural equation modeling. A total of 984 college students in Hunan Province, China participated in the present study. The following tools were used: Perceived Parental Autonomy Support Scale, Basic Psychological Needs Scales, Short Grit Scale, and Achievement Motivation Scale.Results: Parental autonomy support was positively correlated with basic psychological needs and grit, and both basic psychological needs and achievement motivation were positively correlated with grit. Basic psychological needs mediated the effect of parental autonomy support on grit. Achievement motivation moderated the second half of the path of the mediation model.Conclusion: Parental autonomy support influences perseverance through the mediation of basic psychological needs, and achievement motivation plays a moderating role. Findings of this study reveal the influence of family environment on grit, and give reference to the development of grit.Keywords: parental autonomy support, grit, basic psychological needs, achievement motivation, family environment

Lijun Fan,1,2 Hui Xue,1 Qian Wang,3 Yuhan Yan,4 Wei Du1 1School of Public Health, Southeast University, Nanjing, People’s Republic of China; 2School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 4General Hospital of Eastern Theater Command, Nanjing, People’s Republic of ChinaCorrespondence: Wei Du, School of Public Health, Southeast University, Nanjing, 210009, People’s Republic of China, Email duwei@seu.edu.cn Yuhan Yan, General Hospital of Eastern Theater Command, Nanjing, 210009, People’s Republic of China, Email yanyuhan0215@163.comObjective: The identification of older patients at risk of repeated emergency department (ED) visits is crucial for managing preventable adverse outcomes. This study aims to identify risk factors associated with ED revisits and to develop and validate a nomogram for predicting risk of geriatric ED revisits.Methods: This was a cohort study comprising 553 older patients, who attended the two tertiary hospitals EDs in China from August 2018 to February 2019 and were prospectively followed for any unplanned revisit within 1 year after discharge. Patients were randomly assigned to a training or validation set at a ratio of 2:1. Stepwise selection procedure was applied to select factors associated with ED revisits for inclusion in a multivariable logistic model from which a nomogram was elaborated. Discrimination, calibration and clinical utility of the nomogram were assessed using C-statistic, calibration plot, Hosmer-Lemeshow test, and decision curve analysis (DCA).Results: The final nomogram included four predictors for ED revisits: age, BMI, frailty and polypharmacy. Older patients having revisits were more likely to be frail (OR = 1.17, p = 0.031), have polypharmacy (OR = 1.69, p = 0.049) or BMI < 18.5 kg/m2 (OR = 2.45, p = 0.025), and were less likely to be older than 90 years (OR = 0.21, p = 0.002). The nomogram demonstrated acceptable discrimination ability in the training (C-index = 0.661) and validation sets (C-index = 0.651), satisfactory calibration (p > 0.05), and good clinical applicability.Conclusion: A nomogram incorporating four obtainable variables was constructed to individualize ED readmission risk in older patients. These patients may benefit from early triage and better-targeted care if considering the nomogram as a clinical decision aid.Keywords: nomogram, risk prediction, emergency department revisit, acute care, older adults

Jing Hua,1,&ast; Jiajun Lyu,1,&ast; Wenchong Du2 1Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2NTU Psychology, Nottingham Trent University, Nottingham, UK&ast;These authors contributed equally to this workCorrespondence: Wenchong Du, NTU Psychology, Nottingham Trent University, Burton Street, Nottingham, NG1 4BU, UK, Email vivienne.du@ntu.ac.uk Jing Hua, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 2699 Gaoke Road, Shanghai, People’s Republic of China, Email Jinghua@tongji.edu.cnStudy Objectives: This study provides data on the prevalence of clinical sleep disorders in Chinese preschoolers aged 3– 5 years old and examined their sleep behaviours and problems with a nationally representative sample.Methods: A national population-based cohort study was conducted with 114,311 children aged 3– 5 years old from 551 cities in China. Children’s daily sleep hours and pediatric sleep disorders defined by the Children’s Sleep Habits Questionnaire (CSHQ) were reported by parents.Results: The estimated sleep disorder prevalence was 76.78% (95% CI:76.54%, 77.03%). Rates of specific disorders were as follows: Bedtime resistance (97.00%, 95% CI:96.90%, 97.10%), Daytime sleepiness (77.68%,95% CI:77.43%, 77.92%), Sleep duration (70.24%,95% CI:69.97%, 70.50%), Parasomnia (58.52%,95% CI:58.23%, 58.80%), Sleep anxiety (55.53%,95% CI:55.24%, 55.81%), Sleep onset delay (51.99%,95% CI:51.70%, 52.28%) Night wakings (30.37%,95% CI:30.10%, 30.63%) and Sleep-disordered breathing (21.86%, 95% CI: 21.62%, 22.09%). The prevalence of sleep disorder, daily sleep hours and rates of specific disorder varied across children of different sex and ages.Conclusion: A high prevalence of sleep disorder was found in Chinese preschoolers, and the specific sleep problems of Chinese preschoolers vary from other cultures. A local standard may be required when using the CSHQ to define sleep disorders in children in China. An in-depth investigation into the reasons for the high sleep disorder prevalence should be conducted and supportive intervention should be provided to preschoolers in China.Keywords: sleep disorder, Chinese preschooler, national prevalence, the Children’s Sleep Habits Questionnaire

Zhiguo Zhang,1,2,&ast; Fangda Fu,1,2,&ast; Yishan Bian,1,2,&ast; Huihao Zhang,1,2 Sai Yao,1,2 Chengcong Zhou,1,2 Yuying Ge,2 Huan Luo,3 Yuying Chen,4 Weifeng Ji,1 Kun Tian,1 Ming Yue,5 Weibin Du,6 Hongting Jin,1 Peijian Tong,1 Chengliang Wu,1,2 Hongfeng Ruan1,2 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, People’s Republic of China; 2The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5Department of Physiology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 6Research Institute of Orthopedics, The Affiliated Jiangnan Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Chengliang Wu, Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Fax +86 571 86613684, Email rhf@zcmu.edu.cn; wcl@zcmu.edu.cnBackground: With the rapid growth of the elderly population, the incidence of osteoarthritis (OA) increases annually, which has attracted extensive attention in public health. The roles of dietary intake in controlling joint disorders are perhaps one of the most frequently posed questions by OA patients, while the information about the interaction between dietary intake and OA based on scientific research is limited. α-Chaconine is the richest glycoalkaloid in eggplants such as potatoes. Previous evidence suggests that α-Chaconine is a toxic compound to nervous and digestive systems with potentially severe and fatal consequences for humans and farm animals, but its effect on OA development remains obscure.Objective: To determine whether α-Chaconine deteriorates OA progression through sensory innervation and chondrocyte pyroptosis via regulating nuclear factor-κB (NF-κB) signaling, providing evidence for a possible linkage between α-Chaconine and OA progression.Methods: We established a mouse OA model by destabilization of medial meniscus (DMM) surgery and then intra-articular injection of 20 or 100 μM α-Chaconine into the OA mice for 8 and 12 weeks. The severity of OA progression was evaluated by histological staining and radiographic analyses. The expressions of matrix metabolic indicators, Col2, Mmp3, and Mmp13, as well as pyroptosis-related proteins, Nlrp3, Caspase-1, Gsdmd, IL-1β, IL-18, were determined by immunohistochemistry. And the changes in sensory nerve ingrowth and activity of NF-κB signaling were determined by immunofluorescence.Results: We found that α-Chaconine could exacerbate mouse OA progression, resulting in subchondral sclerosis, osteophyte formation, and higher OARSI scores. Specifically, α-Chaconine could augment cartilage matrix degradation and induce chondrocyte pyroptosis and nerve ingrowth. Mechanistical analysis revealed that α-Chaconine stimulated NF-κB signaling by promoting I-κB α phosphorylation and p65 nuclear translocation.Conclusion: Collectively, our findings raise the possibility that α-Chaconine intake can boost chondrocyte pyroptosis and nerve ingrowth to potentiate OA progression by activating NF-κB signaling.Graphical Abstract: Keywords: α-Chaconine, osteoarthritis, pyroptosis, nerve ingrowth, NF-κB signaling

Di Liu,1 Bing Chen,1 Tao Li,1 Lijiang Zheng,1 Jialu Li,2 Weiyan Du,1 Minglei Wang,3 Yinlan Huang1 1Ningxia Medical University, Yinchuan, People’s Republic of China; 2People’s Hospital of Ningxia Hui Autonomous Region, Yinchuan, People’s Republic of China; 3Department of Radiology, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of ChinaCorrespondence: Yinlan Huang, Ningxia Medical University, No. 1160, Shengli Street, Xingqing District, Yinchuan, People’s Republic of China, Tel +86 18209506917, Email lzdbe@163.comPurpose: In this study, we aimed to systematically determine the trend, research hotspots, and directions of the future development of acupuncture for neuropathic pain (NP) by bibliometric analysis.Methods: Based on the relevant literature on acupuncture for NP in the databases of Web of Science from January 2002 to December 2021, Citespace software and VOSviewer were used to determine the use of acupuncture for the treatment of NP. The annual publications, countries, authors, research institutions, keywords, co-cited references, and journals were analyzed to explore the research hotspot and development trends in this field.Results: A total of 1462 records of acupuncture for NP from 2002 to 2021 were obtained. Chingliang Hsieh (20) is the most effective author and Han JS (585 co-citations) is the most influential author. The most productive institutions and countries are Kyung Hee UNIV (88) and China, respectively (480). UNIV Maryland of the USA has the highest centrality (0.12). Evidence-based complementary and alternative medicine (89) is the most prolific journal, and Pain is the most influential journal (4200 co-citations). Ji-sheng Han (2003) is the most frequently cited article (158 co-citations). Electroacupuncture, bee-venom acupuncture, and percutaneous electrical stimulation are the most commonly studied acupuncture types. The analgesic mechanism of acupuncture and acupuncture-neuroimaging was a research hotspot over the years. The clinical evidence of acupuncture for NP should be further studied in the future.Conclusion: The study using bibliometric analysis methods to investigate the publications on acupuncture for NP so as to provide potential research directions in the future.Keywords: acupuncture, neuropathic pain, therapy, bibliometrics, visualized study

Weijia Du1 &ast;, Lulong Bo2 &ast;, Zhendong Xu,1 Zhiqiang Liu1 1Department of Anesthesiology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqiang Liu; Zhendong Xu, Department of Anesthesiology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China, Tel +86 13816877756 ; +86 13817029904, Email drliuzhiqiang@163.com; btxzd123@126.comAbstract: Pregnancy and childbirth are major life events for women and their families, characterized by physical, psychological, and emotional changes that can trigger anxiety, depression, and mental disorders in susceptible individuals. Acute labor pain is an independent risk factor for persistent pain in the postpartum period and is associated with depressive disorders. Epidural analgesia is a well-established technique that has commonly been regarded as the gold standard in pain management during labor. Although the relationships between labor pain, labor epidural analgesia, and postpartum depression have been studied by many investigators, the results of these studies are conflicting. Some literature suggest that labor epidural analgesia is associated with a reduction in the incidence of postpartum depression; however, other studies have failed to demonstrate this association. Unmet analgesic needs expectations, unmet birth expectations, and/or the quality of social support during labor may contribute to postpartum depression. The limitations of the published studies included differential misclassification of study variables and residual confounding, variations in the diagnosis of depression, and incomplete history data. Thus, future studies should include information on sociodemographic and patient-level variables and assessments of pain during labor or in the postpartum period. Better management of labor pain should be provided to prevent long-term morbidity and improve maternal and neonatal outcomes. Anesthesiologists could collaboratively work with obstetricians and perinatal psychiatrists to ensure that hospitals prioritize screening and treatment for postpartum depression.Keywords: epidural labor analgesia, labor pain, neuraxial analgesia, postpartum depressive disorder, pain management in labor

Xiao-Min Zhang, Ming-Hui Lun, Wei Du, Fang Ma, Ze-Qing Huang Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institution, NO.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People’s Republic of ChinaCorrespondence: Xiao-Min Zhang; Ze-Qing Huang Department of Anesthesiology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institution, No.44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning Province, 110042, People’s Republic of China Email zhangxiaomin.99@163.com; huangzeqing0@163.comObjective: To observe the ameliorative effect of kappa opioid receptor (KOR) agonist on rats with neuropathic pain (NP) and investigate the mechanism of action of the calcium ion (Ca2+)/calcium/calmodulin-dependent protein kinase II (CaMKII)/cyclic AMP response element-binding protein (CREB) pathway.Methods: A total of 40 Sprague Dawley rats were randomly divided into four groups: sham-operation group (Sham group), NP model group (NP group), NP + KOR agonist U50488H group (NU group) and NP + specific CaMKII antagonist (KN93) + U50488H group (NKU group). The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of each group of rats were determined. ELISA was applied to examine the changes in inflammatory factors and oxidative stress factors, and the apoptotic rate in dorsal root ganglia was observed using TUNEL staining. Ca2+ concentration, content of oxidative stress index ROS and the release of calcitonin gene-related peptide (CGRP) and N-methyl-D-aspartate receptor (NMDAR) in the dorsal root ganglia were measured by the immunofluorescence assay. Finally, Western blotting was performed to detect expression changes in the Ca2+/CaMKII/CREB pathway.Results: The KOR agonist U50488H could improve the values of TWL and MWT of NP the rats, inhibit inflammatory responses and relieve oxidative stress injury. Its mechanisms of action were associated with U50488H repression of Ca2+ influx, reduction of CGRP and NMDAR releases in the dorsal root ganglia and decreases in CaMKII and CREB phosphorylations in NP rats.Conclusion: The KOR agonist ameliorates NP through suppressing the activity of the Ca2+/CaMKII/CREB pathway.Keywords: KORs, neuropathic pain, Ca2+, CaMKII, CREB

Weijia Du,&ast; Yujie Song,&ast; Jiang Li, Xianjin Zhou, Zhendong Xu, Zhiqiang Liu Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqiang Liu; Zhendong Xu, Department of Anesthesiology, Shanghai First Maternity and Infant Hospital School of Medicine, Tongji University, No. 2699, West Gaoke Road, Shanghai, People’s Republic of China, Email drliuzhiqiang@163.com; btxzd123@126.comBackground: Norepinephrine has been associated with improved heart rate (HR) and cardiac output (CO) compared to phenylephrine as a treatment for post-spinal hypotension during caesarean delivery (CD) in singleton pregnancies. Our current study compared the effects of norepinephrine and phenylephrine in maintaining maternal hemodynamics after spinal anaesthesia in twin pregnancies during elective CD.Methods: This was a double-blinded, randomized, controlled study. From December 2017 to December 2018, 62 women with healthy twin term pregnancies undergoing elective CD under spinal anaesthesia were studied. Following spinal induction, either norepinephrine (6 μg/mL) or phenylepinephrine (75 μg/mL) was infused at 60 mL/h to maintain systolic blood pressure (SBP) near baseline until delivery. HR, SBP, systemic vascular resistance (SVR), and CO were collected using anaesthesia monitors and continuous-pulse waveform analysis. The primary outcome was maternal CO. Other parameters of maternal hemodynamics, umbilical cord blood gases, and adverse events were also compared.Results: Hemodynamic variables (CO, SBP, HR, and SVR) between spinal anaesthesia induction to skin incision were similar between the two groups (P = 0.889, 0.057, 0.977, and 0.416, respectively). The incidence of bradycardia was significantly higher in the phenylephrine group (69%) than in the norepinephrine group (24.2%, P< 0.001). Maternal nausea and vomiting, hypotension, reactive hypertension, and neonatal outcomes did not differ between the groups.Conclusion: When administered as a prophylactic fixed-rate infusion, phenylephrine and norepinephrine are both capable of maintaining maternal blood pressure following spinal anaesthesia in twin pregnancies. There were no differences in the maternal hemodynamics or foetal outcomes between women receiving norepinephrine and phenylephrine.Previous Presentations: Presented at the 51st Society for Obstetric Anesthesia and Perinatology Annual Meeting, Phoenix, Arizona, May 1– 5, 2019.Clinical Trial Number and Registry: No. ChiCTR-IOR-17013358.Keywords: caesarean section, hypotension, norepinephrine, phenylephrine, spinal anaesthesia, twins

Huihao Zhang,1,&ast; Sai Yao,1,&ast; Zhiguo Zhang,1,&ast; Chengcong Zhou,1 Fangda Fu,1 Yishan Bian,1 Huan Luo,2 Yan Li,1 Shuxin Yan,1 Yuying Ge,1 Yuying Chen,3 Kunyu Zhan,4 Yanzhi Ge,1 Zuxiang Chen,1 Ming Yue,5 Xiaofeng Li,6 Weibin Du,1,7 Hongting Jin,1 Peijian Tong,1 Hongfeng Ruan,1,8 Chengliang Wu1 1Institute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Physiology, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Orthopedics and Traumatology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 7Research Institute of Orthopedics, The Affiliated JiangNan Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 8Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongfeng Ruan; Peijian TongInstitute of Orthopaedics and Traumatology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaEmail rhf@zcmu.edu.cn; peijiantongzjtcm@163.comPurpose: To explore the pharmacological mechanisms of Liuwei Dihuang Decoction (LWDHD) against intervertebral disc (IVD) degeneration (IVDD) via network pharmacology analysis combined with experimental validation.Methods: First, active ingredients and related targets of LWDHD, as well as related genes of IVDD, were collected from public databases. The protein–protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed to predict the core targets and pathways of LWDHD against IVDD. Secondly, the IVDD model of mice treated with LWDHD was selected to validate the major targets predicted by network pharmacology.Results: By searching the intersection of the active ingredient targets and IVDD targets, a total of 110 targets matched the related targets of 30 active ingredients in LWDHD and IVDD were retrieved. PPI network analysis indicated that 17 targets, including Caspase-3, IL-1β, P53, etc., were hub targets. GO and KEGG enrichment analyses showed that the apoptosis pathway was enriched by multiple targets and served as the target for in vivo experimental study validation. The results of animal experiments revealed that LWDHD administration not only restored the decrease in disc height and abnormal degradation of matrix metabolism in IVDD mice but also reversed the high expression of Bax, Caspase-3, IL-1β, P53, and low expression of Bcl-2, thereby inhibiting the apoptosis of IVD tissue and ameliorating the progression of IVDD.Conclusion: Using a comprehensive network pharmacology approach, our findings predicted the active ingredients and potential targets of LWDHD intervention for IVDD, and some major target proteins involved in the predictive signaling pathway were validated experimentally, which gave us a new understanding of the pharmacological mechanism of LWDHD in treating IVDD at the comprehensive level.Keywords: intervertebral disc degeneration, Liuwei Dihuang decoction, network pharmacology, pharmacological mechanisms, apoptosis

Sijia Chen,1,&ast; Wenwen Du,1,&ast; Xiuxiu Zhuang,1,&ast; Qinxue Dai,1 Jingwen Zhu,2 Haifeng Fu,1 Junlu Wang,1 Luping Huang1 1Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Luping HuangDepartments of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaTel +86 13587891399Fax +86 577-55578999-689854Email csj0122@wmu.edu.cnPurpose: To determine the characteristics of the acute pain after laparoscopic-assisted vaginal hysterectomy (LAVH), laparoscopic myomectomy (LM), and laparoscopic adnexectomy (LA) and compare them with each other.Patients and Methods: Patients undergoing LAVH, LM, and LA under general anaesthesia at the First Affiliated Hospital of Wenzhou Medical University between December 2017 and December 2019 were selected. Their data were collected before, during, and after the surgery. We evaluated the degrees of pain in each group of patients and compared them.Results: There were differences in the baseline characteristics of the patients in the LAVH, LM, and LA groups. The severity and incidence of postoperative pain were higher in the LAVH group than in the LM and LA groups, followed by the LM and LA groups. Compared with the LA group, the postoperative pain in the LAVH and LM groups was more complicated. The LA group had the lowest incidence of two or more types of moderate to severe pain. The LAVH and LM groups mainly had visceral pain and low back pain, and the LA group mainly had incisional pain. Shoulder pain had the lowest incidence in the three groups.Conclusion: There were different postoperative pain characteristics after the LAVH, LM, and LA, and we should clinically adjust analgesia programs for different gynaecological laparoscopic surgeries.Keywords: postoperative pain, laparoscope-assisted vaginal hysterectomy, laparoscopic myomectomy, laparoscopic adnexectomy

Lijun Fan,1,2 Shiyuan Wang,1,3 Hui Xue,1,3 Yue Ding,1,2 Jingwen Wang,1,2 Yong Tian,1,2 Wei Du1,3 1Key Laboratory of Environmental Medicine Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing, People’s Republic of China; 2Department of Medical Insurance, School of Public Health, Southeast University, Nanjing, People’s Republic of China; 3Department of Epidemiology and Biostatistics, School of Public Health, Southeast University, Nanjing, People’s Republic of ChinaCorrespondence: Wei DuDepartment of Epidemiology and Biostatistics, School of Public Health, Southeast University, No. 87 Dingjiaqiao, Nanjing, 210009, People’s Republic of ChinaEmail duwei@seu.edu.cnPurpose: Population ageing is posing an unprecedented challenge globally, necessitating a better understanding of modifiable factors and underlying pathways that could contribute to health and longevity in older age. We thus aim to investigate how the modifiable social support (and its various sources) is related to mortality among older adults, as well as whether and to what extent geriatric frailty plays a role in mediating the relationship.Methods: We included 11,934 community-dwelling adults (≥ 65) from four waves of the Chinese Longitudinal Healthy Longevity Survey (2008– 2018). Frailty was constructed by 44 health deficits, following a validated frailty index scale. Social support was measured using a sum score of three dimensions (family support, social service and social security) with 22 items. The outcome was all-cause mortality. Multivariate logistic or linear regression models were employed when appropriate to assess the associations among social support, frailty and mortality. Mediation analysis was applied to examine the role of frailty underlying the pathway between social support and mortality risk.Results: A higher sum score of social support at baseline reduced mortality risk during the 10-year follow-up period (AOR=0.947, 95% CI=0.917∼ 0.977). Amongst three sources of social support, family support and social security availability showed significantly protective effect against mortality, while social service revealed only non-significant effect. A higher level in the overall social support (β=− 0.066, 95% CI=− 0.113∼-0.020) or family support (β=− 0.121, 95% CI=− 0.202∼-0.039) was also significantly associated with decreased frailty. Meanwhile, frailty partially mediated the relationship of mortality with the overall social support and family support, where the proportion of mediation equaled to 17.1% and 20.5%, respectively.Conclusion: Social support could be associated with reduced risks for frailty and mortality, and such protective influences are especially manifested in its family support component among Chinese older adults. Frailty functions as potential mediator underlying the association of mortality with social support and family support. Our findings indicate the importance of social support as an integral part of geriatric care and underline the potential benefits of frailty assessment and intervention.Keywords: social support, frailty, mortality, older adults, mediation, China

Wei Du,1,2 Jiali Wang,3,4 Qingsheng Zhou5 1School of Public Health, Southeast University, Nanjing, People’s Republic of China; 2Research School of Population Health, Australian National University, Canberra, Australia; 3Research School of Finance, Actuarial Studies & Statistics, Australian National University, Canberra, Australia; 4Massachusetts Eye and Ear Institute, Harvard University, Cambridge, USA; 5Faculty of Health Science, University of Sydney, Sydney, AustraliaCorrespondence: Wei Du Tel +86 25 8327 2303Email duwei@seu.edu.cnObjective: To investigate factors in association with high psychological distress in people with disabilities.Methods: We used the 2015 national survey on disability in Australia to derive the representative study population of 7936 people with disabilities aged 18+ years. The Kessler Psychological Distress Scale (K10) was used to define high psychological distress (scores ≥ 22). The explanatory variables included socioeconomic status, physical health, social relationships and environment factors. Adjusted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) were evaluated using weighted Logistic regression models with lasso techniques.Results: Approximately 21 in 100 study participants experienced high psychological distress. The risk of high psychological distress decreased with age and high educational attainment. Having non-English speaking background (2.31; 1.87– 2.85) and need for assistance in cognitive or emotional tasks (3.25; 2.65– 3.98) were independently significantly associated with high psychological distress in people with disabilities. Delay seeing a GP was associated with a 2-fold risk increase.Conclusion: Integrated healthcare and social support are warranted with appropriate targeting to improve mental health outcomes in people with disabilities.Keywords: people with disability, high psychological distress, integrated healthcare, social support

Kipling P Sharpe, 1 Richard Berkowitz, 2 William A Tyndall, 3 David Boyer, 4 Stewart W McCallum, 5 Randall J Mack, 5 Wei Du 6 1OrthoArizona, Gilbert, AZ, USA; 2Phoenix Clinical Research, Tamarac, FL, USA; 3University Orthopedics Center, Altoona, PA, USA; 4Shoals Clinical Research Associates, LLC, Florence, SC, USA; 5Baudax Bio, Inc., Malvern, PA, USA; 6Clinical Statistics Consulting, Blue Bell, PA, USACorrespondence: Randall J MackBaudax Bio, Inc., 490 Lapp Road, Malvern, PA 19355, USATel +1 484 395 2470Fax +1 484 395 2471Email rmack@baudaxbio.comObjective: A Phase 3 randomized multicenter, double-blind, placebo-controlled trial (NCT02720692) compared once-daily intravenous (IV) meloxicam 30 mg to placebo, when added to the standard of care pain management regimens, in adults with moderate-to-severe pain following major elective surgery and concluded that meloxicam IV had a safety profile similar to placebo and reduced opioid consumption.Methods: In this post hoc subgroup analysis of orthopedic surgery subjects, 379 subjects received meloxicam IV 30 mg or IV-administered placebo every 24 hrs for ≤ 7 doses. Safety was assessed via AEs, laboratory tests, vital signs, and ECG, with an emphasis on specific AEs, including injection site reactions, bleeding, cardiovascular, hepatic, renal, thrombotic, and wound healing events. Daily opioid consumption was assessed during treatment.Results: Among meloxicam IV-treated subjects, 64.7% experienced ≥ 1 AE versus 68.8% of placebo-treated subjects. Investigators assessed most AEs to be mild or moderate in intensity and unrelated to treatment. Total opioid consumption (36.8 mg versus 50.3 mg IV morphine equivalent dose; P=0.0081) and opioid consumption during time points 0‒24, 24‒48, 0‒48, and 0‒72 hrs were statistically significantly lower in the meloxicam IV group.Conclusion: Meloxicam IV demonstrated no significant differences in the number and frequency of AEs versus placebo in subjects following orthopedic surgery. Opioid consumption was reduced in the meloxicam IV group versus placebo.Trial registration: ClinicalTrials.gov (Identifier: NCT02720692).Keywords: meloxicam IV, NSAID, orthopedic surgery, postoperative pain, safety

Baixia Zhang,1 Wei Du,2 Kang Gan,1 Qigen Fang,2 Xu Zhang21Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Head Neck and Thyroid, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan Province, People’s Republic of ChinaBackground: The main goal of this study was to evaluate the prognosis of young patients with oral squamous cell carcinoma (SCC) with a focus on the value of the pretreatment neutrophil-to-lymphocyte ratio (NLR).Materials and methods: Young (≤40 years old) patients with oral SCC were retrospectively enrolled, and each young patient was matched with an old (≥60 years old) oral SCC patient. Associations between the NLR and clinicopathological variables were analyzed by the chi-square test, and the Kaplan–Meier method was used to analyze recurrence-free survival (RFS) and disease-specific survival (DSS) rates.Results: A total of 103 young patients were enrolled, and compared to the old group, the young group had a significantly lower NLR value (p=0.012). In the young group, the 5-year RFS and DSS rates were 82% and 85%, respectively. In the old group, the 5-year RFS and DSS rates were 65% and 71%, respectively, and the differences between the groups were significant (both p2.56, the 5-year DSS rate was 76%. This difference was significant (p=0.020). A further Cox model analysis confirmed that the NLR was an independent prognostic factor for DSS.Conclusion: Young patients with oral SCC have a better prognosis than old oral SCC patients, and the NLR is significantly associated with DSS in young patients.Keywords: oral squamous cell carcinoma, young patient, head and neck cancer, neutrophil-to-lymphocyte ratio, survival analysis

Danyang Sun,* Junxun Ma,* Jinliang Wang, Fan Zhang, Lijie Wang, Sujie Zhang, Guangying Chen, Xiaoyan Li, Wushuang Du, Pengfei Cui, Yi Hu Department of Oncology, Chinese PLA General Hospital, Beijing, China *These authors contributed equally to this work Background: In recent years, immune checkpoint inhibitors have been used with great success in the treatment of various cancers. However, when used in monotherapy, immune checkpoint inhibitors have a poor effect on pancreatic cancer. This study assessed the efficacy and safety of the use of immune checkpoint inhibitors for the treatment of advanced pancreatic cancer. Patients and methods: We evaluated patients with advanced pancreatic cancer who were treated with PD-1/PD-L1 inhibitors from 2015–2017. All the patients received PD-1/PD-L1 inhibitors as a monotherapy or in combination with other treatments, such as chemotherapy, targeted therapy, and CTLA-4 inhibitors at the recommended dosages. Results: For the 43 patients enrolled, the objective response rate was 10.5%, the disease control rate was 50%, the median progression-free survival was 2.3 months, and the median overall survival (mOS) was 5.1 months. The mOS was longer for patients receiving combined therapy than for those receiving PD-1/PD-L1 inhibitor monotherapy (5.4 vs 2.0 months, P = 0.020). Patients receiving immune therapy as a first-line treatment had prolonged survival compared with those receiving it as a second-line or multiple-line treatment, but the difference was not statistically significant (mOS: 7.0 vs 5.1 vs 2.8 months, P = 0.161). There was a reduction in the serum level of CA19-9 associated with the response to treatment. Adverse events were tolerable and were mainly grade 1 and 2. The immune-related adverse events that occurred were hypothyroidism, diarrhea, and rash. Conclusion: Immune checkpoint inhibitors showed a certain efficacy in the treatment of advanced pancreatic cancer and could confer long-term survival benefits. Combined therapy was more effective and may serve as an alternative option. Further studies should be performed. Keywords: pancreatic cancer, immune therapy, checkpoint inhibitor

Ira J Gottlieb,1 Deborah R Tunick,1 Randall J Mack,2 Stewart W McCallum,2 Campbell P Howard,3 Alex Freyer,2 Wei Du4 1Chesapeake Research Group, Pasadena, MD, USA; 2Recro Pharma, Inc., Malvern, PA, USA; 3Howard Medical Consulting for the Pharmaceutical Industry, Yardley, PA, USA; 4Clinical Statistics Consulting, Blue Bell, PA, USA Objective: This randomized, double-blind, placebo-controlled study evaluated the safety and efficacy of an intravenous (IV) nanocrystal formulation of meloxicam in subjects with moderate-to-severe pain following a standardized unilateral bunionectomy. Methods: Fifty-nine subjects aged 18–72 years were randomized to receive doses of either 30 mg (n=20) or 60 mg (n=20) meloxicam IV or placebo (n=19), administered once daily as bolus IV injections over 15–30 seconds (two or three doses). Safety, the primary objective, was assessed by physical examination, clinical laboratory tests, and the incidence of adverse events (AEs). Efficacy was evaluated by examining summed pain intensity differences over the first 48 hours (SPID48) using analysis of covariance models. Use of opioid rescue analgesic agents was evaluated. Results: Generally, AEs were mild-to-moderate in intensity, and their incidence was similar across the three treatment groups. No serious AEs were reported; there were no withdrawals due to AEs, including injection-related AEs. The estimated effect size for SPID48 versus placebo was 1.15 and 1.01 for meloxicam IV doses 30 mg and 60 mg, respectively (P≤0.01). Both doses produced significantly greater pain reductions versus placebo (P≤0.05) at all evaluated times/intervals during the 48-hour period. The proportions of subjects with ≥30% and ≥50% overall reduction in pain from baseline after 6 and 24 hours were significantly higher with meloxicam IV 30 mg doses versus placebo, but not with meloxicam IV 60 mg doses. The time to first use of rescue medication was significantly longer versus placebo with meloxicam IV 60 mg (P

Wei Du,1,* Jun Liu,2,* Jianlong Zhou,1,* Dan Ye,3 Yan OuYang,4 Qingnan Deng11Respiratory Diseases Group, the 6th Unit, Department of Internal Medicine, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, China; 2Department of Gerontology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, China; 3Luopu Street Community Health Service Centre, Guangzhou 511431, China; 4Department of Respiratory Medicine, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 510010, China *These authors contributed equally to this workObjective: The aim of this study was to investigate the role of obstructive sleep apnea (OSA) on all-cause mortality in patients with COPD.Methods: Data for this cross-sectional study were obtained from the National Health and Nutrition Examination Survey (NHANES) data (year 2005–2008). Eligible subjects were ≥20 years who had no COPD or OSA (n=9,237), had only OSA (n=366), had only COPD (n=695), and had OSA/COPD overlap syndrome (n=90). Univariate and multivariate analyses were used to evaluate factors associated with overall mortality.Results: Multivariate analysis found that the COPD and OSA/COPD overlap syndrome groups had significantly higher chance of all-cause mortality than the group of subjects who did not have OSA or COPD (adjusted hazard ratio [HR] =1.5 for the COPD group and 2.4 for the overlap syndrome group) (P≤0.007). Although not significant, having OSA/COPD overlap syndrome was associated with higher likelihood of death than COPD alone (HR =1.5; P=0.160). Other factors associated with higher overall mortality were aging, poorer family status, current smoker, serum vitamin D deficiency, cardiovascular disease, history of cancer, diabetes, and impaired renal function.Conclusion: The present study found that COPD and OSA/COPD overlap syndrome were associated with higher all-cause mortality compared with patients without either disease and that OSA did not significantly increase mortality in patients with COPD.Keywords: OSA, COPD, overlap syndrome, mortality

Neil Singla,1 Stewart W McCallum,2 Randall J Mack,2 Alex Freyer,2 Sue Hobson,2 Wei Du3 1Lotus Clinical Research, Pasadena, CA, USA; 2Research and Development, Recro Pharma, Inc., Malvern, PA, USA; 3Clinical Statistics Consulting, Blue Bell, PA, USAPostoperative pain after laparoscopic surgery is one of the major concerns of patients. Improper pain management can be associated with varied respiratory, cardiovascular, gastrointestinal, and psychological complications. Pain after laparoscopic surgery may be transient or persistent2 and opioids have traditionally been the mainstay treatment for postoperative pain.3 Increasing evidence exists to support a multimodal treatment approach for postoperative pain that reduces opioid side effects and decreases pain intensity (PI) scores.3 A proprietary nanocrystal intravenous (NIV) formulation of the non-steroidal anti-inflammatory meloxicam, a long-acting preferential cyclooxygenase-2 inhibitor, is being evaluated with the aim of providing rapid and sustained analgesia.

Feng Gao,1 Wen Du,1,4 Mohammad Ishraq Zafar,1 Raja Adeel Shafqat,2 Liumeng Jian,1 Qin Cai,1 Furong Lu3 1Department of Endocrinology, Union Hospital, 2Department of Medicine, Tongji Hospital, 3Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 4Chengdu First People’s Hospital, Sichuan, People’s Republic of China Background: Obesity-associated insulin resistance (IR) is highly correlated with soluble tumor necrosis factor-α (sTNF-α), which is released from transmembranous TNF-α by TNF-α converting enzyme (TACE). In vivo, TACE activity is suppressed by tissue inhibitor of metalloproteinase 3 (TIMP3). Agents that can interact with TACE/TIMP3 to improve obesity-related IR would be highly valuable. In the current study, we assessed whether (2S,3R,4S)-4-hydroxyisoleucine (4-HIL) could modulate TACE/TIMP3 and ameliorate an obesity-induced IR-like state in 3T3-L1 adipocytes. Materials and methods: 3T3-L1 adipocytes were incubated in the presence of 25 mM glucose and 0.6 nM insulin to induce an IR-like state, and were then treated with different concentrations of 4-HIL or 10 µM pioglitazone (positive control). The glucose uptake rate was determined using the 2-deoxy-[3H]-d-glucose method, and the levels of sTNF-α in the cell supernatant were determined using ELISA. The protein expression of TACE, TIMP3, and insulin signaling-related molecules was measured using western blotting. Results: Exposure to high glucose and insulin for 18 hours increased the levels of sTNF-α in the cell supernatant. The phosphorylation of insulin receptor substrate-1 (IRS-1) Ser307 and Akt Ser473 was increased, whereas the protein expression of IRS-1, Akt, and glucose transporter-4 was decreased. The insulin-induced glucose uptake was reduced by 67% in 3T3-L1 adipocytes, which indicated the presence of an IR-like state. The above indexes, which demonstrated the successful induction of an IR-like state, were reversed by 4-HIL in a dose-dependent manner by downregulating and upregulating the protein expression of TACE and TIMP3 proteins, respectively. Conclusion: 4-HIL improved an obesity-associated IR-like state in 3T3-L1 adipocytes by targeting TACE/TIMP3 and the insulin signaling pathway. Keywords: 4-hydroxyisoleucine, obesity-related insulin resistance, soluble TNF-α, TACE, TIMP3, insulin signaling, glucose uptake, Fenugreek seed