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Chunxia Yin,1,* Taohua Lan,2,3,* Yunshan Wu,4,5 Jing Cai,1 Haoxiang Li,1 Xiaolan Kuang,1 Lin Jiao,1 Xiaomin Ou,1 Hua Yang,2 Bo Liu,3– 5 Weihui Lu2,6,7 1The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Cardiology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China; 3State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4Guangzhou Key Laboratory of Chirality Research on Active Components of Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 6State Key Laboratory of Traditional Chinese Medicine Syndrome, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 7Chinese Medicine Guangdong Laboratory, Guangdong Hengqin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihui Lu, Bo Liu, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Email weihui.lu@gzucm.edu.cn; doctliu@gzucm.edu.cnPurpose: This study was designed to evaluate the effect and mechanism of the Qushi Huatan (QSHT) decoction against coronary heart disease (CHD) through network pharmacology and experimental verification.Methods: In the present study, the active ingredients of the QSHT decoction were identified by ultra performance liquid chromatography/tandem mass spectrometry (UPLC/MS), then the potential ingredients and coronary heart disease targets were predicted using the SwissTarget Prediction database and the database of Genecards and OMIM database, respectively. A herb-compound-target network was constructed using Cytoscape. GO and KEGG enrichment analysis were performed using the ClusterProfiler data package of R software. Molecular docking was used to predict the core targets of QSHT against CHD. In addition, we used a myocardial infarction (MI) and high-fat diet ApoE−/− mice model to investigate the cardioprotective effects of QSHT. Western blotting and immunochemistry were used to verify the core targets and the signaling pathway.Results: A total of 68 active ingredients were found in the QSHT decoction. Network pharmacology indicated 28 targets and 147 signal pathways, including AKT1, HIF-1α, GSK-3β, TLR4 and NF-κB, those key targets were also verified by molecular docking. The results of GO and KEGG enrichment analysis showed that the targets of QSHT against CHD were largely associated with inflammatory and oxidative stress, and AKT/HIF-1α and TLR4/NF-κB pathways might be key functional pathways. In vivo, QSHT significantly improved cardiac function and attenuated fibrosis and inflammation. Furthermore, QSHT could significantly inhibit the expression of HIF-1α, TLR4, phosphorylation of AKT1, GSK-3β and NF-κB after MI in ApoE−/− mice.Conclusion: Based on network pharmacology, molecular docking and experimental verification, this study demonstrated that QSHT could improve cardiac function and attenuate cardiac fibrosis by regulating TLR4/NF-κB and AKT/HIF-1α signaling pathway in post- MI and high-fat diet ApoE−/− mice.Keywords: network pharmacology, molecular docking, Qushi Huatan decoction, coronary heart disease

Wenyu Zhang,1,* Linquan Li,1,* Yaguang Wu,1 Chengzhilin Li,1 Zi’ang Xu,1 Nianlei Zhang,1 Xinyu Wang,1 Yingchun Zhao,1 Tingjian Zu,1 Qingbin He,1 Jianwei Jiao,2 Runxiao Zheng1 1School of Clinical and Basic Medical Sciences, Medical Science and Technology Innovation Center, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, People’s Republic of China; 2State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China*These authors contributed equally to this workCorrespondence: Runxiao Zheng, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, People’s Republic of China, Email zhengrunxiao@sdfmu.edu.cn Jianwei Jiao, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China, Email jwjiao@ioz.ac.cnIntroduction: Immunotherapy has led to a paradigm shift in reinvigorating treatment of cancer. Nevertheless, tumor associated macrophages (TAMs) experience functional polarization on account of the generation of suppressive metabolites, contributing to impaired antitumor immune responses.Methods: Hence, metabolic reprogramming of tumor microenvironment (TME) can synergistically improve the efficacy of anti-tumor immunotherapy. Herein, we engineered an iron-based nanoplatform termed ERFe3O4 NPs. This platform features hollow Fe3O4 nanoparticles loaded with the natural product emodin, the outer layer is coated with red blood cell membrane (mRBCs) inserted with DSPE-PEG2000-galactose. This effectively modulates lactate production, thereby reversing the tumor immune suppressive microenvironment (TIME).Results: The ERFe3O4 NPs actively targeted TAMs on account of their ability to bind to M2-like TAMs with high expression of galectin (Mgl). ERFe3O4 NPs achieved efficient ability to reverse TIME via the production of reducing lactate and prompting enrichment iron of high concentrations. Furthermore, ERFe3O4 NPs resulted in heightened expression of CD16/32 and enhanced TNF-α release, indicating promotion of M1 TAMs polarization. In vitro and in vivo experiments revealed that ERFe3O4 NPs induced significant apoptosis of tumor cells and antitumor immune response.Discussion: This study combines Traditional Chinese Medicine (TCM) with nanomaterials to synergistically reprogram TAMs and reverse TIME, opening up new ideas for improving anti-tumor immunotherapy. Keywords: metabolic immunotherapy, nanoparticles, reprograming, iron oxide, macrophages

You Jiang,1,2 Wenbo Li,1,2 Jun Zhang,1 Kun Liu,1 Yuee Wu,3 Zhengguang Wang1 1Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 2Department of General Surgery, The Second People’s Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 3Department of Electrocardiogram Diagnosis, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230060, People’s Republic of ChinaCorrespondence: Zhengguang Wang, Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China, Email wangzhengguang@ahmu.edu.cnBackground: Cysteine desulfurase (NFS1) is closely associated with the occurrence and development of human tumors, but its relationship with the prognosis and immunity of gastric cancer (GC) patients remains unclear.Methods: To study the relationship between NFS1 and GC, GC-related data of TCGA were downloaded and analyzed. At the same time, Tumor Immune Estimation Resource (TIMER) and Kaplan‒Meier Plotter were used for relevant online analysis. Clinical samples were collected for immunohistochemical testing to validate the results.Results: The mRNA and protein levels of NFS1 in GC tissues were significantly higher than those in normal tissues. In terms of the operating characteristic curve (ROC), the area under the curve (AUC) was 0.793, indicating that NFS1 had a high diagnostic value for GC. Further analysis showed that NFS1 expression was highly correlated with the depth of tumor invasion, lymph node metastasis, and tumor stage. Survival analysis showed that patients with high expression of NFS1 had a poorer prognosis, and NFS1 was an independent risk factor. Enrichment analysis by GO, KEGG, and GSEA showed that NFS1 was enriched in immune-related pathways. The expression of NFS1 was significantly positively correlated with the proportion of macrophages M0 and plasma cells but negatively correlated with the proportion of B cells memory, monocytes, and mast cells resting. In addition, NFS1 expression was significantly correlated with TMB levels and responses to immunotherapy.Conclusion: Our results suggest that NFS1 may be a potential biomarker for the diagnosis and prediction of prognosis and immunotherapy efficacy in GC.Keywords: NFS1, gastric cancer, prognostic biomarker, immune infiltration

Shutong Ren,1,&ast; Siyu Chen,2,&ast; Jingru Huang,3 Rong Yu,1 Yunli Wu,4 Xian-E Peng1,4 1Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, 361104, People’s Republic of China; 3Department of Clinical Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China; 4Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xian-E Peng; Yunli Wu, Email fmuxe@163.com; wuyunli422@163.comObjective: This study aimed to explore the association between serum uric acid (sUA) levels and metabolic-associated fatty liver disease (MAFLD) in Southeast China.Methods: We performed a cross-sectional study of 2605 subjects who underwent physical examination between 2015 and 2017 in Southeast China. To explore the association between sUA levels and the risk of MAFLD, we employed logistic regression, restricted cubic spline (RCS), subgroups and multiplicative interaction analysis.Results: Logistic regression analysis showed a positive association between sUA and MAFLD [aOR total population (95% CI)= 1.90 (1.49 ~ 2.42)], [aOR male (95% CI)= 2.01 (1.54 ~ 2.62)], [aOR female (95% CI)= 1.15 (0.62 ~ 2.11)], respectively. The RCS plot presented a significant nonlinear dose–response relationship between sUA levels and MAFLD risk, and the risk of MAFLD increased significantly when sUA> 5.56 mg/dL (Pnonlinear< 0.001). Subgroups analysis revealed that the positive association between sUA and MAFLD was consistent across strata of gender, age, BMI, drinking status, smoking status and tea drinking status. Significant associations between sUA and MAFLD were not only found in males but also existed in subjects whose age ≤ 60, BMI ≥ 24 kg/m2, drinkers, smokers and tea-drinkers. Adjusted ORs were estimated to be 2.01, 1.95, 2.11, 2.29, 2.64 and 2.20, respectively. Multiplicative interactions were not observed between gender, age, drinking status, smoking status, tea drinking status and sUA (all P interaction> 0.05).Conclusion: According to our study, sUA was positively associated with the risk of MAFLD. Additionally, the risk of MAFLD increased significantly when sUA levels exceeded 5.56 mg/dL. Our study may help clarify whether sUA plays a diagnostic role in MAFLD.Keywords: metabolic-associated fatty liver disease, serum uric acid, risk, cross-sectional study

Donglin Jiang,1 Yangxue Wu,1 Ling Liu,1 Yajing Shen,1 Tiandong Li,1 Yin Lu,1 Peng Wang,2 Changqing Sun,2 Kaijuan Wang,2 Keyan Wang,3 Hua Ye1 1College of Public Health, Zhengzhou University, Gaoxin District, Zhengzhou, Henan, 450001, People’s Republic of China; 2Henan Key Laboratory of Tumor Epidemiology and State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 3Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaCorrespondence: Hua Ye, College of Public Health, Zhengzhou University, Gaoxin District, Zhengzhou, Henan, 450001, People’s Republic of China, Tel +86 186-3853-6001, Fax +86 371-67781018, Email yehua@zzu.edu.cnBackground: Gastrointestinal tumors represent a significant component of the cancer burden in Asia. This study aims to evaluate the burden of gastrointestinal tumors in Asia from 1990 to 2021 using data from the Global Burden of Disease Study 2021 (GBD 2021).Methods: The absolute incidence, mortality, and disability adjusted life years (DALYs) number and rate of six gastrointestinal tumors(colon and rectum cancer (CRC), stomach cancer (SC), pancreatic cancer (PC), esophageal cancer (EC), liver cancer (LC) and gallbladder and biliary tract cancer (GBTC)) in 48 Asian countries were extracted from GBD 2021. Differences were analyzed based on gender, age, year, location and socio-demographic index (SDI).Results: In 2021, SC accounted for the highest disease burden in Asia (DALYs=16.41million [95% UI: 13.70, 19.62]). From 1990 to 2021, the age-standardized incidence rates of EC, LC, and SC in Asia declined, while the incidence rates of CRC and PC increased significantly, with CRC showing the largest rise (AAPC=1.08 [95% CI: 1.02 to 1.12]). Gastrointestinal tumors DALY rates peaked at age 70 and above, with males generally exhibiting higher rates than females. Furthermore, East Asia bears a higher burden compared to other Asian subregions. A higher SDI correlates with increased DALY rates for PC, but no linear relationship was observed for other gastrointestinal tumors.Conclusion: The burden of gastrointestinal tumors in Asia remains high and may continue to increase. Therefore, effective prevention and treatment measures are essential to address the challenge posed by gastrointestinal tumors.Keywords: Asia, gastrointestinal tumors, burden, trends

Chuanjiang Dong,1,&ast; Yueqing Wang,2,3,&ast; Yi Cai,4,&ast; Yuhuang Wu,2,3 Wei Chen,2,3 Lu Wang,2,3 Xiaowen Liu,2 Lili Zou,2,3 Jun Wang5 1Department of Urology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong province, 523718, People’s Republic of China; 2Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People’s Republic of China; 3Yichang Key Laboratory of Infection and Inflammation, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People’s Republic of China; 4Department of Laboratory Medicine, Xiaogan Central Hospital, Xiaogan, Hubei Province, 432099, People’s Republic of China; 5The Second People’s Hospital of China Three Gorges University, Yichang, Hubei Province, 443002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lili Zou; Jun Wang, Email zoulili@ctgu.edu.cn; wangjfox@ctgu.edu.cnPurpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs.Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model.Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity.Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.Keywords: Ebselen, antibiotic adjuvant, thioredoxin reductase, reactive oxygen species

Yan Wu,1 Zhenzhen Xu,2 Jing Dong,3 Wenzhong Zhang,2 Jing Li,2 Hong Ji1 1Department of Nursing, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan, Shandong, 250014, People’s Republic of China; 2School of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014, People’s Republic of China; 3School of Nursing, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, Shandong Province, 271016, People’s Republic of ChinaCorrespondence: Hong Ji, Department of Nursing, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan, Shandong, 250014, People’s Republic of China, Tel +86-13791120369, Email honghongji-2005@163.comBackground: Older age and female sex are risk factors for osteoarthritis and osteoporosis (OP). This study evaluated the knowledge, attitudes, and practices of patients with knee osteoarthritis (KOA) in China regarding OP and its prevention. This cross-sectional, questionnaire-based study enrolled patients with KOA at four grade-A tertiary hospitals in Shandong Province between 1st September and 20th November 2022.Methods: The administered questionnaire contained 55 items across four dimensions (demographic information, knowledge, attitude, and practice). Logistic regression analyses were performed to identify factors associated with an overall questionnaire score ≥ 70% of the maximum possible score. SPSS 26.0 was used for the analyses; P< 0.05 was considered significant.Results: The analysis included 434 participants (261 females). The median knowledge, attitude, and practice scores were 7 (interquartile range: 5– 10) (possible range, 0– 17 points), 44 (interquartile range: 42– 49) (possible range, 11– 55 points), and 43 (interquartile range: 38– 47) (possible range, 13– 65 points), respectively. Multivariable logistic regression indicated that female sex (odds ratio [OR], 2.421; 95% confidence interval [95% CI] 1.558– 3.762; P< 0.001), age 56– 65 years-old (OR, 4.222; 95% CI, 1.763– 10.109; P=0.001 vs ≤ 55 years-old), age > 65 years-old (OR, 4.358; 95% CI, 1.863– 10.195; P=0.001 vs ≤ 55 years-old), middle/high/technical secondary school education (OR, 1.853; 95% CI, 1.002– 3.428; P=0.049 vs primary school or below), and having KOA for 4– 5 years (OR, 2.682; 95% CI, 1.412– 5.094; P=0.003 vs ≤ 3 years) were independently associated with a high KAP score.Conclusion: There is room for improvement in the knowledge and practices of patients with osteoarthritis in China regarding OP. The findings of this study may facilitate the design and implementation of education programs to increase awareness about OP prevention among patients with KOA.Keywords: osteoarthritis of the knee, osteoporosis, disease prevention, surveys and questionnaires, health knowledge, attitudes, practice

Bowen Wei,1,2,&ast; Qingyun Yue,1,2,&ast; Yuxiu Ka,1,2,&ast; Chenyang Sun,1,2 Yuxing Zhao,1,2 Xiaomei Ning,1,2 Yue Jin,1,2 Jingyue Gao,1,2 Yuanhao Wu,1,2 Wei Liu1,2 1Department of Rheumatism and Immunity, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Liu, Email fengshiliuwei@163.comBackground: Primary Sjögren’s syndrome (pSS) is an autoimmune condition marked by lymphocyte infiltration in the exocrine glands. Our study aimed to identify a novel biomarker for pSS to improve its diagnosis and treatment.Methods: The gene expression profiles of pSS were obtained from the Gene Expression Omnibus (GEO) database. The specific differentially expressed genes (DEGs) were screened by the Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest (RF), and Recursive Feature Elimination with Support Vector Machines (SVM-RFE). A biomarker was picked out based on correlation and diagnostic performance, the connection between the biomarker and clinical traits and immune infiltrating cells was explored, and the biomarker’s protein expression level in the serum of pSS patients was detected by enzyme-linked immunosorbent assay (ELISA). The competitive endogenous RNA (ceRNA) network regulated by the biomarker was predicted to verify the reliability of the biomarker in diagnosing pSS.Results: IFI44, XAF1, GBP1, EIF2AK2, IFI27, and IFI6 showed prominent diagnostic ability, with the high accuracy (AUC = 0.859) and significance (R ≥ 0.8) of IFI44 within the training dataset. IFI44 strongly exhibited a negative correlation with resting NK cells, macrophages M0, and eosinophils, and a positive correlation with activated dendritic cells, naive B cells, and activated CD4 memory T cells. Furthermore, IFI44 was significantly positively correlated with clinical traits such as IgG, SSA, SSB, ANA, and ESSDAI, with its protein expression level in the serum of pSS patients being notably elevated compared to controls (p < 0.001). Finally, the ceRNA regulatory network showed that hsa-miR-944, hsa-miR-9-5p, hsa-miR-126-5p, and hsa-miR-335-3p were significantly targeted IFI44, suggesting that IFI44 may serve as a dependable biomarker for pSS.Conclusion: In this study, we dug out IFI44 as a biomarker for pSS, systematically studied the potential regulatory mechanism of IFI44, and verified its reliability as a biomarker for pSS.Keywords: primary Sjögren’s syndrome, machine learning, immune cell infiltration, biomarker, IFI44

Yucheng Wu,1,&ast; Jie Qiu,1,&ast; Xiang Sha,1,&ast; Benbingdi Gong,1 Jian Wang,1 Wei Yuan,1 Jie Lin,1 Lichun Wang,1 Qingqing Zhang2 1Department of Cardiology, Taizhou School of Clinical Medicine, Nanjing Medical University, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 2Panvascular Management Center, Taizhou School of Clinical Medicine, Nanjing Medical University, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lichun Wang, Department of Cardiology, Taizhou School of Clinical Medicine, Nanjing Medical University, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, No. 366 Taihu Road, Taizhou, 225300, Jiangsu Province, People’s Republic of China, Email 18652711566@163.com Qingqing Zhang, Panvascular Management Center, Taizhou School of Clinical Medicine, Nanjing Medical University, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, No. 366 Taihu Road, Taizhou, 225300, Jiangsu Province, People’s Republic of China, Email 18061986120@189.cnBackground: Management strategies for stable angina include pharmacotherapy, revascularization, and exercise-based cardiac rehabilitation (CR). The optimal treatment for stable angina patients with severe coronary artery stenosis remains unclear. This study aimed to compare interventional therapy with exercise rehabilitation in this population.Methods: Fifty stable angina patients with severe coronary stenosis who underwent stent implantation were included in the optimal medical therapy (OMT) plus percutaneous coronary intervention (PCI) group, and 50 patients who did not undergo interventional treatment were included in OMT plus CR group receiving exercise rehabilitation guidance for one year. Cardiovascular composite endpoint events, cardiopulmonary fitness, and quality of life scale scores were assessed after one year.Results: No significant difference in incidence of cardiovascular composite endpoint events was observed between OMT plus PCI group with OMT plus CR group (20.0% vs 14.6%) after one year. Cardiopulmonary fitness represented as peak VO2 (19.2± 3.5 vs 17.6± 3.2 mL/kg/min), peak load (120± 19 vs 108± 20 W), and AT (13.5± 1.5 vs 12.1± 1.3 mL/kg/min) were significantly higher in the rehabilitation group than the intervention group after one year. Both groups showed improvement in their quality of life, but the rehabilitation group improved in more scales.Conclusion: Interventional therapy did not reduce cardiovascular events compared to exercise-based rehabilitation in stable angina patients with severe coronary artery stenosis, but the rehabilitation can improve cardiovascular fitness and quality of life more.Keywords: cardiac rehabilitation, stable angina, percutaneous coronary intervention, cardiopulmonary fitness

Min Tang,1,2 Yijun Wu,1,2 Xiufeng Bai,3,4 You Lu1,2 1Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Laboratory of Human Disease and Immunotherapies, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Institute of Inflammation and Immunology (I3), Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: You Lu, West China Hospital, West China School of Clinical Medicine, Sichuan University, 37, Guoxue Lane, Chengdu, 610041, Email radyoulu@hotmail.comAbstract: Rat sarcoma virus (RAS) GTPase is one of the most important drivers of non-small cell lung cancer (NSCLC). RAS has three different isoforms (Harvey rat sarcoma viral oncogene homolog [HRAS], Kirsten rat sarcoma viral oncogene homolog [KRAS] and Neuroblastoma ras viral oncogene homolog [NRAS]), of which KRAS is most commonly mutated in NSCLC. The mutated KRAS protein was historically thought to be “undruggable” until the development of KRASG12C inhibitors. In this review, from the aspect of brain metastasis, we aim to provide an overview of the advances in therapies that target KRASG12C, the limitations of the current treatments, and future prospects in patients with KRAS p.G12C mutant NSCLC.Keywords: KRAS, G12C, non-small cell lung cancer, brain metastases

Zhangnan Sun,1,&ast; Ji Shi,2,&ast; Chaolei Liu,1 Jingjing Zhang,1 Yue Liu,1 Yini Wu,3 Xin Han,3 Hong Dai,3 Jimin Wu,3 Lijun Bo,1 Faxing Wang3 1Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Anesthesiology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Anesthesiology, Lishui People’s Hospital, Lishui Hospital of Wenzhou Medical University, Lishui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Faxing Wang, Department of Anesthesiology, Lishui People’s Hospital, Lishui Hospital of Wenzhou Medical University, No. 15, Dazhong Street, Lishui, Zhejiang Province, 323000, People’s Republic of China, Email wfx2023@wmu.edu.cn Lijun Bo, Department of Anesthesiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China, Email 27901566@hebmu.edu.cnObjective: This study investigates the effect of low-dose dexmedetomidine infusion on perioperative neurocognitive function in elderly patients undergoing endoscopic retrograde cholangiopancreatography (ERCP).Patients and Methods: This double-blind trial enrolled 80 elderly ERCP patients randomized to receive dexmedetomidine (Group D) or placebo (Group S). Group D received dexmedetomidine at 0.4 μg·kg− 1·h− 1 starting 15 minutes before surgery until completion, along with propofol at 1.5 mg/kg for anesthesia. Group S received saline and propofol in a similar manner. Anesthesia was maintained with dexmedetomidine at 0.4 μg·kg− 1·h− 1 and propofol at 1– 2 mg/kg during surgery. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and on postoperative days 1, 3, and 5. Primary outcome was perioperative neurocognitive disorder (PND) incidence on day 5; secondary outcomes included changes in perioperative IL-6, cortisol, S100-β, hemodynamics, anesthesia parameters, postoperative pain, agitation scores, and adverse events.Results: All 80 patients completed the trial. On postoperative day 5, the cumulative probability of PND incidence was significantly lower in Group D than in Group S (12.5% vs 35%, P=0.018). Group D also had lower levels of IL-6 (F=199.472, P< 0.001), S100-β (F=2681.964, P< 0.001), and cortisol (F=137.637, P< 0.001). Propofol doses were lower in Group D (706.1 ± 202.4 vs 1003.3 ± 203.7, P< 0.001), and bradycardia rates were higher (45% vs 15%, P=0.003), though atropine use did not significantly differ between groups. Group D showed greater stability in mean arterial pressure. Postoperative complications and adverse reactions were similar across groups.Conclusion: Perioperative low-dose dexmedetomidine infusion with propofol in elderly ERCP patients ensures safe and effective monitored anesthesia care (MAC), reducing PND incidence by mitigating peripheral inflammation and stress responses. Long-term follow-up is needed to fully evaluate PND incidence.Keywords: ERCP, PND, dexmedetomidine, elderly patients

Zheng Wang,1,2,&ast; Yifan Wu,1,2,&ast; Wanrong Yi,1,2 Yifeng Yu,1,2 Xue Fang,1,2 Zonghuan Li,1,2 Aixi Yu1,2 1Department of Orthopedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Hubei Clinical Medical Research Center of Trauma and Microsurgery, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aixi Yu; Zonghuan Li, Email yuaixi@whu.edu.cn; lizonghuan@whu.edu.cnBackground: Traumatic heterotopic ossification (HO) is a devastating sequela of orthopedic surgeries and traumatic injuries; however, few studies have explored the effects of the estrogen-deficient state on HO formation. In the present study, we investigated the impact of estrogen deficiency on ectopic cartilage and bone formation in tendon after Achilles tenotomy in an ovariectomized mouse model.Methods: A total of 45 female C57BL/6 mice were randomly divided into three groups: sham-operated (control), estrogen depletion by ovariectomy (OVX) and OVX with 17β-estradiol supplementation (OVX + E2), with 15 animals in each group. Three weeks after OVX, all mice were subjected to an Achilles tenotomy using a posterior midpoint approach to induce HO. At 1, 3 and 9 weeks after tenotomy, the left hind limbs were harvested for histology, immunohistochemistry and immunofluorescence evaluations. The volume of ectopic bone was assessed by micro-CT.Results: Mice in the OVX group formed more ectopic cartilage 3 weeks after tenotomy, as well as ectopic bone 9 weeks after tenotomy, compared to the control group. Estrogen deficiency resulted in more severe inflammatory infiltration at the injury sites 1 week after tenotomy, involving the recruitment of more macrophages and mast cells, as well as increasing the expressions of pro-inflammatory mediators, including IL-1β, IL-6, and TNF-α. Moreover, the local TGF-β/SMAD signaling pathway was dysregulated after OVX, which manifested as upregulated expressions of TGF-β and pSMAD2/3. E2 supplementation protected against OVX-induced HO deterioration, inhibited inflammatory infiltration, and downregulated the TGF-β/SMAD signaling pathway.Conclusion: Estrogen deficiency exacerbated HO formation in the Achilles tenotomy model. These findings might be attributable to the disturbance of the inflammatory response and the activation of TGF-β/SMAD signaling at the injury sites during the early stages of HO development.Keywords: heterotopic ossification, estrogen deficiency, inflammation, TGF-β/SMAD signaling

Yunxia Wu,1,&ast; Yue Zhang,1,&ast; Zishan Wang,1 Yun Lu,1 Yabei Wang,1 Jie Pan,1 Chenxi Liu,1 Wen Zhu,2,&ast; Yue Wang2,&ast; 1Academy of First Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of Rheumatology & Immunology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yue Wang; Wen Zhu, Department of Rheumatology & Immunology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China, Email wangyue@njucm.edu.cn; zhuwen@njucm.edu.cnBackground: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and inflammatory cell infiltration. The traditional Chinese medicine prescription, Bitongqing (BTQ) exhibited significant efficacy in the clinical treatment of RA. However, the potential therapeutic mechanisms of BTQ in treating RA have not been fully investigated. This study aims to elucidate the effect of BTQ on collagen-induced arthritis (CIA) rat macrophage pyroptosis, providing a theoretical basis for treating RA.Methods: This research employed liquid chromatography-mass spectrometry (LC-MS) to identify the primary components of BTQ. The therapeutic effects of BTQ were evaluated in a rat model of CIA. In vivo experiments were conducted using pathohistological staining, immunofluorescence, micro-CT, and Western blotting. Next, Mouse leukemia cells of monocyte macrophage cells (RAW264.7) were induced to undergo pyroptosis using lipopolysaccharide (LPS) and adenosine triphosphate (ATP), and the impact of BTQ on RAW264.7 macrophages was assessed through cell viability, immunofluorescence analysis, lactate dehydrogenase (LDH) secretion measurement, and Western blotting.Results: BTQ had a therapeutic effect on CIA rats, which was mainly manifested as a reduction in joint inflammation, foot swelling, bone erosion, and amelioration of pathological changes in these rats. Further studies revealed that BTQ inhibited the levels of cytokine production interleukin-18 (IL-18) and interleukin-1β (IL-1β), and likewise, it inhibited the expression of key proteins in the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) mediated pyroptosis in the synovial tissues of CIA rats. The results of in vitro experiments demonstrated that BTQ attenuated LDH secretion, decreased IL-18 and IL-1β cytokine production, and downregulated expression of key proteins involved in the NLRP3-mediated pyroptosis on RAW264.7 macrophages.Conclusion: The therapeutic potential of BTQ in CIA lies in its ability to inhibit NLRP3-mediated macrophage pyroptosis, thereby suggesting a promising strategy for the treatment of RA. Keywords: rheumatoid arthritis, Bitongqing, pyroptosis, NLRP3 inflammasome, macrophage

Yiqiong Zhang,1,2,&ast; Shanshan Li,1,2,&ast; Xiaojuan Fan,1 Yue Wu1,2 1Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaojuan Fan; Yue Wu, Email colors727@163.com; yue.wu@xjtu.edu.cnBackground: Patients with sepsis frequently develop septic cardiomyopathy, which is known to be closely related to excessive inflammatory responses. Indole-3-propionic acid (IPA) is a tryptophan metabolite with anti-inflammatory properties that have been demonstrated in various studies. In this study, we investigated the underlying mechanisms and therapeutic role of IPA in septic cardiomyopathy.Methods: To investigate the role of IPA in septic cardiomyopathy, we constructed a lipopolysaccharide (LPS)-induced rat model of septic cardiomyopathy, and treated rats with IPA. Inflammatory factors and the NF-κB/NLRP3 pathway were evaluated in myocardial tissues and cells after IPA treatment using RT-qPCR, ELISA, Western blotting, and immunohistochemistry. To further elucidate the role of the aryl hydrocarbon receptor (AhR), we detected changes in inflammatory mediators and the NF-κB/NLRP3 pathway in in vivo and in vitro models of septic cardiomyopathy, which were treated with the AhR antagonist CH-223191 and/or AhR agonist FICZ.Results: IPA supplementation improved cardiac dysfunction in rats with septic cardiomyopathy. IPA reduced inflammatory cytokine release and inhibited NF-κB/NLRP3 signaling pathway in myocardial tissue and in H9c2 cells. CH-223191 impaired the anti-inflammatory effect of IPA in LPS-treated cells, whereas FICZ exerted the same effect as IPA. IPA also exhibited anti-inflammatory activity by binding to the AhR. Our results indicated that IPA attenuated septic cardiomyopathy in rats via AhR/NF-κB/NLRP3 signaling.Conclusion: Our study revealed that IPA improved left heart dysfunction and myocardial inflammation caused by sepsis via AhR/NF-κB/NLRP3 signaling, suggesting that IPA is a potential therapy for septic cardiomyopathy.Keywords: Indole-3-propionic acid, septic cardiomyopathy, cardiac function, inflammation, aryl hydrocarbon receptor

Li Zhou,1,&ast; Youlin Wu,1,2,&ast; Jiani Wang,1 Haiyun Wu,1 Yongjun Tan,1 Xia Chen,1,3 Xiaosong Song,1,4 Yu Ren,1 Qin Yang1 1Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Neurology, Chongzhou People’s Hospital, Sichuan, People’s Republic of China; 3Department of Neurology, the Seventh People’s Hospital of Chongqing, Chongqing, People’s Republic of China; 4Department of Neurology, the Ninth People’s Hospital of Chongqing, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin Yang, Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-023-89012008, Fax +86-023-68811487, Email xyqh200@126.comBackground and Purpose: Ischemic stroke is a leading cause of mortality and disability globally, necessitating accurate prediction of intra-hospital mortality (IHM) for improved patient care. This study aimed to develop a practical nomogram for personalized IHM risk prediction in ischemic stroke patients.Methods: A retrospective study of 422 ischemic stroke patients (April 2020 - December 2021) from Chongqing Medical University’s First Affiliated Hospital was conducted, with patients divided into training (n=295) and validation (n=127) groups. Data on demographics, comorbidities, stroke risk factors, and lab results were collected. Stroke severity was assessed using NIHSS, and stroke types were classified by TOAST criteria. Least absolute shrinkage and selection operator (LASSO) regression was employed for predictor selection and nomogram construction, with evaluation through ROC curves, calibration curves, and decision curve analysis.Results: LASSO regression and multivariate logistic regression identified four independent IHM predictors: age, admission NIHSS score, chronic obstructive pulmonary disease (COPD) diagnosis, and white blood cell count (WBC). A highly accurate nomogram based on these variables exhibited excellent predictive performance, with AUCs of 0.958 (training) and 0.962 (validation), sensitivities of 93.2% and 95.7%, and specificities of 93.1% and 90.9%, respectively. Calibration curves and decision curve analysis validated its clinical applicability.Conclusion: Age, admission NIHSS score, COPD history, and WBC were identified as independent IHM predictors in ischemic stroke patients. The developed nomogram demonstrated high predictive accuracy and practical utility for mortality risk estimation. External validation and prospective studies are warranted for further confirmation of its clinical efficacy.Keywords: ischemic stroke, nomogram, predictors, lasso, intra-hospital mortality

Xiaobing Li,1 De Wu,2 Jing Tang,3 Yuebing Wu3 1Department of Thoracic Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pathology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Lymphoma, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Yuebing Wu, Department of Lymphoma, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, 116&num; South Zhuodaoquan Road, Hongshan District, Wuhan, 430079, People’s Republic of China, Tel/Fax +86-27-87670351, Email wuyuebing0328@126.comBackground: Existing research data indicates that albumin-bound paclitaxel (nab-ptx), anlotinib, and PD-1/L1 inhibitors have individually shown efficacy in second-line and subsequent treatments for advanced non-small cell lung cancer (NSCLC). This study seeks to investigate the potential of an optimized treatment regimen in this context by combining these three drugs and evaluating both efficacy and safety outcomes.Patients and Methods: Between January 2020 and January 2022, we collected data from pre-treated advanced NSCLC patients who received a combination therapy of nab-ptx, anlotinib, and PD-1/L1 inhibitors as a second-line or later treatment. The primary endpoints for the study included the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR) and overall survival (OS), while adverse events (AEs) were also recorded.Results: Our findings revealed that the ORR of this regimen in pretreated NSCLC patients was 35.71%, with mean PFS of 5.0 months and mean OS of 10.0 months. Further analysis suggested correlations between the efficacy of the regimen and factors such as PD-L1 expression levels, the occurrence of certain types of adverse events, and the status of NK cell activity. Additionally, the tolerable toxicity profile of this regimen indicates its potential applicability in the treatment of pretreated advanced NSCLC.Conclusion: Our study displayed that triple-drug combination of nab-ptx, anlotinib and PD-1/L1 inhibitors showed promising efficiency and tolerated cytotoxicity in the 2nd or above line treatment of advanced NSCLC, indicating the potential of such regimen as an important option for second-line treatment of advanced NSCLC. However, due to limitations in patient numbers, its actual clinical value awaits further research confirmation.Keywords: nab-ptx, anlotinib, PD-1/L1, NSCLC, triple drug combination

Minmin Shen,1– 3,* Qiaojing Lin,1,2,* Xi Zou,1– 3 Yufan Wu,1,2 Zhihong Lin,1,2 Linglong Shao,1,2 JinSheng Hong,1– 3 Jinmei Chen1– 3 1Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2Department of Radiotherapy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, People’s Republic of China; 3Key Laboratory of Radiation Biology of Fujian Higher Education Institutions, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China*These authors contributed equally to this workCorrespondence: JinSheng Hong; Jinmei Chen, Department of Radiotherapy, Cancer Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China, Email hjs703@126.com; cjm1303@126.comPurpose: The aim of the present study was to assess the clinical outcomes and prognostic factors of lung adenocarcinoma patients with brain metastases (BMs) after intracranial local therapy.Patients and Methods: A total of 83 lung adenocarcinoma patients with BMs who underwent craniotomy combined with radiotherapy or intracranial radiotherapy alone were retrospectively analyzed. The intracranial tumor response was determined according to the Response Assessment in Neuro-Oncology of Brain Metastases (RANO-BM) criteria. The median overall survival (OS), intracranial progression-free survival (iPFS), and related prognostic factors were analyzed with the Kaplan‒Meier estimator method and Cox proportional hazards regression model.Results: Among 83 patients, 20 patients received craniotomy combined with radiotherapy, and 63 patients received intracranial radiotherapy alone. Following intracranial local therapy, 11 patients (13.3%) achieved complete response (CR); among them, 8 patients underwent neurosurgical resection. In addition, 32 patients (38.55%) achieved partial response (PR), 32 patients (38.55%) experienced stable disease (SD), and 8 (9.6%) experienced progressive disease (PD). The median follow-up period was 25.4 months (range 0.8– 49.6 months). The median follow-up time for the iPFS was 16.2 months (range 0.6– 41.2 months). The median OS, iPFS were 28.2 months and 24.7 months. Epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) mutations (HR 3.216, 95% confidence interval (CI) 1.269– 8.150, p = 0.014) and iPFS (HR 0.881, 95% CI 0.836– 0.929, p < 0.001) were found to be beneficial factors for OS. An intracranial-tumor CR was associated with a longer iPFS (PR: HR 0.052, 95% CI 0.009– 0.297, p = 0.001; SD: HR 0.081, 95% CI 0.025– 0.259, p < 0.001; PD: HR 0.216, 95% CI 0.077– 0.606, p = 0.004).Conclusion: Prolonged iPFS was associated with better OS in lung adenocarcinoma patients with BMs following intracranial local therapy, and mutations of EGFR / ALK or an intracranial-tumor CR are independent prognostic factors for prolonged survival.Keywords: lung adenocarcinoma, brain metastases, intracranial local therapy, survival, prognostic factors

Lei Tan,1,2,&ast; Han She,1,2,&ast; Yi Wang,1,2,&ast; Yuanlin Du,1 Jun Zhang,1 Yunxia Du,1 Yinyu Wu,1 Wei Chen,1 Bingqiang Huang,1 Duanyang Long,1 Xiaoyong Peng,2 Qinghui Li,2 Qingxiang Mao,1 Tao Li,2 Yi Hu1 1Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China; 2State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion Department, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Li; Yi Hu, Email lt200132@163.com; huyi921@sina.comBackground: Hemorrhagic shock was a leading cause of death worldwide, with myocardial injury being a primary affected organ. As commonly used solutions in fluid resuscitation, acetated Ringer’s (AR) and Lactate Ringer’s solution (LR) were far from perfect for their adverse reactions such as lactic acidosis and electrolyte imbalances. In previous studies, TPP@PAMAM-MR (TPP-MR), a novel nanocrystal resuscitation fluid has been found to protect against myocardial injury in septic rats. However, its role in myocardial injury in rats with hemorrhagic shock and underlying mechanism is unclear.Methods: The hemorrhagic shock rats and hypoxia-treated cardiomyocytes (H9C2) were utilized to investigate the impact of TPP-MR on cardiac function, mitochondrial function, and lipid peroxidation. The expressions of ferritin-related proteins glutathione peroxidase 4 (GPX4), Acyl CoA Synthase Long Chain Family Member 4 (ACSL4), and Cyclooxygenase-2(COX2) were analyzed through Western blotting to explore the mechanism of TPP-MR on hemorrhagic myocardial injury.Results: TPP-MR, a novel nanocrystalline resuscitation fluid, was synthesized using TPP@PAMAM@MA as a substitute for L-malic acid. We found that TPP-MR resuscitation significantly reduced myocardial injury reflected by enhancing cardiac output, elevating mean arterial pressure (MAP), and improving perfusion. Moreover, TPP-MR substantially prolonged hemorrhagic shock rats’ survival time and survival rate. Further investigations indicated that TPP-MR improved the mitochondrial function of myocardial cells, mitigated the production of oxidative stress agents (ROS) and increased the glutathione (GSH) content. Additionally, TPP-MR inhibited the expression of the ferroptosis-associated GPX4 protein, ACSL4 and COX2, thereby enhancing the antioxidant capacity.Conclusion: The results showed that TPP-MR had a protective effect on myocardial injury in rats with hemorrhagic shock, and its mechanism might be related to improving the mitochondrial function of myocardial cells and inhibiting the process of ferroptosis.Keywords: myocardial injury, hemorrhagic shock, mitochondria, ferroptosis

Yanan Li,1,2,&ast; Jingyi Hu,1,2,&ast; Ryan Au,1– 3 Cheng Cheng,1,2 Feng Xu,1,2 Weiyang Li,1,2 Yuguang Wu,1,2 Yuan Cui,1,2 Lei Zhu,1,2 Hong Shen1,2 1Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 2Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 3Academy of Chinese Culture and Health Sciences, Oakland, CA, 94612, USA&ast;These authors contributed equally to this workCorrespondence: Hong Shen; Lei Zhu, Jiangsu Provincial Hospital of Chinese Medicine (Affiliated Hospital of Nanjing University of Chinese Medicine), 155 Hanzhong Road, Qinhuai District, Nanjing, Jiangsu Province, People’s Republic of China, Tel\Fax +86-025- 86617141, Email shenhong999@njucm.edu.cn; zhulei5100@njucm.edu.cnBackground: Qingchang Tongluo Decoction (QTF) is clinically used for the treatment of intestinal fibrosis in Crohn’s Disease (CD). However, the role of QTF in CD-associated fibrosis and its potential pharmacological mechanism remains unclear.Purpose: The objective of this study was to elucidate the potential mechanism of QTF in treating CD-associated fibrosis, employing a combination of bioinformatics approaches — encompassing network pharmacology and molecular docking — complemented by experimental validation.Methods: To investigate the material basis and potential protective mechanism of QTF, a network pharmacology analysis was conducted. The core components and targets of QTF underwent molecular docking analysis to corroborate the findings obtained from network pharmacology. In vitro, a colon fibrotic model was established by stimulating IEC-6 cells with 10 ng/mL of transforming growth factor(TGF-β 1). In vivo, an intestinal fibrosis model was induced in BALB/c mice by TNBS. The role of QTF in inhibiting the TGF-β 1/Smad signaling pathway was investigated through RT-qPCR, Western blotting, immunohistochemistry staining, and immunofluorescence staining.Results: Network pharmacology analysis revealed that QTF could exert its protective effect. Bioinformatics analysis suggested that Flavone and Isoflavone might be the key components of the study. Additionally, AKT1, IL-6, TNF, and VEGFA were identified as potential therapeutic targets. Furthermore, experimental validation and molecular docking were employed to corroborate the results obtained from network pharmacology. RT-qPCR, Immunofluorescence, and Western blotting results demonstrated that QTF significantly improved colon function and inhibited pathological intestinal fibrosis in vivo and in vitro.Conclusion: Through the application of network pharmacology, molecular docking, and experimental validation, QTF could be confirmed to inhibit the proliferation of intestinal fibroblasts associated with CD and reduce the expression of Collagen I and VEGFA. This effect is achieved through the attenuation of ECM accumulation, primarily via the inhibition of the TGF-β 1/Smad signaling pathway. Keywords: Qingchang Tongluo Decoction, Crohn’s Disease, intestinal fibrosis, network pharmacology, Pharmacology

Xiaowei Zhou, Liyong Zou, Haoyue Deng, Yuanqun Zhou, Yue Wu, Xingnan Ouyang, Liangming Liu, Li Wang,&ast; Tao Li&ast; Department of Shock and Transfusion, Army Medical Center of Army Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Wang; Tao Li, Department of Shock and Transfusion, Army Medical Center of Army Medical University, Chongqing, People’s Republic of China, Email wangli8134@163.com; lt200132@tmmu.edu.cnPurpose: Cold seawater immersion aggravates hemorrhagic shock-induced homeostasis imbalance and organ dysfunction, leading to increased mortality. Previous studies have shown that treatments targeting oxidative stress and mitochondrial dysfunction have limited efficacy for cold seawater immersion combined with hemorrhagic shock (SIHS). Thus, the mechanisms responsible for SIHS need further investigation.Methods and Results: Data from the hemorrhagic shock transcriptome and cold seawater immersion targets used for bioinformatics analysis revealed the involvement of endoplasmic reticulum stress (ERS) in SIHS occurrence and progression. Based on these findings, the effects and possible mechanism of inhibiting ERS in SIHS rats were investigated. SIHS causes a lethal triad and impairment of vital organ function, leading to death. Compared to lactated Ringer’s solution, the ERS inhibitor 4-phenylbutyric acid (PBA)significantly ameliorated acidosis and coagulopathy and protected vital organ function while prolonging survival and the golden treatment time. Through target screening and validation, 7 targets were identified for the ERS inhibitor PBA for the treatment of SIHS, among which S1PR1, MMP8 and CFTR may play more important roles.Conclusion: ERS plays a crucial role in the progression of SIHS. Inhibition of ERS caused by SIHS alleviates the lethal triad, protects organ function, and prolongs survival and the golden treatment time. The ERS inhibitor PBA may be an effective therapeutic measure for treating SIHS.Keywords: cold seawater immersion, hemorrhagic shock, lethal triad, organ function, ER stress, 4-phenylbutyric acid

Qiming Gan,1,&ast; Quanzhen Liu,1,2,&ast; Yanjuan Wu,1,&ast; Xiaofeng Zhu,1,2 Jingcun Wang,1 Xiaofen Su,1 Dongxing Zhao,1 Nuofu Zhang,1 Kang Wu1 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Disease, Department of Sleep Medicine Center, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510160, People’s Republic of China; 2Nanshan School, Guangzhou Medical University, Guangzhou, Guangdong, 511436, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kang Wu; Nuofu Zhang, Department of Pulmonary and Critical Care Medicine, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, No. 28 Qiaozhong Mid Road, Guangzhou, Guangdong, 510160, People’s Republic of China, Email d102_wk@126.com; nfzhanggird@163.comPurpose: Obstructive sleep apnea (OSA) had been associated with asthma in observational studies, but the effect of OSA on the onset of asthma in childhood or adulthood remains unclear, and the causal inferences have not been confirmed. This study aims to investigate the potential causal association between OSA with asthma, including different age-of-onset subtypes, providing reliable basis for the clinical treatment of OSA and asthma.Patients and Methods: Causality between OSA and asthma was assessed using a two-sample bi-directional Mendelian randomization (MR) analysis. OSA data were obtained from the FinnGen consortium R9, while asthma and its subtypes (adult-onset asthma, child-onset asthma, and moderate-to-severe asthma) were sourced from the IEU OpenGWAS project. The inverse-variance weighted (IVW) method was chosen as the primary analysis and was complemented by various sensitivity analyses. The MR-PRESSO outlier test was employed to systematically identify and remove outlier variants, mitigating heterogeneity and potential effects of horizontal pleiotropy.Results: The MR analyses provided evidence of genetically predicted OSA having a promoting effect on child-onset asthma (OR,1.49; 95% CI, 1.05– 2.11; P=0.025) and moderate-to-severe asthma (OR,1.03; 95% CI, 1.00– 1.06; P=0.046). However, no causal association between OSA with asthma and adult-onset asthma was observed.Conclusion: Our study revealed a causal association between OSA and child asthma, but not in adults. Moderate-to-severe asthma may have a potential promoting effect on OSA. These findings underscore the importance of age-specific considerations in managing asthma and suggests the need for personalized approaches in clinical practice.Keywords: asthma, obstructive sleep apnea, Mendelian randomization, genetic

Yan Jiang,1 Yuanyuan Peng,1 Yingyi Wu,1 Qing Sun,1 Tebo Hua2 1Department of Ultrasound, Ningbo Medical Centre Lihuili Hospital, Ningbo, Zhejiang, People’s Republic of China; 2Department of Thyroid Breast Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Tebo Hua, Department of Thyroid Breast Surgery, Ningbo Medical Centre Lihuili Hospital, Ningbo, Zhejiang, 315040, People’s Republic of China, Email huatebo@163.comObjective: To develop a clinical-radiomics model using a multimodal machine learning method for distinguishing ductal carcinoma in situ (DCIS) from breast fibromatosis.Methods: The clinical factors, ultrasound features, and related ultrasound images of 306 patients (198 DCIS patients) were retrospectively collected. Patients in the development and validation cohort were 184 and 122, respectively. The independent clinical and ultrasound factors identified by the multivariable logistic regression analysis were used for the clinical-ultrasound model construction. Then, the region of interest of breast lesions was delineated and radiomics features were extracted. Six machine learning algorithms were trained to develop a radiomics model. The algorithm with higher and more stable prediction ability was chosen to convert the output of the results into the Radscore. Further, the independent clinical predictors and Radscore were enrolled into the logistic regression analysis to generate a combined clinical-radiomics model. The receiver operating characteristic curve analysis, DeLong test, and decision curve analysis were adopted to compare the prediction ability and clinical efficacy of three different models.Results: Among the six classifiers, logistic regression model was selected as the final radiomics model. Besides, the combined clinical-radiomics model exhibited a superior ability in distinguishing DCIS from breast fibromatosis to the clinical-ultrasound model and the radiomics model.Conclusion: The combined model by integrating clinical-ultrasound factors and radiomics features performed well in predicting DCIS, which might promote prompt interventions to improve the early diagnosis and prognosis of the patients.Keywords: multimodal machine learning, clinical-ultrasound features, radiomics, ductal carcinoma in situ

Jiejie Zhu,1,2 Yumei Wu,1,2 Xiaoyuan Ge,1,2 Xinwen Chen,1,2 Qiao Mei1,2 1Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, People’s Republic of China; 2Key Laboratory of Digestive Diseases of Anhui Province, Hefei, People’s Republic of ChinaCorrespondence: Qiao Mei, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, Anhui Province, 230022, People’s Republic of China, Email meiqiao@hotmail.comBackground: Ulcerative colitis (UC) is a long-lasting idiopathic condition, but its precise mechanisms remain unclear. Meanwhile, evidence has demonstrated that ferroptosis seems to interlock with the progress of UC. This research sought to identify hub genes of UC related to ferroptosis.Methods: First, the relevant profiles for this article were obtained from GEO database. From the FerrDb, 479 genes linked to ferroptosis were retrieved. Using analysis of the difference and WGCNA on colonic samples from GSE73661, the remaining six hub genes linked to ferroptosis and UC were discovered. Through logistic regression analyses, the diagnostic model was constructed and was then evaluated by external validation using dataset GSE92415. Afterwards, the correlation between immune cell filtration in UC and hub genes was examined. Finally, a mice model of colitis was established, and the results were verified using qRT-PCR.Results: We acquired six hub genes linked to ferroptosis and UC. In order to create a diagnostic model for UC, we used logistic regression analysis to screen three of the six ferroptosis related genes (HIF1A, SLC7A11, and LPIN1). The ROC curve showed that the three hub genes had outstanding potential for disease diagnosis (AUC = 0.976), which was subsequently validated in samples from GSE92415 (AUC = 0.962) and blood samples from GSE3365 (AUC = 0.847) and GSE94648 (AUC = 0.769). These genes might be crucial for UC immunity based upon the results on the immune system. Furthermore, mouse samples examined using qRT-PCR also verified our findings.Conclusion: In conclusion, the findings have important implications for ferroptosis and UC, and these hub genes may also offer fresh perspectives on the aetiology and therapeutic approaches of UC.Keywords: ulcerative colitis, ferroptosis, hub genes, immune, bioinformatics analysis

Heng Yang, Lixia Chen, Danjuan Ye, Ying Wu, Huafang Zhang Department of Nursing, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, People’s Republic of ChinaCorrespondence: Huafang Zhang, Department of Nursing, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, N1 Shangcheng Avenue, Yiwu, Zhejiang, 322000, People’s Republic of China, Email wuyizhangyichi@zju.edu.cnPurpose: The objective of this study was to investigate latent classes of oral health and the factors associated with them in acutely admitted elderly inpatients.Patients and Methods: A cross-sectional study was conducted using purposive sampling to survey Chinese older-adult acutely inpatients. Data was collected utilizing several instruments, including a general information questionnaire, Brief Oral Health Status Examination (BOHSE), Oral Frailty Index-8 (OFI-8), Mini-Nutritional Assessment Short Form (MNA-SF), and Frailty Screening Questionnaire (FSQ). Latent class analysis was applied to identify distinct categories of oral health among elderly inpatients, and multinomial logistic regression was employed to analyze the factors associated with different oral health categories.Results: In this study, a total of 504 elderly patients were ultimately included, leading to the identification of three latent classes of oral health: “oral health-low level group (41.27%)”, “oral health-moderate level group (25.4%)”, and “oral health-high level group (33.33%)”. The findings revealed that patients with advanced age, elevated neutrophil percentage, and higher C-reactive protein (CRP) values were more likely to be classified in the low oral health group. Additionally, individuals experiencing malnutrition and frailty had a higher risk of falling into the low oral health category. Those with comorbidities and oral frailty were more prevalent in the moderate oral health group. At the same time, elderly patients with higher BMI (22.95± 3.043) ratios were more likely to be categorized in the high oral health group.Conclusion: This study sheds light on three distinct latent classes of oral health among acutely admitted elderly inpatients. These findings underscore the importance of healthcare professionals focusing on the assessment and health education of elderly patients’ oral health. Furthermore, personalized interventions should be developed to promote healthy aging, with particularly attention to enhancing oral health outcomes in this population.Keywords: emergency department, oral health, factors, older people, latent class analysis, frailty

Ming Cheng,1,2 Cong Ma,1– 3 Hong-Duo Chen,1,2 Yan Wu,1,2 Xue-Gang Xu1,2 1Department of Dermatology, The First Hospital of China Medical University, Shenyang, 110000, People’s Republic of China; 2Key Laboratory of Immunodermatology, Ministry of Education and NHC; National Joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, 110000, People’s Republic of China; 3Department of Dermatology and Sexually Transmitted Diseases, The First Hospital of Inner Mongolia University for Nationalities, Tongliao, 028000, People’s Republic of ChinaCorrespondence: Xue-Gang Xu; Yan Wu, Department of Dermatology, The First Hospital of China Medical University, Shenyang, 110000, People’s Republic of China, Email xuxuegang2749290@163.com; jlwuyan@126.comAbstract: Alopecia is considered a widespread yet troubling health issue, with limited treatment options. As membranous structures derived from cells carrying proteins, nucleic acids and lipids, exosomes functionally medicate intercellular communication and alter the responses of recipient cells, resulting in disease restraint or promotion. Exosomes have broad prospects in diagnosis and treatment of diseases. Studies using animal models and at the cellular level have clearly shown that exosomes from several types of cells, including dermal papilla cells and mesenchymal stem cells, have a notable capacity to promote hair growth, suggesting that exosomes may provide a new option to treat alopecia. Here, we present a thorough review of the most recent progress in the application of exosomes to hair growth.Keywords: exosome, hair follicle, alopecia

Lin Shen,1,&ast; Zixuan Chen,1,&ast; Zhi Zhang,2,&ast; Yunjiang Wu,3 Yue Ren,1 Ying Li,1 Yue Li,1 Xudong Yin,1 Fang Han,1 Yong Chen1 1Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China; 2Department of Medical Oncology, Baoying Clinical College, Medical College of Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China; 3Department of Thoracic Surgery, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou City, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Chen, Department of Radio-Chemotherapy, Affiliated Hospital of Yangzhou University, Yangzhou University, Hanjiang Middle Road No. 368, Yangzhou, Jiangsu, 225009, People’s Republic of China, Tel +86-18051062926, Email chenyong_jsyz@sina.comPurpose: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line standard treatment for locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). The evidence also demonstrates improved synergistic effects of chemotherapy when combined with delayed administration of ICIs. In this study, we conducted a retrospective investigation into the treatment efficacy of taxol plus platinum (TP) chemotherapy combined with delayed administration of PD-1 inhibitors for ESCC patients.Patients and Methods: Clinical data of ESCC patients who received PD-1 inhibitors 3– 5 days after TP chemotherapy as first-line treatment was retrospectively reviewed between January 2019 and April 2023. Clinical outcomes and treatment safety were analyzed. The potential roles of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV) were investigated.Results: A total of 34 locally advanced, recurrent or metastatic ESCC patients received PD-1 inhibitors 3– 5 days following TP chemotherapy were included. The objective response rate (ORR) and disease control rate (DCR) were 85.3% and 97.1% respectively. The median progression-free survival (PFS) and overall survival (OS) were 13.2 and 19.1 month respectively. Seven patients received radical surgery, 1 patient achieved pathologic complete response (pCR) and 3 patients achieved major pathologic response (MPR). Among the 27 patients without surgery, the median PFS and OS were 9.7 and 19.1 month respectively. A more favorable prognosis was correlated with NLR less than 3 at the 3rd and 4th cycle of immunochemotherapy. No significant correlations between other parameters (PLR, MLR and PIV) and prognosis were observed. A total of 22 patients developed grade 3– 4 toxicity events.Conclusion: The optimized sequence of PD-1 inhibitors administered 3– 5 days after TP chemotherapy as the first-line treatment of ESCC demonstrated favorable treatment efficacy. Pretreatment NLR of less than 3 at the 3rd and 4th cycle of immunochemotherapy is associated with a better prognosis.Keywords: immune checkpoint inhibitors, chemotherapy, rational sequence, esophageal squamous cell carcinoma, peripheral blood parameters

Qin Zhang,1 Rui Zhao,1 Yaqing Wu,2 Liming Zhang,1 Yi Feng2 1Endoscopy Center, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Department of Anesthesiology, Peking University People’s Hospital, Beijing, People’s Republic of ChinaCorrespondence: Yi Feng, Department of Anesthesiology, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China, Email doctor_yifeng@sina.comPurpose: Remimazolam is a novel short-acting benzodiazepine used for sedation and general anesthesia. This study aimed to evaluate the efficacy and safety of remimazolam besylate in elderly patients who underwent diagnostic gastrointestinal endoscopy.Patients and Methods: A total of 120 patients aged 60– 75 years were randomly allocated to one of two groups. Remifentanil 0.3μg/kg was used for analgesia. Patients were administered remimazolam besylate 7 mg (R group) or etomidate 0.1 mg/kg combined with 1% propofol 0.5 mg/kg (EP group) for induction, supplemental repeated doses were given as needed. Some time metrics, vital signs, adverse events were evaluated. Patients’ Mini-cog score and recovery questionnaires were compared.Results: Compared to the EP group, the induction time was slightly longer in the R group (1.50 VS 1.15 minutes) (P< 0.05), the time spent in the post-anesthesia care unit (PACU) was shorter (15.17 VS 17.40 minutes) (P< 0.05). Compare with EP group, SBP was lower in R group at T15 and T25 time point, but heart rate was higher in T2, T3, T5 (P< 0.05). The Mini-Cog score was higher after the procedure (2.83 VS 2.58) (P< 0.05). The incidence of respiratory adverse events was higher in the EP group than R group (18.3% VS 5.0%, P < 0.05). The most common adverse event in R group was hiccups. The sedation satisfaction rate and degree of amnesia were higher in the R group (66.7% VS 11.7%) (P < 0.05), and the effect on patient’s life within 24 hours was lower (12.0% VS 30.5%) (P < 0.05).Conclusion: The safety and efficacy of remimazolam besylate are not inferior to those of etomidate combined with propofol, rendering it a safe option for sedation during gastrointestinal endoscopy in ASA I-II elderly patients, but care should be taken to monitor the occurrence of hiccups.Keywords: gastrointestinal endoscopy, anesthesia, remimazolam besylate, etomidate, propofol

Shanshan Li,1,2 Le Zhang,3 Boyi Yang,3 Yi Huang,3 Yuqi Guan,3 Nanbo Huang,1 Yingnan Wu,1 Wenshuo Wang,1 Qing Wang,1 Haochen Cai,1 Yong Sun,1 Zijun Xu,1 Qin Wu1,2 1Medical College, Jiangsu Vocational College of Medicine, Yancheng, People’s Republic of China; 2Jiangsu Engineering Research Centers for Cardiovascular and Cerebrovascular Disease and Cancer Prevention and Control, Jiangsu Vocational College of Medicine, Yancheng, People’s Republic of China; 3Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Qin Wu, Medical College, Jiangsu Vocational College of Medicine, No. 283, South Jiefang Road, Yancheng, 224005, People’s Republic of China, Tel +86-515-88159750, Email hhwuq@163.comBackground: In elderly diabetic patients, depression is often overlooked because professional evaluation requires psychiatrists, but such specialists are lacking in the community. Therefore, we aimed to create a simple depression screening model that allows earlier detection of depressive disorders in elderly diabetic patients by community health workers.Methods: The prediction model was developed in a primary cohort that consisted of 210 patients with diabetes, and data were gathered from December 2022 to February 2023. The independent validation cohort included 99 consecutive patients from February 2023 to March 2023. Multivariable logistic regression analysis was used to develop the predictive model. We incorporated common demographic characteristics, diabetes–specific factors, family structure characteristics, the self–perceived burden scale (SPBS) score, and the family APGAR (adaptation, partnership, growth, affection, resolution) score. The performance of the nomogram was assessed with respect to its calibration (calibration curve, the Hosmer–Lemeshow test), discrimination (the area under the curve (AUC)), and clinical usefulness (Decision curve analysis (DCA)).Results: The prediction nomogram incorporated 5 crucial factors such as glucose monitoring status, exercise status, monthly income, sleep disorder status, and the SPBS score. The model demonstrated strong discrimination in the primary cohort, with an AUC of 0.839 (95% CI, 0.781– 0.897). This discriminative ability was further validated in the validation cohort, with an AUC of 0.857 (95% CI, 0.779– 0.935). Moreover, the nomogram exhibited satisfactory calibration. DCA suggested that the prediction of depression in elderly patients with diabetes mellitus was of great clinical value.Conclusion: The prediction model provides precise and user–friendly guidance for community health workers in preliminary screenings for depression among elderly patients with diabetes.Keywords: prediction model, depression, elderly, diabetes, community–based

Jun Zhang,1,&ast; Yinyu Wu,1,&ast; Yuanlin Du,1,&ast; Yunxia Du,1 Daiqin Bao,1 Haibin Lu,2 Xiaoqiong Zhou,1 Rui Li,1 Haoyu Pei,1 Han She,1 Qingxiang Mao1 1Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China; 2Department of Intensive Care Unit, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Han She; Qingxiang Mao, Email mazuishehan@163.com; qxmao@tmmu.edu.cnBackground: This study aimed to discover diagnostic and prognostic biomarkers for sepsis immunotherapy through analyzing the novel cellular death process, cuproptosis.Methods: We used transcriptome data from sepsis patients to identify key cuproptosis-related genes (CuRGs). We created a predictive model and used the CIBERSORT algorithm to observe the link between these genes and the septic immune microenvironment. We segregated sepsis patients into three subgroups, comparing immune function, immune cell infiltration, and differential analysis. Single-cell sequencing and real-time quantitative PCR were used to view the regulatory effect of CuRGs on the immune microenvironment and compare the mRNA levels of these genes in sepsis patients and healthy controls. We established a sepsis forecast model adapted to heart rate, body temperature, white blood cell count, and cuproptosis key genes. This was followed by a drug sensitivity analysis of cuproptosis key genes.Results: Our results filtered three key genes (LIAS, PDHB, PDHA1) that impact sepsis prognosis. We noticed that the high-risk group had poorer immune cell function and lesser immune cell infiltration. We also discovered a significant connection between CuRGs and immune cell infiltration in sepsis. Through consensus clustering, sepsis patients were classified into three subgroups. The best immune functionality and prognosis was observed in subgroup B. Single-cell sequencing exposed that the key genes manage the immune microenvironment by affecting T cell activation. The qPCR results highlighted substantial mRNA level reduction of the three key genes in the SP compared to the HC. The prediction model, which combines CuRGs and traditional diagnostic indicators, performed better in accuracy than the other markers. The drug sensitivity analysis listed bisphenol A as highly sensitive to all the key genes.Conclusion: Our study suggests these CuRGs may offer substantial potential for sepsis prognosis prediction and personalized immunotherapy.Keywords: sepsis, cuproptosis, prognosis, immune cell infiltration, nomogram

Jiaying Lao,1,2,&ast; Hang Tan,3,&ast; Yuyu Wu,2,&ast; Ting Ding,4 Xinqian Liu,1 Lanrong Sun,2 Xiyi Chen,2 Chongrong Zhu,2 Yiming Kang,5 Yu-Hsin Chen,2,6 Chonghui Tang,1 Fan Wang,7 Yanlong Liu2,6 1Department of Neurosurgery, Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, People’s Republic of China; 2School of Mental Health, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of neurosurgery, Hangzhou Mingzhou Brain Rehabilitation Hospital, Hangzhou, People’s Republic of China; 4Department of Infectious Diseases, The Affiliated Xiangshan Hospital of Wenzhou Medical University, Ningbo, People’s Republic of China; 5Psychosomatic Medicine Research Division, Inner Mongolia Medical University, Huhhot, People’s Republic of China; 6Zhejiang Provincial Clinical Research Center for Mental Disorders, The Affiliated Wenzhou Kangning Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of China; 7Beijing Hui−Long−Guan Hospital, Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanlong Liu, School of Mental Health, Medical University, Wenzhou, 325035, People’s Republic of China, Email benjaminlyl@wmu.edu.cn Chonghui Tang, Department of Neurosurgery, Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, 315300, People’s Republic of China, Email tangegg@163.comObjective: Cigarette smoking and low peripheral nitric oxide synthase (NOS) levels are strongly associated with sleep disorders. However, whether cerebrospinal fluid (CSF) NOS relates to sleep disorders and whether CSF NOS mediates the relationship between cigarette smoking and sleep disorders is unclear.Methods: We measured CSF levels of total NOS (tNOS) and its isoforms (inducible NOS [iNOS] and constitutive NOS [cNOS]) in 191 Chinese male subjects. We applied the Pittsburgh Sleep Quality Index (PSQI).Results: The PSQI scores of active smokers were significantly higher than those of non-smokers, while CSF tNOS, iNOS, and cNOS were significantly lower (all p < 0.001). CSF tNOS, iNOS, and cNOS were negatively associated with PSQI scores in the general population (all p < 0.001). Mediation analysis suggested that CSF tNOS, iNOS, and cNOS mediate the relationship between smoking and PSQI scores, and the indirect effect accounted for 78.93%, 66.29%, and 81.65% of the total effect, respectively.Conclusion: Cigarette smoking is associated with sleep disorders. Active smokers had significantly lower CSF levels of tNOS, iNOS, and cNOS. Furthermore, tNOS, iNOS, and cNOS mediate the relationship between cigarette smoking and sleep quality. This study provides insights into how cigarette smoke affects sleep disorders.Keywords: cerebrospinal fluid nitric oxide synthase, cigarette smoking, Pittsburgh Sleep Quality Index, sleep disorders, mediation

Yumei Wu,1– 3,&ast; Chunhua Zeng,1– 3,&ast; Jiajia Lv,1– 3 Hongyu Li,1– 3 Jie Gao,1– 3 Zhidong Liu,4 Zeli Yuan1– 3 1Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 2Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 3Guizhou International Scientific and Technological Cooperation Base for Medical Photo-Theranostics Technology and Innovative Drug Development, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 4Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhidong Liu, Tianjin University of Traditional Chinese Medicine, No. 10 Poyanghu Road, Tianjin, Jinghai District, 301617, People’s Republic of China, Email lonerliuzd@163.com Zeli Yuan, Zunyi Medical University, Zunyi, 563000, People’s Republic of China, Email zlyuan@zmu.edu.cnBackground: Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly because of increased toxicity from drug interactions and challenges in achieving the desired spatial and temporal distribution of drug delivery. Optimizing synergistic drug combination ratios to ensure uniform targeting and distribution across space and time, particularly in vivo, is a significant challenge. In this study, cRGD-coated liposomes encapsulating optimized synergistic cepharanthine (CEP; a chemotherapy drug) and IR783 (a phototherapy agent) were developed for combined chemotherapy and photothermal therapy in vitro and in vivo.Methods: An MTT assay was used to evaluate the combination index of CEP and IR783 in five cell lines. The cRGD-encapsulated liposomes were prepared via thin-film hydration, and unencapsulated liposomes served as controls for the loading of CEP and IR783. Fluorescence and photothermal imaging were used to assess the efficacy of CEP and IR783 encapsulated in liposomes at an optimal synergistic ratio, both in vitro and in vivo.Results: The combination indices of CEP and IR783 were determined in five cell lines. As a proof-of-concept, the optimal synergistic ratio (1:2) of CEP to IR783 in 4T1 cells was evaluated in vitro and in vivo. The average diameter of the liposomes was approximately 100 nm. The liposomes effectively retained the encapsulated CEP and IR783 in vitro at the optimal synergistic molar ratio for over 7 d. In vivo fluorescence imaging revealed that the fluorescence signal from cRGD-CEP-IR783-Lip was detectable at the tumor site at 4 h post-injection and peaked at 8 h. In vivo photothermal imaging of tumor-bearing mice indicated an increase in tumor temperature by 32°C within 200 s. Concurrently, cRGD-CEP-IR783-Lip demonstrated a significant therapeutic effect and robust biosafety in the in vivo antitumor experiments.Conclusion: The combination indices of CEP and IR783 were successfully determined in vitro in five cell lines. The cRGD-coated liposomes encapsulated CEP and IR783 at an optimal synergistic ratio, exhibiting enhanced antitumor effects and targeting upon application in vitro and in vivo. This study presents a novel concept and establishes a research framework for synergistic chemotherapy and phototherapy treatment. Keywords: drug delivery, liposomes, synergistic effects, phototherapy

Keke Li,1,&ast; Yaozhou Wu,1,2,&ast; Meng Liu,1 Junwen Yan,1 Lianhua Wei1 1Department of Clinical Laboratory, Gansu Provincial Hospital, Lanzhou, 730000, People’s Republic of China; 2First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lianhua Wei; Junwen Yan, Department of Clinical Laboratory, Gansu Provincial Hospital, No. 204 Donggang West Road, Chengguan District, Lanzhou, 730000, People’s Republic of China, Email 3752131518@qq.com; 249380017@qq.comPurpose: Accurate detection and identification of pathogens and their associated resistance mechanisms are essential prerequisites for implementing precision medicine in the management of Carbapenem-resistant Enterobacterales (CRE). Among the various resistance mechanisms, the production of KPC carbapenemase is the most prevalent worldwide. Consequently, this study aims to develop a convenient and precise nucleic acid detection platform specifically for the blaKPC gene.Methods: The initial phase of our research methodology involved developing a CRISPR/Cas12a detection framework, which was achieved by designing highly specific single-guide RNAs (sgRNAs) targeting the blaKPC gene. To enhance the sensitivity of this system, we incorporated three distinct amplification techniques—polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), and recombinase polymerase amplification (RPA)—into the CRISPR/Cas12a framework. Subsequently, we conducted a comparative analysis of the sensitivity and specificity of these three amplification methods when used in combination with the CRISPR/Cas12a system. Additionally, we assessed the clinical applicability of the methodologies by evaluating fluorescence readouts from 80 different clinical isolates. Furthermore, we employed lateral flow assay technology to provide a visual representation of the results, facilitating point-of-care testing.Results: Following a comparative analysis of the sensitivity and specificity of the three methods, we identified the RPA-Cas12a approach as the optimal detection technique. Our findings demonstrated that the limit of detection (LoD) of the RPA-Cas12a platform was 1 aM (~1 copy/μL) for plasmid DNA and 5 × 10³ fg/μL for genomic DNA. Furthermore, both the sensitivity and specificity of the platform achieved 100% upon validation with 80 clinical isolates.Conclusion: These findings suggest that the developed RPA-Cas12a platform represents a promising tool for the cost-effective, convenient, and accurate detection of the blaKPC gene.Keywords: Klebsiella pneumoniae carbapenemase, CRISPR-Cas12a, isothermal amplification, polymerase chain reaction, loop-mediated isothermal amplification, recombinase polymerase amplification, lateral flow strips

Kang Wang,1,&ast; Zihui Yang,1,&ast; Boyu Zhang,1,&ast; Song Gong,2 Yiping Wu1 1Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Division of Endocrinology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Song Gong, Division of Endocrinology, Tongji Hospital, Tongji Medical College, Wuhan, Hubei, People’s Republic of China, Email gongsong@tjh.tjmu.edu.cn Yiping Wu, Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Wuhan, Hubei, People’s Republic of China, Email tongjiplastic@163.comAbstract: Wound healing in diabetic patients is frequently hampered. Adipose-derived stem cell exosomes (ADSC-eoxs), serving as a crucial mode of intercellular communication, exhibit promising therapeutic roles in facilitating wound healing. This review aims to comprehensively outline the molecular mechanisms through which ADSC-eoxs enhance diabetic wound healing. We emphasize the biologically active molecules released by these exosomes and their involvement in signaling pathways associated with inflammation modulation, cellular proliferation, vascular neogenesis, and other pertinent processes. Additionally, the clinical application prospects of the reported ADSC-eoxs are also deliberated. A thorough understanding of these molecular mechanisms and potential applications is anticipated to furnish a theoretical groundwork for combating diabetic wound healing.Keywords: diabetes, wound healing, ADSC-exos, tissue regeneration, skin cells, inflammation

Yuling Liang,1,&ast; Yuqing Xie,1,&ast; Xiaoli Liu,1 Lihua Yu,1 Huiwen Yan,1 Zimeng Shang,1 Yuan Wu,1 Xue Cai,2 Wanxin Shi,2 Juan Du,3 Zhiyun Yang1 1Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China; 2Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 3Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Juan Du, Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Email duj656@163.com Zhiyun Yang, Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China, Tel +86-10-84322148, Email yangzhiyun2016@163.comPurpose: Traditional Chinese medicine (TCM) therapy is an important means to treat hepatocellular carcinoma (HCC), Astragalus (Latin name: Hedysarum Multijugum Maxim; Chinese name: Huangqi, HQ) and Atractylodes (Latin name: Atractylodes Macrocephala Koidz; Chinese name: Baizhu, BZ) (HQBZ), a classic herb pair, is often used in combination to HCC. However, the main components and potential mechanisms of HQBZ therapy in HCC remain unclear. This study aimed to identify the potential active ingredients and molecular mechanisms of action of HQBZ in HCC treatment.Methods: The HQBZ-Compound-Target-HCC network and HQBZ-HCC transcriptional regulatory network were constructed to screen the core active compound components and targets of HQBZ therapy for HCC. Molecular docking techniques are used to verify the stability of binding core active compound components to targets. GO and KEGG enrichment analysis were used to explore the signaling pathway of HQBZ in HCC treatment, the mechanism of HQBZ treatment of HCC was verified based on in vivo H22 tumor bearing mice and in vitro cell experiments.Results: Network pharmacology and molecular docking studies showed that HQBZ treatment of HCC was related to the targeted regulation of IL-6 and STAT3 by the active compound biatractylolide, KEGG pathway enrichment analysis suggest that HQBZ may play a role in the treatment of HCC through IL-6/STAT3 signaling pathway. In vitro experiment results proved that HQBZ could regulate IL-6/STAT3 signaling pathway transduction on CD8+T cells, inhibit CD8+T cell exhaustion and restore the function of exhausted CD8+T cells. In vivo experiment results proved that HQBZ can regulate IL-6/STAT3 signaling pathway transduction in H22 liver cancer model mouse tumor tissue, increased the proportion of tumor infiltrating CD8+T cells.Conclusion: This study found that HQBZ may play a therapeutic role in HCC by targeting IL-6 and STAT3 through biatractylolide, its mechanism of action is related to regulating IL-6/STAT3 signaling pathway, reversing T cell failure and increasing tumor infiltration CD8+T cells.Keywords: Astragalus–Atractylodes herb pair, hepatocellular carcinoma, IL-6/STAT3 signaling pathway, molecular docking, network pharmacology

Wanxin Shi,1,2,&ast; Huiwen Yan,1,&ast; Xiaoli Liu,1 Lihua Yu,1 Yuqing Xie,1 Yuan Wu,1 Yuling Liang,1 Zhiyun Yang1 1Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2First Clinical Medical College, Beijing University of Chinese Medicine, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiyun Yang, Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jing Shun East Street, Beijing, 100015, People’s Republic of China, Tel/Fax +86-10-84322148, Email yangzhiyun2016@163.comPurpose: Portal vein tumor thrombosis (PVTT) is one of the hallmarks of advanced Hepatocellular carcinoma (HCC). Platelet (PLT) function parameters and CD8+T cells (CD8+Ts) play an important role in HCC progression and metastasis. This study is committed to establishing an efficient prognosis prediction model and exploring the combined effect of PLT and CD8+Ts on PVTT prognosis.Patients and Methods: This retrospective study collected 932 HCC patients with PVTT from 2007 to 2017 and randomly divided them into a training cohort (n = 656) and a validation cohort (n = 276). We performed multivariable Cox and Elastic-net regression analysis, constructed a nomogram and used Kaplan–Meier survival curves to compare overall survival and progression-free survival rates in different substrata. Relationships between indicators involved were also analyzed.Results: We found tumor number, size, treatment, PLT, γ-glutamyl transferase, alpha-fetoprotein, mean platelet volume, and CD8+Ts were related to the 5-year OS of patients with PVTT, and established a nomogram. The area under the receiver operating characteristic curve (AUCs) for predicting the 1-year OS rates were 0.767 and 0.794 in training and validation cohorts. The calibration curve and decision curve indicated its predictive consistency and strong clinical utility. We also found those with low PLT (< 100&ast;10^9/L) and high CD8+Ts (> 320 cells/μL) had a better prognosis.Conclusion: We established a well-performing prognostic model for PVTT based on platelet functional parameters and CD8+Ts, and found that PT-8 formed by PLT and CD8+Ts was an excellent predictor of the prognosis of PVTT.Keywords: hepatocellular carcinoma, portal vein tumor thrombus, platelet, CD8+T cells counts, prognostic model, correlation analysis

Jiaru Zhuang,1,2 Shan Wang,1 Yuan Wang,1 Renjing Hu,2 Yibo Wu1 1Human Reproductive Medicine Center, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214026, People’s Republic of China; 2Department of Laboratory Medicine, Jiangnan University Medical Center, Wuxi, Jiangsu, 214000, People’s Republic of ChinaCorrespondence: Yibo Wu; Renjing Hu, Email 9862016107@jiangnan.edu.cn; weiweihuhu112@163.comPurpose: In recent years, female infertility has become a research hotspot in the field of health management, and its cause may be related to insulin resistance (IR). We used a novel and practical IR indicator, the TyG index to explore its association with infertility.Patients and Methods: We calculated the TyG index using data from adult women who participated in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2018. Then, we used multivariate logistic regression, smooth curve fitting, and subgroup analysis to examine the association between the TyG index and infertility in women.Results: Logistic regression models showed a positive correlation between the TyG index and infertility, which remained significant even after adjusting for all confounders (OR=1.51,95% CI:1.14– 2.00, p=0.005). This association was consistent in all subgroups (age, education level, marital status, BMI, smoking, alcohol consumption, hypertension, diabetes, pelvic inflammatory disease/PID treatment, and menstrual regularity in the past 12 months) (p> 0.05 for all interactions). However, the diagnostic power of the TyG index for infertility was limited (AUC=0.56, 95% CI: 0.52– 0.61).Conclusion: The TyG index is positively correlated with infertility, but its diagnostic value is limited. Further research is needed on the TyG index as an early predictor of infertility.Keywords: cross-sectional study, NHANES, infertility, insulin resistance, triglyceride glucose index, TyG

Lijuan Zhang,1 Zhe Wang,2 Yingge Liu,1 Xiaobao Zhang,1 Yong Wu1 1Department of Anesthesiology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, People’s Republic of ChinaCorrespondence: Yong Wu, Department of Anesthesiology, Lianyungang Clinical College of Nanjing Medical University, No. 6 East Zhenhua Road, Lianyungang, Jiangsu, 222061, People’s Republic of China, Tel +8618961325621, Email 18961325621@163.comPurpose: Remimazolam tosilate is a novel ultrafast-acting benzodiazepine that has a rapid emergence even after continuous infusion when using flumazenil. So far, relatively few articles are still focusing on the quality of recovery after general anesthesia with remimazolam, especially in day surgery. This study aimed to compare the early postoperative quality of recovery of remimazolam tosilate with flumazenil and propofol in patients undergoing day surgery.Patients and Methods: 137 patients scheduled for day surgery were randomly divided into the remimazolam tosilate or propofol group. The primary endpoint was the incidence of overall recovery assessed with the early postoperative quality of recovery scale (PostopQRS) on postoperative day 1 (POD 1). The Richmond Agitation-Sedation Scale (RASS) scores in the post-anesthesia care unit (PACU), extubation time, postoperative recovery profiles, and perioperative data were documented. Any adverse events were recorded.Results: The incidence of overall recovery on POD1 was 47.7% in the remimazolam tosilate group and 65.1% in the propofol group (odds ratio, 0.52; 95% confidence interval (CI) 0.26 to 1.06; P = 0.072). In general, the overall recovery of the PostopQRS increased over time, and its interaction between time and group was significant (P = 0.003). Among the five dimensions of PostopQRS, there exist statistical differences between groups including emotional state and cognitive recovery. Upon arrival at the PACU, the remimazolam group was more sedated and took longer to recover to a RASS score similar to propofol. The frequency of application of vasoactive drugs during anesthesia was similar in both groups (P = 0.119). Despite rapid emergence with remimazolam after flumazenil reversal, re-sedation (10.8%) or somnolence (60%) in the PACU was observed, and the length of PACU stay in patients treated with remimazolam tosilate was longer than that of the propofol (35 min vs 30 min, P< 0.001).Conclusion: General anesthesia with remimazolam tosilate in conjunction with flumazenil reversal permits rapid recovery of consciousness in day surgery, but there was a notable occurrence of re-sedation or somnolence observed in PACU.Keywords: remimazolam tosilate, flumazenil, propofol, day surgery, quality of recovery

Xiangwen Shi,1,2,&ast; Haonan Ni,3,&ast; Linmeng Tang,4,&ast; Mingjun Li,2 Yipeng Wu,2 Yongqing Xu3 1Graduate School, Kunming Medical University, Kunming, People’s Republic of China; 2Laboratory of Yunnan Traumatology and Orthopedics Clinical Medical Center, Yunnan Orthopedics and Sports Rehabilitation Clinical Medical Research Center, Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force of PLA, Kunming, People’s Republic of China; 3First People’s Hospital of Huzhou, the First affiliated Hospital of Huzhou University, Huzhou, People’s Republic of China; 4Department of Radiology, the Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongqing Xu, Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Xi Shan District, Kunming, Yunnan, 650031, People’s Republic of China, Email xuyongqingkm@163.net Yipeng Wu, Department of Orthopedic Surgery, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Xi Shan District, Kunming, Yunnan, 650031, People’s Republic of China, Email 20201497@kmmu.edu.cnObjective: Osteomyelitis is a challenging disease in the field of bone infections, with its immune and molecular regulatory mechanisms still poorly understood. The aim of this study is to explore the value and potential mechanisms of cuproptosis-related genes (CRGs) in Staphylococcus aureus (S. aureus)-infected osteomyelitis from an immunological perspective.Methods: Initially, three transcriptomic datasets from public databases were integrated and analyzed, and consistent expression of CRGs in S. aureus-infected osteomyelitis was identified. Subsequently, immune infiltration analysis was performed, and M2 macrophage-related CRGs (M2R-CRGs) were further identified. Their potential molecular mechanisms were evaluated using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA). Finally, distinct osteomyelitis subtypes and diagnostic models based on characteristic M2R-CRGs were constructed.Results: Through correlation analysis with immune cell infiltration, three characteristic M2R-CRGs (SLC31A1, DLD, and MTF1) were identified. Further analysis using unsupervised clustering and immune microenvironment analysis indicated that cluster 1 might activate pro-inflammatory responses, while cluster 2 was shown to exhibit anti-inflammatory effects in osteomyelitis. Compared to Cluster A, Cluster B demonstrated higher levels and a greater diversity of immune cell infiltrations in CRG-related molecular patterns, suggesting a potential anti-inflammatory role in osteomyelitis. A diagnostic model for S. aureus-infected osteomyelitis, based on the three M2R-CRGs, was constructed, exhibiting excellent diagnostic performance and validated with an independent dataset. Significant upregulation in mRNA and protein expression levels of the three M2R-CRGs was observed in rat models of S. aureus-infected osteomyelitis, aligning with bioinformatic results.Conclusion: The M2R-CRGs (SLC31A1, DLD, and MTF1) may be considered characteristic genes for early diagnosis and personalized immune therapy in patients with S. aureus-infected osteomyelitis.Keywords: osteomyelitis, cuproptosis, Staphylococcus aureus, M2 macrophage, immune infiltration, diagnosis

Lang Liu,1,&ast; Binghua Zhang,1,&ast; Zhenwei Zhou,2 Jie Yang,1 Ailin Li,1 Yongji Wu,1 Zeyu Peng,1 Xiangyan Li,2 Zhonghua Liu,3 Xiangyang Leng,1 Changwei Zhao,4 Haisi Dong,2 Wenhai Zhao4 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 2Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 3Department of Orthopaedics, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 4Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haisi Dong, Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China, Tel/Fax +86 431-18604361976, Email adonghaisi@163.com Wenhai Zhao, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China, Tel/Fax +86 431-86177836, Email zwh9899@163.comBackground: Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA.Methods: The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK‐8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments.Results: In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1β and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1β-induced chondrocytes and DMM-induced rats.Conclusion: RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.Keywords: knee osteoarthritis, RAR, cartilage degeneration, network pharmacology, Mapk1

Siyan Pang,1,2 Chenchen Geng,1,2 Zihan Fan,2 Min Hou,1,3 Huilan Mao,1,2 Shuang Tao,1,4 Jing Wang,1,4 Yulun Wu,1,2 Ke Wei,1,4 Yunhao Li,1,2 Liuyang Yan,1,2 Qingling Yang,1,4,5 Changjie Chen,1,4,5 Wenrui Wang1,2,6 1Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical University, Anhui, People’s Republic of China; 2Department of Life Sciences, Bengbu Medical University, Anhui, People’s Republic of China; 3School of Basic Courses, Bengbu Medical University, Anhui, People’s Republic of China; 4Clinical Testing and Diagnose Experimental Center, Bengbu Medical University, Anhui, People’s Republic of China; 5Department of Biochemistry and Molecular Biology, Bengbu Medical University, Anhui, People’s Republic of China; 6Department of Biotechnology, Bengbu Medical University, Anhui, People’s Republic of ChinaCorrespondence: Wenrui Wang; Changjie Chen, Anhui Province Key Laboratory of Cancer Translational Medicine, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, Anhui, 233030, People’s Republic of China, Email wenrui-wang1983@163.com; tochenchangjie@163.comBackground: Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.Methods: In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer.Results: The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe2+ in cells through the release of Fe3+, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis.Conclusion: In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis−apoptosis combined anticancer therapy.Keywords: layered double hydroxides, apoptosis, ferroptosis, simvastatin, breast cancer

Fangmin Gong,1 Zhuliu Gong,1 Haimeng Liu,2 Pei Yi,1 Yuhan Jia,3 Jingwen Zhuang,1 Jilin Shu,1 Xincheng Huang,4 Yibo Wu5 1College of Literature and Journalism Communication, Jishou University, Jishou, People’s Republic of China; 2College of Minority Preparatory Education, Jishou University, Zhangjiajie, People’s Republic of China; 3Office of the Party and Administration, Hebei Academy of Fine Arts, Shijiazhuang, People’s Republic of China; 4School of Economics and Management, Beijing Institute of Graphic Communication, Beijing, People’s Republic of China; 5School of Public Health, Peking University, Beijing, People’s Republic of ChinaCorrespondence: Haimeng Liu, Zhangjiajie Campus, Jishou University, Dayongqiao Street, Ziwu Road, Yongding District, Zhangjiajie, Hunan Province, 427000, People’s Republic of China, Tel +86 15074328922, Email Liu.Haimeng@outlook.com Yibo Wu, Peking University School of Public Health, No.38 Xueyuan Road, Haidian District, Beijing, 100191, People’s Republic of China, Tel +86 18810169630, Email bjmuwuyibo@outlook.comPurpose: To explore the relationship between adolescents’ problematic Internet use and loneliness and the mediating roles of social support and family communication.Methods: A questionnaire survey of 2483 adolescents aged 12– 17 years in 148 cities in China was conducted using the Problematic Internet Use Scale, the Collaborative Social Support Scale, the Family Communication Scale, and the Loneliness Scale. The data were statistically analyzed by SPSS 26.0 and validated by AMOS 28.0. Structural equation modelling (SEM) was conducted to test the effects of problematic Internet use on adolescents’ loneliness and the mediating effects of perceptions of social support and family communication.Results: There was a significant positive effect of adolescents’ problematic Internet use on loneliness (B-0.471, P< 0.001), and the mediating effects of perceptual social support (0.003, 0.012) and family communication (0.008, 0.019) were found to play a chain effect between adolescents’ problematic Internet use and loneliness, respectively. Use and feelings of loneliness played a chain mediating role (0.002, 0.006).Conclusion: This study identified the effects of adolescent problematic Internet use on loneliness and its mechanism of action, emphasized the importance of social support and family communication, and provided practical insights for improving family parenting styles and preventing and intervening in adolescent loneliness problems.Keywords: problematic internet use, adolescents, loneliness, perceived social support, family communication

Xiaohua Li,1,&ast; Guoxia Fu,1,&ast; Chunrong Zhang,1,&ast; Yu Wu,2 Hua Guo,1 Weiming Li,1 Xuefeng Zeng1 1Department of Respiratory and Critical Care Medicine, Sixth People’s Hospital of Chengdu, Chengdu, Sichuan, 61005, People’s Republic of China; 2West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiming Li; Xuefeng Zeng, Department of Respiratory and Critical Care Medicine, Sixth People’s Hospital of Chengdu, No. 16 Jianshe South Street, Chengdu, Sichuan Province, 610051, People’s Republic of China, Email Lwming1989@163.com; ZXFeng1616@163.comPurpose: Investigate the efficacy of blood microRNAs (miRNAs) as diagnostic biomarkers for Chronic Obstructive Pulmonary Disease (COPD).Patients and Methods: We conducted a comprehensive search in English and Chinese databases, selecting studies based on predetermined criteria. Diagnostic parameters like summarized sensitivity (SSEN), summarized specificity (SSPE), summarized positive likelihood ratio (SPLR), summarized negative likelihood ratio (SNLR), and diagnostic odds ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic (SROC) curves were analyzed using a bivariate model. Each parameter was accompanied by a 95% confidence interval (CI).Results: Eighteen high-quality studies were included. For diagnosing COPD with blood miRNAs, the SSEN was 0.83 (95% CI 0.76– 0.89), SSPE 0.76 (95% CI 0.70– 0.82), SPLR 3.50 (95% CI 2.66– 4.60), SNLR 0.22 (95% CI 0.15– 0.33), DOR 15.72 (95% CI 8.58– 28.77), and AUC 0.86 (95% CI 0.82– 0.88). In acute exacerbations, SSEN was 0.85 (95% CI 0.76– 0.91), SSPE 0.80 (95% CI 0.73– 0.86), SPLR 4.26 (95% CI 3.05– 5.95), SNLR 0.19 (95% CI 0.12– 0.30), DOR 22.29 (95% CI 11.47– 43.33), and AUC 0.89 (95% CI 0.86– 0.91).Conclusion: Blood miRNAs demonstrate significant accuracy in diagnosing COPD, both in general and during acute exacerbations, suggesting their potential as reliable biomarkers.Keywords: miRNAs, chronic obstructive pulmonary disease, biomarker, meta-analysis, diagnosis

Ling Shi,1 Yunjun Zhou,2 Yongkui Yin,1 Jin Zhang,3 Kaiyuan Chen,1 Sen Liu,1 Peijian Chen,1 Hua Jiang,2 Jieting Liu,1 Yan Wu1 1College of Life Science, Mudanjiang Medical University, Mudanjiang, 157000, People’s Republic of China; 2The Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, 157000, People’s Republic of China; 3Clinical Laboratory, Zhejiang Medical & Health Group Quzhou Hospital, Quzhou, 324004, People’s Republic of ChinaCorrespondence: Yan Wu; Jieting Liu, College of Life Science, Mudanjiang Medical University, 3 Tong Xiang Street, Ai Min District, Mudanjiang, 157000, People’s Republic of China, Tel +86-0453-6984647, Email wuyan@mdjmu.edu.cn; ttiebj1@163.comAbstract: Geriatric diseases are a group of diseases with unique characteristics related to senility. With the rising trend of global aging, senile diseases now mainly include endocrine, cardiovascular, neurodegenerative, skeletal, and muscular diseases and cancer. Compared with younger populations, the structure and function of various cells, tissues and organs in the body of the elderly undergo a decline as they age, rendering them more susceptible to external factors and diseases, leading to serious tissue damage. Tissue damage presents a significant obstacle to the overall health and well-being of older adults, exerting a profound impact on their quality of life. Moreover, this phenomenon places an immense burden on families, society, and the healthcare system.In recent years, stem cell-derived exosomes have become a hot topic in tissue repair research. The combination of these exosomes with biomaterials allows for the preservation of their biological activity, leading to a significant improvement in their therapeutic efficacy. Among the numerous biomaterial options available, hydrogels stand out as promising candidates for loading exosomes, owing to their exceptional properties. Due to the lack of a comprehensive review on the subject matter, this review comprehensively summarizes the application and progress of combining stem cell-derived exosomes and hydrogels in promoting tissue damage repair in geriatric diseases. In addition, the challenges encountered in the field and potential prospects are presented for future advancements.Keywords: exosomes, biomaterials, hydrogels, geriatric diseases, injury repair

Yu Huang,1,&ast; Shuyang Wu,1,&ast; Jingjing Li,1,2 Chenglin He,1 Yanfen Cheng,3 Nan Li,1 Yitao Wang,1,4 Yihan Wu,1 Jinming Zhang1 1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Hong Kong, SAR, People’s Republic of China; 3Chengdu University, Chengdu, People’s Republic of China; 4Macau Center for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinming Zhang; Yihan Wu, State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China, Email cdutcmzjm@126.com; yihanwuone@126.comBackground: Chemo-photodynamic combination therapy has demonstrated significant potential in the treatment of cancer. Triptolide (TPL), a naturally derived anticancer agent, when combined with the photosensitizer Chlorin e6 (Ce6), has shown to provide enhanced anti-tumor benefits. However, the development of stimuli-responsive nanovehicles for the co-delivery of TPL and Ce6 could further enhance the efficacy of this combination therapy.Methods: In this study, we synthesized a pH/ROS dual-responsive mPEG-TK-PBAE copolymer, which contains a pH-sensitive PBAE moiety and a ROS-sensitive thioketal (TK) linkage. Through a self-assembly process, TPL and Ce6 were successfully co-loaded into mPEG-TK-PBAE nanoparticles, hereafter referred to as TPL/Ce6 NPs. We evaluated the pH- and ROS-sensitive drug release and particle size changes. Furthermore, we investigated both the in vitro suppression of cellular proliferation and induction of apoptosis in HepG2 cells, as well as the in vivo anti-tumor efficacy of TPL/Ce6 NPs in H22 xenograft nude mice.Results: The mPEG-TK-PBAE copolymer was synthesized through a one-pot Michael-addition reaction and successfully co-encapsulated both TPL and Ce6 by self-assembly. Upon exposure to acid pH values and high ROS levels, the payloads in TPL/Ce6 NPs were rapidly released. Notably, the abundant ROS generated by the released Ce6 under laser irradiation further accelerated the degradation of the nanosystem, thereby amplifying the tumor microenvironment-responsive drug release and enhancing anticancer efficacy. Consequently, TPL/Ce6 NPs significantly increased PDT-induced oxidative stress and augmented TPL-induced apoptosis in HepG2 cells, leading to synergistic anticancer effects in vitro. Moreover, administering TPL/Ce6 NPs (containing 0.3 mg/kg of TPL and 4 mg/kg of Ce6) seven times, accompanied by 650 nm laser irradiation, efficiently inhibited tumor growth in H22 tumor-bearing mice, while exhibiting lower systemic toxicity.Conclusion: Overall, we have developed a tumor microenvironment-responsive nanosystem for the co-delivery of TPL and Ce6, demonstrating amplified synergistic effects of chemo-photodynamic therapy (chemo-PDT) for hepatocellular carcinoma (HCC) treatment.Keywords: triptolide, PDT, ROS, Ce6, pH responsive, hepatic carcinoma

Zhilin Sha,1,&ast; Qingxiang Gao,1,&ast; Lei Wang,2,&ast; Ni An,3 Yingjun Wu,1 Dong Wei,4 Tong Wang,5 Chen Liu,1 Yang Shen1 1Department I of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of General Surgery, Yancheng Hospital of Traditional Chinese Medicine, Yancheng, Jiang Su, People’s Republic of China; 3Department of Anesthesiology, the Eighth Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of General Surgery (Second Ward), the No.1 People’s Hospital of Pinghu, Pinghu, Zhe Jiang, People’s Republic of China; 5Department of Anesthesiology, No.32295 Troop of Chinese PLA, Liaoyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Shen, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, No. 700 of North Moyu Road, Jia Ding District, Shanghai, 201823, People’s Republic of China, Email drbruceshen@163.com Chen Liu, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, No. 700 of North Moyu Road, Jia Ding District, Shanghai, 201823, People’s Republic of China, Email dinoliu@126.comBackground: Colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Liver metastasis (LM) is the main cause of death in patients with CRC. Therefore, identification of patients with the greatest risk of liver metastasis is critical for early treatment and reduces the mortality of patients with colorectal cancer liver metastases.Methods: Initially, we characterized cell composition through single-cell transcriptome analysis. Subsequently, we employed copy number variation (CNV) and pseudotime analysis to delineate the cellular origins of LM and identify LM-related epithelial cells (LMECs). The LM-index was constructed using machine learning algorithms to forecast the relative abundance of LMECs, reflecting the risk of LM. Furthermore, we analyzed drug sensitivity and drug targeted gene expression in LMECs and patients with a high risk of LM. Finally, functional experiments were conducted to determine the biological roles of metastasis-related gene in vitro.Results: Single-cell RNA sequencing analysis revealed different immune landscapes between primary CRC and LM tumor. LM originated from chromosomal variants with copy number loss of chr1 and chr6p and copy number gain of chr7 and chr20q. We identified the LMECs cluster and found LM-associated pathways such as Wnt/beta-catenin signaling and KRAS signaling. Subsequently, we identified ten metastasis-associated genes, including SOX4, and established the LM-index, which correlates with poorer prognosis, higher stage, and advanced age. Furthermore, we screened two drugs as potential candidates for treating LM, including Linsitinib_1510, Lapatinib_1558. Immunohistochemistry results demonstrated significantly elevated SOX4 expression in tumor samples compared to normal samples. Finally, in vitro experiments verified that silencing SOX4 significantly inhibited tumor cell migration and invasion.Conclusion: This study reveals the possible cellular origin and driving factors of LM in CRC at the single cell level, and provides a reference for early detection of CRC patients with a high risk of LM.Keywords: colorectal cancer, liver metastasis, single-cell sequencing, SOX4, prognostic

Qingqing Zhang,1,2,&ast; Liang Cheng,3,&ast; Boliang Li,4,&ast; Yu Lu,1 Shufang Yang,1 Yucheng Wu5 1Department of Endocrinology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, People’s Republic of China; 2Department of Pan-Vascular Management Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, People’s Republic of China; 3Department of Endocrinology, the Affiliated Huai’an Hospital of Xuzhou Medical University and the Second People’s Hospital of Huai’an, Huai’an, People’s Republic of China; 4Department of Nuclear Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, People’s Republic of China; 5Department of Cardiology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shufang Yang; Yucheng Wu, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, 366 Taihu Road, Hailing District, Taizhou, Jiangsu, 225300, People’s Republic of China, Email 47607369@qq.com; 2567181759@qq.comBackground: Early-onset diabetes appears to be an aggressive phenotype of type 2 diabetes (T2D). The impact of the age of onset of T2D on albuminuria, especially high urinary albumin excretion, remains to be investigated.Objective: To determine whether adults diagnosed with T2D between the ages of 18 and 45 more aggressively develop albuminuria.Methods: Conducted at Taizhou People’s Hospital from November 2018 to August 2020, this cross-sectional study enrolled T2D patients. Anthropometric measures, metabolic profiles, and urinary albumin creatinine ratio were examined. Patients were categorized into early-onset (≤ 45 years) and late-onset (> 45 years) groups. Univariate and multivariate analyses were performed to identify albuminuria risk factors. Subgroups were formed based on age at diabetes diagnosis and gender. Multivariate ordinal logistic regression analysis was then conducted to identify distinct risk factors within each subgroup.Results: Analyzing 1900 T2D patients, it was found significantly higher albuminuria prevalence in early-onset patients (35.08% vs 29.92%, P = 0.022). The risk of albuminuria in early-onset patients was 1.509 times higher than that in late-onset patients, especially among male patients, where the risk increased to 1.980. For late-onset patients, disease duration and glycated hemoglobin (HbA1c) were identified as risk factors, whereas for early-onset patients, body-mass index (BMI) and systolic blood pressure were associated with increased risk. Among male patients, age at diagnosis of diabetes, blood pressure, and BMI were identified as risk factors, while for female patients, disease duration and HbA1c played a significant role. Additionally, high-density lipoprotein cholesterol was found to be a protective factor against albuminuria.Conclusion: Individuals diagnosed with T2D before 45 face heightened albuminuria risk, especially males. Risk factors vary by gender and onset age, highlighting the need for tailored management strategies.Keywords: diabetes complications, diabetes mellitus, type 2, albuminuria

Yanghaotian Wu,1– 3 Xuemei Han,3 Jingfu Qiu1 1Department of Social Medicine and Health Service Management, School of Public Health, Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Social Medicine, School of Public Health, Southwest Medical University, Luzhou, People’s Republic of China; 3Institute of Social Medicine and Health Management, School of Public Health, Lanzhou University, Lanzhou, People’s Republic of ChinaCorrespondence: Jingfu Qiu, School of Public Health, Chongqing Medical University, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Email jfqiucqmu@163.comBackground: In 2016, an innovative medical pricing reform called zero-markup drug policy (ZMDP) was implemented in selected pilot cities in China, which focuses on curbing the unreasonable growth of medical expenses. This study aimed to evaluate the impacts of ZMDP on medical expenditure of stroke in western China.Methods: The quantitative data of inpatients diagnosed with stroke was extracted from the medical insurance system in 7 tertiary public hospitals. An interrupted time series (ITS) was used to analyze the instantaneous level and long-term trend changes of hospitalization expenses per visit from January 2015 to November 2018.Results: A total of 22,407 stroke inpatients were extracted. The total hospitalization expense per visit had the highest proportion of 20,000 CNY and above (33.66%). After the ZMDP, the median total hospitalization expense and western medicine expense per visit decreased by 631.74 CNY and 966.35 CNY, respectively (P < 0.001). Before the policy, the total hospitalization expense, traditional Chinese medicine (TCM) expense, examination expense, treatment expense, laboratory expense and surgical expense per visit showed upward trends (P< 0.05), while the anesthesia expense per visit showed a downward trend (P< 0.001). When the policy was implemented, the anesthesia expense per visit instantaneously increased by 91.70% (P< 0.001). After the policy, the total hospitalization expense, western medicine expense, TCM expense, treatment expense and surgical expense per visit changed from upward trends to downward trends (P< 0.05). The anesthesia expense per visit changed from a downward trend to an upward trend (P< 0.001), and the examination expense per visit maintained an upward trend (P=0.005).Conclusion: The economic burden of stroke inpatients decreased significantly with the implementation of the ZMDP, especially for the drug expenses. The medical service expenses increased significantly, reflecting the improvement in the value of medical staff’s technical labor. However, the unexpected increase in the examination expenses was likely to be associated with the unreasonable medical compensation mechanism.Keywords: zero-markup drug policy, stroke, interrupted time series, hospitalization expenses, drug expenses

Keyang Li,1,&ast; Debao Li,2,&ast; Hongliang Dong,1 Dongmei Ren,2 Dandan Gong,1 Shubo Wang,1 Yang Li,1 Yuanyuan Wu,1 Jikang Yang,3 Wenjuan Yan,4 Yi Li4 1Department of Clinical Pharmacy, Jiaozuo People’s Hospital, Jiaozuo, Henan, People’s Republic of China; 2Department of Clinical Laboratory, Jiaozuo People’s Hospital, Jiaozuo, Henan, People’s Republic of China; 3Infectious Diseases Department, Jiaozuo People’s Hospital, Jiaozuo, Henan, People’s Republic of China; 4Department of Clinical Laboratory, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjuan Yan; Yi Li, Department of Clinical Laboratory, Henan Provincial People’s Hospital, Weiwu Road 7&num;, Jinshui District, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86 15225061830 ; +86 15939039006, Email yanwenjuan2008@126.com; liyilabmed@henu.edu.cnPurpose: Since the introduction of ceftazidime–avibactam (CZA) in the Chinese market, accumulating clinical evidence has substantiated its efficacy in the treatment of infections caused by carbapenem-resistant gram-negative bacteria (CR-GNB). Nevertheless, an ongoing debate persists concerning the choice between monotherapy and combination therapy when devising clinical anti-infection protocols.Patients and Methods: This retrospective, single-center observational study enrolled patients with CR-GNB infections who received CZA treatment between December 2019 and August 2023. The primary outcome assessed was 30-day mortality, and the secondary outcome measured was 14-day bacterial clearance. A multivariate Cox regression model was used to identify variables that were independently associated with 30-day mortality rate.Results: Eighty-three patients were enrolled in the study; of which, 45 received CZA monotherapy, whereas 38 received combination therapy. The overall 30-day mortality rate was 31.3%, and no significant difference was observed in the 30-day mortality rates between the CZA combination therapy and monotherapy groups (31.6% vs 31.1%, p=0.963). After adjustment by propensity score matching, the 30-day mortality rate was not significantly different between the two groups (28.6% vs 31.4%, p=0.794). Multivariate COX analysis revealed that age and SOFA score were independent predictors of 30-day mortality.Conclusion: Combination therapy with CZA and other antimicrobials was not found to have an advantage over monotherapy in reducing the 30-day mortality rate.Keywords: ceftazidime-avibactam, carbapenem-resistant gram-negative bacteria, combination therapy K. pneumoniae carbapenemase

Jinli Xue,1 Yige Wu,1 Meng Chen2 1Research Center for Energy Economics, School of Business Administration, Henan Polytechnic University, Jiaozuo, People’s Republic of China; 2Shandong Provincial Territorial Spatial Ecological Restoration Center, Jinan, People’s Republic of ChinaCorrespondence: Meng Chen, Email yuanlinlin8807@163.comPurpose: Idiosyncratic deals (I-deals), a novel human resource management implement, has significantly contributed to attracting, retaining and motivating personnel to enhance creativity. Building upon self-categorization theory, this study investigates the impact of I-deals on creativity and the moderating role of psychological safety in this process by perceived insider status.Participants and Methods: To mitigate common method bias and causal lag effects, this study was conducted in three phases with a half-month interval for data collection. In this study, a total of 331 employees from six enterprises in China were selected to test the hypotheses using Bootstrap and Johnson-Neyman methods.Results: Results show that I-deals have a positive influence on creativity. Perceived insider status acts as intermediary between I-deals and creativity; Psychological safety strengthens the influence of I-deals on perceived insider status and further enhances the indirect influence of I-deals on creativity through perceived insider status.Conclusion: This study demonstrates that organizations can leverage the unique characteristics of I-deals to fully showcase the diverse talents of their personnel, while simultaneously enhancing their psychological security. This, in turn, empowers employees to confidently propose new ideas and methods, thus catalyzing the generation of creativity.Keywords: I-deals, perceived insider status, psychological safety, creativity, self-categorization theory

Jiaru Zhuang,1,&ast; Shan Wang,2,&ast; Yuan Wang,2 Yibo Wu,2 Renjing Hu1 1Department of Laboratory Medicine, Jiangnan University Medical Center, Wuxi, People’s Republic of China; 2Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Renjing Hu, Department of Laboratory Medicine, Jiangnan University Medical Center, 68 Zhongshan Road, Wuxi, Jiangsu, 214000, People’s Republic of China, Email weiweihuhu112@163.com Yibo Wu, Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, 1000 Hefeng Road, Wuxi, Jiangsu, 214000, People’s Republic of China, Email 9862016107@jiangnan.edu.cnPurpose: According to the 2023 global cancer data, breast cancer is the most common malignant tumor among women in the world. Its occurrence and development is influenced by inflammation, nutrition, and immune status. Therefore, this study combines C-reactive protein (CRP), albumin, and lymphocyte, which can reflect the above states, to form the CRP-albumin-lymphocyte (CALLY) index, an indicator to evaluate its relationship with overall survival (OS) and disease-free survival (DFS) in breast cancer patients.Patients and Methods: We retrospectively analyzed the clinical and follow-up data of 174 patients with breast cancer. The optimal cutoff for the preoperative CALLY index was identified by considering the area under the receiver operating characteristic curve; subsequently, the discriminatory ability of the cutoff was determined. The effect of the CALLY index on overall survival (OS) and disease-free survival (DFS) was analyzed using the Kaplan–Meier method and the Cox proportional hazards model. The CALLY index was calculated as: (Albumin × Lymphocyte)/(CRP × 104).Results: The cut-off value of the CALLY index was determined at 2.285. With a cut-off value of 2.285, patients were divided into two groups: those with CALLY < 2.285 and those with CALLY ≥ 2.285. CALLY Index ≥ 2.285 was associated with better survival outcomes. Multivariate Cox analysis showed that TNM stage and CALLY index were prognostic factors that affected OS and DFS.Conclusion: The CALLY index is a new prognostic biomarker for breast cancer patients after surgery. This new CALLY index allows for suitable patients with a poor prognosis to receive postoperative adjuvant therapy.Keywords: breast cancer, prognosis, CALLY index, survival