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Hongmei Xu,1 Ningning Wu,2 Hui Yu,3 Chuanqing Wang,4 Jikui Deng,5 Hongmei Wang,5 Chunzhen Hua,6 Yinghu Chen,6 Xuejun Chen,7 Ting Zhang,8 Hong Zhang,9 Yiping Chen,10 Shifu Wang,11 Qing Cao,12 Huiling Deng,13 Sancheng Cao,14 Jianhua Hao,15 Wei Gao,16 Chunmei Jing2 1Infectious Disease Department, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University; National Clinical Research Center for Child Health and Disorders; Ministry of Education Key Laboratory of Child Development and Disorders; Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Chongqing, People’s Republic of China; 3Infectious Disease Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 4Department of Clinical Microbiology Laboratory, Nosocomial Infection Control Department, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, People’s Republic of China; 5Infectious Disease Department, Shenzhen Children’s Hospital, Shenzhen, People’s Republic of China; 6Infectious Disease Department, Children’s Hospital of Zhejiang University, Zhejiang, People’s Republic of China; 7Department of Medical Laboratory, Children’s Hospital of Zhejiang University, Zhenjiang, People’s Republic of China; 8Digestive and Infectious Disease Department, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 9Department of Medical Laboratory, Children’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 10Pediatric Infectious Disease Department, Second Affiliated Hospital, and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 11Department of Medical Laboratory, Qilu Children’s Hospital, Shandong University, Shandong, People’s Republic of China; 12Infectious Disease Department, Shanghai Children’s Medical Center, Shanghai, People’s Republic of China; 13Infectious Disease Department, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 14Department of Medical Laboratory, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 15Infectious Disease Department, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of China; 16Department of Medical Laboratory, Children’s Hospital of Kaifeng City, Kaifeng, People’s Republic of ChinaCorrespondence: Chunmei Jing, Department of Clinical Laboratory, Children’s Hospital of Chongqing Medical University, Chongqing Medical University, No. 136 Zhongshan Er Road, Yu Zhong District, Chongqing, 400014, People’s Republic of China, Email jcm791203@163.comObjective: Aim to investigate the pathogens distribution and drug resistance of gram-negative bacteria causing bloodstream infection (BSIs) in Infectious Disease Surveillance of Pediatric from 2016 to 2022. The prevalence of four important drug resistance phenotypes was studied: difficult-to-treat resistance, fluoroquinolone resistance, carbapenem resistance, and extended-spectrum cephalosporin resistance, and to provide reference basis for preventing and treating BSIs diseases in children.Methods: Strain identification and antimicrobial susceptibility tests were independently performed at each hospital. Data were analyzed using Whonet 5.6 and GraphPad Prism 8 software. The Mann–Whitney U-test was used to examine and compare temporal changes.Results: A total of 39977 BSIs strains were isolated, with 27.1% of the negative bacteria causing BSIs (10824 strains). The highest bacteria detected were E. coli and S. maltophilia in the neonatal and pediatric groups. The detection rate of carbapenem-resistant-K. pneumoniae (CRKPN) in neonate group was 31.4%, significantly increased compared with pediatric group, whose detection rate was 24.7%. The rates of resistance to levofloxacin and trimethoprim/sulfamethoxazole were significantly lower in neonatal groups than pediatric groups in BSIs caused by K. pneumoniae. To imipenem and meropenem were 3.6% and 3.9% among neonatal isolates, which was lower than 4.7% and 5.8 among pediatric BSIs caused by E. coli. Isolated from neonatal BSIs caused by A. baumannii showed lower resistance ratios to all the agents tested than those from pediatric. However, only the prevalence of piperacillin/tazobactam resistance was statistically lower than that in pediatric BSIs caused by P. aeruginosa. The average detection rates of carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance for K. pneumoniae and E. coli were 28.1%,41.4%,11.6% and 4.0%,24.3%,31.1%, respectively.Conclusion: The detection rate of gram-negative pathogens showed an increasing trend among the bloodstream infection. The detection rate of CRKPN assumed a downward trend in 2018. There are differences types of pathogens between the neonatal group and the pediatric group, The detection rate of CRKPN in the neonate group was significantly higher than pediatric group. The first average detection rates for carbapenem resistance, extended-spectrum cephalosporin resistance, and fluoroquinolone resistance were obtained for A. baumannii, K. pneumoniae, and Escherichia coli, respectively. Those data showed a high level of antimicrobial resistance, which has posed an urgent threat to Children’s health, suggested that effective monitoring of antimicrobial resistance and antimicrobial stewardship among children in China are required.Keywords: bloodstream infection, pathogenic bacterium, difficult-to-treat resistance, carbapenem resistance, extended-spectrum cephalosporin resistance, fluoroquinolone resistance

Xiaowei Zhou, Liyong Zou, Haoyue Deng, Yuanqun Zhou, Yue Wu, Xingnan Ouyang, Liangming Liu, Li Wang,* Tao Li* Department of Shock and Transfusion, Army Medical Center of Army Medical University, Chongqing, People’s Republic of China*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

Yue Lu,1– 3,* Simin Pan,4,* Wenzhen Li,5 Yao Qi,6,7 Li Li,1– 3 Yu-Hong Yan,1– 3 Jianan Wei,1– 3 Dan-Ni Yao,1– 3 Jingjing Wu,1– 3 Hao Deng,1– 3 Shuyan Ye,1– 3 Haiming Chen,1– 3 Qubo Chen,1– 3 Hengjun Gao,6,7 Ling Han,1– 3 Chuanjian Lu1– 3 1State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, People’s Republic of China; 3Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 4The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 5The Clinical College of Acupuncture Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 6Shanghai Molecular Medicine Engineering Technology Research Center, Shanghai, People’s Republic of China; 7Shanghai National Engineering Research Center of Biochip, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling Han; Chuanjian Lu, Email linghan99@gzucm.edu.cn; lcj@gzucm.edu.cnBackground: Psoriasis is a widespread chronic, immune-mediated skin disease with frequent recurrences, and is extremely harmful to the physical and mental health of patients, causing enormous suffering and exerting considerable economic burdens on the health care system as a whole. In more than a decade of clinical use, the optimized formula of Yinxieling (PSORI-CM01) has consistently demonstrated its effectiveness for treating psoriasis. However, its underlying mechanism remains largely unexplored.Methods: The network pharmacology analysis was conducted to predict the mechanism and protective effect of PSORI-CM01 in treating psoriasis. Subsequently, we collected blood samples from 21 patients with psoriasis as part of a randomized, double-blind, and double-dummy clinical trial for microRNA expression profiling. Finally, it was experimentally confirmed that PSORI-CM01 improved psoriasis by regulating miR-20a-3p and miR-3184-3p expression.Results: As a result of the network pharmacology analysis, PSORI-CM01 improved psoriasis through the regulation of autophagy, cellular apoptosis, cellular proliferation, and anti-inflammatory processes. In the target-miRNA regulatory network, these key targets were mainly associated with the regulation of hsa-miR-20a-3p, hsa-miR-155-5p, has-miR-3184-3p, hsa-miR-328-3p and hsa-miR-124-3p. Based on the microRNA expression profiling results, the PSORI-CM01 treatment group exhibited five up-regulated genes and 16 down-regulated genes compared with the healthy control group. In particular, miR-20a-3p and miR-3184-3p were the primary differentially expressed microRNAs, and they were significantly enriched in the signaling pathways involving autophagy, apoptosis, proliferation, and anti-inflammation. Further experiments confirmed that PSORI-CM01 effectively regulates miR-20a-3p and miR-3184-3p, resulting in increased autophagy.Conclusion: We demonstrated by combining network pharmacology and clinical studies of miRNA expression profiles in PBMCs that PSORI-CM01 effectively modulated miR-20a-3p and miR-3184-3p, leading to an increase in autophagy and a decrease in keratinocyte proliferation.Keywords: PSORI-CM01, Psoriasis vulgaris, MicroRNA expression profile, network pharmacology, autophagy

Shipeng Chen,1– 3 Mengna Li,1– 3 Changning Xue,1– 3 Xiangting Zhou,1– 3 Jianxia Wei,1– 3 Lemei Zheng,1– 3 Yumei Duan,1– 3 Hongyu Deng,1 Faqing Tang,1 Wei Xiong,1– 3 Bo Xiang,1– 3 Ming Zhou1– 3 1NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China; 2Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China; 3The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of ChinaCorrespondence: Ming Zhou; Bo Xiang, Email zhouming2001@163.com; xiangbolin@csu.edu.cnPurpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition.Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings.Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay.Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs. Keywords: cinobufotalin injection, liver cancer, cinobufagin, network pharmacology, cell cycle, core ingredients

Zhenhua Liu,1,* Mingxi Cai,2,* Haoteng Ke,2,* Huazong Deng,2 Weijia Ye,2 Tao Wang,1 Qifan Chen,1 Shuizhong Cen1 1Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2The Second Clinical School, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuizhong Cen, Department of Spinal Surgery, Orthopedic Medical Center, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China, Tel +86 13480297160, Email censhzh3@mail2.sysu.edu.cnPurpose of the Review: Emerging evidence has shown that ankylosing spondylitis fibroblasts (ASFs) act as crucial participants in inflammation and abnormal ossification in ankylosing spondylitis (AS). This review examines the investigations into ASFs and their pathological behavior, which contributes to inflammatory microenvironments and abnormal bone formation. The review spans the period from 2000 to 2023, with a primary focus on the most recent decade. Additionally, the review provides an in-depth discussion on studies on ASF ossification at the cellular level.Recent Findings: ASFs organize immune functions by recruiting immune cells and influencing their differentiation and activation, thus mediate the inflammatory response in the early phase of disease. ASFs promote joint destruction at sites of cartilage and actively promote abnormal ossification by recruiting osteoblasts, differentiation into myofibroblasts or ossification directly. Many signaling pathways and cytokines such as Wnt signaling and BMP/TGF-β signaling are involved in ASF ossification.Summary: ASFs play a key role in AS inflammation and osteogenesis. Further studies are required to elucidate molecular mechanisms behind that and provide new targets and directions for AS diagnosis and treatment from a new perspective of fibroblasts.Keywords: ankylosing spondylitis, fibroblast, inflammation, ossification

Zhongxin Hou,1,&ast; Yang Chen,1,2,&ast; Yunrui Sun,1 Chongwei Song,1 Haoyuan Deng,3 Nan Cheng,4 Xiaoyu Han,2 Jianghui Zhang,5 Qian Wang,1 Yi Li,1 Jianzhong Yin,1,6 Qiong Meng1 1School of Public Health, Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Institute for Acute Communicable Disease Prevention and Control, Yunnan Provincial Center for Disease Control and Prevention, Kunming, Yunnan, People’s Republic of China; 3Medical Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 4Department of Hospital Infection, Wuhan Mental Health Center, Wuhan, Hubei, People’s Republic of China; 5AIDS Care Center, Yunnan Provincial Hospital of Infectious Disease, Anning, Yunnan, People’s Republic of China; 6Baoshan College of Traditional Chinese Medicine, Baoshan, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiong Meng, School of Public Health, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming, Yunnan, 650500, People’s Republic of China, Tel +8615559789771, Email mengqiong2006@163.com Jianzhong Yin, Baoshan College of Traditional Chinese Medicine, Baoshan Longyang District Qingyang District Vocational Education Park, Baoshan, Yunnan, 678000, People’s Republic of China, Tel +8613987645337, Email yinjianzhong2005@sina.comPurpose: Depression and anxiety are two highly prevalent mental disorders that commonly coexist. However, little is known about the association between sleep and comorbid depressive and anxiety symptoms (CDAS). Therefore, this study aims to explore the relationship between sleep duration, insomnia and CDAS.Methods: This is a cross-sectional study of 22,004 community adults who participated in the China Multi-Ethnic Cohort (CMEC) study. Chinese version of Patient Health Questionnaire-2 and Generalized Anxiety Disorder-2 were used to screen CDAS in community adults. A positive score on each scale was considered indicative of CDAS. All participants received face-to-face interviews, medical examinations, and biochemical examinations to assess sleep duration and insomnia and collect covariates. The self-reported sleep duration was divided into three groups: < 7 hr, 7– 9 hr and > 9 hr groups. Logistic regression was used to analyze the association between sleep duration, insomnia and CDAS. A restricted cubic spline (RCS) was used to explore the dose–response relationship between sleep duration and CDAS. Stratified analysis based on gender and age was conducted.Results: Overall, 2.8% (95% CI 2.6%~3.0%) of participants reported having CDAS. After adjusting the potential covariates, sleep duration < 7 hr (OR=1.635, 95% CI=1.335~2.004) was significantly associated with CDAS, compared with sleep 7– 9 hr. After RCS analysis, there was a nonlinear relationship between sleep duration and CDAS. The increase in the number of types of insomnia, the greater the likelihood of CDAS (p for trend< 0.05). In sensitivity analysis, it was found that the results were consistent with those of the main analysis. After stratification by gender and age, the association between sleep duration and CDAS was only observed in female and young and middle-aged adults, not in men and older adults.Conclusion: Both insufficient sleep duration and insomnia are associated with a higher prevalence of CDAS in Chinese adults.Keywords: sleep duration1, insomnia2, comorbid depressive and anxiety symptoms3, adults4, cross-sectional study5

Ran Chen, Haibo Deng, Lijun Zou Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Lijun Zou; Haibo Deng, Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 39 Yanhu Avenue, Wuhan, Hubei, 430077, People’s Republic of China, Email zhlj112@163.com; dhb0376@163.comBackground: Diabetic foot ulcers (DFUs) represent a severe complication of diabetes associated with reduced quality of life, lower limb amputations, hospitalizations, increased incidence, and mortality. Importantly, a significant number of pathogenic genes remain unexplored in DFUs.Methods: A series of bioinformatics analyses were performed on publicly available bulk transcriptome sequencing datasets GSE134431 and GSE80178 to explore the transcriptomic changes in DFUs and select core genes for in vitro functional validation. In a focused examination, the differential expression analysis unveiled distinctions in gene expression patterns between DFUs and non-ulcerated diabetic skin tissues. Enriched functional annotations of differentially expressed genes were explored using the DAVID online tool. Protein-protein interaction analysis was conducted to investigate interactions among differentially expressed genes and select core genes. Knockdown or overexpression of core genes in HaCaT keratinocytes was performed to assess their impact on cell proliferation and migration.Results: Ten core genes were identified. Cell Counting Kit-8 (CCK-8) and scratch assays demonstrated that downregulation of the core gene SIN3A significantly inhibited the migration and proliferation of HaCaT keratinocytes, while overexpression of SIN3A reversed the high-glucose-induced suppression of HaCaT cell viability and migration.Conclusion: SIN3A expression is downregulated in DFUs. In vitro, SIN3A promotes the proliferation and migration of HaCaT keratinocytes, suggesting it may be a potential therapeutic target for DFUs.Keywords: diabetic foot ulcers, SIN3A, bioinformatics, cell proliferation, cell migration, histone modification

Guangyou Duan,1,&ast; Haibo Deng,2,&ast; Hong Fu,3 Lingzhi Wang,4 Hanyu Yang5 1Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing City, 400000, People’s Republic of China; 2Department of Anesthesiology, Huizhou Third People’s Hospital, Guangzhou Medical University, Guangzhou, 516002, People’s Republic of China; 3Department of Anesthesiology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, 400014, People’s Republic of China; 4Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 051026, People’s Republic of China; 5Department of Anesthesiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangyou Duan, Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Chongqing City, 400000, People’s Republic of China, Email duangy@hospital.cqmu.edu.cnPurpose: This study aimed to compare the electrolyte balance efficacies of two Gelatin-Balanced Crystalloid in clinical applications.Methods: A multi-center, prospective, randomized, single-blind, parallel controlled study was conducted among non-cardiac surgery patients, with clinical registration number ChiCTR2200062999. They were randomized into Succinylated Gelatin, Multiple Electrolytes and Sodium Acetate Injection (SG-MESAI) group (experimental group) and Succinylated Gelatin Injection (SGI) infusion group (control group). The same anesthetic induction technique, anesthetic method, and calculation method for the volume of colloid infusion were used in the two groups. Between-group differences in the changes in base excess (BE), Chloride ion (Cl−), bicarbonate radical (HCO3⁻) and other parameters were recorded at 15 min, 30 min after the infusion relative to the baseline. Hemodynamic indicators were determined at 30 min after colloid infusion. Safety follow-up was conducted by administering the following tests within 48 h± 12 h after surgery.Results: A total of 225 subjects (full analysis set) were finally enrolled, with 110 subjects in the experimental group and 115 subjects in the control group. The baseline data were comparable between the two groups. At 15 min after infusion, the mean changes in BE, Cl− and HCO3⁻ concentration in the experimental group were smaller than those of the control group (P< 0.001). At 30 min after surgery, the mean changes in BE, Cl−, HCO3⁻concentration and pH value were smaller in the experimental group than in the control group (P< 0.05). The incidences of adverse events and adverse reactions in the experimental group was less than the control group, but the difference was not statistically significant (P≥ 0.05). Besides, no serious adverse events or adverse reactions were reported in any subjects.Conclusion: Succinylated Gelatin, Multiple Electrolytes and Sodium Acetate Injection maintained the balance of BE, Cl−, HCO3⁻ and pH value in a better way than Succinylated Gelatin Injection in non-cardiac surgery patients under general anesthesia.Keywords: anesthesia, non-cardiac surgery, fluid therapy, drug clinical trial, succinylated gelatin, multiple electrolytes and sodium acetate injection

Wenyu Zhou,1,&ast; Song Hu,1,2,&ast; Yutong Wu,1,&ast; Huan Xu,1,&ast; Lina Zhu,1 Huimin Deng,1 Sheng Wang,1 Yuanli Chen,1 Huanping Zhou,1 Xin Lv,1 Quanfu Li,1 Hao Yang1 1Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, People’s Republic of China; 2Graduate School, Wannan Medical College, Wuhu, AnHui, 241002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Yang, Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 507 Zhengmin Road, Shanghai, 200433, People’s Republic of China, Email yanghaozunyi@sina.com Quanfu Li, Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Shanghai, 200433, People’s Republic of China, Email quanfuli185@163.comBackground: Mesenchymal stem cell-derived exosomes (MSC-exosomes) have been found to effectively improve the systemic inflammatory response caused by acute lung injury and acute respiratory distress syndrome (ALI/ARDS), regulate systemic immune disorders, and help injured cells repair. The purpose of this study was to take a holistic view of the current status and trends of MSC-exosomes research in ALI/ARDS.Methods: Bibliometrix, Citespace and VOSviewer software were used for bibliometric analysis of the data. We analysed the world trends, country distribution, institution contribution, most relevant journals and authors, research hotspots, and research hotspots related to Coronavirus Disease 2019 (COVID-19) based on the data collected.Results: China possessed the largest number of publications, while the USA had the highest H-index and the number of citations. Both China and the USA had a high influence in this research field. The largest number of publications in the field of MSC-exosomes and ALI/ARDS were mainly from the University of California system. Stem Cell Research & Therapy published the largest number of papers in this scope. The author with the greatest contribution was LEE JW, and ZHU YG published an article in Stem Cell with the highest local citation score. The most frequent keyword and the latest research hotspot were “NF-κB” and “Coronavirus Disease 2019”. Furthermore, our bibliometric analysis results demonstrated that MSC-exosomes intervention and treatment can effectively alleviate the inflammatory response caused by ALI/ARDS.Conclusion: Our bibliometric study suggested the USA and China have a strong influence in this field. COVID-19-induced ALI/ARDS had become a hot topic of research.Keywords: acute respiratory distress syndrome, mesenchymal stem cells, exosome, bibliometrix, Citespace, VOSviewer

Peigen Wu,1– 3 Churui Chang,3 Guanglin Zhu,4 Lixiang Zhai,5 Xu Zhang,3 Qiuchan Huan,1,3 Zhengxian Gao,1,3 Huan Deng,2 Yue Liang,1 Haitao Xiao2,3 1Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China; 2School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, People’s Republic of China; 3School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guizhou, People’s Republic of China; 4Traditional Chinese Medicine Hospital of Qijiang, Chongqing, People’s Republic of China; 5School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong Special Administrative Region, People’s Republic of ChinaCorrespondence: Haitao Xiao, School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, People’s Republic of China, Email xhaitao@szu.edu.cn Yue Liang, Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China, Email bmqueen@163.comPurpose: To explore the potential mechanism of glycosidic fraction of Picrorhiza scrophulariiflora Pennell (GPS) extract for the treatment of colitis using UPLC-QTOF-MS analysis, network pharmacology and experimental research.Methods: The active components of GPS extract were identified by UPLC-QTOF-MS analysis and extracted their targets from the databases, which was used for network pharmacology analysis. Kyoto Encyclopedia of genes and genomes (KEGG) pathway analysis was performed to discover potential therapeutic mechanisms, and the network pharmacology results were then validated by in vivo and in vitro experiments.Results: The results showed that GPS extract significantly alleviated the clinical signs of colitis, including body weight, disease activity index, colon shortening, and colon tissue damage, and inhibited the transcription and production of colonic IL-1β and IL-6 in DSS-induced colitis mice. In vitro, GPS extract also significantly suppressed nitric oxide (NO) production, iNOS expression, IL-1β and IL-6 transcription of LPS-activated RAW 264.7 cells. Network pharmacology integrated with experimental validation identified that GPS extract significantly suppressed Akt, p38, ERK, and JNK phosphorylation in vivo and in vitro, and luteolin, apocynin, caffeic acid, caffeic acid methyl ester, luteoloside, picroside II, aucubin, cinnamic acid, vanillic acid, and sweroside were the main components responsible for the anti-inflammatory effect of GPS. These findings demonstrate that the potential anti-inflammatory effect of GPS extract against colitis is achieved through suppressing PI3K/Akt and MAPK pathways, and that the abovementioned active components mainly exerted its anti-inflammatory effect.Conclusion: The therapeutic effect of GPS extract on colitis is related to PI3K/Akt and MAPK pathways, which is a promising remedy for colitis therapy.Graphical Abstract: Keywords: Picrorhiza scrophulariiflora, colitis, bioactive compounds, molecular mechanism, network pharmacology

Hao Deng,1,&ast; Yumei Wang,1,&ast; Yue Zhou,1,&ast; Dongliang Zhai,1 Jie Chen,1 Shilei Hao,2 Xiaoliang Chen1 1Department of Nuclear Medicine, Chongqing University Cancer Hospital, Chongqing, 400030, People’s Republic of China; 2Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoliang Chen, Department of Nuclear Medicine, Chongqing University Cancer Hospital, No. 181 HanYu St, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel/Fax +86 023-65079156, Email chenxiaoliang26@163.com Shilei Hao, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, 174 Shazhengjie, Shapingba District, Chongqing, 400030, People’s Republic of China, Tel +86023-135 9463 5765, Email Shilei_hao@cqu.edu.cnBackground: Prostate cancer (PCa) ranks second in the incidence of all malignancies in male worldwide. The presence of multi-organ metastases and tumor heterogeneity often leads to unsatisfactory outcomes of conventional radiotherapy treatments. This study aimed to develop a novel folate-targeted nanohydroxyapatite (nHA) coupling to deliver adriamycin (Doxorubicin, DOX), 32P, and 99mTc simultaneously for the diagnosis and treatment of prostate-specific membrane antigen (PSMA) positive prostate cancer.Methods: The spherical nHA was prepared by the biomimetic method and characterized. Folic acid (FA) was coupled to nHA with polyethylene glycol (PEG), and the grafting ratio of PEG-nHA and FA-PEG-nHA was determined by the thermogravimetric analysis (TGA) method. In addition, 32P, 99mTc, and DOX were loaded on nHA by physisorption. And the labeling rate and stability of radionuclides were measured by a γ-counter. The loading and release of DOX at different pH were determined by the dialysis method. Targeting of FA-PEG-nHA loaded with 99mTc was verified by in vivo SPECT imaging. In vitro anti-tumor effect of 32P/DOX-FA-PEG-nHA was assessed with apoptosis assay. The safety of the nano-drugs was verified by histopathological analysis.Results: The SEM images showed that the synthesized nHA was spherical with uniform particle size (average diameter of about 100nm). The grafting ratio is about 10% for PEG and about 20% for FA. The drug loading and the delayed release of DOX at different pH confirmed its long-term therapeutic ability. The labeling of 32P and 99mTc was stable and the labeling rate was great. SPECT showed that FA-PEG-nHA showed well in vivo tumor targeting and less damage to normal tissues.Conclusion: FA-targeted nHA loaded with 32P, 99mTc, and DOX may be a new diagnostic and therapeutic strategy for targeting PSMA-positive prostate cancer tumors, which may achieve better therapeutic results while circumventing the severe toxic side effects of conventional chemotherapeutic agents.Keywords: prostate cancer, folic acid targeting, nanohydroxyapatite, 99mTc/ 32P, adriamycin

Jian Lin,1,&ast; Tianpeng Shi,2,&ast; Yi Wang,1 Zhiqi He,1 Zhixiang Mu,1 Xiaojun Cai,1 Hui Deng,1 Jianliang Shen,3– 5 Fen Liu6 1School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Stomatology, PLA Strategic Support Force Medical Center, Beijing, People’s Republic of China; 3State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, People’s Republic of China; 5Department of Regenerative Medicine, Vision, and Brain Health, Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), Wenzhou, People’s Republic of China; 6Department of Histology and Embryology, Wenzhou Medical University, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Deng; Fen Liu, Email dh0726@gmail.com; liufen6459@163.comBackground: Much attention has been paid to sustained drug release and anti-infection in wound management. Hydrogels, which are biocompatible materials, are promising tools for controlled drug release and infective protection during wound healing. However, hydrogels also demonstrate limitations in the highly efficient treatment of wounds because of the diffusion rate. In this work, we explored pH-sensitive hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties.Methods: We constructed a hybrid gelatin methacrylate (GelMA) system with sustainable antibacterial properties combining hyaluronic acid (HA)-coated mesoporous silica nanoparticles (MSN), which loaded host-guest complexes of chlorhexidine (CHX) with β-cyclodextrins (β-CD) (CHX⊂CD-MSN@HA@GelMA). The release mechanism of CHX was explored using UV-vis spectra after intermittent diffusion of CHX. The hybrid hydrogels were characterized, and the drug content in terms of the release profile, bacterial inhibition, and in vivo experiments were investigated.Results: Except for dual protection from both hydrogels, MSN in the HA improved the drug loading efficiency to promote the local drug concentration. It showed that complicated CHX-loaded MSN releases CHX more gradually and over a longer duration than CHX-loaded MSNs. This demonstrated a 12-day CHX release time and antibacterial activity, primarily attributable to the capacity of β-CD to form an inclusion complex with CHX. Meanwhile, in vivo experiments revealed that the hydrogels safely promote skin wound healing and enhance therapeutic efficacy.Conclusion: We constructed pH-sensitive CHX⊂CD-MSN@HA@GelMA hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties. The combination of β-CD and MSN would be better suited to release a reduced rate of active molecules over time (slow delivery), making them great candidates for wound dressing anti-infection materials.Keywords: mesoporous silica, cyclodextrin, pH-responsive, antibacterial property, wound healing

Xuegang Yang,1,2 Heping Deng,3 Yanyuan Sun,1 Yi Zhang,3 Yujie Lu,3 Guohui Xu,1,&ast; Xiaoqi Huang2,&ast; 1Department of Interventional Therapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, People’s Republic of China; 2Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Radiology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohui Xu, Department of Interventional Therapy, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, 55 Renmin South Road 4th Section, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-13708010123, Fax +86-02885420195, Email xgh0913@hotmail.com Xiaoqi Huang, Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, Department of Radiology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, People’s Republic of China, Tel +86-18980605806, Fax +86-02885420195, Email julianahuang@163.comPurpose: We compare the efficacy and safety of regorafenib plus immune checkpoint inhibitors (ICIs) with transarterial chemoembolization (R+ICIs+TACE) versus regorafenib plus ICIs (R+ICIs) as the second-line treatment for patients with advanced hepatocellular carcinoma (HCC).Methods: This retrospective study included patients with advanced HCC who received R+ICIs+TACE or R+ICIs as the second-line treatment from January 2019 to April 2022. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between the two groups. The propensity score matching (PSM) was used to reduce the influence of confounding factors on the outcomes. Factors affecting PFS and OS were analyzed using a Cox proportional-hazards regression model.Results: In total, 52 patients were included in this study, of whom 28 patients received R+ICIs+TACE and 24 patients received R+ICIs. After PSM (n=23 in each group), patients who received R+ICIs+TACE had a higher ORR (34.8% vs 4.3%, P=0.009), a longer PFS (5.8 vs 2.6 months, P< 0.0001), and a longer OS (15.0 vs 7.5 months, P=0.014) than those who received R+ICIs. Age ≤ 50 years old, Child-Pugh class A6 and B7, and R+ICIs were found as independent prognostic factors for poor PFS. R+ICIs, α-fetoprotein > 400 ng/mL, and platelet-to-lymphocyte ratio > 133 were noted as independent prognostic factors for poor OS. The difference in the incidence of TRAEs between the two groups was not statistically significant (P> 0.05).Conclusion: Compared to regorafenib plus ICIs, regorafenib plus ICIs with TACE was tolerated and improved survival as the second-line treatment for patients with advanced HCC.Keywords: advanced hepatocellular carcinoma, regorafenib, immune checkpoint inhibitors, transarterial chemoembolization, second-line treatment

Liwen Kuang,1,&ast; Chenchen Zhang,1,&ast; Binghui Li,1 Haibo Deng,1 Ran Chen,1 Gongchi Li2 1Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430062, People’s Republic of China; 2Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gongchi Li, Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan, Hubei, 430022, People’s Republic of China, Tel +8613618615209, Email ligongchi@foxmail.comPurpose: Diabetic wound is a highly prevalent and refractory disease. Extensive studies have confirmed that keratinocytes and macrophages play an important role in the process of wound healing. Additionally, exosomes are regarded as a vital intercellular communication tool. This study aimed to investigate the role of human keratinocyte-derived exosomal MALAT1 in the treatment of diabetic wound by influencing the biological function of macrophages.Methods: We mainly assessed the function of MALAT1 on the biological changes of macrophages, and the expression of MALAT1 in the keratinocyte-exosomes analyzed by quantitative real-time polymerase chain reaction (RT-qPCR). The downstream interaction between RNAs or proteins was assessed by mechanistic experiments. Besides, we evaluated the effects of human keratinocyte-derived exosomal MALAT1 on diabetic wound healing in vivo to verify in vitro results.Results: We demonstrated that human keratinocyte-derived exosomal MALAT1 enhanced the biological functions of high glucose-injured macrophages, including phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. Mechanistically, MALAT1 accelerated the expression of MFGE8 by competitively binding to miR-1914-3p, thereby affecting the function of macrophages and the signal axis of TGFB1/SMAD3, and finally promoting the healing of diabetic wounds. Human keratinocyte-derived exosomal MALAT1 might promote collagen deposition, ECM remodeling, and expression of MFGE8, VEGF, and CD31 but reduce the expression of TGFB and SMAD3 in an in vivo model of diabetic mice wounds, which accelerated diabetic wound healing and restored its function.Conclusion: The current study revealed that human keratinocyte-derived exosomal MALAT1 would suppress miR-1914-3p to activate MFGE8 and eventually promote wound healing by enhancing macrophage phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. It proposed that keratinocyte-derived exosomes might have the capacity to serve as a new method for the clinical treatment of diabetic wound.Graphical Abstract: Keywords: exosomes, keratinocytes, macrophages, MALAT1, diabetic wound healing

Yan Wu,1– 3,&ast; Shuaifeng Liu,4,&ast; Liuxi Chu,1– 3 Quan Zhang,5,6 Jin Yang,3,7 Shan Qiao,5 Xiaoming Li,5 Yuejiao Zhou,4 Huihua Deng,1– 3 Zhiyong Shen4 1Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, Nanjing, People’s Republic of China; 2Key Laboratory of Child Development and Learning Science (Southeast University), Ministry of Education, Nanjing, People’s Republic of China; 3Institute of Child Development and Education, Research Center for Learning Science, Southeast University, Nanjing, People’s Republic of China; 4Unit of AIDS Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Nanning, People’s Republic of China; 5Department of Health Promotion, Education and Behavior, South Carolina SmartState Center for Healthcare Quality (CHQ), Arnold School of Public Health, University of South Carolina, Columbia, SC, USA; 6College of Graduate Health Sciences, The University of Tennessee Health Science Center, Memphis, TN, USA; 7Department of Preventive Medicine, School of Public Health, Southeast University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huihua Deng, Department of Brain and Learning Science, School of Biological Science & Medical Engineering, Southeast University, No. 2 Sipailou, Nanjing, 210096, People’s Republic of China, Tel +86 25 8379 5664, Fax +86 25 8379 3779, Email dengrcls@seu.edu.cn Zhiyong Shen, Unit of AIDS Prevention and Control, Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, No. 18 Jinzhou Road, Nanning, 530028, People’s Republic of China, Tel +86 771 251 8838, Email shenzhiyong99999@sina.comBackground: Hair antiretroviral concentrations are an objective and non-invasive measure of adherence to long-term antiretroviral therapy (ART) and can further predict virologic outcomes among people living with HIV/AIDS (PLWH). Zidovudine, one of the mainstream antiretrovirals in China, has been verified to have high reliability in adherence assessment, especially for its hair concentrations. However, data are limited in its predicting virologic outcomes. Therefore, this study aimed to characterize whether hair zidovudine concentrations can predict virologic suppression among Chinese PLWH compared with hair lamivudine concentrations and two self-reported measures, the overall frequency of adherence behaviors and percentage adherence.Methods: This cross-sectional study randomly recruited 564 PLWH currently treated with zidovudine, lamivudine, and other ART agents (efavirenz, nevirapine, or lopinavir/ritonavir) in Guangxi, China. Hair antiretroviral concentrations were determined using the LC-ESI+-MS/MS method. Receiver operating characteristic (ROC) curves were used to estimate the optimal classification thresholds of hair concentrations of zidovudine and lamivudine, and the two self-reported measures. Based on those optimal classification thresholds, logistic regression was used to examine whether those four adherence measures can predict virologic suppression (HIV-1 RNA < 200 copies/mL).Results: ROC curves demonstrated good classification performance for association with virologic suppression of zidovudine with the optimal threshold at 58 pg/mg and lamivudine at 255 pg/mg but no self-reported measures. PLWH with hair zidovudine concentrations > 58 pg/mg had an adjusted odds ratio (aOR) of 43.191 (95% confidence interval (CI) = 10.171‒183.418, p < 0.001) for virologic suppression. Hair lamivudine concentrations were also associated with virologic suppression (aOR = 10.656, 95% CI = 3.670‒30.943, p < 0.001). However, two self-reported measures did not predict virologic suppression (aORs = 1.157 and 2.488, ps > 0.149).Conclusion: Hair zidovudine concentrations can be served as an alternative tool for clinically predicting virologic suppression among PLWH in China.Keywords: hair antiretroviral concentrations, zidovudine, virologic suppression, PLWH, LC-MS/MS

Lu Zhao,1 Junting Wang,2 Haoyuan Deng,3 Junfeng Chen,2 Ding Ding2 1Department of Medical Sociology, School of Humanities and Social Sciences, Dalian Medical University, Dalian, 116044, People’s Republic of China; 2Department of Social Medicine, School of Public Health, Dalian Medical University, Dalian, 116044, People’s Republic of China; 3Department of Nutrition and Food Health, School of Public Health, Dalian Medical University, Dalian, 116044, People’s Republic of ChinaCorrespondence: Junfeng Chen; Ding Ding, Department of Social Medicine, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian, 116044, People’s Republic of China, Tel +86 13009493030 ; +86 18249517190, Email john5151@126.com; dingdingmail0000@126.comPurpose: This study aimed to assess the prevalence of depressive symptoms and ADL/IADL disabilities and explore their correlation and associated factors for depressive symptoms among community-dwelling older adults from low-income families in Dalian, Liaoning Province, China.Methods: This cross-sectional study included 522 participants aged 60 years and older from low-income families in Dalian. The 30-Item Geriatric Depression Scale was employed to measure depressive symptoms. The Katz ADL Scale and IADL Scale were used to evaluate the performance of activities necessary for independent life. SPSS 22.0 was employed to analyze the data. Logistic regression was used to estimate the relationship between depressive symptoms and ADL/IADL disabilities in five models.Results: The prevalence of depressive symptoms among older people from low-income families in Dalian was 57.3%. A total of 19.0% had difficulties performing ADLs, and 40.2% had difficulties performing IADLs. Logistic regression analysis revealed that ADL/IADL disabilities were associated with depressive symptoms even after controlling for people’s sociodemographic characteristics, welfare, health conditions and informal care. The following factors were associated with depressive symptoms: education, self-reported health, number of chronic diseases, and emotional support from families.Conclusion: Given that older people from low-income families in Dalian have a notable prevalence rate of depressive symptoms, and ADL/IADL disabilities were independently associated with these symptoms, it is crucial to give priority to this particular group in geriatric health services due to economic and health disparities.Keywords: depressive symptoms, ADL disabilities, IADL disabilities, older adults from low-income families, China

Lijuan Yang, Huihui Deng, Wei Pan, Xiaoyan Huang, Ke Xu, Xingxing Zhang, Xiang Hu, Xuejiang Gu Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Xiang Hu; Xuejiang Gu, Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, 325000, People’s Republic of China, Tel/Fax +86-577-55579381, Email huxiang@wmu.edu.cn; guxuejiang@wmu.edu.cnPurpose: Recent studies revealed that high levels of thigh fat were independently associated with better glucose and lipid metabolism, as well as lower risk of hypertension and cardiometabolic disease. Therefore, the purpose of this study was to evaluate the association between leg fat mass (FM) and osteoporosis (OP) in individuals with type 2 diabetes (T2DM).Patients and Methods: In this cross-sectional study, a total of 1,259 individuals aged 50 years or older with T2DM (female 536, male 723) were included. A bioelectrical impedance analyser was used to assess the segment body composition containing FM and lean mass (LM) of arms, legs, and trunk. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry.Results: Leg FM was positively correlated with BMD of all sites in females and BMD of femoral neck and total hip in males after adjusting age, diabetes duration, glucose and lipid metabolism indexes, and lifestyle (all P< 0.05). LM was positively associated with BMD at almost sites (P< 0.001), while leg FM/LM ratio had no relationship with BMD at any skeleton sites (P> 0.05). Compared with the bottom tertile group of leg FM, the risk of OP was significantly lower in the top tertile group both in females (T3 vs T1: OR=0.206, 95% CI=0.098– 0.433, P< 0.001) and males (T3 vs T1: OR=0.385, 95% CI=0.182– 0.815, P< 0.05), even after adjusting for LM.Conclusion: In the present study, higher leg FM was correlated with the lower risk of OP in both men and postmenopausal women with T2DM independently of total LM.Keywords: leg fat mass, bone mineral density, osteoporosis, type 2 diabetes mellitus

Xiaoman Chen,1,2,&ast; Jing Zhou,3,&ast; Lili Wu,1 Xiang Zhu,1 Hong Deng1 1Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Infectious Disease Center, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; 3Department of Pathology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Deng; Xiang Zhu, Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, People’s Republic of China, Tel +86-2085252506, Fax +86-2085252063, Email dhong@mail.sysu.edu.cn; zhuxiang@mail.sysu.edu.cnPurpose: Chronic hepatitis B (CHB) and metabolic associated fatty liver disease (MAFLD) are both important public health problems. The effect of concomitant MAFLD on patients with CHB is still unclear. This study aimed to explore the influence of MAFLD on liver fibrosis and inflammation in CHB patients with different hepatitis B e antigen (HBeAg) status.Patients and Methods: We retrospectively collected the clinical data of 399 treatment-naïve CHB patients who underwent liver biopsy. All patients were divided into two groups (HBeAg± group). Logistic regression analysis was used to identify factors associated with liver inflammatory activity and significant fibrosis in patients with CHB. Multivariable logistic regressions were repeated in subgroups stratified by HBeAg status.Results: In patients with CHB, MAFLD was independently associated with a risk of moderate-to-severe liver activity and significant fibrosis (P < 0.05). In the HBeAg-negative group, patients with MAFLD had significantly higher levels of alanine aminotransferase (ALT) (P < 0.05) and more severe liver inflammatory activity and fibrosis (P < 0.05) compared to those without MAFLD. MAFLD was independently associated with a risk of moderate-to-severe liver activity (A ≥ 3: OR 3.97, 95% CI 1.71– 9.22, P =0.001) and significant fibrosis (F ≥ 2: OR 2.02, 95% CI 1.09– 3.73, P =0.026). In the HBeAg-positive group, MAFLD was found to be independently associated with moderate-to-severe liver activity (OR 2.44, 95% CI 1.03– 5.79, P =0.044) but not fibrosis (P =0.618).Conclusion: MAFLD is associated with the risk of liver fibrosis and inflammatory activity in HBeAg-negative CHB patients. Sufficient attention should be paid to the prevention and treatment of MAFLD in patients with CHB, especially in HBeAg-negative patients.Keywords: chronic hepatitis B, metabolic associated fatty liver disease, nonalcoholic fatty liver disease, hepatitis B e antigen

Weifeng Kong,1 Qingwu Wu,1 Yubin Chen,1 Yong Ren,2 Weihao Wang,1 Rui Zheng,1 Huiyi Deng,1 Tian Yuan,1 Huijun Qiu,1 Xinyue Wang,1 Xin Luo,1 Xuekun Huang,1 Qintai Yang,1 Gehua Zhang,1 Yana Zhang1 1Department of Otolaryngology-Head and Neck Surgery, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Digestive Cancer Research, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, People’s Republic of ChinaCorrespondence: Yana Zhang; Gehua Zhang, Department of Otolaryngology-Head and Neck Surgery, the Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, People’s Republic of China, Tel +86-20-85252310, Email zhangyn95@mail.sysu.edu.cn; zhanggeh@mail.sysu.edu.cnPurpose: Histopathologic characterizations of central compartment atopic disease (CCAD) by whole-slide imaging remains lacking. We aim to study clinical presentations and cellular endotyping diagnosis of Chinese CCAD using artificial intelligence (AI).Methods: A total of 72 patients diagnosed with chronic rhinosinusitis with nasal polyps (CRSwNP) were enrolled. CCAD was defined by positive result of serology specific IgE, endoscopic and radiological findings. The aeroallergen sensitization status, endoscopic results, radiological findings, and symptoms were evaluated and compared between patients with CCAD (n=14), eosinophilic CRSwNP (ENP, n=32) and non-eosinophilic CRSwNP (NENP, n=26). The cellular endotypes including eosinophils, neutrophils, lymphocytes, and plasma cells were analyzed by the AI chronic rhinosinusitis evaluation platform 2.0.Results: CCAD was most common in male (71.43%). The positive rate of aeroallergen in patients with CCAD is 100%, which is much higher than those in patients with ENP (40.63%) and NENP (23.08%). Allergic rhinitis incidence was found to be 57.14% in Chinese CCAD subjects, which is obviously higher when compared with those in patients with ENP (21.88%) or NENP (0.00%). The presence of asthma was not significantly different between groups. Chinese CCAD population demonstrated mild symptoms and lower endoscopic and radiological scores than those in patients with ENP and NENP. For cellular endotypes in CCAD subjects, the median of eosinophils, neutrophils, lymphocytes, and plasma cells was 26.55%, 0.49%, 60.85%, and 7.33%, respectively. The proportion of eosinophils in nasal tissue and peripheral blood mononuclear cells from the CCAD group is between the proportions in those patients with ENP and NENP.Conclusion: Chinese CCAD was associated with aeroallergen sensitivity, and displayed an eosinophil-dominant inflammatory pattern. Thus, proper management with allergy control and topical steroids could be recommended for CCAD treatment.Keywords: central compartment atopic disease, deep learning, chronic rhinosinusitis with nasal polyps, eosinophil, aeroallergen

Hong Wang,1,&ast; Tao Yang,2,&ast; Xiaodan Yu,3,&ast; Zhihong Chen,4 Yajuan Ran,5 Jiajia Wang,6 Guangming Dai,1 Huojin Deng,7 Xinglong Li,8 Tao Zhu8 1Respiratory Medicine, First People’s Hospital of Suining City, Suining, 629000, Sichuan, People’s Republic of China; 2Thoracic Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 3Respiratory Medicine, Fifth People’s Hospital of Chengdu, Chengdu, 610000, Sichuan, People’s Republic of China; 4Respiratory Medicine, Zhongshan Hospital of Fudan University, Shanghai, 20032, People’s Republic of China; 5Pharmacy Department, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 6Rheumatology Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China; 7Respiratory Medicine, ZhuJiang Hospital of Southern Medical University, Guangzhou, Guangdong, 510280, People’s Republic of China; 8Respiratory Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Zhu, Respiratory Medicine, Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China, Tel +86 23 63693094, Email zhutao063020@163.comBackground/Purpose: A patient’s length of hospital stay (LHS) is associated with the severity and outcome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Therefore, identification of patients with prolonged LHS at an early stage can potentially reduce the risk of adverse events and treatment costs in patients with AECOPD. Therefore, this study aimed to explore the independent predictors of prolonged LHS in AECOPD patients.Patients and Methods: This multicenter cross-sectional study was conducted at two tertiary hospitals between January 2019 and August 2020. Demographic data, underlying diseases, symptoms, and laboratory findings were collected. Univariate analysis was used to identify variables with significant differences. A collinearity diagnostic was applied to the selected variables before the establishment of the regression model. Ordinal logistic regression was performed to explore the independent risk factors for prolonged LHS in patients with AECOPD.Results: In total, 598 patients with AECOPD were screened. Finally, the LHS of 111, 218, and 100 patients was < 7, 7– 10, and ≥ 11 days, respectively. Significant differences in the 12 variables were found in the univariate analysis. Because collinearities among white blood cells (WBC), neutrophils (NS), and NS% were observed, WBC and NS% were excluded. Subsequently, an ordinal logistic regression model identified that rates of hypertension and chronic cor pulmonale (CCP), neutrophil–lymphocyte ratio (NLR), and erythrocyte sedimentation rate (ESR) were independent predictors of prolonged LHS in AECOPD patients.Conclusion: Collectively, our results showed that inflammatory status, hypertension, and CCP were independently associated with LHS in patients with AECOPD. These data indicate that early and appropriate administration of antibiotics and anti-inflammatory drugs is essential for reducing LHS. Hypertension and CCP were independent predictors of worse outcomes in patients with AECOPD. Therefore, advanced management and care should be provided to AECOPD patients with hypertension and/or CCP on admission.Keywords: acute exacerbation of chronic obstructive pulmonary disease, chronic cor pulmonale, erythrocyte sedimentation rate, hypertension, length of hospital stay, neutrophil–lymphocyte ratio

Xiaolan Mo,1,2,&ast; Xiujuan Chen,3,&ast; Xianggui Wang,2,&ast; Xiaoli Zhong,2 Huiying Liang,3 Yuanyi Wei,1 Houliang Deng,1 Rong Hu,1 Tao Zhang,1 Yilu Chen,1 Xia Gao,4 Min Huang,2 Jiali Li2 1Department of Pharmacy, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, People’s Republic of China; 2Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 3Department of clinical Data Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 4Division of Nephrology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, 510623, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiali Li; Min Huang, Tel +86-20-39943034 ; +86-20-39943011, Fax +86-20-39943004 ; +86-20-39943000, Email lijiali5@mail.sysu.edu.cn; huangmin@mail.sysu.edu.cnPurpose: Tacrolimus (TAC) is a first-line immunosuppressant for patients with refractory nephrotic syndrome (NS). However, there is a high inter-patient variability of TAC pharmacokinetics, thus therapeutic drug monitoring (TDM) is required. In this study, we aimed to employ machine learning algorithms to investigate the impact of clinical and genetic variables on the TAC dose/weight-adjusted trough concentration (C0/D) in Chinese children with refractory NS, and then develop and validate the TAC C0/D prediction models.Patients and Methods: The association of 82 clinical variables and 244 single nucleotide polymorphisms (SNPs) with TAC C0/D in the third month since TAC treatment was examined in 171 children with refractory NS. Extremely randomized trees (ET), gradient boosting decision tree (GBDT), random forest (RF), extreme gradient boosting (XGBoost), and Lasso regression were carried out to establish and validate prediction models, respectively. The best prediction models were validated on a cohort of 30 refractory NS patients.Results: GBDT algorithm performed best in the whole group (R2=0.444, MSE=591.032, MAE=20.782, MedAE=18.980) and CYP3A5 nonexpresser group (R2=0.264, MSE=477.948, MAE=18.119, MedAE=18.771), while ET algorithm performed best in the CYP3A5 expresser group (R2=0.380, MSE=1839.459, MAE=31.257, MedAE=19.399). These prediction models included 3 clinical variables (ALB0, AGE0, and gender) and 10 SNPs (ACTN4 rs3745859, ACTN4 rs56113315, ACTN 4 rs62121818, CTLA4 rs4553808, CYP3A5 rs776746, IL2RA rs12722489, INF2 rs1128880, MAP3K11 rs7946115, MYH9 rs2239781, and MYH9 rs4821478).Conclusion: The association between the clinical and genetic variables and TAC C0/D was described, and three TAC C0/D prediction models integrating clinical and genetic variables were developed and validated using machine learning, which may support individualized TAC dosing.Keywords: tacrolimus, nephrotic syndrome, machine learning, prediction model, genetic polymorphism

Hongbin Deng,1,&ast; Xianqiang Yu,2,&ast; Kun Gao,1 Yang Liu,3 Zhihui Tong,1 Yuxiu Liu,1 Weiqin Li1– 3 1Department of Critical Care Medicine, Jinling Hospital, Nanjing Medical University, Nanjing, People’s Republic of China; 2School of Medicine, Southeast University, Nanjing, People’s Republic of China; 3Department of Critical Care Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiqin Li; Yuxiu Liu Email liweiqindr@nju.edu.cn; Liu_yuxiu@163.comObjective: Thrombocytopenia increases the risk of hemorrhage in patients with acute pancreatitis (AP), leading to poor clinical outcomes. Currently, there is no reliable tool for the early assessment of thrombocytopenia in these patients. We aimed to develop a nomogram based on available clinical parameters and validate its efficacy in predicting thrombocytopenia.Methods: This was a retrospective study. All the data were extracted from an electronic database from May 2018 to May 2019. Patients with a diagnosis of AP and staying in the intensive care unit for more than 3 days were retrospectively analyzed. A clinical signature was built based on reproducible features, using the least absolute shrinkage and selection operator method (LASSO), and logistic regression established the model (P < 0.05). Nomogram performance was determined by its discrimination, calibration, and clinical usefulness.Results: A total of 594 eligible patients were enrolled, of whom 399 were allocated to the training sets and the 195 in the test sets. The clinical features, including blood urea nitrogen (BUN), fibrinogen (FIB), and antithrombase III, were significantly associated with the incidence of thrombocytopenia after acute pancreatitis (p < 0.05) in training sets. The individualized nomogram showed good discrimination in the training sample (area under the receiver operating characteristic curve [AUC], 0.881) and in the validation sample (AUC, 0.883) with good calibration.Conclusion: The proposed nomogram has good performance for predicting thrombocytopenia in patients with acute pancreatitis and may facilitate clinical decision-making.Keywords: acute pancreatitis, thrombocytopenia, systemic inflammatory response syndrome, coagulopathy, nomogram

Wen Deng,1,&ast; Gongxian Wang,1,&ast; Huanhuan Deng,2,&ast; Yan Yan,3,&ast; Ke Zhu,1,&ast; Ru Chen,1,4 Xiaoqiang Liu,1 Luyao Chen,1 Tao Zeng,2 Bin Fu1 1Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China; 2Department of Urology, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China; 3Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China; 4Department of Urology, The First Hospital of Putian City, Putian City, Fujian Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Fu; Tao Zeng Tel + 86 13879103861; +86 18779101830Fax +86 0791-88698102; +86 0791-86120120Email urofbin@163.com; taozeng40709@sina.comPurpose: This study aimed to evaluate the functions of critical N6-methyladenosine (m6A)-related long non-coding RNAs (lncRNAs) and their correlations with immunotherapeutic targets in clear cell renal cell carcinoma (ccRCC).Methods: m6A-related lncRNAs were analyzed using the dataset from The Cancer Genome Atlas database via Pearson correlation analysis. Then, their prognostic functions in patients with ccRCC were determined via univariate Cox analysis. A prognostic m6A-related lncRNA signature (MRLS) in ccRCC was established using the least absolute shrinkage and selection operator (LASSO) Cox regression model. In addition, the correlations between these prognostic m6A-related lncRNAs with immune checkpoints were further evaluated in clinical samples.Results: MRLS was established by the LASSO Cox regression model on the basis of seven prognostic m6A-related lncRNAs. The risk score for each patient was calculated using the MRLS model, and the patients were further stratified into high- and low-risk subgroups. The MRLS model was validated with a robust prognostic ability by the stratification analysis. On the basis of age, grade, stage, and risk score, a nomogram was developed with a strong reliability in forecasting the overall survival percentages of the patients with ccRCC. Moreover, seven prognostic m6A-related lncRNAs enrolled in the MRLS model were found to be correlated with various immunotherapeutic targets, namely, PD-1, PD-L1, CTLA4, and LAG3, and the expression levels of which in the high-risk subgroup were significantly higher than those in the low-risk subgroup. The significant correlations between LINC00342 and the aforementioned immunotherapeutic targets were also confirmed in clinical samples.Conclusion: In this study, seven m6A-related lncRNAs were identified as potential biomarkers for forecasting the prognosis of patients with ccRCC and evaluating the efficacy of immunotherapy for these patients. Furthermore, a prognostic and predictive MRLS model with a high reliability was constructed to predict the overall survival probability of patients with ccRCC.Keywords: immunotherapy, N6-methyladenosine modification, long non-coding RNA, renal cell carcinoma, prognosis

Qunying Han,1 Huan Deng,1 Xiude Fan,1 Xiaoyun Wang,1 Xiaoge Zhang,1 Kun Zhang,1 Na Li,1 Yi Lv,2,3 Zhengwen Liu1,3 1Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Zhengwen LiuDepartment of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, 710061, Shaanxi Province, People’s Republic of ChinaEmail liuzhengwen113@xjtu.edu.cnBackground: Hepatocellular carcinoma (HCC) is a major cause of liver-related mortality. Serum pentraxin 3 (PTX3) has been revealed to be associated with the development of hepatitis B virus (HBV)-related HCC. This study evaluated whether serum PTX3 is related to the survival of HBV-related HCC patients.Methods: One hundred and seven patients with HBV-related HCC were included. Baseline serum PTX3 levels were quantified using quantitative immunoassay. The HCC patients were followed-up for a median of 24 months and divided into high serum PTX3 level and low PTX3 level groups according to the baseline serum PTX3 levels. The overall survivals of the HBV-related HCC patients according to the serum PTX3 levels were compared. Factors potentially influencing the prognosis of the patients with HBV-related HCC were analyzed.Results: HCC patients with high serum PTX3 levels [PTX3 > 9.25ng/mL (n=85)] had a shorter overall survival time than HCC patients with low serum PTX3 levels [PTX3 ≤ 9.25ng/mL (n=22)] (P = 0.049). HCC patients with serum PTX3 levels between > 9.25ng/mL and ≤ 9.25ng/mL had significant difference in HCC histology grade. Multivariate analysis showed that PTX3 level was an independent risk factor related to the overall survival of HCC patients (hazard ratio: 1.058, 95% confidence interval: 1.031– 1.085, P < 0.001).Conclusion: These results support the involvement of PTX3 in the disease progression of HCC and suggest the potential of using serum PTX3 levels as a biomarker for the prognostic prediction of HBV-related HCC patients.Keywords: hepatocellular carcinoma, pentraxin 3, chronic HBV infection, survival, prognosis

Weixuan Wang,1,&ast; Changmei Yang,2,&ast; Haiteng Deng2 1Institute of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, People’s Republic of China; 2MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiteng DengMOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing, People’s Republic of ChinaTel +86-10-62790498Email dht@mail.tsinghua.edu.cnPurpose: Lung cancer is one of the most commonly diagnosed cancer as well as the leading cause of cancer-related mortality worldwide, among which lung adenocarcinoma (LUAD) is the most frequent form of lung cancer. Previous studies have shown that 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of prostaglandins to reduce their biological activities and behaves as a tumor suppressor in various cancers. Thus, we aimed to systematically examine the effects of 15-PGDH overexpression on cellular processes in lung adenocarcinoma cells.Methods: The stable 15-PGDH-overexpressing A549 cell line was constructed using lentivirus particles. CCK-8 assay was used to determine the cell proliferation rate and sensitivity to cisplatin. Tandem mass tag (TMT)-based quantitative proteomic analysis was used to identify differentially expressed proteins between control and 15-PGDH-overexpression cells. The cell cycle was determined by a flow cytometer. The expression levels of mesenchymal and epithelial markers were measured using Western blotting. Wound healing and transwell assays were used to detect the cell migration and cell invasion ability, respectively.Results: Analysis of datasets in The Cancer Genome Atlas revealed that the PGDH gene expression level in the lung adenocarcinoma tissues was significantly lower than that in the pericarcinous tissues. 15-PGDH overexpression in A549 cells reduced cell proliferation rate. Quantitative proteomics revealed that 15-PGDH overexpression inhibited PI3K/AKT/mTOR signaling pathway, which is a signaling pathway driving tumor cell growth and epithelial-mesenchymal transition (EMT) process. In addition, both cell cycle and DNA repair-related proteins were down-regulated in 15-PGDH overexpressed cells. 15-PGDH overexpression induced G1/S cell cycle arrest and increased susceptibility to DNA damaging reagent cisplatin. Importantly, overexpression of 15-PGDH inhibited EMT process with the downregulation of β-catenin and Snail-1 as well as upregulation of E-cadherin and ZO-1.Conclusion: 15-PGDH is a tumor suppressor in lung cancer and may serve as a potential therapeutic target to prevent lung adenocarcinoma.Keywords: 15-PGDH, proteomics, lung adenocarcinoma, cell proliferation, cell cycle arrest, epithelial-mesenchymal transition