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Junhai Zhen,1 Chuan Liu,2 Jixiang Zhang,2 Fei Liao,2 Huabing Xie,1 Cheng Tan,2 Ping An,2 Zhongchun Liu,3 Changqing Jiang,4 Jie Shi,5 Kaichun Wu,6 Weiguo Dong2 1Department of General Practice, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People’s Republic of China; 2Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People’s Republic of China; 3Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 4Department of Clinical Psychology, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, People’s Republic of China; 5Department of Medical Psychology, Chinese People’s Liberation Army Rocket Army Characteristic Medical Center, Beijing, 100032, People’s Republic of China; 6Department of Gastroenterology, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of ChinaCorrespondence: Kaichun Wu, Department of Gastroenterology, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of China, Tel/Fax +8629-84771600, Email kaicwu@fmmu.edu.cn Weiguo Dong, Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Tel/Fax +8627-88041911, Email dongweiguo@whu.edu.cnPurpose: Impaired quality of life (QOL) is common in patients with inflammatory bowel disease (IBD). A tool to more quickly identify IBD patients at high risk of impaired QOL improves opportunities for earlier intervention and improves long-term prognosis. The purpose of this study was to use a machine learning (ML) approach to develop risk stratification models for evaluating IBD-related QOL impairments.Patients and Methods: An online questionnaire was used to collect clinical data on 2478 IBD patients from 42 hospitals distributed across 22 provinces in China from September 2021 to May 2022. Eight ML models used to predict the risk of IBD-related QOL impairments were developed and validated. Model performance was evaluated using a set of indexes and the best ML model was explained using a Local Interpretable Model-Agnostic Explanations (LIME) algorithm.Results: The support vector machine (SVM) classifier algorithm-based model outperformed other ML models with an area under the receiver operating characteristic curve (AUC) and an accuracy of 0.80 and 0.71, respectively. The feature importance calculated by the SVM classifier algorithm revealed that glucocorticoid use, anxiety, abdominal pain, sleep disorders, and more severe disease contributed to a higher risk of impaired QOL, while longer disease course and the use of biological agents and immunosuppressants were associated with a lower risk.Conclusion: An ML approach for assessing IBD-related QOL impairments is feasible and effective. This mechanism is a promising tool for gastroenterologists to identify IBD patients at high risk of impaired QOL.Keywords: clinical research, artificial intelligence, model development, clinical decision support system

Qiming Gan,1,* Quanzhen Liu,1,2,* Yanjuan Wu,1,* 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*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

Shulin Wei,1,2,* Mingxing Li,1,2,* Qin Wang,1,2,* Yueshui Zhao,1,2 Fukuan Du,1,2 Yu Chen,1,2 Shuai Deng,1,2 Jing Shen,1,2 Ke Wu,1,2 Jiayue Yang,1,2 Yuhong Sun,1 Li Gu,1 Xiaobing Li,1 Wanping Li,1 Meijuan Chen,1 Xiao Ling,3 Lei Yu,3 Zhangang Xiao,1,2 Lishu Dong,3 Xu Wu1,2 1Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China; 2South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China; 3Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lishu Dong, Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China, Email 1275607519@qq.com Xu Wu, Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China, Email wuxulz@126.comAbstract: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.Keywords: mesenchymal stem cells, immunomodulation, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, cell therapy

Jing-Chun Xia,1,2,* Yu-Cheng Huang,1,2,* Ke Wu,1,2 Jian Pang,1,2 Ying Shi1,2 1Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Institute of Traumatology & Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian Pang; Ying Shi, Email pangjian@shutcm.edu.cn; shiying1974@126.comPurpose: Chinese herbal medicine and electroacupuncture (EA) have been used to control pain for many decades in China. We aim to explore the efficacy of intervening patients whose discogenic sciatica symptoms lasting longer than 3 months with these conservative treatments.Patients and Methods: This is a single-center, parallel-group, patient-unblinded Randomized Controlled Trial (RCT) with blinded outcome assessment and statistician. One hundred and twenty-four patients will be assigned randomly into 2 groups including conservative treatment group (Shenxie Zhitong capsule combined with EA treatment) and Nonsteroidal Anti-inflammatory Drugs (Nonsteroidal Anti-inflammatory Drugs, NSAIDs) control group (Celecoxib) in a 1:1 ratio. The trial involves a 4-week treatment along with follow-up for 6 months. The primary outcome is the leg pain intensity measured by the visual analogue scale (VAS) at 6 months after randomization. Secondary outcomes include leg pain intensity at other time points, back pain intensity, leg pain and back pain frequency, functional status, quality of life, return to work status and satisfaction of patients. Adverse events will also be recorded.Strengths and Limitations of This Study: Through this study, we want to observe the efficacy of electroacupuncture combined with Chinese herbal medicine on pain intensity for chronic sciatica secondary to Lumbar Disc Herniation. If the final results are favorable, it is expected to be a safe, economical, and effective treatment for patients. The study design has the following limitations: the setup of control group was less than perfect; patients and doctors could not be blinded in this trial; we skipped the feasibility study. We have tried our best to minimize adverse impacts.Trial Registration: ChiCTR2300070884 (Chinese Clinical Trial Registry, http://www.chictr.org.cn, registered on 25th April 2023).Keywords: sciatica of lumbar disc herniation, shenxie zhitong capsule, electroacupuncture treatment, celecoxib, single-center randomized controlled trial, protocol

Kangze Wu, Feizhuan Lin Department of Hepatobiliary Surgery, Shaoxing People’s Hospital, Shaoxing, People’s Republic of ChinaCorrespondence: Feizhuan Lin, Department of Hepatobiliary Surgery, Shaoxing People’s Hospital, Shaoxing, People’s Republic of China, Email linfeizhuan@163.comAbstract: Hepatocellular carcinoma (HCC) stands as a severe malignant tumor with a profound impact on overall health, often accompanied by an unfavorable prognosis. Despite some advancements in the diagnosis and treatment of this disease, improving the prognosis of HCC remains a formidable challenge. It is noteworthy that lipid metabolism plays a pivotal role in the onset, development, and progression of tumor cells. Existing research indicates the potential application of targeting lipid metabolism in the treatment of HCC. This review aims to thoroughly explore the alterations in lipid metabolism in HCC, offering a detailed account of the potential advantages associated with innovative therapeutic strategies targeting lipid metabolism. Targeting lipid metabolism holds promise for potentially enhancing the prognosis of HCC.Keywords: cholesterol, fatty acid, hepatocellular carcinoma, lipid uptake, lipid catabolism, lipid synthesis

Enyi Zhu,1,2,* Ming Zhong,3,* Tiantian Liang,4,* Yu Liu,3,* Keping Wu,1,2 Zhijuan Zhang,1,2 Shuping Zhao,1,2 Hui Guan,5 Jiasi Chen,6 Li-Zhen Zhang,7 Yimin Zhang1,2 1The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, 510000, People’s Republic of China; 2Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, 510000, People’s Republic of China; 3Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 517108, People’s Republic of China; 4Nephrology Division, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, People’s Republic of China; 5Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, People’s Republic of China; 6Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510030, People’s Republic of China; 7Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yimin Zhang, The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, People’s Republic of China, Email zhangyim@mail.sysu.edu.cn Li-Zhen Zhang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China, Email zhanglzh3@mail2.sysu.edu.cnObjective: Diabetic nephropathy (DN) represents the principal cause of end-stage renal diseases worldwide, lacking effective therapies. Fatty acid (FA) serves as the primary energy source in the kidney and its dysregulation is frequently observed in DN. Nevertheless, the roles of FA metabolism in the occurrence and progression of DN have not been fully elucidated.Methods: Three DN datasets (GSE96804/GSE30528/GSE104948) were obtained and combined. Differentially expressed FA metabolism-related genes were identified and subjected to DN classification using “ConsensusClusterPlus”. DN subtypes-associated modules were discovered by “WGCNA”, and module genes underwent functional enrichment analysis. The immune landscapes and potential drugs were analyzed using “CIBERSORT” and “CMAP”, respectively. Candidate diagnostic biomarkers of DN were screened using machine learning algorithms. A prediction model was constructed, and the performance was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The online tool “Nephroseq v5” was conducted to reveal the clinical significance of the candidate diagnostic biomarkers in patients with DN. A DN mouse model was established to verify the biomarkers’ expression.Results: According to 39 dysregulated FA metabolism-related genes, DN samples were divided into two molecular subtypes. Patients in Cluster B exhibited worse outcomes with a different immune landscape compared with those in Cluster A. Ten potential small-molecular drugs were predicted to treat DN in Cluster B. The diagnostic model based on PRKAR2B/ANXA1 was created with ideal predictive values in early and advanced stages of DN. The correlation analysis revealed significant association between PRKAR2B/ANXA1 and clinical characteristics. The DN mouse model validated the expression patterns of PRKAR2B/ANXA1.Conclusion: Our study provides new insights into the role of FA metabolism in the classification, immunological pathogenesis, early diagnosis, and precise therapy of DN.Keywords: diabetic nephropathy, fatty acid metabolism, molecular subtypes, immune landscape, pharmacotherapy, diagnostic model

Enyu Tong,1,* Ying Zhou,1,* Zhengwei Liu,2 Yelei Zhu,2 Mingwu Zhang,2 Kunyang Wu,2 Junhang Pan,2 Jianmin Jiang1– 3 1School of Public Health, Hangzhou Normal University, Hangzhou, 311100, People’s Republic of China; 2Tuberculosis Control Department, Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, 310051, People’s Republic of China; 3Key Laboratory of Vaccine, Prevention and Control of Infectious Disease of Zhejiang Province, Hangzhou, 310051, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junhang Pan; Jianmin Jiang, Email jhpan@cdc.zj.cn; jmjiang@cdc.zj.cnPurpose: This study aimed to determine the prevalence and molecular characterization of bedaquiline (BDQ) resistance among rifampicin-resistant tuberculosis (RR-TB) isolates collected from Zhejiang, China.Patients and Methods: A total of 245 RR-TB isolates were collected from 19 municipal TB hospitals in Zhejiang province, China between January and December 2021. Microplate assays were used to determine the minimum inhibitory concentrations (MIC) of BDQ. Whole-genome sequencing (WGS) was performed on isolates with MIC values for BDQ ≥ 0.25 μg/mL.Results: Five (2.04%) BDQ-resistant strains were isolated from 245 tuberculosis patients. The resistance rate of BDQ was not correlated to the sex, age, treatment history, or occupation of patients. Four BDQ-resistant isolates and three BDQ-sensitive isolates were found to carry Rv0678 mutations, and one BDQ-resistant strain carried both Rv0678 and pepQ mutations. No mutations within the atpE and Rv1979c genes were observed.Conclusion: BDQ demonstrated strong in vitro antibacterial activity against RR-TB isolates, and the Rv0678 gene was identified as the primary mechanism contributing to BDQ resistance among RR-TB isolates from Zhejiang, China. Furthermore, in addition to the four currently known resistance-associated genes (atpE, Rv0678, Rv1979c, and pepQ), other mechanisms of resistance to BDQ may exist that need further study.Plain language summary: This study looked at a bacterial species called Mycobacterium tuberculosis, which causes the highly problematic disease, tuberculosis. Certain strains of this bacterium have developed resistance to conventional antibiotics used in tuberculosis treatment, necessitating an investigation into the efficacy of the newer antibiotic, bedaquiline. We collected 245 rifampicin-resistant tuberculosis samples from patients in Zhejiang, China, subjecting them to bedaquiline susceptibility testing. Concurrently, we conducted a genetic analysis of the bacteria to pinpoint mutations linked to bedaquiline resistance. Out of the 245 samples, 5 were found to be resistant to bedaquiline. We found that mutations in a gene called Rv0678 were the main reason for this resistance. This gene had mutations in four of the bedaquiline-resistant samples and three of the bedaquiline-susceptible samples. One of the bedaquiline-resistant samples had mutations in both Rv0678 and another gene called pepQ. We also found that bedaquiline was effective at killing drug-resistant tuberculosis bacteria in the lab. However, there may be other genes or mechanisms that make other bacteria resistant to the drug, which will need further study. Overall, this study helps us understand how bedaquiline works against drug-resistant tuberculosis bacteria and identifies a genetic mechanism that can cause resistance to the drug.Keywords: Mycobacterium tuberculosis, rifampicin-resistant tuberculosis, bedaquiline, whole-genome sequencing

Guanglan Li,1,2 Jing Yu,1,2 Simin Jiang,1,2 Kefei Wu,1,2 Yiping Xu,1,2 Xiaohui Lu,1,2 Yating Wang,1,2 Jianxiong Lin,1,2 Xiao Yang,1,2 Zhibin Li,3 Haiping Mao1,2 1Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China; 2NHC Key Laboratory of Clinical Nephrology (Sun Yat-sen University) and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, 510080, China; 3Epidemiology Research Unit, Translational Medicine Research Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361005, ChinaCorrespondence: Haiping Mao, Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China, Email maohp@mail.sysu.edu.cnPurpose: The prognosis of patients receiving peritoneal dialysis (PD) is associated with inflammation. Systemic immune-inflammation index (SII) is one of inflammatory markers, and the role in predicting clinical outcomes in PD patients is unclear. We aimed to investigate the relationship between the SII and all-cause and cardiovascular-specific mortalities in patients undergoing PD.Patients and Methods: A total of 1419 PD patients from the First Affiliated Hospital of Sun Yat-sen University between January 1, 2007 and December 31, 2019 were retrospectively included at baseline, and the patients were followed up until November 31, 2021. SII was calculated as platelet count×neutrophil count/lymphocyte count. Kaplan–Meier curves and Cox proportional hazards regression models were used to determine the relationship between SII levels and all-cause and cardiovascular-specific mortalities.Results: During follow-up (median period was 42 months), 321 patients died (171 died of cardiovascular disease). With adjustment for the potential confounding factors, each 1-SD increase in the SII was associated with 20.2% increase in all-cause mortality (hazard ratio [HR]: 1.202, 95% confidence interval [CI]: 1.088– 1.327, P< 0.001) and 28.0% increase in cardiovascular-specific mortality (HR: 1.280, 95% CI: 1.126– 1.456, P< 0.001). High SII (vs low SII) was significantly associated with increased risks of all-cause mortality (HR: 1.391, 95% CI: 1.066– 1.815, P-value: 0.015) and cardiovascular-specific mortality (HR: 1.637, 95% CI: 1.185– 2.261, P-value: 0.003). Subgroups analyses showed similar results for those younger than 65-year-old only.Conclusion: Elevated SII level was independently associated with increased risks of all-cause and cardiovascular-specific mortalities in PD patients, especially for those younger than 65-year-old.Keywords: all-cause mortality, cardiovascular mortality, peritoneal dialysis, systemic immune-inflammation index

Yajun Jiang,1 Longfang Huang,1 Yu Guo,1 Qin Yang,2 Haixia Li,1 Huiling Zhou,1 Ke Wu3 1College of Tourism & Landscape Architecture, Guilin University of Technology, Guangxi, 541004, People’s Republic of China; 2School of Preschool Education, Changsha Normal University, Changsha, 410100, People’s Republic of China; 3School of Economics & Management, Hunan University of Science and Technology, Yongzhou, 425199, People’s Republic of ChinaCorrespondence: Ke Wu, School of Economics & Management, Hunan University of Science and Technology, Yongzhou, 425199, People’s Republic of China, Tel +15674662800, Email huse_chn@163.comPurpose: The COVID-19 has greatly affected the tourism industry in China, leading to an increase in psychological distress among tour guides. This study explores the mechanisms by which tour guides’ fear of the COVID-19 affects psychological distress, using job insecurity as a mediating variable and psychological resilience as a moderating variable.Patients and Methods: From August 11 to 30, 2022, 447 Chinese tour guides were invited online to fill in a questionnaire, and SPSS and Mplus tools were used for statistical analysis and hypothesis testing to conduct an empirical analysis of the relationship between COVID-19 fear and psychological distress.Results: A total of 417 questionnaires (effective rate was 93.3%) were collected, among which female (n = 243) and male (41.7%) (n =174). The age concentration of participants was 46.5% between 26 and 35 years old, 9.1% under 25 years old, and 9.8% over 46 years old. Guides’ fear of COVID-19 positively and significantly influenced psychological distress (β= 0.3051), and the relationship between fear of COVID-19 and psychological distress was mediated by job insecurity (β=0.196, 95% CI = 0.141, 0.255). In addition, psychological resilience significantly moderated the pathway from fear of COVID-19 to job insecurity and from fear of COVID-19 to guided psychological distress (β= 0.1371; β=0.116).Conclusion: The diversion of fear of COVID-19 and job insecurity can alleviate the psychological distress of tour guides; strengthening their own psychological construction also helps to alleviate the effects of fear of COVID-19 on job insecurity and psychological distress. The findings of the study can provide theoretical support for the prevention and counseling of psychological problems of tourism employees in public health crises.Keywords: fear of COVID-19, job insecurity, psychological distress, psychological resilience

Rong Yu,1,&ast; Chuan Liu,1,&ast; Jixiang Zhang,1,&ast; Jiao Li,1,&ast; Shan Tian,2 Fugui Ding,1 Zhengru Liu,3 Ting Wang,4 Zhongchun Liu,5 Changqing Jiang,6 Jie Shi,7 Kaichun Wu,8 Weiguo Dong1 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Department of Infectious Diseases, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, People’s Republic of China; 3Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 4Department of Gastroenterology, First Affiliated Hospital of Hainan Medical College, Haikou, 570102, People’s Republic of China; 5Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 6Department of Clinical Psychology, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, People’s Republic of China; 7Department of Medical Psychology, Chinese People’s Liberation Army Rocket Army Characteristic Medical Center, Beijing, 100088, People’s Republic of China; 8Department of Gastroenterology, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiguo Dong, Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Tel +86 027-88041911, Email dongweiguo@whu.edu.cn Kaichun Wu, Department of Gastroenterology, Xijing Hospital, Air Force Medical University, No. 127 West Changle Road, Xi’an, Shaanxi Province, 710032, People’s Republic of China, Tel +86 029-84771600, Email kaicwu@fmmu.edu.cnObjective: To explore the correlation between disease activity and anxiety, depression, sleep quality, and quality of life in patients with inflammatory bowel disease (IBD).Methods: The disease activity of IBD patients was evaluated by 66 gastroenterologists from 42 hospitals in 22 provinces in China from September 2021 to May 2022. Anxiety, depression, sleep quality and quality of life of IBD patients were investigated and statistically analyzed by different scales, including Generalized Anxiety Disorder 7-item Scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and Inflammatory Bowel Disease Quality-of-Life Questionnaire (IBD-Q).Results: A total of 2478 IBD patients were included, of which 1532 (61.8%) were in active stage and 946 (38.2%) were in remission. The proportions of active IBD with anxiety, depression, sleep disturbance, and poor quality of life were 29.5%, 29.7%, 71.1%, and 50.1%, respectively, while the proportions of remission IBD with anxiety, depression, sleep disturbance, and poor quality of life were 19.1%, 24.4%, 69.3%, and 17.4%, respectively. IBD patients who also had anxiety, depression, sleep disturbances and poor quality of life had 80 cases (8.46%) in remission and 114 cases (7.44%) in active stage, with 54 cases (9.18%) in mild activity, 51 cases (6.95%) in moderate activity and 9 cases (4.49%) in severe activity. IBD patients with different disease activity levels differed in GAD-7 scores, PHQ-9 scores, PSQI scores, and IBD-Q scores (all P< 0.001). In IBD patients, anxiety, depression, and sleep disturbance, which interact with each other, can further aggravate their disease activity (all P< 0.001).Conclusion: Anxiety, depression, sleep disturbances, and quality of life are strongly correlated with disease activity in IBD patients, and IBD patients with psychological disturbances are most often in the active stage and have a poor quality of life.Keywords: inflammatory bowel disease, disease activity, anxiety, depression, sleep quality, quality of life, survey

Donghao Wang,1,&ast; Yingying Ren,2,&ast; Riken Chen,1,&ast; Xiangxia Zeng,1,&ast; Qiming Gan,1,&ast; Zhiyang Zhuang,1 Xiaofen Su,1 Kang Wu,1 Sun Zhang,1 Yongkang Tang,1 Shiwei Li,1 Haojie Zhang,1,3 Yanyan Zhou,1 Nuofu Zhang,1 Dongxing Zhao1 1State Key Laboratory of Respiratory Disease, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, National Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Medical Records and Statistics Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3The Clinical Medicine Department, Henan University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongxing Zhao; Nuofu Zhang, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, National Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Tel +86-13650901411 ; +86-13600460056, Email rieast@msn.com; nfzhanggird@163.comObjective: Obstructive sleep apnea (OSA) is a common sleep-disordered breathing disease. We aimed to establish an improved screening questionnaire without physical examinations for OSA named the CNCQ-OSA (Chinese community questionnaire for OSA).Methods: A total of 2585 participants who visited sleep medicine center and underwent overnight polysomnography were grouped into two independent cohorts: derivation (n = 2180) and validation (n = 405). The CNCQ-OSA was designed according to the baseline of patients in derivation cohort. We comprehensively analyzed the data to evaluate the predictive value of the CNCQ-OSA, compared to the GOAL questionnaire, STOP-Bang questionnaire (SBQ) and NoSAS questionnaire.Results: The CNCQ-OSA included seven variables: loud snoring, BMI ≥ 25 kg/m2, male gender, apnea, sleepiness, hypertension and age ≥ 30, with a total score ranging from 7 to 16.7 points (≥ 13.5 points indicating high risk of OSA, ≥ 14.5 points indicating extremely high risk). In the derivation and validation cohorts, the areas under the curve of the CNCQ-OSA were 0.761 and 0.767, respectively. In the validation cohort, the sensitivity and specificity of a CNCQ-OSA score ≥ 13.5 points for the apnea–hypopnea index (AHI) ≥ 5/h were 0.821 and 0.559, respectively (Youden index, 0.380), and the score ≥ 14.5 points were 0.494 and 0.887, respectively (Youden index, 0.375). The CNCQ-OSA had a better predictive value for AHI ≥ 5/h, AHI > 15/h and AHI > 30/h, with the highest Youden index, compared to the other questionnaires.Conclusion: The CNCQ-OSA can effectively identify the risk of OSA, which is appropriate for self-screening at home without physical examinations.Keywords: obstructive sleep apnea, screening, GOAL, STOP-Bang, NoSAS

Meijing Shen,&ast; Xianghao Chen,&ast; Jingyue He, Lin Xiong, Rengui Tian, Guangwu Yang, He Zha, Kaifeng Wu Department of Laboratory Medicine, the First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kaifeng Wu; He Zha, Department of Laboratory Medicine, the First People’s Hospital of Zunyi (The Third Affiliated Hospital of Zunyi Medical University), Zunyi, People’s Republic of China, Email kiphoonwu@126.com; zhahe666@126.comPurpose: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has seriously threatened public health worldwide. This study aimed to investigate the antimicrobial resistance patterns, sequence types (STs), virulence and carbapenemase genes of CRKP isolates from patients in Zunyi, China.Methods: CRKP isolates were collected from the First People’s Hospital of Zunyi between January 2018 and December 2020. Antimicrobial susceptibility was determined using a VITEK® 2 analyzer and confirmed using either the broth dilution method, Kirby–Bauer method, or E-test assays. Carbapenemase production was examined using a modified carbapenem inactivation method. STs of the studied isolates were determined by multilocus sequence typing, and the presence of carbapenemase and virulence genes was examined using polymerase chain reaction assays.Results: In total, 94 CRKP isolates were collected. All studied isolates produced carbapenemase, and the most common carbapenemase gene was New Delhi metallo-β-lactamase (NDM; 72.3%), followed by Klebsiella pneumoniae carbapenemase (KPC; 24.5%), and Verona integron-encoded metallo-β-lactamase (VIM; 3.2%). Of the studied isolates, 74.3% exhibited multidrug-resistant (MDR) phenotype, and 25.7% were either pandrug-resistant (PDR) or extensively drug-resistant (XDR) phenotypes. The most prevalent sequence type was ST2407 (37.2%), followed by ST76 (21.3%) and ST11 (11.7%). The NDM gene was present in 97.1% of ST2407 isolates and 90.0% of ST76 isolates, whereas the KPC gene was present in 90.9% of ST11 isolates. The majority of the isolates carried wabG, uge, and fimH virulence genes, with prevalence rates of 94.7%, 92.6%, and 94.7%, respectively.Conclusion: This study describes NDM-producing ST2407 and ST76, as well as KPC-producing ST11, as the major clonal types of CRKP isolates in Zunyi, China. All CRKP isolates were resistant to multiple types of antibiotics, and the majority of isolates carried carbapenemase and virulence genes. Clonal spread of NDM-producing CRKP ST2407 and ST76, and KPC-producing CRKP ST11 should be strictly monitored.Keywords: Klebsiella pneumoniae, antimicrobial resistance patterns, virulence genes, sequence types, carbapenemase genes

Yang Liu,1 Chao Zhang,2 Qianwen Wang,1 Kangze Wu,3 Zhouyi Sun,1 Zhe Tang,1 Bo Zhang3 1The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, People’s Republic of China; 2Center for Evidence-Based Medicine and Clinical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 3The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310000, People’s Republic of ChinaCorrespondence: Bo Zhang, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang, 310000, People’s Republic of China, Tel/Fax +86-0571-87783563, Email jjs10@zju.edu.cnBackground: This study aimed to evaluate the global colorectal cancer(CRC) trend and the relevant risk factors from 1990 to 2019 and for better policymaking and resource allocation.Methods: Data on CRC, including incidence, mortality and disability adjusted life year (DALY) rates, were extracted from the 2019 Global Burden of Disease (GBD) study. The estimated annual percentage changes (EAPCs) were calculated to assess the temporal trend of incidence, mortality and DALYs. The Bayesian age-period-cohort model(BAPC) was used to predict the future burden of CRC.Results: In 2019, a total of 2.17 million CRC cases were reported worldwide, a 157% increase from 1990. In high-social demographic index (SDI) regions, the trend of age-standardized incidence rate(ASIR) tended to decrease, while the proportion of people under 50 years of age tended to increase. Although the number of deaths and DALYs increased, the age-standardized death rate (ASDR) and age-standardized DALY rate decreased. The CRC burden was growing fastest in middle-SDI regions, especially in East Asia, followed by low SDI regions. In addition, the milk intake, High-BMI and high fasting plasma glucose play a more important role in on CRC. The predicted cases and deaths in global continued to increase to 2044. And there is an upward trend in ASIR for both men and women.Conclusion: In developed regions, the CRC burden continues to decrease, while the CRC burden become more and more severe in developing regions. Overall, the burden of CRC will rising in the near future. Therefore, reasonable resource allocation and prevention policies should be implemented. Developing countries needs more attention.Keywords: global burden of disease, colorectal cancer, disability-adjusted life year, estimated annual percentage change, age-standardized incidence rate, Bayesian age-period-cohort

Kui Wu,&ast; Hui-Hui Ke,&ast; Wei Gong, Hua Hu, Li Chen Department of Obstetrics and Gynecology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Chen; Hua Hu, Department of Obstetrics and Gynecology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai, 201399, People’s Republic of China, Tel +86 21 5802 2995, Email chenli8369@163.com; Huhua20212022@163.comAim: To assess the impact of maternal pre-pregnancy body mass index (BMI) on gestational diabetes mellitus (GDM) based on different pre-pregnancy hemoglobin levels.Methods: This retrospective cohort study included 1289 pregnant women between June 2020 and January 2022. Clinical data were collected by reviewing their medical and antepartum screening records between 24 and 28 gestational weeks, including pre-pregnancy BMI and pre-pregnancy hemoglobin (Hb) levels. The diagnosis of GDM mainly depended on oral glucose tolerance test (OGTT) during 24– 28 weeks. Restricted cubic spline (RCS) was used to investigate the association between the pre-pregnancy Hb level and the risk of GDM. Univariate and multivariate logistic regression analyses were applied to evaluate the relative risk of GDM.Results: Of the 1289 included pregnant women, 187 (14.5%) women were diagnosed with GDM in this study. The pre-pregnancy Hb level was significantly associated with GDM risk, and the pre-pregnancy Hb level of 123 g/L was identified as the threshold to stratify and assess the association between the GDM risk and the pre-pregnancy BMI. For women with a pre-pregnancy Hb level ≥ 123 g/L, the pre-pregnancy BMI showed a significant association with GDM risk, and the estimated incidence rate of GDM was 7.7%, 14.8%, 36.3% and 44% for underweight, normal-weight, overweight and obese pregnant women, respectively. After adjusting for potential influencing factors of GDM, the respective relative risk was 1.0 (reference), 2.04 (95% CI 0.84, 4.99), 7.06 (2.66, 18.61), and 10.77 (2.85, 40.63) (P for trend < 0.001).Conclusion: In pregnant women with a pre-pregnancy Hb level ≥ 123 g/L, pre-pregnancy BMI showed a more significant association with GDM risk as compared with those with a pre-pregnancy Hb level < 123 g/L.Keywords: pregnancy, body mass index, hemoglobin, gestational diabetes mellitus, overweight, obese

Sun F, Wu K, Yao Z, et al. Onco Targets Ther. 2020;13:6755–6765. We, the Editors and Publisher of OncoTargets and Therapy, have retracted the following article. Since publication, concerns have been raised about the integrity of the data in the article. This includes the duplication of images from Figures 5 and 6. Specifically, The image for Figure 5C, NC, has overlap with the image for Figure 6D, NC. When approached for an explanation, the authors did not respond to our queries, nor did they provide original data for their study. As verifying the validity of the published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors were notified of this. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Siyan Liu,1 Jing Li,2 Lin Gu,3 Kunzhe Wu,2 Hua Xing1 1Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China; 3Breast Surgery, Jilin Province Tumor Hospital, Changchun, People’s Republic of ChinaCorrespondence: Hua Xing, Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Xian Tai Street, No. 126, Changchun, Jilin, 130033, People’s Republic of China, Tel +86 139 4412 7842, Email xingh@jlu.edu.cnAbstract: Triple-negative breast cancer (TNBC) exhibits high recurrence and mortality rates because of the lack of effective treatment targets. Surgery and traditional chemotherapy are the primary treatment options. Immunotherapy shows high potential for treating various cancers but exhibits limited efficacy against TNBC as a monotherapy. Chemoimmunotherapy has broad prospects for applications for cancer treatment conferred through the synergistic immunomodulatory and anti-tumor effects of chemotherapy and immunotherapeutic strategies. However, improving the efficacy of synergistic therapy and reducing the side effects of multiple drugs remain to be the main challenges in chemoimmunotherapy against TNBC. Nanocarriers can target both cancer and immune cells, promote drug accumulation, and show minimal toxicity, making them ideal delivery systems for chemotherapeutic and immunotherapeutic agents. In this review, we introduce the immunomodulatory effects of chemotherapy and combined mechanisms of chemoimmunotherapy, followed by a summary of nanoparticle-mediated chemoimmunotherapeutic strategies used for treating TNBC. This up-to-date synthesis of relevant findings in the field merits contemplation, while considering avenues of investigation to enable advances in the field.Keywords: chemotherapy, drug-delivery system, immunotherapy, mechanism, targeted delivery

Fan Zhang,1,&ast; Jiayu Liang,1 You Lu,2,&ast; Yongquan Tang,3 Shengzhuo Liu,1 Kan Wu,1 Fuxun Zhang,1 Yiping Lu,1 Zhihong Liu,1 Xianding Wang1 1Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Pediatrics, West China Second University Hospital, Chengdu, Sichuan University, Chengdu, 610041, People’s Republic of China; 3Department of Pediatric Urology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xianding Wang; Jiayu Liang, Email xiandingwang66@126.com; drliangjiayu@163.comBackground: Cathepsin Z (CTSZ) is a cathepsin family member that plays a dual role in the adhesion and migration of immune and tumor cells.Methods: The expression pattern of CTSZ in clear cell renal cell carcinoma (ccRCC) was observed by immunohistochemistry and validated by using double-labeling immunofluorescence. Publicly available single-cell sequencing data was used to further define the cell type-specific CTSZ expression in ccRCC. Methylation modification, immune infiltration, and tumor-related signaling enrichment analyses involving CTSZ were performed using multi-omics data. Data from two independent cohorts of anti-programmed death-1 (PD-1) therapeutic clinical trials were used to investigate correlations between CTSZ levels and treatment responses.Results: CTSZ was upregulated in ccRCC tissues compared with adjacent normal tissues at the RNA but not in ccRCC cells. Immunohistochemistry indicated that CTSZ was expressed in tumors infiltrated with lymphocytes. Double immunofluorescence demonstrated that CTSZ was co-expressed with CD68 but not CD8. Single-cell transcriptome data showed macrophage-specific expression of CTSZ in ccRCC. High CTSZ expression was significantly correlated with the enrichment of interferon-γ, epithelial‐to‐mesenchymal transition, cell cycle, apoptosis pathways, and B cell, macrophage, neutrophil, and dendritic cell infiltrations, as well as the expression of immune checkpoints CTLA4, LAG3, HAVCR2, PDCD1LG2, PDCD1, TIGIT, and SIGLEC15. Hypomethylation modification of cg02744249, cg02744249, and cg22145559 were negatively correlated with CTSZ expression, suggesting an epigenetic mechanism for the regulation of CTSZ expression. Clinically, CTSZ levels were associated with the prognosis of patients with ccRCC (hazard ratio=1.5, P=0.007). Notably, patients with higher CTSZ expression had a worse prognosis with anti-PD-1 monotherapy (hazard ratio=1.51, P=0.039).Conclusion: Macrophage-specific CTSZ was associated with activation of epithelial‐to‐mesenchymal transition, cell cycle signatures, and a higher infiltration level of B cells, macrophages, neutrophils, and dendritic cells in the tumor microenvironment. High expression of CTSZ could be considered as a prognostic and treatment response biomarker for patients with ccRCC receiving anti-PD-1 immunotherapy.Keywords: ccRCC, CTSZ, macrophage, single-cell, prognosis

Limin Yan1 &ast;, Dedong Xu2 &ast;, Ying Xiao,1 Mingming Dai,1 Ting Wang,1 Xinhong Zhuang,3 Kunliang Wu4 1Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China; 2Department of Neurosurgery, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China; 3Department of Nephrology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China; 4Department of Infectious Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinhong Zhuang, Department of Nephrology, The Second Affiliated Hospital of Hainan Medical University, No. 48, Baishuitang Road, Haikou, Hainan, 570311, People’s Republic of China, Tel +86-0890-66809015, Email zhuang_xinhong@163.com Kunliang Wu, Department of Infectious Diseases, The Second Affiliated Hospital of Hainan Medical University, No. 48, Baishuitang Road, Haikou, Hainan, 570311, People’s Republic of China, Tel +86-0890-66809015, Email kun4821583@163.comPurpose: NAD(P)H: Quinone Oxidoreductase 1 gene (NQO1) polymorphism is associated with the risk of cardiovascular disease. This study was designed to investigate the relationship between NQO1 gene polymorphism and ischemic stroke susceptibility in Chinese Han nationality.Patients and Methods: One hundred and forty-one patients diagnosed with ischemic stroke and 139 matched control groups were recruited in this study. The polymorphism distribution of rsl800566 locus and rs10517 locus of NQO1 gene was genotyped via TaqMan assay, and the concentration of Oxidized low-density lipoprotein (ox-LDL) in the blood of the subjects was detected by enzyme linked immunosorbent assay (ELISA). The relationship between the polymorphism distribution and the susceptibility to ischemic stroke was evaluated.Results: The frequency distribution of the three genotypes of NQO1 rs1800566 between the case group and the control group was statistically significant, and cases carrying CT and TT genotype were less likely to suffer from ischemic stroke. Compared with individuals carrying T allele, C allele carriers have higher risk of ischemic stroke. However, there was no significant difference in frequency distribution among the three genotypes of NQO1 rs10517 between controls and patients.Conclusion: The NQO1 rs1800566 C allele may be a novel marker associated with ischemic stroke susceptibility in Chinese Han population. Polymorphism of rsl800566 locus in NQO1 gene may be protective against ischemic stroke risk.Keywords: genetic polymorphism, ischemic stroke, NQO1, oxidized low-density lipoprotein

Jichan Shi,1,&ast; Gexin Gao,2,&ast; Zhijie Yu,3,&ast; Kaihuai Wu,4 Youquan Huang,5 Lian-Peng Wu,6 Zhengxing Wu,1 Xinchun Ye,1 Chaochao Qiu,1 Xiangao Jiang1 1Department of Infectious Disease, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 2Department of Nursing School, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 3Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 4Departments of Infectious Diseases, Taishun People’s Hospital, Wenzhou, 325000, People’s Republic of China; 5Departments of Infectious Diseases, Yongjia People’s Hospital, Wenzhou, 325000, People’s Republic of China; 6Department of Laboratory, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiangao Jiang, Department of Infectious Disease of Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, 252 Baili East Road, Lucheng District, Wenzhou, Zhejiang, 325000, People’s Republic of China, Tel +86 13587691822, Fax +86 577 88070007, Email jiang_xiangao@126.comBackground: Tuberculosis (TB) is still the single pathogen infectious disease with the largest number of deaths worldwide. The relationship that intestinal microbiota disorder and de novo fatty acid synthesis metabolism have with disease progression in multi-drug resistant TB (MDR-TB) has not yet been fully studied.Objective: To investigate the effects of long periods of MDR-TB, pre-extensively drug-resistant TB (pre-XDR-TB), or rifampicin-resistant TB (RR-TB) on gut microbiome dysbiosis and advanced disease.Methods: The sample was chosen between March 2019 and September 2019 in Wenzhou Central Hospital and comprised 11 patients with pre-XDR-TB, 23 patients with RR-TB, and 28 patients with MDR-TB. Healthy individuals were chosen as the control group (CK group). An overnight fast blood sample was drawn via venipuncture into tubes without anticoagulant. For analysis, 300 mg of faeces from patients from the same group was mixed and analysed using DNA extraction, NGS sequencing, and bioinformatics. A QIAamp Fecal DNA Mini Kit was used to isolate the DNA. The extracted DNA was stored at − 20°C.Results: Advanced TB was concurrent with an elevated level of the proportions of acetyl-CoA carboxylase (ACC1) to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and fatty acid synthase (FASN) to GAPDH in de novo fatty acids synthesis, and Eubacterium, Faecalibacterium, Roseburia, and Ruminococcus were increased significantly in RR-TB patients compared to healthy individuals, whereas their abundance in the pre-XDR-TB and MDR-TB groups showed little change in comparison with the control group. Proteobacteria levels were greatly increased in the RR-TB and MDR-TB patient groups but not in the patients with pre-XDR-TB or the healthy subjects. The pre-XDR-TB group exhibited alterations of the intestinal microbiome: coliform flora showed the highest abundance of Verrucomicrobiales, Enterobacteriales, Bifidobacteriales and Lactobacillales. De novo fatty acids synthesis was enhanced in patients and was associated with the gut microbiome dysbiosis induced by the antimicrobials, with Bacteroidetes, Bacteroidales, and Bacteroidaceae displaying the most important correlations on a phylum, order, and family level, respectively.Conclusion: The progression to advanced TB was observed to be a result of the interaction between multiple interrelated pathways, with gut–lung crosstalk potentially playing a role in patients with drug-resistant TB.Keywords: multi-drug resistant TB disease, gut commensal, microbial imbalance, de novo fatty acids synthesis, microbiome biosignature alterations

Chunkang Liu,1,&ast; Kunzhe Wu,2,&ast; Huan Gao,3 Jianyang Li,3 Xiaohua Xu3 1Department of Gastrointestinal Surgery, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China; 3Department of Nephrology, China-Japan Union Hospital of Jilin University, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohua Xu, Email xu_xh@jlu.edu.cnAbstract: Diabetic nephropathy (DN), a severe microvascular complication of diabetes mellitus (DM), is the most common form of chronic kidney disease (CKD) and a leading cause of renal failure in end-stage renal disease. No currently available treatment can achieve complete cure. Traditional treatments have many limitations, such as painful subcutaneous insulin injections, nephrotoxicity and hepatotoxicity with oral medication, and poor patient compliance with continual medication intake. Given the known drawbacks, recent research has suggested that nanoparticle-based drug delivery platforms as therapeutics may provide a promising strategy for treating debilitating diseases such as DN in the future. This administration method provides multiple advantages, such as delivering the loaded drug to the precise target of action and enabling early prevention of CKD progression. This article discusses the development of the main currently used nanoplatforms, such as liposomes, polymeric NPs, and inorganic NPs, as well as the prospects and drawbacks of nanoplatform application in the treatment of CKD.Keywords: diabetic nephropathy, DN, nanoplatform, route of administration

Yachen Ji,&ast; Xiangjun Xu,&ast; Kangfei Wu, Yi Sun, Hao Wang, Yapeng Guo, Ke Yang, Junfeng Xu, Qian Yang, Xianjun Huang, Zhiming Zhou Department of Neurology, The First Affiliated Hospital of Wannan Medical College, Wuhu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xianjun Huang; Zhiming Zhou, Department of Neurology, The First Affiliated Hospital of Wannan Medical College, 2# East Zheshan Road, Wuhu, 241000, People’s Republic of China, Tel +86-25-80860124, Fax +86-25-84664563, Email doctorhuangxj@hotmail.Com; neuro_depar@hotmail.ComPurpose: The systemic immune inflammatory index (SII), as a new marker, is widely used to predict the disease prognosis. We investigated the predictive value of SII for malignant cerebral edema (MCE) and whether postoperative MCE mediates the relationship between SII and functional prognosis in patients undergoing endovascular thrombectomy (EVT).Patients and Methods: A total of 829 patients with anterior circulation large-vessel occlusive stroke (LVOS) were registered, and 675 (81.4%) met the inclusion criteria. We collected baseline data upon admission, including SII. Postoperative computed tomography was performed to assess the presence and grading of cerebral edema (CED), and MCE was defined as a CED score of 3. A good prognosis was defined as a modified Rankin Scale (mRS) score of 0– 2 at the 90-day follow-up.Results: A total of 132 patients developed MCE after EVT. The patients were divided into MCE and non-MCE groups, and univariate and multifactorial analyses were performed. Among these risk factors, an elevated SII was independently correlated with the occurrence of MCE. In addition, the receiver operating characteristic (ROC) curve was used to assess the predictive capability of SII levels for prognosis. The area under the ROC was 0.69, and the optimal critical value was 2.14. In addition, postoperative MCE may partially account for the poorer functional prognosis of patients with elevated SII (regression coefficient changed by 40.3%).Conclusion: The SII is an independent predictor of malignant brain edema after EVT. Postoperative MCE is partly the reason for the poorer prognosis in patients with elevated SII.Keywords: acute ischemic stroke, endovascular treatment, systemic immune inflammatory index, malignant cerebral edema

Yinhui Pei, Xiaoling Chen, Yiwei Tan, Xiuping Liu, Fang Duan, Kaili Wu State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, People’s Republic of ChinaCorrespondence: Kaili Wu, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yan-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, People’s Republic of China, Email wukaili@mail.sysu.edu.cn Fang Duan, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yan-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, People’s Republic of China, Email duanfangg@126.comPurpose: This study aims to assess the testing methods used to detect fungal pathogens as well as the pathogenic profiles and drug susceptibility among fungal isolates from ocular sources collected in a tertiary eye hospital.Methods: The laboratory test records of patients with suspected ocular fungal infection from January 2010 to December 2019 at a tertiary eye care center in southern China were retrospectively evaluated. The isolated pathogens identified by smear examination and culture combined with microscopy were analyzed. For 2017– 2019 fungal isolates, their antifungal susceptibilities to four antifungal agents were evaluated.Results: A total of 22,233 specimens (16,315 for culture and 5918 for direct smear examination) from 16,209 individuals were assessed, and 3317 specimens (2169 for culture and 1148 for smear examination) from 2395 patients had confirmed fungal infection. The mean age of patients was 50.6± 14.2 years and 63.4% were male. The positive rate of smear examination was 19.4% and significantly higher than 13.3% of fungal culture (p< 0.001). Of 5812 patients who were simultaneously examined for culture and smear staining, 897 (15.43%) had positive findings for fungi. Among the 2420 positive findings, 2138 (88.3%) were from the cornea, and 133 (5.5%) were from intraocular samples. Fusarium spp. (40.5%) and Aspergillus spp. (22.0%) were the major fungal genera among the molds, whereas Candida spp. (4.6%) constituted the major yeast. Fusarium spp. had a lower antifungal susceptibility than Aspergillus spp. against voriconazole and amphotericin. And yeast spp. had the highest susceptibility to caspofungin.Conclusion: This study provided a 10-year assessment of fungi in ocular infections in southern China, giving support to epidemiological understanding and guiding empiric antimicrobial therapy.Keywords: fungal infection, eye, corneal scrape, fungal culture, keratomycosis, antifungal susceptibility, endophthalmitis

Ruhan Liu,1,2,&ast; Chenyang Li,1,&ast; Huajun Xu,1 Kejia Wu,1 Xinyi Li,1 Yupu Liu,1 Jie Yuan,1 Lili Meng,1 Jianyin Zou,1 Weijun Huang,1 Hongliang Yi,1 Bin Sheng,2 Jian Guan,1 Shankai Yin1 1Department of Otolaryngology Head and Neck Surgery and Shanghai Key Laboratory of Sleep Disordered Breathing & Otolaryngological Institute of Shanghai Jiao Tong University, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China; 2Department of Computer Science and Engineering, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Sheng; Jian Guan, Tel +86 13124853285, Email shengbin@sjtu.edu.cn; guanjian0606@sina.comPurpose: Misdiagnosis and missed diagnosis of sleep-disordered breathing (SDB) is common because polysomnography (PSG) is time-consuming, expensive, and uncomfortable. The use of recording methods based on the oxygen saturation (SpO2) signals detected by wearable devices is impractical and inaccurate for extracting signal features and detecting apnoeic events. We propose a method to automatically detect the apnoea-based SpO2 signal segments and compute the apnoea–hypopnea index (AHI) for SDB screening and grading.Patients and Methods: First, apnoea-related desaturation segments in raw SpO2 signals were detected; global features were extracted from whole night signals. Then, the SpO2 signal segments and global features were fed into a bi-directional long short-term memory convolutional neural network model to identify apnoea-related and non-apnoea-related events. The apnoea-related segments were used to assess the AHI.Results: The model was trained on 500 individuals and tested on 8131 individuals from two public hospitals and one private centre. In the testing data, the classification accuracy for apnoea-related segments was 84.3%. Individuals with SDB (AHI 15) were identified with a mean accuracy of 88.95%.Conclusion: Using automatic SDB detection based on SpO2 signals can accurately screen for SDB.Keywords: sleep apnea hypopnea syndrome, AHI, SDB severity classification, Bi-LSTM-CNN, desaturation events

Chen Wang,1,&ast; Chunyan Peng,2,&ast; Leping Ning,3,&ast; Xueping Qiu,1 Kaisong Wu,4 Na Yang,1 Bingyu Jin,1 Yue Zhao,1 Fang Zheng1 1Center for Gene Diagnosis, Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Laboratory Medicine, Taihe hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China; 3Department of Laboratory Medicine, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China; 4Department of Respiratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Zheng, Center for Gene Diagnosis & Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, People’s Republic of China, Tel +86-27-67813233, Fax +86 27 67813497, Email zhengfang@whu.edu.cnPurpose: SARS-CoV-2 is extremely infectious, and the incidence of nosocomial infection is conceivably high. We aimed to develop and validate a nomogram to assist monitoring nosocomial SARS-CoV-2 infection in hospitalized patients.Patients and Methods: There were 437 COVID-19 hospitalized cases and 420 negative inpatients enrolled from two hospitals in Hubei province, China. We compared the demographic and clinical characteristics of participants between the two groups. Then, LASSO regression and logistic regression were applied to build a nomogram for SARS-CoV-2 infection prediction in the development cohort. Our nomogram was assessed by area under the curve (AUC), calibration curve, decision curve (DCA) and clinical impact curve analysis (CICA).Results: After LASSO regression filtration, eleven laboratory indicators were correlated with SARS-CoV-2 infection. Then, we integrated these features and constructed a nomogram, which showed a high AUC 0.863 (95% CI: 0.834– 0.892) in the development cohort with a sensitivity of 80.41% and specificity of 77.38% and 0.813 (95% CI: 0.760– 0.866) in validation cohort with a sensitivity of 82.98% and specificity of 70.43%. The calibration plot displayed that the predicted outcomes were in good concordance with the actual observations. DCA and CICA further showed a larger clinical net benefit.Conclusion: We constructed and validated a nomogram that integrated eleven laboratory indexes to assist monitoring of nosocomial SARS-CoV-2 infection in hospitalized patients. Our nomogram is remarkably informative for clinical practice, which will be helpful for preventing SARS-CoV-2 further transmission in hospital and avoiding nosocomial infection.Graphical Abstract: Keywords: COVID-19, nomogram, nosocomial SARS-CoV-2 infection, machine learning

Zhi Yang,1– 3 Peng Duan,2 Weihong Li,2 Ronghui Nie,2,3 Xiaoyang Lou,2,4 Lina Wang,2 Kexia Wu,2 Jiang Liu,2 Ping Tu,2 Xiaoyang Lai1 1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330008, Jiangxi, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang, 330000, Jiangxi, People’s Republic of China; 3Jiangxi Medical College of Nanchang University, Nanchang, 330036, Jiangxi, People’s Republic of China; 4Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, Jiangxi, People’s Republic of ChinaCorrespondence: Xiaoyang Lai Tel +86 13607916298Email 1640852510@qq.comObjective: We investigated the relationship between thyroid hormones and the risk of diabetic kidney disease (DKD) progression.Methods: A total of 452 patients with type 2 diabetes were included, and a cross-sectional analysis was performed. Urine albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were used to diagnose persistent albuminuria and stage chronic kidney disease, respectively. The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline was used to describe the risk of DKD progression (low, moderate, and high or very high risks).Results: The DKD group had higher levels of thyroid-stimulating hormone (TSH) and lower levels of free triiodothyronine (FT3) and free thyroxine (FT4) than the non-DKD group. The prevalence of thyroid dysfunction in the DKD group was significantly higher than in the non-DKD group, especially the prevalence of subclinical hypothyroidism. FT3 levels decreased gradually with the deterioration of DKD. TSH levels increased with an increasing KDIGO category. FT3 and FT4 levels were negatively correlated with serum creatinine levels and ACR, and positively correlated with eGFR. Contrastingly, TSH was positively correlated with ACR, and negatively correlated with eGFR. After adjustment, an increase in FT3 levels significantly reduced the risk of DKD [odds ratio, OR (95% confidence interval, CI)=0.58 (0.42– 0.79)] and DKD progression [ORs (95% CIs)=0.65 (0.45– 0.93) for the moderate risk group and 0.50 (0.33– 0.74) for the high or very high-risk group, using the low-risk group as a reference]. FT3 levels below 4.30 pmol/L in men and 3.99 pmol/L in women were the cut-off points for an increased risk of DKD progression.Conclusion: Low FT3 level is an independent risk factor for DKD and DKD progression. FT3 ≤ 4.30 pmol/L in men and ≤ 3.99 pmol/L in women will greatly increase the risk of kidney disease progression in patients with type 2 diabetes.Keywords: thyroid hormone, prognosis of chronic kidney disease, type 2 diabetes mellitus