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Na Yang,1,2,* Yong-Bo Hou,2,3,* Tian-Hao Cui,2 Jun-Ma Yu,2 Shu-Fang He,4,5 Hai-Juan Zhu1 1Department of Anesthesiology, Maternal and Child Medical Center of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Anesthesiology, The Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, People’s Republic of China; 3Department of Anesthesiology, Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 4Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 5Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shu-Fang He; Hai-Juan Zhu, Email sfhe@ahmu.edu.cn; 35880762@qq.comBackground: Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism.Methods: Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI.Results: IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-β (TGF-β) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-β 1in MI rats.Conclusion: IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-β pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair. Keywords: ischemic preconditioning, myocardial infarction, Exosomes, MicroRNAs, cardiac function, myocardial fibrosis

Haiping Xie,1,* Xuexin Zhong,1,* Junlin Chen,2 Shuang Wang,1 Yuefang Huang,2 Niansheng Yang1 1Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China; 2Department of Pediatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Niansheng Yang, Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, 510080, People’s Republic of China, Tel +86-20-87755766 ext 8150, Email yangnsh@mail.sysu.edu.cnBackground: Interstitial lung disease (ILD), characterized by pulmonary fibrosis (PF), represents the end-stage of various ILDs. The immune system plays an important role in the pathogenesis of PF. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is an immune checkpoint with immune suppressive functions. However, its specific role in the development of PF and the underlying mechanisms remain to be elucidated.Methods: We assessed the expression of VISTA in CD4 T cells from patients with connective tissue disease-related interstitial lung disease (CTD-ILD). Spleen cells from wild-type (WT) or Vsir−/− mice were isolated and induced for cell differentiation in vitro. Additionally, primary lung fibroblasts were isolated and treated with interleukin-17A (IL-17A). Mice were challenged with bleomycin (BLM) following VISTA blockade or Vsir knockout. Moreover, WT or Vsir−/− CD4 T cells were transferred into Rag1−/− mice, which were then challenged with BLM.Results: VISTA expression was decreased in CD4 T cells from patients with CTD-ILD. Vsir deficiency augmented T-helper 17 (Th17) cell differentiation in vitro. Furthermore, IL-17A enhanced the production of inflammatory cytokines, as well as the differentiation and migration of lung fibroblasts. Both VISTA blockade and knockout of Vsir increased the percentage of IL-17A-producing Th17 cells and promoted BLM-induced PF. In addition, mice receiving Vsir−/− CD4 T cells exhibited a higher percentage of Th17 cells and more severe PF compared to those receiving WT CD4 T cells.Conclusion: These findings demonstrate the significant role of VISTA in modulating the development of PF by controlling Th17 cell differentiation. These insights suggest that targeting VISTA could be a promising therapeutic strategy for PF. Keywords: VISTA, lung fibrosis, Th17 cells, IL-17A, fibroblast

Ying Wang,1,* Yiyan Xu,2,* Jiayu Song,1 Xueting Liu,1 Sijia Liu,1 Nan Yang,1 Le Wang,1 Yujie Liu,1 Yiwei Zhao,1 Wenhu Zhou,3,4 Yunyan Zhang1 1Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, People’s Republic of China; 2Department of Vascular Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China; 3Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410013, People’s Republic of China; 4Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha, 410219, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunyan Zhang, Department of Gynecological Radiotherapy, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13604843878, Fax +86 451 85718392, Email zhangyunyan@hrbmu.edu.cn Wenhu Zhou, Xiangya School of Pharmaceutical Sciences, Central South University, 172 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel +86 15111469284, Fax +86 731 88710591, Email zhouwenhuyaoji@163.comPurpose: Phototherapy, known for its high selectivity, few side effects, strong controllability, and synergistic enhancement of combined treatments, is widely used in treating diseases like cervical cancer.Methods: In this study, hollow mesoporous manganese dioxide was used as a carrier to construct positively charged, poly(allylamine hydrochloride)–modified nanoparticles (NPs). The NP was efficiently loaded with the photosensitizer indocyanine green (ICG) via the addition of hydrogen phosphate ions to produce a counterion aggregation effect. HeLa cell membrane encapsulation was performed to achieve the final M-HMnO2@ICG NP. In this structure, the HMnO2 carrier responsively degrades to release ICG in the tumor microenvironment, self-generates O2 for sensitization to ICG-mediated photodynamic therapy (PDT), and consumes GSH to expand the oxidative stress therapeutic effect [chemodynamic therapy (CDT) + PDT]. The ICG accumulated in tumor tissues exerts a synergistic PDT/photothermal therapy (PTT) effect through single laser irradiation, improving efficiency and reducing side effects. The cell membrane encapsulation increases nanomedicine accumulation in tumor tissues and confers an immune evasion ability. In addition, high local temperatures induced by PTT can enhance CDT. These properties of the NP enable full achievement of PTT/PDT/CDT and targeted effects.Results: Mn2+ can serve as a magnetic resonance imaging agent to guide therapy, and ICG can be used for photothermal and fluorescence imaging. After its intravenous injection, M-HMnO2@ICG accumulated effectively at mouse tumor sites; the optimal timing of in-vivo laser treatment could be verified by near-infrared fluorescence, magnetic resonance, and photothermal imaging. The M-HMnO2@ICG NPs had the best antitumor effects among treatment groups under near-infrared light conditions, and showed good biocompatibility.Conclusion: In this study, we designed a nano-biomimetic delivery system that improves hypoxia, responds to the tumor microenvironment, and efficiently loads ICG. It provides a new economical and convenient strategy for synergistic phototherapy and CDT for cervical cancer.Keywords: phototherapy, reactive oxygen species, hypoxia relief, collaborative therapy

Rongyao Liang,1,* Pei Li,1,2,* Na Yang,1 Xiaoyi Xiao,1 Jing Gong,1 Xingyuan Zhang,1 Yunuan Bai,1 Yanlong Chen,1 Zhiyong Xie,3 Qiongfeng Liao1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People’s Republic of China; 2Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province, People’s Republic of China; 3School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiongfeng Liao, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China, Tel +86 2039358081, Email zyfxliao@gzucm.edu.cn Zhiyong Xie, School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, 510006, People’s Republic of China, Tel +86 075523260207, Email xiezhy@mail.sysu.edu.cnPurpose: Given the potent immunostimulatory effects of bacterial outer membrane vesicles (OMVs) and the significant anti-colon tumor properties of Parabacteroides distasonis (Pd), this study aimed to elucidate the role and potential mechanisms of Pd-derived OMVs (Pd-OMVs) against colon cancer.Methods: This study isolated and purified Pd-OMVs from Pd cultures and assessed their characteristics. The effects of Pd-OMVs on CT26 cell uptake, proliferation, and invasion were investigated in vitro. In vivo, a CT26 colon tumor model was used to investigate the anti-colon tumor effects and underlying mechanisms of Pd-OMVs. Finally, we evaluated the biosafety of Pd-OMVs.Results: Purified Pd-OMVs had a uniform cup-shaped structure with an average size of 165.5 nm and a zeta potential of approximately − 9.56 mV, and their proteins were associated with pathways related to immunity and apoptosis. In vitro experiments demonstrated that CT26 cells internalized the Pd-OMVs, resulting in a significant decrease in their proliferation and invasion abilities. Further in vivo studies confirmed the accumulation of Pd-OMVs in tumor tissues, which significantly inhibited the growth of colon tumors. Mechanistically, Pd-OMVs increased the expression of CXCL10, promoting infiltration of CD8+ T cells into tumor tissues and expression of pro-inflammatory factors TNF-α, IL-1β, and IL-6. Notably, Pd-OMVs demonstrated a high level of biosafety.Conclusion: This paper elucidates that Pd-OMVs can exert significant anti-colon tumor effects by upregulating the expression of the chemokine CXCL10, thereby increasing the infiltration of CD8+ T cells into tumors and enhancing antitumor immune responses. This suggests that Pd-OMVs may be developed as a novel nanoscale potent immunostimulant with great potential for application in tumor immunotherapy. As well as developed as a novel nano-delivery carrier for combination with other antitumor drugs. Keywords: Parabacteroides distasonis, outer membrane vesicles, colon tumor, CXCL10, CD8+ T cells

Kang Zhao,1,&ast; Hanfei Zhu,1,&ast; Lidong Huang,1,&ast; Ningli Yang,2 Saleh Mohammed Alhaj Othman,1 Wenbing Shi,1 Hongxia Hua,2 Hui Liang,2 Qin Xu1 1School of Nursing, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin Xu, School of Nursing, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, Jiangsu, 211166, People’s Republic of China, Tel +86 13601587208, Email qinxu@njmu.edu.cn Hui Liang, Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Gulou District, Nanjing, Jiangsu, 210029, People’s Republic of China, Tel +86 13951601358, Email lianghui@jsph.org.cnBackground: Diet and physical activity (PA) are pivotal behaviors for managing energy balance post-bariatric surgery. Given the need for dual behavioral management, understanding the interplay of cognitive factors influencing these behaviors is crucial. This study applied the compensatory carry-over action model (CCAM) to explore the impact of cognitive factors on behaviors and their subsequent effects on subjective health outcomes.Methods: This cross-sectional study was conducted among patients at the third month after bariatric surgery in China. Data on diet and PA status, behavioral cognitive factors (intention, self-efficacy, compensatory belief, transfer cognition), and subjective health outcomes (perceived stress, well-being, quality of life) were collected. Structural equation model (SEM) was employed to test hypotheses in CCAM and assess mediation relationships.Results: Analysis of data from 239 patients revealed the following: (1) Among antecedent cognitive factors, only compensatory belief significantly influenced diet (P< 0.001). (2) Intention and self-efficacy directly correlated with their respective behaviors, while compensatory belief affected intention, and transfer cognition impacted self-efficacy (P< 0.05), aligning with CCAM hypotheses. (3) PA demonstrated significant influence only on perceived stress (P=0.004), whereas diet significantly affected all subjective health outcomes (P< 0.05). (4) Mediation analysis indicated intention partially mediated the relationship between compensatory belief and diet and fully mediated the relationship between compensatory belief and PA. Self-efficacy completely mediated the relationship between transfer cognition and diet and PA.Conclusion: Transfer cognition’s carry-over effect did not directly influence behaviors among antecedent cognitions. Interventions should primarily target improving diet by mitigating compensatory belief. Moreover, diet exhibited a more pronounced impact on overall health compared to PA. Consequently, prioritizing dietary intervention over PA intervention is warranted based on the analysis of CCAM and the aim of promoting joint behaviors post-bariatric surgery.Keywords: bariatric surgery, compensatory carry-over action model, diet, physical activity, cognitive factors

Zhen-Zhen Wang,1– 3,&ast; Hang Li,4,&ast; Anish R Maskey,2,&ast; Kamal Srivastava,2,5,&ast; Changda Liu,6,&ast; Nan Yang,2,5 Taoyun Xie,7 Ziyi Fu,8 Junxiong Li,9 Xiaohong Liu,10 Hugh A Sampson,6 Xiu-Min Li2,11 1Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China; 2Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA; 3Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou, Henan, People’s Republic of China; 4Central Lab, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People’s Republic of China; 5General Nutraceutical Technology, Elmsford, NY, USA; 6Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 8The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 9Guangdong Province Hospital of Integrated Chinese and Western Medicine, Foshan, Guangdong, People’s Republic of China; 10Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 11Department of Otolaryngology, Westchester Medical Center New York Medical College, Valhalla, NY, USA&ast;These authors contributed equally to this workCorrespondence: Xiu-Min Li, Tel +1 914-594-4197, Email XiuMin_Li@NYMC.eduIntroduction: Neutrophil predominant airway inflammation is associated with severe and steroid-resistant asthma clusters. Previously, we reported efficacy of ASHMI, a three-herb TCM asthma formula in a steroid-resistant neutrophil-dominant murine asthma model and further identified Ganoderic Acid C1 (GAC1) as a key ASHMI active compound in vitro. The objective of this study is to investigate GAC1 effect on neutrophil-dominant, steroid-resistant asthma in a murine model.Methods: In this study, Balb/c mice were systematically sensitized with ragweed (RW) and alum and intranasally challenged with ragweed. Unsensitized/PBS challenged mice served as normal controls. Post sensitization, mice were given 4 weeks of oral treatment with GAC1 or acute dexamethasone (Dex) treatment at 48 hours prior to challenge. Pulmonary cytokines were measured by ELISA, and lung sections were processed for histology by H&E staining. Furthermore, GAC1 effect on MUC5AC expression and on reactive oxygen species (ROS) production in human lung epithelial cell line (NCI-H292) was determined by qRT-PCR and ROS assay kit, respectively. Computational analysis was applied to select potential targets of GAC1 in steroid-resistant neutrophil-dominant asthma. Molecular docking was performed to predict binding modes between GAC1 and Dex with TNF-α.Results: The result of the study showed that chronic GAC1 treatment, significantly reduced pulmonary inflammation (P < 0.01– 0.001 vs Sham) and airway neutrophilia (P < 0.01 vs Sham), inhibited TNF-α, IL-4 and IL-5 levels (P < 0.05– 0.001 vs Sham). Acute Dex treatment reduced eosinophilic inflammation and IL-4, IL-5 levels, but had no effect on neutrophilia and TNF-α production. GAC1 treated H292 cells showed decreased MUC5AC gene expression and production of ROS (P < 0.001 vs stimulated/untreated cells). Molecular docking results showed binding energy of complex GAC1-TNF was − 10.8 kcal/mol.Discussion: GAC1 may be a promising anti-asthma botanical drug for treatment of steroid-resistant asthma.Keywords: asthma, mouse model, neutrophilic inflammation, Ganoderma, ganoderic acid

Nongnong Yang,1,&ast; Haiyan Ma,1,2 Mengyi Huang,1,&ast; Esther Yuet Ying Lau,3– 5 Daniel Yee Tak Fong,6 Meng Wang,7 Pengqiao Wang,1 Siyi Xu,8 Jiale Xu,1 Chen Jiang,1 Yi Luo,9 Runtang Meng1,2,&ast; 1School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 2Engineering Research Center of Mobile Health Management System, Ministry of Education, Hangzhou, Zhejiang, People’s Republic of China; 3Sleep Laboratory, Department of Psychology, The Education University of Hong Kong, Hong Kong, People’s Republic of China; 4Centre for Psychosocial Health, The Education University of Hong Kong, Hong Kong, People’s Republic of China; 5Centre for Religious and Spirituality Education, The Education University of Hong Kong, Hong Kong, People’s Republic of China; 6School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People’s Republic of China; 7Ophthalmology Center, Ningbo Yinzhou No.2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 8School of Nursing, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 9School of Nursing, Ningbo College of Health Sciences, Ningbo, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Runtang Meng; Haiyan Ma, School of Public Health, Hangzhou Normal University, No. 2318, Yuhangtang Road, Yuhang District, Hangzhou, Zhejiang, 311121, People’s Republic of China, Email mengruntang@hznu.edu.cn; mahaiyan@hznu.edu.cnPurpose: The World Health Organization-Five Well-Being Index (WHO-5) is widely used to assess subjective well-being. Nevertheless, measurement invariance and optimal cutoff point of the WHO-5 have not been examined in Chinese samples. We aimed to assess measurement properties of the Chinese version of the WHO-5 (WHO-5-C) among healthcare students.Patients and Methods: A two-wave longitudinal assessment was conducted among 343 Chinese healthcare students from September to November 2022. Measurement properties of the WHO-5-C were assessed through structural validity using confirmatory factor analysis (CFA), measurement invariance using multigroup CFA (MGCFA) and longitudinal CFA (LCFA), convergent validity using correlation analysis with the Self-Rated Health Questionnaire (SRHQ) and Patient Health Questionnaire-4 (PHQ-4), reliability using internal consistency and test–retest reliability, and optimal cutoff point using receiver operating characteristic (ROC) analysis.Results: The WHO-5-C demonstrated satisfactory structural validity with comparative fit index (CFI) of 0.968 at baseline and 0.980 at follow-up, and adequate measurement invariance in different sociodemographic variables at baseline (gender, age, major, home location, being only child, monthly household income, part-time job, physical exercise, hobby, frequency of visiting home, and stress coping strategy) (CFI changes [ΔCFI] = − 0.009– 0.003) and over a week (ΔCFI = − 0.006– 0.000). The WHO-5-C also had good internal consistency (Cronbach’s α = 0.907– 0.934; McDonald’s ω = 0.908– 0.935) and test–retest reliability (intraclass correlation coefficient [ICC] = 0.803). Convergent validity was supported by moderate correlations of the WHO-5-C with the SRHQ and PHQ-4. The optimal cutoff point of the WHO-5-C was found to be 50, with an area under the ROC curve of 0.882 at baseline data, with sensitivity of 0.803 and specificity of 0.762 at follow-up.Conclusion: The WHO-5-C demonstrated adequate measurement properties, especially concerning cross-sectional and longitudinal measurement invariance, with a recommended optimal cutoff point of ≥ 50 for assessing adequate level of psychological well-being in healthcare students.Keywords: WHO-5 Well-Being Index, subjective well-being, measurement properties, diagnostic performance, observational longitudinal design, healthcare students

Ying Lan,1 Nan Yang,2 Yirong Wang,1 Yan Yang,1 Min Xu,1 Qin He1 1Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, the Third People’s Hospital of Chengdu, Chengdu, Sichuan, 610031, People’s Republic of China; 2West China School of Pharmacy, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Ying Lan, Email lanying0212@126.comPurpose: Tiotropium/olodaterol (TIO/OLO) fixed-dose combination (FDC) can improve lung function and quality of life for patients with chronic obstructive pulmonary disease (COPD), and is not inferior to other LAMA/LABAs. The aim of this study was to assess the cost-effectiveness of TIO/OLO FDC in patients with moderate to very severe COPD in China.Methods: A Markov model was developed to estimate the cost-effectiveness of TIO/OLO FDC versus TIO in the treatment of COPD from Chinese health system perspective. Four health states were based on 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021), which included moderate (GOLD II, 50% ≤ FEV1 ≤ 80% of predicted), severe (GOLD III, 30% ≤ FEV1 ≤ 50% of predicted) and very severe (GOLD IV, FEV1 > 30% of predicted) COPD and death. The model simulated in cycles yearly. The indicators of total costs, number of COPD exacerbations, life years (LYs) and quality-adjusted life-years (QALYs) were used as the model output. Costs and outcomes were discounted at a 5% annual rate. A cost-effectiveness analysis was conducted over a 10-year time horizon. The threshold of incremental total cost per unit effectiveness gained (ICER) was 1.5 times of GDP per capita. Uncertainty was assessed by one-way and probabilistic sensitivity analysis.Results: TIO/OLO was 0.007 QALYs more than TIO but 0.012 LYs lower, which increased the total cost by &dollar;2268.17 per patient, but the total exacerbations number was less. Incremental cost effectiveness analysis had shown that the ICER exceeded the willingness to pay threshold. Results were robust under most parameter variation, except the parameters of total drug cost of TIO/OLO FDC in univariate sensitivity analyses.Conclusion: Although TIO/OLO FDC could reduce the exacerbation risk, it was not cost-effective, and needed to be repriced.Keywords: tiotropium, olodaterol, cost-effectiveness, chronic obstructive pulmonary disease, COPD, Markov

Yongde Zhou,1,&ast; Xiaoxiao Wang,2,3,&ast; Zhengqian Li,2,4 Yu Ma,5 Cuiping Yu,1 Yao Chen,1 Jian Ding,1 Jianfeng Yu,1 Rongsong Zhou,5 Ning Yang,2,4 Taotao Liu,2,4 Xiangyang Guo,2,4 Ting Fan,1 Chengmei Shi2,4 1Department of Anesthesiology, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China; 2Department of Anesthesiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 3Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 4Beijing Center of Quality Control and Improvement on Clinical Anesthesia, Beijing, 100191, People’s Republic of China; 5Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengmei Shi, Department of Anesthesiology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China, Tel +86-13811592813, Email shichengmei@bjmu.edu.cn Ting Fan, Department of Anesthesiology, Tsinghua University Yuquan Hospital, Beijing, 100040, People’s Republic of China, Tel +86-13681100715, Email 13681100715@163.comBackground: A simple, rapid, and effective cognitive screening test appropriate for fast-paced settings with limited resources and staff is essential, especially preoperatively. This study aimed to develop and validate the short versions of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) for predicting postoperative delirium (POD) in patients with Parkinson’s disease (PD) who were scheduled for surgery.Methods: The current study was a secondary analysis of data collected from 128 inpatients scheduled for deep brain stimulation of the subthalamic nuclei (STN-DBS) lasting > 60 min, at Tsinghua University Yuquan Hospital, China. Preoperative cognitive screening was performed during the preoperative visit using the MMSE and MoCA. The optimal MMSE and MoCA cut-off scores for detecting PD-MCI was 27 and 23 respectively. The POD was assessed twice a day on the first postoperative day until discharge by the confusion assessment method. The backward conditional logistic regression analysis was used to organize the reduced versions of the MMSE or MoCA. Also, the areas under the receiver operating characteristic curves (AUCs) were examined using the DeLong test.Results: 125/128 PD patients were included in the analysis, and 27 (21.6%) developed POD. The MMSE reduced version (orientation to time, attention and calculation, and comprehension) demonstrated performance similar to the original MMSE in predicting POD (z=0.820, p=0.412). The AUC of the original MoCA and the short MoCA (visuospatial and executive attention and orientation) were 0.808 and 0.826, respectively. There was no significantly difference in the AUC values between the tests (z=0.561, p=0.575).Conclusion: Our simplified MMSE and MoCA could be efficiently used to identify patients at risk for POD. Also, short cognitive tests could be considered while predicting POD in fast-paced preoperative settings with limited resources and staff.Plain Language Summary: Routine preoperative cognitive screening is very important in predicting postoperative delirium.MMSE and MoCA are the most commonly used cognitive testing method which normally takes a long time.The short variant of MMSE and MoCA show a predictive performance similar to the original tests.Keywords: Parkinson’s disease, preoperative cognitive impairment, mini-mental state examination, Montreal Cognitive Assessment, postoperative delirium

Jingzhong Ouyang,1,&ast; Zhengzheng Wang,1,&ast; Kun Yuan,2,&ast; Yi Yang,3,4 Yanzhao Zhou,1 Qingjun Li,1 Nanmu Yang,1 Haitao Zhao,5 Hong Zhao,3,4 Jinxue Zhou1 1Department of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of China; 2School of Public Health, Capital Medical University, Beijing, People’s Republic of China; 3Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 4Key Laboratory of Gene Editing Screening and Research and Development (R&D) of Digestive System Tumor Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hong Zhao, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100020, People’s Republic of China, Email zhaohong@cicams.ac.cn Jinxue Zhou, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, 450003, People’s Republic of China, Email zhoujx888@126.comPurpose: To evaluate the efficacy and safety of lenvatinib plus programmed death-1 (PD-1) antibody as postoperative adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risks of recurrence.Patients and Methods: A series of 137 patients with HCC at high risks of recurrence who underwent hepatectomy at our hospital between October 2019 and January 2022 were retrospectively analyzed. Recurrence-free survival (RFS), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Landmark analysis was used to compare short- and long-term RFS. Univariable and multivariable analyses were used to identify prognostic factors, and subgroup analyses were performed according to high risks of recurrence.Results: A total of 85 patients underwent hepatectomy alone and 52 patients received postoperative adjuvant therapy. Compared with the hepatectomy group (HG), RFS was significantly improved in the adjuvant therapy group (ATG) (P < 0.001), but OS was not (P = 0.098). Landmark analysis revealed that RFS within 6 months of the HG was significantly different from that of the ATG (P < 0.001) but not after 6 months (P = 0.486). Multivariable analysis showed that without adjuvant therapy, high Child-Pugh classification, high alpha-fetoprotein levels, microvascular invasion, and satellite lesions were independent risk factors for recurrence within 6 months after hepatectomy. Subgroup analysis revealed that patients with MVI significantly benefited from adjuvant therapy in RFS. But for OS, adjuvant therapy was only significantly effective in patients with single tumor. The most common treatment-related adverse events during adjuvant therapy were hypertension (36.5%), rash or itching (28.8%), diarrhea (23.1%), and fatigue (21.2%).Conclusion: Postoperative adjuvant lenvatinib plus PD-1 antibody significantly improved RFS in patients with HCC at high risks of recurrence with acceptable safeties.Keywords: hepatocellular carcinoma, postoperative adjuvant therapy, lenvatinib, PD-1 antibody, efficacy, safety

Fei Song,1,2,&ast; Yan Wang,1,&ast; Xiao-ge Wei,1,2 Nan Yang,1 Wenjing Sun,1 Kaiying Li,1 Huisheng Ma,1,2 Jing Mu1 1College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Key Laboratory of Modernization of Minority Medicine, Ministry of Education, Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Mu; Huisheng Ma, Email mujing930@163.com; madoctor@163.comObjective: In this study, we analyzed the differential expression and key signaling pathways of proteins in the skin of guinea pigs with melanin deposition caused by two different modeling methods by utilizing proteomics techniques.Methods: Guinea pig skin melanin deposition models were: (1) induced by ultraviolet (UV) irradiation alone (U group), (2) induced by UV combined with progesterone injection (P group), and guinea pigs treated without any treatment were used as blank group (B group). H&E staining and Masson staining were used to observe the extent of skin damage and melanin deposition in guinea pigs. The differentially expressed proteins (DEPs) in the skin tissues of melanin-deposited guinea pigs were screened by proteomic techniques, the functions of DEPs were analyzed, and a protein-protein interaction network (PPI) was constructed.Results: There was a significant difference in grayscale between the U and P groups of guinea pig skin before and after modeling (P < 0.01). H&E and Masson staining showed that the U and P groups both exhibited incomplete keratinization of the stratum corneum, increased proliferation of epidermal cells with large nuclei and disordered arrangement, neovascularization of the dermis, and increased the number of melanin particles in the epidermis of the U and P groups of guinea pigs compared with the B group. Proteomics analysis showed that there were 171 DEPs between the U and P groups. These DEPs focused on biological processes such as fibrillar collagen trimer, extracellular matrix containing collagen proteins, metalloproteinase activity, and peroxidase activity.Conclusion: The melanin pigmentation model induced solely by UV radiation negatively regulates biological processes such as extracellular matrix and collagen synthesis, while inducing significant skin photoaging. The combination of progesterone injections and UV radiation-induced melanin pigmentation model can cause abnormal protein expression in fatty acid and phospholipid metabolism, possibly being closer to the environment of melasma formation.Keywords: melasma, skin melanin, melanin deposition, ultraviolet, progesterone

Xin Zhao,1,&ast; Pingyuan Ge,1,&ast; Shaohua Lei,1 Siqi Guo,1 Peng Zhou,1 Li Zhao,1 Yiyu Qi,1 Xiaotong Wei,2 Weizhen Wu,2 Ningjing Wang,2 Rui Guo,3 Nianyun Yang,1 Qingqing Xiao,1 Qichun Zhang,1,2 Huaxu Zhu1 1Department of Traditional Chinese Medicine Processing and Preparation, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 3School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qichun Zhang; Huaxu Zhu, Email zhangqichun@njucm.edu.cn; zhuhx@njucm.edu.cnIntroduction: Neuroinflammation is one of the major pathogeneses in Alzheimer’s disease (AD) and mainly involves abnormal inflammatory activation of microglia by multiple pathological stimuli. The treatment of AD remains a major challenge due to the multifactorial characterization of AD and the inefficient ability of therapeutic drugs to permeate through the blood‒brain barrier (BBB). Accordingly, drug combination treatment and drug carrier delivery have become important therapeutic tools for the treatment of multifactorial diseases, especially AD.Methods: Inflammatory cytokine levels in microglia, including NO, TNF-α, IL-1β, IL-4, and IL-10, were detected. The Morris water maze and object location task were used to investigate the learning and memory functions of APP/PS1 mice in different treatment groups. The number of neurons and plasticity of synapses were evaluated by immunofluorescence double labelling. Additionally, the ratio of β-amyloid plaques and the number of activated microglia were evaluated by immunofluorescence staining. The concentrations of β-amyloid plaques and inflammatory factors in the hippocampus were determined by ELISA. Microglia-derived exosomes (Exos) were extracted and purified by size exclusion chromatography. The distribution of exosomes and drugs was investigated in vitro and in vivo.Results: Compared to single drug interventions, the combination of Ber and Pal (Ber/Pal) modulated microglial inflammatory cytokine levels. Ber/Pal promoted the recovery of learning and memory impairment in APP/PS1 mice. Immunofluorescence staining indicated that Ber/Pal restored neurons, inhibited Aβ plaque formation and microglial activation, and regulated the secretion of inflammatory factors. Exos promoted the accumulation of drugs in cells and tissues and improved the targeting of drugs across the BBB.Conclusion: Ber/Pal could offer a synergistic and more comprehensive therapeutic effect in AD. Additionally, the microglia-derived Exos-Ber/Pal delivery system promoted the targeting and permeation of drugs into the brain, suggesting a creative strategy for targeting AD therapy by regulating neuroinflammation in microglial cells.Keywords: Alzheimer’s disease, neuroinflammation, phytoconstituents, drug combination, BBB permeability, exosomes

Na Yang,1,&ast; Qing-Yu Tao,1,&ast; Jing-Yi Niu,1 Hao Sun,1 Yan He,1,2 Yong-Bo Hou,1,2 Hong Luo,1 Zhi Zhang,3 Jun-Ma Yu1 1Department of Anesthesiology, the Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), Hefei, Anhui, People’s Republic of China; 2Department of Anesthesiology, Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 3Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhi Zhang; Jun-Ma Yu, Email zhizhang@ustc.edu.cn; majuny163@163.comPurpose: This study was conducted to explore whether incisional infiltration using a local anesthetic injection kit could better relieve postoperative pain and enhance the quality of recovery compared with ultrasound-guided rectus sheath block (RSB) or conventional local anesthetic infiltration in patients undergoing transumbilical single-incision laparoscopic cholecystectomy (SILC).Patients and Methods: A total of 60 patients undergoing SILC with American Society of Anesthesiology functional status scores of I-II were randomized into the rectus sheath block group (RSB group), conventional local wound infiltration group (LAI-I group) and incisional infiltration using a local anesthetic injection kit group (LAI-II group). The primary outcomes were the patient-controlled intravenous analgesia (PCIA) demand frequency within 48 hours after the operation and postoperative pain measured by a visual analog scale (VAS) at 2 h, 4 h, 8 h, 24 h, and 48 h after surgery. Secondary outcomes were the total procedure times, cumulative consumption of anesthetic drugs, duration of surgery, duration and awaking time of anesthesia, early recovery indicator and side effects.Results: The PCIA demand frequency in LAI-II group was significantly lower compared with patients in the RSB and LAI-I group (both P < 0.001). Moreover, the total procedure times in LAI-I and LAI-II group was significantly shorter than that in the RSB group (P < 0.001, respectively), but it was comparable between LAI-I and LAI-II group (P = 0.471). Though lower at 2h and 4h postoperative in LAI-II group, pain scores at each time point had no statistical differences among three groups. There were no significant differences among three groups for other outcomes as well.Conclusion: The effect of ultrasound-guided RSB and conventional local anesthetic infiltration in SILC patients were found to be similar in terms of relieving postoperative pain and promoting recovery. Incisional infiltration using a local anesthetic injection kit can significantly reduce the demand frequency of PCIA, which serves as a rescue analgesic.Keywords: laparoscopic cholecystectomy, rectus sheath block, local infiltration analgesia, recovery, pain

Min Wang,1,2,&ast; Na Yang,1,2,&ast; Xu Wu,3 Ting Zou,3 Jiahui Zheng,3 Huaijun Zhu,1 Chongbo Zhao,3 Jing Wang3 1Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 2China Pharmaceutical University Nanjing Drum Tower Hospital, Nanjing, People’s Republic of China; 3College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chongbo Zhao; Jing Wang, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, People’s Republic of China, Email 2051077@sntcm.edu.cn; wangjing19890126@126.comBackground: Arisaematis Rhizome (AR) has been used as a damp-drying, phlegm-resolving, wind-expelling, pain-alleviating, and swelling-relieving drug for thousands of years. However, the toxicity limits its clinical applications. Therefore, AR is usually processed (Paozhi in Chinese) prior to clinical use. In this study, the integration of ultra-high performance liquid chromatography-quadrupole/ time-of-flight mass spectrometry-based metabolomics and network analysis was adopted to investigate the metabolic shifts induced by AR and explore the processing mechanism.Materials and Methods: Extracts of crude and processed AR products (1g/kg) were intragastrically administered to rats once daily for four consecutive weeks. The renal function was evaluated by blood urea nitrogen, creatinine, interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), super oxide dismutase (SOD), the ratio of glutathione/glutathione disulfide (GSH/GSSH), glutathione peroxidase (GSH-Px) and histopathological examination. Furthermore, the chemical composition of AR was clarified by ultra-high performance liquid chromatography-quadrupole/ time-of-flight mass spectrometry, after which the integration of metabolomics and network analysis was adopted to investigate the metabolic shifts induced by AR and explore the processing mechanism.Results: Crude AR caused renal damage by stimulating inflammation and oxidative stress, as confirmed by the increased production of IL-1β, TNF-α and MDA, and decreased levels of SOD, GSH/GSSH and GSH-Px. Processing with ginger juice, alumen and bile juice alleviated the damage to kidney. Metabolomics results showed that a total of 35 potential biomarkers enriched in amino acid metabolism, glycerophospholipid metabolism, fatty acid-related pathways, etc. were deduced to be responsible for the nephrotoxicity of AR and the toxicity-reducing effect of processing.Conclusion: This work provided theoretical and data support for the in-depth study of the processing mechanism, showing that processing reduces AR nephrotoxicity through multiple metabolic pathways.Graphical Abstract: Keywords: Arisaematis rhizome, nephrotoxicity, processing, UPLC-Q/TOF-MS, metabolomics

Yushan Liu,1,2 Gezhi Zheng,1,3 Jing Li,1,3 Nan Yang,1– 4 Juan Li,1,2 Zhengwen Liu,1– 4 Qunying Han,1– 4 Yingren Zhao,1– 4 Fenjing Du,1,3 Yingli He,1,&ast; Taotao Yan1,&ast; 1Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Institution of Hepatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Clinical Research Center for Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 4Shaanxi Clinical Research Center for Infectious Diseases, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingli He; Taotao Yan, Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta Road(w), Xi’an, Shaanxi, People’s Republic of China, Tel +86 189-9123-2863 ; +86 186-9148-5175, Email heyingli2000@xjtu.edu.cn; yantaotao_sweet@163.comAbstract: Anthrax is caused by Bacillus anthracis. Humans are mainly infected through contact with the fur and meat of livestock. The cutaneous form is the most common form. The skin lesions of typical cutaneous anthrax are characterized by shallow ulcers with black crusts, surrounded by small blisters and nonpitting edema of nearby tissues. Metagenomic next-generation sequencing (mNGS) is a new pathogenic detection method which is rapid and unbiased. We reported the first case of cutaneous anthrax diagnosed by mNGS. Ultimately, the man received prompt antibiotic therapy and had a good prognosis. In conclusion, mNGS is proved to be a good method for etiological diagnosis, especially for rare infectious diseases.Keywords: cutaneous anthrax, metagenomic next-generation sequencing, mNGS, case report, etiology diagnosis

Bing Chen,1,&ast; Di Liu,2,&ast; Tao Li,1 Lijiang Zheng,1 Ling Lan,1 Niu Yang,1 Yinlan Huang1,3 1Ningxia Medical University, Yinchuan, People’s Republic of China; 2Traditional Chinese Medicine Orthopedics and Traumatology Department, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 3Key Laboratory of Ningxia Ethnomedicine Modernization, Ministry of Education, Ningxia Medical University, Yinchuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yinlan Huang, Ningxia Medical University, No. 1160, Shengli Street, Xingqing District, Yinchuan, People’s Republic of China, Tel +86 18209506917, Email lzdbe@163.comPurpose: We here explored the research status, research hotspots, and development trend of acupuncture against inflammation from both quantitative and qualitative aspects through bibliometrics.Methods: We used CiteSpace and VOSviewer to analyze the literature about acupuncture against inflammation from 2011 to 2021 in the Web of Science Core Collection database by using a visual knowledge map.Results: In total, 1479 articles were included, and the number of articles published each year exhibited an upward trend. The largest number of articles were published in China (661), followed by the United States (287) and South Korea (164). The most productive institution is Beijing University of Chinese Medicine (72), while the most influential institution is the Capital Medical University (0.28). Evidence-based Complementary and Alternative Medicine (131) is the journal that published most articles on the topic. Lin Yiwen is the most prolific author, and Borovikova L is the most influential co-cited author. The keywords that have burst in the last 2 years are inflammation and activation. The keywords with the highest frequency of use are electroacupuncture (EA), inflammation, and expression.Conclusion: The number of publications on acupuncture for anti-inflammation research is rapidly increasing. China is a productive country, but the influence of centrality is poor. Research institutions are concentrated in universities, and the whole collaborative network needs to be strengthened. The anti-inflammatory mechanism of acupuncture is the main focus of research in this field. Regulation of immune cell balance by acupuncture may be a hot topic in mechanism research. At present, immune cells, vagus nerve, signal pathway, inflammatory corpuscles, cytokines and neurotransmitters are popular research topics. In the future, the basic research of acupuncture for anti-inflammation transformed into clinical practice may be a trend. EA and bee venom acupuncture may be promising research directions for acupuncture treatment for inflammatory diseases.Keywords: acupuncture, anti-inflammation, bibliometric analysis, CiteSpace, VOSviewer

Jia Kang,1,&ast; Guangqi Li,1,&ast; Miao Ma,2 Min Lan,3 Yuting Kang,4 Ningai Yang,4 Wei Jia,1,4 Zhijun Zhao1,4 1Medical Experimental Center, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 2Clinical Laboratory Center, Shaanxi Provincial People’s Hospital, Xi’an, People’s Republic of China; 3School of Clinical Medicine, Ningxia Medical University, Yinchuan, People’s Republic of China; 4Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Jia; Zhijun Zhao, Medical Experimental Center, General Hospital of Ningxia Medical University, Yinchuan, 750001, People’s Republic of China, Tel +86 951-6743543, Email Jiawei220803@163.com; zhaozhijun@nxmu.edu.comPurpose: Carbapenem-resistant Klebsiella pneumoniae (CR-KP) has emerged as an important public health threat. Intestinal colonization with CR-KP increases the risk of infection and death, especially in intensive care unit patients. To clarify the source of colonizing bacteria is very important to prevent the spread of CR-KP, so the purpose of this study was to explore the relationship between the ward environment and intestinal colonization of CR-KP.Methods: In this study, 353 environmental swabs from ICU (Intensive Care Unit) wards and 241 anal swab samples from ICU patients were collected and screened on MacConkey plates containing 2 μg/mL ertapenem, and the origin and genotype of CR-KP were analyzed by PCR and sequencing. The sequence type of the strains was also obtained by multi-locus sequence type (MLST) analysis, and plasmid conjugation test was used to clarify whether CR-KP can promote the transmission of drug resistance genes through plasmid integration and rearrangement.Results: A total of 20 CR-KP environmental strains and 7 intestinal strains were obtained, most of which were blaOXA-48 resistant genotypes. Four different STs were identified by multi-locus sequence type (MLST) analysis, among which the large logarithm was ST485 type, and PFGE clustering showed that the similarity between them was > 85%. In the plasmid transcoupling assay, we report that one of the Klebsiella pneumoniae drug-resistant plasmids was successfully transferred to E. coli, indicating that it may promote the spread of drug-resistant genes through plasmid integration and rearrangement.Conclusion: Our research suggests that the environment may be a potential source of CR-KP and that there is a need for us to adopt more effective disinfection measures.Keywords: carbapenem-resistant Klebsiella, intestinal, colonization, environment, ICU, homology

Lili Chen,1 Junling Zhang,2 Na Yang,1 Ningping Tan,1 Di Meng,1 Fei Zhang,1 Yuyang Qi,1 Guangqi Wu,1 Zhenyu Li3 1Department of Hematology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, People’s Republic of China; 2The Medical Department, 3D Medicines Inc., Shanghai, People’s Republic of China; 3Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Zhenyu Li, Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, People’s Republic of China, Email lizhenyumd@163.com Guangqi Wu, Department of Hematology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, 223800, People’s Republic of China, Email wgqjssq@163.comBackground: Chronic myeloid leukaemia (CML) is a clonal malignant disorder of a pluripotent hematopoetic stem cell characterized by the presence of Philadelphia (Ph) chromosome in more than 90% of patients. However, about 5– 10% of CML patients show a variant Ph translocation, involving one or more chromosomes in addition to 9 and 22. The treatment and prognostic impact of such additional abnormalities is not known. Herein, we report a unique case of a three-way translocation variant in CML and responded to flumatinib.Case Presentation: A 22-year-old Asian female who presented with leukocytosis was diagnosed with CML. Cytogenetic karyotyping analysis showed 46,XX,t(6;9;22)(p21.3;q34;q11.2). She was treated with flumatinib, and MR5.0 (BCR-ABL1 IS≤ 0.001%, international scale) was achieved after three months of continuous treatment.Conclusion: This was the 5th case of t(6;9;22), in particular, a new variant Ph translocation, and the first successful case treated with flumatinib in the world.Keywords: t(6;9;22)(p21.3;q34;q11.2), CML, Philadelphia chromosome, flumatinib, case report

Ming Hu,1,&ast; Pan Ding,1,&ast; Jinfang Ma,2 Nan Yang,1 Jinping Zheng,2 Naitong Zhou1 1West China School of Pharmacy Sichuan University, Chengdu, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Naitong Zhou, West China School of Pharmacy Sichuan University, No. 17, 3rd Section, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel +86-13881962880, Fax +86-28-85501387, Email zhou-2316@163.com Jinping Zheng, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, 510120, People’s Republic of China, Tel +86 20 8306 2869, Fax +86 20 8306 2729, Email jpzhenggy@163.comIntroduction: Traditional Chinese medicine (TCM) is becoming increasingly important as it provides further options for treating many diseases worldwide. The TCM “Yupingfeng” has been used in China for over 800 years, and its clinical efficacy and safety for COPD treatment have been proven in previous studies. The objective of this study was to compare the long-term cost-effectiveness of Yupingfeng granules and the current conventional treatment for COPD patients in China.Methods: A Markov model was constructed from the perspective of the Chinese healthcare system using TreeAge Pro 2011. The model cycle length was 12 months, and the cycle time was set to 10 years. Data from a randomized controlled trial were used to generate the number of acute exacerbations, COPD assessment test (CAT) score and actual medication used. The state transition probabilities, costs and quality-adjusted life years (QALYs) were derived from available sources. A threshold of 72,447 yuan per QALY gained was used as a cost-effectiveness criterion. One-way and probabilistic sensitivity analyses were conducted to verify the model. In addition, the cost-effectiveness of a 35-year cycle was evaluated as a scenario analysis.Results: In the basic-case analysis, the ICER of adding Yupingfeng granules to the current conventional treatment drugs was ¥ 2123.04 per QALY, which was less than the threshold (one-time per capita GDP).Sensitivity analyses showed the results to be robust. Probabilistic sensitivity analysis showed that the probability of the ICER being less than the one-time per capita GDP threshold was 100%. In the scenario analysis, the incremental cost-effectiveness was ¥ 12,051.27 per QALY which was also under the one-time per capita GDP.Conclusion: By reducing the number of acute exacerbations of COPD, thereby correspondingly reducing the follow-up treatment cost, Yupingfeng granules combined with conventional treatment were found to provide a cost-effective therapeutic strategy for COPD.Keywords: Yupingfeng granule, traditional Chinese medicine, COPD, Markov model, cost-effectiveness analysis

Chunlong Li,1 Yuexia Liu,2 Ning Yang,3 Zhihong Lan,4 Shumei Huang,3 Yunfan Wu,3 Xiaofen Ma,3 Guihua Jiang3 1Department of Medical Imaging, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’ s Republic of China; 2Department of Ultrasound, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’ s Republic of China; 3Department of Medical Imaging, Guangdong Second Provincial General Hospital, Guangzhou, People’s Republic of China; 4Department of Medical Imaging, Zhuhai City People’s Hospital, Zhuhai, People’s Republic of ChinaCorrespondence: Guihua Jiang; Xiaofen Ma, Email GH.jiang2002@163.com; xiaofenma12@163.comIntroduction: In recent years, people have gained a profound understanding of chronic insomnia disorder (CID), but the pathophysiological mechanism of CID is still unclear. There is some evidence that the locus coeruleus (LC) is involved in the regulation of wakefulness in CID, but there have been few studies using brain functional imaging. The purpose of this study was to evaluate the resting-state functional connectivity (FC) between the LC and other brain voxels in CID and whether these abnormal FC are involved in the regulation of wakefulness.Methods: A total of 49 patients with chronic insomnia disorder and 47 healthy controls (HC) matched for gender, age, and education were examined with rs-fMRI in this study. The LC was selected as the region of interest, and then seed-based analysis was conducted on the LC and other voxels to obtain the brain regions with abnormal FC. The correlation between the FC value of the abnormal connection area and the clinical scale score was analyzed.Results: Compared with the HC, the FC between the LC and right precuneus, right posterior cingulate cortex, left middle temporal gyrus, left calcarine, and right superior orbitofrontal cortex was significantly enhanced (p < 0.05, FDR correction), and the functional connectivity signal value between the locus coeruleus and left middle temporal gyrus was positively correlated with the Self-Rating Depression Scale (p = 0.021).Conclusion: The abnormal FC between the LC and multiple brain regions may contribute to a better understanding of the neurobiological mechanism of CID.Keywords: chronic insomnia disorder, default mode network, functional connectivity, locus coeruleus, seed-based analysis

Shu-Jie Pang,1,&ast; Zhe Sun,1,&ast; Wen-Feng Lu,1,&ast; Hui Si-Ma,1 Zhi-Peng Lin,2 Yang Shi,1 Ying-Cheng Yang,1 Xi-Jun Zhao,1 Guang-Shun Yang,1 Guang-Zhi Jin,3 Ning Yang1 1Department V of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People’s Republic of China; 2Department of Hepatobiliary Surgery, The 940th Hospital of CPLA Joint Logistics Support Force, Lanzhou, 730050, People’s Republic of China; 3Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Yang, Department V of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People’s Republic of China, Tel +86 21 81877591, Fax +86 21 6556 6851, Email lancet00@163.com Guang-Zhi Jin, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, People’s Republic of China, Email jgzhi@hotmail.comBackground: RBM10ʹs function in hepatocellular carcinoma (HCC) has rarely been addressed. We intend to explore the prognostic significance and therapeutic meaning of RBM10 in HCC in this study.Methods: Multiple common databases were integrated to analyze the expression status and prognostic meaning of RBM10 in HCC. The relationship between RBM10 mRNA level and clinical features was also assessed. Multiple enrichment analyses of the differentially expressed genes between RBM10 high- and low- transcription groups were constructed by using R software (version 4.0.2). A Search Tool for Retrieval of Interacting Genes database was used to construct the protein–protein interaction network between RBM10 and other proteins. A tumor immune estimation resource database was employed to identify the relationship between RBM10 expression and immune cell infiltrates. The prognostic value of RBM10 expression was validated in our HCC cohort by immunohistochemistry test.Results: The transcription of RBM10 mRNA was positively correlated with tumor histologic grade (p < 0.001), T classification (p < 0.001), and tumor stage (p < 0.001). High transcription of RBM10 in HCC predicted a dismal overall survival (p = 0.0037) and recurrence-free survival (p < 0.001). Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis all revealed that RBM10 was involved in the regulation of cell cycle, DNA replication, and immune-related pathways. Tumor immune estimation analysis revealed that RBM10 transcription was positively related to multiple immune cell infiltrates and the expressions of PD-1 and PD-L1.Conclusion: RBM10 was demonstrated to be a dismal prognostic factor and a potential biomarker for immune therapy in HCC in that it may be involved in the immune-related signaling pathways.Keywords: RBM10, hepatocellular carcinoma, prognosis, differentially expressed gene, integrated bioinformatics analysis

Ying Lan,1 Nan Yang,2 Yirong Wang,1 Yujie Yang,1 Min Xu,1 Qin He1 1Department of Pharmacy, The Third People’s Hospital of Chengdu, Chengdu, People’s Republic of China; 2West China School of Pharmacy, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Ying Lan, Email lanying0212@126.comBackground: Fixed dose dual bronchodilators such as long-acting muscarinic antagonists (LAMAs) plus long-acting β 2-agonists (LABAs) are a new and important inhaled preparation for COPD treatment in China. Among these, umeclidinium/vilanterol (UMEC/VIL) is increasingly being used in China, especially among the elderly.Purpose: This study aimed to assess the cost-effectiveness of maintenance treatment with UMEC/VIL compared with salmeterol/fluticasone (FSC) as one of the main therapeutic drugs for moderate to very severe COPD in China.Methods: A Markov model was developed to estimate the costs and outcomes from a societal perspective in a 10-year time horizon. Patients with moderate-to-very severe COPD were treated with UMEC/VIL (62.5/25μg) or FSC (50/500ug). Data concerning clinical efficacy, costs, utilities, transition probability, exacerbation rate, and mortality were obtained from the published literature and official government datasets. The costs were presented in US dollars based on 2021 prices. The indicators of total costs, life years (LYs), quality-adjusted life-years (QALYs), and mortality were used as the model output. Costs and outcomes were discounted at a 5% annual rate. Incremental cost-effectiveness ratios were calculated considering the threshold recommended by WHO. One-way and probabilistic sensitivity analyses were conducted to assess the stability of results.Results: Compared with FSC, treatment with UMEC/VIL could save $1947.18, with a gain of 0.12 life-years and 0.05 QALYs. Further, 28.0% patients treated with UMEC/VIL and 29.2% patients treated with FSC were predicted to die after 10 years. Incremental cost effectiveness analysis showed that UMEC/VIL was dominant to FSC. Sensitivity analyses confirmed that the results were robust.Conclusion: UMEC/VIL is a cost-effective treatment option compared with FSC among patients with moderate-to-very severe COPD.Keywords: umeclidinium, vilanterol, salmeterol, fluticasone, cost-effectiveness, COPD, Markov

Yiyu Qi,1 Saijia Ni,2 Xia Heng,1 Shuyue Qu,1 Pingyuan Ge,1 Xin Zhao,1 Zengying Yao,2 Rui Guo,3 Nianyun Yang,1 Qichun Zhang,2 Huaxu Zhu1 1Department of Traditional Chinese Medicine Processing and Preparation, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 2Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 3Department of Physiological, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Qichun Zhang; Huaxu Zhu, Email zhangqichun@njucm.edu.cn; zhuhx@njucm.edu.cnBackground: Serious mental illness is a disease with complex etiological factors that requires multiple interventions within a holistic disease system. With heat-clearing and detoxifying effects, Coptis chinensis Franch. is mainly used to treat serious mental illness.Aim of the Study: To explore the underlying mechanisms and therapeutic effect by which Coptis chinensis Franch. treats serious mental illnesses at a holistic level.Methods: A viable network pharmacology approach was adopted to obtain the potential active ingredients of Coptis chinensis Franch., and serious mental illnesses-related targets and signaling pathways. The interactions between crucial target HTR2A and constituents were verified by molecular docking, and the dynamic behaviors of binding were studied by molecular dynamics simulation. In addition, the anti-anxiety effect of Rhizoma Coptidis (the roots of Coptis chinensis Franch.) extract on lipopolysaccharide-stimulated mice was verified. The anxiety-like behavior was measured through the elevated plus-maze test, light–dark box test, and open field test. Radioimmunoassays detected the levels of interleukin-1β, tumor necrosis factor-α, interleukin-10, interleukin-4, 5-hydroxytryptamine, and dopamine in the serum, hippocampus, medial prefrontal cortex, and amygdala. Meanwhile, immunohistochemistry protocols for the assessment of neuronal loss (neuron-specific nuclear protein) and synaptic alterations (Synapsin I) were performed in the hippocampus.Results: Based on scientific analysis of the established networks, serious mental illnesses-related targets mostly participated in the calcium signaling pathway, cyclic adenosine monophosphate signaling pathway, mitogen-activated protein kinase signaling pathway, serotonergic and dopaminergic synapse. Molecular docking and molecular dynamics simulation studies illustrated that berberine, epiberberine, palmatine, and coptisine presented favorable binding patterns with HTR2A. The in vivo experiments confirmed that Rhizoma Coptidis extract ameliorated anxiety-like behaviors by improving the survival of neurons, regulating synaptic plasticity, and inhibiting neuroinflammation.Conclusion: These findings in the present study led to potential preventative and therapeutic strategies for serious mental illnesses with traditional Chinese medicine.Graphical Abstract: Keywords: Coptis chinensis Franch, serious mental illness, multitarget, network pharmacology, molecular mechanism

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

Alei Feng,1,2 Ning Yang,1 Ruoying Yu,3 Jingwen Liu,3 Jiaohui Pang,3 Xue Wu,3 Yang Shao,3,4 Zhe Yang,1 Honghai Dai1 1Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 2Shandong Qidu Pharmaceutical Co. Ltd., Shandong Provincial Key Laboratory of Neuroprotective Drugs, Zibo, 255400, People’s Republic of China; 3Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, People’s Republic of China; 4School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Honghai Dai; Zhe YangTumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of ChinaEmail dhhcp@163.com; sdslyyyz@sina.comBackground: Esophageal cancer (EC), especially esophageal squamous cell carcinoma, remained as one of the most aggressive tumors in China with a five-year survival rate of around 40%. Molecular characteristics through next-generation sequencing are becoming an emerging method in identifying prognostic biomarkers for better treatment management for EC patients.Methods: Targeted next-generation sequencing using a 422-gene pan-cancer panel was performed with tumor tissue samples from a total of 69 Asian non-surgical esophageal carcinoma patients (AEC) treated with chemoradiotherapy. A TCGA cohort of 143 EC patients and another Asian ESCC cohort of 47 patients were employed for validation.Results: In the AEC cohort, alterations in TP53 (94.2%) and NOTCH1 (55.1%) were the two most frequently observed alterations, whereas in the TCGA cohort, only TP53 alterations were observed at a high ratio (85.3%). Co-amplifications of FGF19 and CCND1 were found at a similar ratio in both cohorts. Multiple alterations in the DNA damage pathway were identified but not associated with overall survival in AEC. Using univariate and multivariate Cox regression analyses, six gene alterations including YAP1 amplification, RB1 alteration, BAP1 mutation, MYC amplification, WRN mutation, and BRIP1 mutation were identified as adverse prognostic factors in the AEC cohort. A Cox proportional hazard model based on the six prognosis-related genes was constructed and showed the ability in distinguishing EC patients with poorer disease outcomes in AEC and two validation cohorts.Conclusion: Six gene alterations were found to be potential unfavorable prognostic markers that might provide guidance in the treatment management for EC patients.Keywords: esophageal cancer, YAP1, RB1, BAP1, MYC, BRIP1, WRN, overall survival, chemoradiotherapy

Fuchao Liang,1,2,&ast; Yueqing Tang,1,3,&ast; Kaipeng Bi,1,2 Xuchen Liu,2 Chao Li,4,5 Si Chen,6 Chao Zhang,4,5 Lei Yan,1 Zhonghua Xu,1 Ning Yang4,5,7 1Department of Urology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Andrology, Shandong University, Jinan, People’s Republic of China; 4Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, People’s Republic of China; 5Shandong Key Laboratory of Brain Function Remodeling, Jinan, 250012, People’s Republic of China; 6Department of Neurology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 7Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, 250012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning YangDepartment of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, People’s Republic of ChinaTel/Fax +86 531-82166631Email yangning@sdu.edu.cnZhonghua XuDepartment of Urology, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaTel/Fax +86 531-82166701Email xuzhonghua1963@163.comPurpose: This study aimed to investigate the characteristics of urodynamics in female parkinsonian patients with lower urinary tract symptoms (LUTS) and evaluate the outcomes of deep brain stimulation (DBS) based on overactive bladder (OAB) scores and quality of life (QOL) scores.Patients and Methods: Urodynamic assessment was performed in 20 female parkinsonian patients with LUTS. OAB scores and QOL scores were collected before and 6 months after DBS treatment (The target of DBS is STN). We evaluated the related factors affecting QOL score and also the changes in QOL score after DBS treatment.Results: The mean age of 20 patients was 60.6± 6.3 years, with 65% of patients identified with OAB in urodynamic studies. The mean OAB total score and QOL score at baseline were 7.3± 3.7 and 5.0± 1.1, respectively. Four items in the OAB score were found to be independent factors and they influenced the baseline QOL scores. Six months after DBS treatment, the OAB total score and the QOL score were significantly decreased (3.7± 3.2 (p = 0.002) and 3.4± 1.4 (p < 0.001), respectively). Improvements in OAB item 2 (nocturia) and item 3 (urgency) scores were found to be independent factors, which had an influence on the improvement in QOL scores from multivariate analysis. Improvement of OAB item 2 (nocturia) exhibited the greatest influence on improvement in the QOL score. After DBS treatment, 40% of the patients showed significant improvement in urination symptoms (≥ 2 points reduction in QOL score), 30% of the patients showed mild improvement (1 point reduction in QOL score), and 30% patients showed no improvement (no change in QOL score). No patients exhibited worsening urination symptoms.Conclusion: Most parkinsonian female patients with lower urinary tract symptoms were diagnosed with OAB. DBS treatment improved OAB symptoms. Improvement of nocturia and urgency positively impacts the QOL of female parkinsonian patients.Keywords: Parkinson’s disease, urodynamics, OAB score, QOL score

Hanfei Zhu,1,&ast; Ziqi Ren,2,&ast; Hongxia Hua,3 Kang Zhao,1 Lingyu Ding,1 Shuqin Zhu,1 Ningli Yang,3 Hui Liang,3 Qin Xu1 1School of Nursing, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2School of Nursing, Fudan University, Shanghai, People’s Republic of China; 3Department of Bariatric and Metabolic Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin XuSchool of Nursing, Nanjing Medical University, 818 Tianyuan East Road, Jiangning District, Nanjing, Jiangsu, 210029, People’s Republic of ChinaTel +86-25-86869553; +86-13601587208Fax +86-25-86869555Email qinxu@njmu.edu.cnPurpose: This study was aimed to develop a questionnaire to assess the determinants of dietary adherence among patients after bariatric surgery based on the attitude-social influence-efficacy (ASE) model and to evaluate its psychometric properties.Patients and Methods: According to semi-structured interview, Delphi expert consultation and pilot study, the initial questionnaire was formed and applied to investigate 319 patients after bariatric surgery in a tertiary hospital in Jiangsu Province, China. The reliability and validity of the scale were tested.Results: The 28-item of the attitude-social influence-efficacy questionnaire after bariatric surgery (ASEQBS) was formed. The results of exploratory factor analysis showed that four factors, including intention, attitude, social influence, and self-efficacy, could be extracted, and the cumulative variance contribution rate reached 59.98%. Confirmatory factor analysis showed the model fit well. The content validity index of each item was 0.800– 1.000, and the content validity index of the ASEQBS was 0.857. The total Cronbach’s α of the ASEQBS was 0.920, the split-half reliability was 0.774, and the retest reliability was 0.922.Conclusion: The results suggest that ASEQBS is a valid and reliable measure of determinants of dietary adherence. It may be useful to evaluate the influence factors of dietary adherence and helpful to evaluate the efficacy of tailored dietary intervention programs.Keywords: bariatric surgery, dietary adherence, attitude-social influence-efficacy model, questionnaire, validation

Kang Zhao,1 Xinyi Xu,1,2 Hanfei Zhu,1 Ziqi Ren,3 Tianzi Zhang,4 Ningli Yang,5 Shuqin Zhu,1 Qin Xu1 1School of Nursing, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Faculty of Health, The Queensland University of Technology, Brisbane, Queensland, Australia; 3School of Nursing, Fudan University, Shanghai, People’s Republic of China; 4Department of Nursing, Jiangsu College of Nursing, Huai’an, Jiangsu, People’s Republic of China; 5Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Qin Xu; Shuqin Zhu Tel +86 13601587208; +86 13851946413Email qinxu@njmu.edu.cn; zsq@njmu.edu.cnBackground: The weight loss in Chinese patients after sleeve gastrectomy is different, and the differences can be evaluated through the trajectories of the percentage of body fat (BF%). Patients’ baseline psychosocial factors may be associated with these trajectories.Materials and Methods: We selected 267 patients who received sleeve gastrectomy for the first time. The BF% at baseline and 1, 3, 6, 12 months after surgery and baseline psychosocial variables were retrospectively collected. The trajectory model was established according to BF% based on the growth mixture model. The baseline psychosocial variables were compared among different trajectory classes.Results: Four types of trajectory classes were obtained. The differences in preoperative dietary self-efficacy, exercise self-efficacy, depression, social support, working status, alcohol consumption, and gender among the classes were statistically significant. The pairwise comparison of the above variables revealed that the differences of gender, dietary self-efficacy and exercise self-efficacy among classes were highly effective.Conclusion: Female gender, low dietary self-efficacy and low exercise self-efficacy were predictors for poor BF% trajectory in sleeve gastrectomy patients. Health professionals can early identify patients who are most likely to lose weight in a not-ideal manner based on the above predictors.Keywords: bariatric surgery, body fat, psychosocial aspects, sleeve gastrectomy, trajectory

Hui Zhang,1 Yunzhu Zhu,1 Ning Yang,1 Qinxiang Kong,2 Yahong Zheng,1 Na Lv,1 Haoran Chen,1 Chengcheng Yue,1 Yanyan Liu,1,3,4 Jiabin Li,1– 4 Ying Ye1 1Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Infectious Diseases, The Chaohu Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, People’s Republic of China; 4Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Ying Ye; Jiabin LiDepartment of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Jixi Road no. 218, Hefei, Anhui, People’s Republic of ChinaTel +86-551-62922713Fax +86-551-62922281Email yeying2@139.com; lijiabin@ahmu.edu.cnPurpose: To study the in vitro and in vivo antibacterial activities of polymyxin B (PB) and other five antimicrobial agents, including imipenem (IMP), meropenem (MEM), tigecycline (TGC), sulbactam (SUL), and rifampicin (RIF), alone or in combination against carbapenem-resistant Acinetobacter baumannii (CRAB).Methods: Microbroth dilution method was used to determine the minimum inhibitory concentration (MIC) of ten strains of CRAB against six antibacterial drugs, and the checkerboard method was used to determine the fractional inhibitory concentration index (FICI). A mouse pneumonia model was established by intranasal instillation of Ab5075 to evaluate the antibacterial activity in vivo.Results: The resistance rate of ten CRAB strains to IMP, MEM, and SUL was 100%, that to PB and TGC was 0%, and that to RIF was 20%. When PB was used in combination with the other five antibiotics in vitro, it mainly showed synergistic and additive effects on CRAB. The synergistic effect of PB and RIF was maximal, followed by MEM and IMP but was weak with SUL and TGC. In vivo, compared to the model group (untreated with antibiotics), treatment group (six antibiotics alone and PB combined with the other five antibiotics) reduced the bacterial load in the lung tissue and the serum inflammatory factors (IL-1β, IL-6, and TNF-α). The bacterial load and the inflammatory factors of the combined group decreased significantly than that of the single group (P< 0.05). The IL-6 and TNF-α values of the PB combined with the RIF group were significantly lower than the two drugs used individually.Conclusion: The combination of PB and IMP, MEM, and RIF exerted robust in vitro synergistic effects on CRAB isolates. The combination of PB and the other five antimicrobial agents had a better effect in the mouse pneumonia model than single agent, while the combination of PB and RIF had the best effect.Keywords: Acinetobacter baumannii, carbapenem-resistant, pneumonia infection model, polymyxin B, combination treatment

Maoti Wei,1,&ast; Li Dong,2,&ast; Fenghua Wang,1 Kai Cui,3 Delong Ma,2 Ning Yang,4 Yuming Li4 1Center of Clinical Epidemiology, TEDA International Cardiovascular Hospital, Tianjin, People’s Republic of China; 2Department of Pediatrics, Center Hospital of Beikuo Town, Rizhao City, Shandong Province, People’s Republic of China; 3Department of Disease Prevention and Control, Hospital of Gaoxing Town, Rizhao City, Shandong Province, People’s Republic of China; 4Department of Hypertension, TEDA International Cardiovascular Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Yang; Yuming Li Email yangningzxdl@sina.com; cardiolab@live.comObjective: To understand the prevalence and control of type 2 diabetes mellitus (T2DM) in a rural area, a cross-sectional study was carried out.Methods: Blood glucose was determined in residents over 60 years during the National Basic Public Health Service project carrying on in a rural town of Shandong province. Combined with detail information of diabetic history, the prevalence rate of this disease was calculated with a cutoff of more than 7.0 mmol/L of fasting plasma glucose (FPG). Furthermore, according to FPG levels, the control rate of diabetes was evaluated. Basic information and clinical laboratory tests were analyzed with proper methods for univariate analysis. Multivariable logistic analysis was used to explore multiple variables associated with the control effect of T2DM.Results: The prevalence rate of T2DM was 13.5% (95% CI 12.4%∼ 14.7%) without age difference in residents over 60-year old (X2= 1.078, P = 0.898). And the rate was higher in the female (16.1%, 95% CI 14.4%∼ 17.8%) than that in the male (11.3%, 95% CI 9.7%∼ 12.9%). The control rate of diabetes was 44.5% (95% CI 39.4– 49.6%, cutoff < 6.1 mmol/L for FPG) and 59.6% (95% CI 54.5– 64.6%, cutoff < 7.0 mmol/L for FPG), respectively. Most T2DM residents had balance foods, and a high proportion of drugs or insulin were used; however, the proportion of keeping exercise and modifying behaviors was low. Nearly 80% of the diabetic individuals used at least one drug or insulin. However, the more drugs or insulin used, the higher the FPG level was.Conclusion: A relative high level of T2DM prevailed in the rural area under fast economy-transforming. T2DM was controlled poor and measures should be further optimized to achieve ideal effect, especially for the use of anti-diabetic drugs.Keywords: rural area, type 2 diabetes mellitus, the control of diabetes

Wei Wang, Ni Yang, Yu-Hang Yang, Ri Wen, Chun-Feng Liu, Tie-Ning Zhang Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of ChinaCorrespondence: Chun-Feng Liu; Tie-Ning ZhangDepartment of Pediatrics, Shengjing Hospital of China Medical University, No. 36 SanHao Street, Shenyang City, Liaoning Province, 110004, People’s Republic of ChinaTel +86-18940251826; +86-18940253339Email zhliu258@hotmail.com; cmuztn@vip.qq.comAbstract: Emerging data indicates that non-coding RNAs (ncRNAs) represent more than just “junk sequences” of the genome and have been found to be involved in multiple diseases by regulating various biological process, including the activation of inflammasomes. As an important aspect of innate immunity, inflammasomes are large immune multiprotein complexes that tightly regulate the production of pro-inflammatory cytokines and mediate pyroptosis; the activation of the inflammasomes is a vital biological process in inflammatory diseases. Recent studies have emphasized the function of ncRNAs in the fine control of inflammasomes activation either by directly targeting components of the inflammasomes or by controlling the activity of various factors that control the activation of inflammasomes; consequently, ncRNAs may represent potential therapeutic targets for inflammatory diseases. Understanding the precise role of ncRNAs in controlling the activation of inflammasomes will help us to design targeted therapies for multiple inflammatory diseases. In this review, we summarize the regulatory role and therapeutic potential of ncRNAs in the activation of inflammasomes by focusing on a range of inflammatory diseases, including microbial infection, sterile inflammatory diseases, and fibrosis-related diseases. Our goal is to provide new ideas and perspectives for future research.Keywords: ncRNAs, inflammasomes, infection, immune, inflammation, fibrosis

Ningning Yang,1,2 Hongchun Chen,1,2 Yuchen Huang,1,2 Xuexue Song,3 Panpan Yang,4 Shan Zhang,5 Wentian Yan,1,2 Nan Li,1,2 Zhenzhong Feng1,2 1Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, People’s Republic of China; 2Department of Pathology, Bengbu Medical College, Bengbu, 233000, People’s Republic of China; 3Department of Pathology, First Affiliated Hospital of University of Science and Technology of China, Hefei, 230000, People’s Republic of China; 4Department of Pathology, Second Affiliated Hospital of Anhui Medical University, Hefei, 230000, People’s Republic of China; 5Department of Pathology, Second People’s Hospital of Hefei, Hefei, 230000, People’s Republic of ChinaCorrespondence: Zhenzhong Feng; Nan LiDepartment of Pathology, First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Bengbu, Anhui Province, People’s Republic of ChinaTel +86 15055289508Email fzz18297301626@163.com; linanangel100@sina.comPurpose: As a non-classical ligand of Wnt, the abnormal regulation of Wnt5a contributes to the progression of malignant tumors; however, its effects differ depending on tumor type. Here, we evaluated the expression and significance of Wnt5a in endometrioid adenocarcinoma and its relationship with epithelial–mesenchymal transition (EMT)-related proteins.Patients and Methods: Immunohistochemical streptavidin-peroxidase method and reverse transcription polymerase chain reaction (RT-PCR) method were used to analyze the expression and correlation of Wnt5a, and EMT-related protein β-catenin, E-cadherin and enhancer of zeste homolog 2 (EZH2) in endometrial cancer tissues and cell samples of each group.Results: The expression of Wnt5a and E-cadherin decreased in the following order, normal endometrium > atypical hyperplasia endometrium > endometrioid adenocarcinoma. In contrast, the expression of β-catenin and EZH2 increased gradually. Moreover, Wnt5a expression was associated with the degree of tissue differentiation, International Federation of Gynecology and Obstetrics (FIGO) stage, and lymph node metastasis (all P< 0.05). Wnt5a expression was also negatively correlated with β-catenin and EZH2 expression and positively correlated with E-cadherin expression. RT-PCR results further indicated that E-cadherin mRNA expression was upregulated in a Wnt5a-overexpressing Ishikawa cell line compared to cells transfected with an empty vector or negative control cells (P< 0.01). Furthermore, the expression of EZH2 and β-catenin mRNA was downregulated in overexpressing cells compared to empty vector and negative control cells (P< 0.01).Conclusion: Wnt5a may elicit a suppressive effect on endometrioid adenocarcinoma by inhibiting EMT. This study provides a theoretical basis for the pathological diagnosis and targeted therapy of endometrioid adenocarcinoma and extends our understanding of the Wnt5a signaling pathway.Keywords: endometrioid adenocarcinoma, Wnt5a, epithelial–mesenchymal transition, immunohistochemistry

Shanze Li,* Yuming Wang,* Chunyan Li, Na Yang, Hongxin Yu, Wenjie Zhou, Siyu Chen, Shenshen Yang, Yubo Li Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shenshen Yang; Yubo LiTianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, West Zone, Tuanbo New City, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel +86-22-5959-6223Fax +86-22-5959-6223Email shine2099@163.com; yaowufenxi001@sina.comBackground: Rhubarb, as a traditional Chinese medicine, is the preferred drug for the treatment of stagnation and constipation in clinical practice. It has been reported that rhubarb possesses hepatotoxicity, but its mechanism in vivo is still unclear.Methods: In this study, the chemical components in rhubarb were identified based on UPLC-Q-TOF/MS combined with data postprocessing technology. The metabolic biomarkers obtained through metabolomics technology were related to rhubarb-induced hepatotoxicity. Furthermore, the potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology involving the above components and metabolites. Meanwhile, GO gene enrichment analysis and KEGG pathway analysis were performed on the common targets.Results: Twenty-eight components in rhubarb were identified based on UPLC-Q-TOF/MS, and 242 targets related to rhubarb ingredients were predicted. Nine metabolic biomarkers obtained through metabolomics technology were closely related to rhubarb-induced hepatotoxicity, and 282 targets of metabolites were predicted. Among them, the levels of 4 metabolites, namely dynorphin B (10– 13), cervonoyl ethanolamide, lysoPE (18:2), and 3-hydroxyphenyl 2-hydroxybenzoate, significantly increased, while the levels of 5 metabolites, namely dopamine, biopterin, choline, coenzyme Q9 and P1, P4-bis (5ʹ-uridyl) tetraphosphate significantly decreased. In addition, 166 potential targets of rhubarb-induced hepatotoxicity were obtained by network pharmacology. The KEGG pathway analysis was performed on the common targets to obtain 46 associated signaling pathways.Conclusion: These data suggested that rhubarb may cause liver toxicity due to its action on dopamine D1 receptor (DRD1), dopamine D2 receptor (DRD2), phosphodiesterase 4B (PDE4B), vanilloid receptor (TRPV1); transient receptor potential cation channel subfamily M member 8 (TRPM8), prostanoid EP2 receptor (PTGER2), acetylcholinesterase (ACHE), muscarinic acetylcholine receptor M3 (CHRM3) through the cAMP signaling pathway, cholinergic synapses, and inflammatory mediators to regulate TRP channels. Metabolomics technology and network pharmacology were integrated to explore rhubarb hepatotoxicity to promote the reasonable clinical application of rhubarb.Keywords: rhubarb, hepatotoxicity, metabolomics, network pharmacology

Xiang Li, Nan Yang, Qi Cheng, Han Zhang, Fen Liu, Yunxiao Shang Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of ChinaCorrespondence: Yunxiao ShangDepartment of Pediatrics Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People’s Republic of ChinaEmail shangpangbo035@163.comBackground: Asthma is usually associated with airway inflammation and airway remodeling. Epithelial mesenchymal transition (EMT) often occurs in airway remodeling. The purpose of this study is to identify the effect of miR-21-5p and Smad7 signaling pathway in macrophage-derived exosomes on EMT of airway epithelial cells.Methods: HE staining and Masson staining were used to verify the successful establishment of the asthma model. The levels of epithelial cell adhesion factor and stromal cell markers were detected by Western blot. The levels of miR-21-5p were detected by qRT-PCR. The expression of miR-21-5p in lung tissue was further verified by fluorescence in situ hybridization (FISH). Exosome morphology was observed by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Luciferase reporter assay was applied to analyze the interaction of miR-21-5p with Smad7.Results: The expression of miR-21-5p was upregulated in macrophages of rats in vivo with OVA-induced asthma. In vitro cultured alveolar macrophages stimulated by LPS could secrete exosomes with high levels of miR-21-5p. The exosome-derived miR-21-5p promotes EMT in rat tracheal epithelial cells through TGFβ 1/Smad signaling pathway by downregulating Smad7. This process can be blocked by miR-21-5p inhibitor.Conclusion: Rat alveolar macrophages produced high levels of miR-21-5p-containing exosomes, which transported miR-21-5p to tracheal epithelial cells, thus promoting EMT through TGF-β 1/Smad signaling pathway by targeting Smad7.Keywords: asthma, exosomes, miRNA, miR-21-5p, Smad7, epithelial mesenchymal transition

Yueping Chen,1,* Junli Ren,2,3,* Naiping Yang,2,3,* Honghao Huang,2,3 Xueting Hu,2,3 Fangyue Sun,2,3 Tian Zeng,2,3 Xinbo Zhou,2,3 Wenjing Pan,2,3 Jingyu Hu,2,3 Beibei Gao,4 Shunkai Zhang,2 Guangyong Chen2 1Clinical Laboratory, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Internal Medicine, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China*These authors contributed equally to this work.Correspondence: Shunkai Zhang; Guangyong ChenDepartment of Neurology, The Third Affiliated Hospital of Wenzhou Medical University, No. 108 Wansong Road, Wenzhou, 325000, Zhejiang, People’s Republic of ChinaEmail shunkaizhang@126.com; gychen6@126.comBackground: Eosinophil and monocyte have been demonstrated separately to be independent predictors of acute ischemic stroke (AIS). This study aimed to evaluate the association between eosinophil-to-monocyte ratio (EMR) and 3-month clinical outcome after treatment with recombinant tissue plasminogen activator (rt-PA) for AIS patients. Simultaneously, we made a simple comparison with other prognostic indicators, such as 24h neutrophil-to-lymphocyte ratio (NLR) and 24h platelet-to-lymphocyte ratio (PLR) to investigate the prognostic value of EMR.Methods and Results: A total of 280 AIS patients receiving intravenous thrombolysis were retrospectively recruited for this study. Complete blood count evaluations for EMR were conducted on 24 hours admission. The poor outcome at 3-month was defined as the modified Rankin Scale (mRS) of 3– 6 and the mRS score for death was 6. The EMR levels in patients with AIS were lower than those in the healthy controls and showed a negative correlation with the NIHSS score. At the 3-month follow-up, multivariate logistic regression analysis indicated an association among EMR, poor outcome and mortality. In addition, EMR had a higher predictive ability than popular biomarkers like NLR and PLR for 3-month mortality.Conclusion: The lower levels of EMR were independently associated with poor outcome and dead status in AIS patients.Keywords: acute ischemic stroke, eosinophil-to-monocyte ratio, intravenous thrombolysis, treatment outcome, modified rankin scale

Hongchun Chen,1,2 Yuchen Huang,1,2 Ningning Yang,1,2 Wentian Yan,1,2 Ruxue Yang,3 Shan Zhang,4 Panpan Yang,5 Nan Li,1,2 Zhenzhong Feng1,2 1Department of Pathology, Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 2Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 3Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of China; 4Department of Pathology, Second People’s Hospital of Hefei, Hefei, Anhui Province, 230000, People’s Republic of China; 5Department of Pathology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of ChinaCorrespondence: Zhenzhong FengDepartment of Pathology, First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Longzihu District, Bengbu, Anhui, 233000, People’s Republic of ChinaTel +86 1 505 528 9508Email fzz18297301626@163.comPurpose: Solid-pseudopapillary neoplasm (SPN) of the pancreas, a rare tumor, has low malignant potential. However, some patients develop metastasis and recurrence after resection, with aggressive biological behaviors. This study aimed to explore the features and risk factors associated with the aggressive biological behaviors of SPNs.Patients and Methods: We retrospectively analyzed the clinicopathological and long-term follow-up data of 63 patients diagnosed with SPN at the First Affiliated Hospital of Bengbu Medical College between January 2007 and February 2019.Results: Sixty-three patients presented atypical clinical symptoms. The median tumor size was 7.0 cm (range, 2.4– 17 cm), and imaging features were solid and cystic or solid tumors with uneven density. Frequent and diffuse nuclear LEF1 protein expression (94.2%) was observed with LEF1 having a higher sensitivity and specificity. Overall survival significantly correlated with tumor size, Ki-67 index, and lymph node metastasis (P < 0.05).Conclusion: SPN is a rare low-grade malignancy with a specific pseudopapillary structure. LEF1 is an effective biomarker of SPNs. Although SPNs generally display indolent biological behavior, a large tumor size, high proliferation index, and lymph node metastasis may be risk factors for the aggressive behavior and poor prognosis of SPN.Keywords: pancreatic tumor, LEF1, retrospective study, overall survival, metastasis

Xue Lv,1 Kun Fang,2 Wenqing Hao,1 Yuxin Han,1 Nailong Yang,1 Qing Yu1 1Department of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Division of Health Management Center, Qingdao Municipal Hospital, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Nailong YangDepartment of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao University of Medicine, No. 1677, Wutai Mountain Road, Huangdao District, Qingdao, Shandong 266555, People’s Republic of ChinaTel +86 18661806185Email nailongy@163.comQing YuDepartment of Endocrinology and Metabolism, Affiliated Hospital of Qingdao University, Qingdao University of Medicine, No. 1677, Wutai Mountain Road, Huangdao District, Qingdao, Shandong 266555, People’s Republic of ChinaEmail yuqing121985@126.comPurpose: To identify the population susceptible to reactive hypoglycemia and explain the possible reasons for their susceptibility.Methods: Ninety-four patients were divided into normal weight, overweight and obese groups before a 75-gram prolonged oral glucose tolerance test (POGTT). The incidence of reactive hypoglycemia (blood glucose ≤ 3.1 mmol/L or 55 mg/dL at points of 0– 4 hours) was compared among three groups, and blood glucose and insulin levels were monitored simultaneously from 0 - 4 hours to assess the level of insulin resistance and insulin sensitivity. Furthermore, the degree of insulin resistance among three groups and within each subgroup (whether hypoglycemia events occurred) was compared.Results: Among the three groups, the incidence of hypoglycemia was significantly different at 3 (P=0.033) and 4 hours (P=0.020). At 4 hours, the incidence of reactive hypoglycemia in the obese group was approximately 3 times that in the normal weight group. The insulin level in obese group at 4 hours was nearly 4 times higher than that in normal group, and the same result also exists in the same subgroup of different groups. In addition, the hypoglycemia subgroup of obese group had higher insulin level than non-hypoglycemia (P=0.000). The homeostasis model assessment of insulin resistance index increased with increasing BMI among the three groups (P=0.000), while the Matsuda index decreased (P=0.000). The comparison of the homeostasis model assessment of insulin resistance index between subgroups in each group showed that the P values were 0.021, 0.038 and 0.085, successively, and the P values for the Matsuda index were 0.019, 0.013 and 0.119, respectively.Conclusion: Obese people has higher rate of reactive hypoglycemia than other groups in POGTT, in which insulin resistance may play an important role. But patients who are evaluated for reactive hypoglycemia need to be observed for at least 3 or 4 hours.Keywords: reactive hypoglycemia, prolonged oral glucose tolerance test, insulin resistance, low-carb ketogenic diet

Liyun He, Na Yang, Fan Ping, Lingling Xu, Wei Li, Yuxiu Li, Huabing Zhang Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Huabing ZhangAddress: Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of ChinaTel/Fax +86-010-69155073Email huabingzhangchn@163.comPurpose: High-sensitivity C-reactive protein (hs-CRP) has been shown as an important predictor of cardiovascular risk, and sleep duration is an important factor influencing health outcomes. However, the association between hs-CRP and sleep duration among Chinese adults remained unknown and controversial. We aimed to explore the associations between sleep duration and hs-CRP levels among Chinese adults, and the differences in sex and geographical regions.Methods: This cross-sectional study was based on nationally representative Chinese samples from the 2009 China Health and Nutrition Survey, which employed multistage, random cluster designs. Habitual sleep duration was self-reported with short and long sleep duration defined as ≤ 6h and ≥ 9h per day, respectively. Participants were divided into 4 groups based on the categories of self-reported sleep duration (≤ 6h, 7h, 8h, ≥ 9h per day), excluding hs-CRP levels ≥ 10 mg/L. Subset samples were stratified by sex and geographical regions.Results: A total of 8170 Chinese adults with a mean age of 50.0± 14.9 years and 4369 (53.5%) men were included. Participants sleeping eight hours had the lowest hs-CRP levels. Long sleep duration (≥ 9h) was significantly associated with elevated hs-CRP levels after adjusting for multiple covariates in full samples (β=0.0356; 95% CI: 0.0050– 0.0663; P=0.0228), but the associations of short sleep duration (≤ 6h) were limited to the unadjusted model. Long sleep duration was associated with elevated hs-CRP levels in women (β= 0.0512; 95% CI: 0.0097– 0.0927; P=0.0155) and in the northern region of China (β=0.0699; 95% CI: 0.0210– 0.1187; P=0.0051), but not in men or the southern region.Conclusion: Long but not short sleep duration was positively associated with elevated hs-CRP levels, independent from traditional risk factors among Chinese adults, and sex and geographical differences were observed. Our findings imply that modifications of long sleep duration might be added to behavioral therapy to reduce cardiovascular risk in Chinese adults.Keywords: high-sensitivity C-reactive protein, sleep duration, cardiovascular risk, Chinese population

Ning Yang,1 Feng Qiu,2 Feng Zhu,3 Lei Qi4 1Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of China; 2Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; 3Department of Thoracic Surgery, Shandong Provincial Chest Hospital, Jinan, Shandong 250013, People’s Republic of China; 4Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, People’s Republic of ChinaCorrespondence: Lei QiDepartment of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhuaxi Road, Jinan, Shandong Province 250012, People’s Republic of ChinaEmail walker789sdu@sina.comIntroduction: Lung cancer is one of the most aggressive forms of cancer that leads to a high mortality rate amongst several cancer types and it is a widely recurrent cancer globally. The use of zinc oxide nanoparticles (ZnONPs) in the formulation of sun cream, food flavors, and colorings due to its varied biological properties. The extensive significance of nanoparticles encourages their production but the approaches are a common challenge in concluding the direct beneficial effect for the disease treatment. Hence, in the present study, zinc oxide-loaded syringic acid (ZnO-SYR) phytochemical was used to elucidate the therapeutic effect against lung cancer.Methods: The ZnO-SYR nanoparticles were synthesized and characterized by UV-visible spectroscopy, X-ray diffraction, dynamic light scattering, and FT-IR analysis. The characterized ZnO-SYR was tested on in vivo mouse model of lung cancer (benzo(a)pyrene (BAP)) and in vitro A549 cells.Results: The results demonstrated the significant restoration of body weight with attenuated serum marker enzymes compared to BAP-treated animals. In addition, cytokine estimation revealed ameliorated levels of TNF-α, interleukins, IL-6, IL-1β with evidenced histological observations in ZnO-SYR-treated mice compared to BAP-induced lung cancer mice.Discussion: Furthermore, cytotoxicity analysis demonstrated the altered mitochondrial membrane potential (MMP), with a profound increase in reactive oxygen species (ROS) levels, and apoptosis mechanism by ZnO-SYR compared to control cells. The conclusions of the present study put forward an evident confirmation of the protective and beneficial effects of zincoxide-loaded syringic acid against the BAP-induced lung cancer model.Keywords: zinc oxide nanoparticles, syringic acid, lung cancer, apoptosis, A549

Yunlu Liu,1,2 Lin Wang,1 Feng Wan,3 Na Yang1 1Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China; 2Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, People’s Republic of China; 3College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of ChinaCorrespondence: Na YangInstitute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Ying Long Community, Zhong he Street Office, High Tech Zone, Chengdu 610212, People’s Republic of ChinaTel +86 13880145342Fax +86 2867087558Email nayang@glpcd.comPurpose: Anisodine hydrobromide (Ani) is isolated from the medicinal plant Anisodus tanguticus (Maxim.) Pascher for clinical use. Although considerable research regarding Ani has been reported, the safety profiles of Ani are currently unknown. This study investigated the cardiorespiratory effects of Ani in conscious dogs to provide clinicians a detailed safety profile of Ani on the cardiorespiratory system.Materials and Methods: Using the Latin square design, the study was divided into six phases, where in each phase, six telemetered beagle dogs received one dose of normal saline or sotalol hydrochloride or Ani (0.1, 0.4, 1.6, or 6.4 mg/kg). Electrocardiogram, blood pressure (BP) and respiratory parameters were collected before and after administration for 24 hours. Statistical comparisons were performed at scheduled time-points.Results: The heart rate was significantly increased, PR and QTCV intervals were significantly shortened in Ani 0.4, 1.6, 6.4 mg/kg treatment group after drug administration. Compared with the saline group, a significant increase in heart rate and shortening of PR, QTCV intervals were observed in the Ani 1.6, 6.4 mg/kg treatment groups from 5 min to 4 h time-points. Diastolic and mean BP were significantly increased in Ani 1.6, 6.4 mg/kg from 1 h to 2 h time-points compared to those of the saline control. Accelerated breathing was observed in the first 20 min after Ani 0.4, 1.6, and 6.4 mg/kg treatment, although not statistically significant. Furthermore, no significant differences were observed in any of the corresponding indexes of Ani 0.1 mg/kg treatment group at different time-points compared to those of the saline group.Conclusion: Ani may have adverse effects on the cardio-respiratory systems of dogs at doses above 0.4 mg/kg, whereas Ani 0.1 mg/kg was devoid of potentially deleterious effects on cardiorespiratory function.Keywords: anisodine hydrobromide, electrocardiogram, blood pressure, cardio-respiratory function, telemetered dogs, safety

Chen Qiu,1– 3,* Xin Zhang,3,4,* Bin Huang,3,4 Shuai Wang,3,4 Wenjing Zhou,3,4 Chao Li,3,4 Xingang Li,3,4 Jian Wang,3– 5 Ning Yang3,4,6 1Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, People’s Republic of China; 4Shandong Key Laboratory of Brain Function Remodeling, Jinan, People’s Republic of China; 5K. G. Jebsen Brain Tumor Research Center, Department of Biomedicine, University of Bergen, Bergen, Norway; 6Department of Epidemiology and Health Statistics, School of Public Health, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning Yang Email yangning@sdu.edu.cnIntroduction: Disulfiram (DSF), a drug used in the treatment of alcoholism since 1948, has been shown to have antitumor properties in various tumor types possibly due to the induction of a type cell death, ferroptosis, and the sensitization of cells to chemo- and radiotherapy. In this study, we explored the antitumor properties of DSF in glioblastoma (GBM) and investigated the underlying molecular mechanisms.Methods: GBM cell lines U251 and LN229 were treated with DSF to assess cytotoxicity and activity of the molecule in vitro. Response of cells to treatment was examined using cell viability, flow cytometry, LDH release assay, immunofluorescence and Western blot analysis.Results: DSF inhibited cell growth of GBM U251 and LN229 cell lines in vitro in a concentration-dependent manner. Flow cytometry demonstrated that DSF caused G0-G1 growth arrest. DSF treatment led to increased ROS and lipid peroxidation levels relative to controls indicating the involvement of ferroptosis. Furthermore, DSF triggered lysosomal membrane permeabilization (LMP), a critical mechanism promoting cell death, in a ROS-dependent manner. Finally, DSF enhanced radiosensitivity of U251 and LN229 cells.Discussion: Our findings indicated that DSF induced ferroptosis and LMP and enhanced the radiosensitivity of GBM cells. Therefore, DSF might have efficient antitumor activity in the treatment of human GBM.Keywords: disulfiram, ferroptosis, lysosomal membrane permeabilization, ROS, glioblastoma

Guoqing Yang1 ,* Chenchang Xiao2 ,* Shiyue Li,3 Ningxi Yang1 1College of Humanities and Social Sciences, Harbin Engineering University, Harbin, People’s Republic of China; 2City College, Wuhan University of Science and Technology, Wuhan, People’s Republic of China; 3School of Health Sciences, Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ningxi Yang College of Humanities and Social SciencesHarbin Engineering University, NO. 145 Nantong Road, Harbin, Heilongjiang, People’s Republic of ChinaTel +86 45182569608Email yangningxi@bjmu.edu.cnBackground and Aim: Coronavirus disease 2019 (COVID-19) is currently prevalent worldwide. This research aimed to explore the effect of adverse childhood experience (ACE) on suicide ideation in young cancer patients during the COVID-19 pandemic. Self-reported questionnaires analyzed the mediating effects of sleep quality, anxiety symptoms, and inflammatory conditions between ACE and suicide ideation.Materials and Methods: A total of 197 young cancer patients (age 18– 40) completed questionnaires and a blood test. Correlation analysis and structural equation model were used to explore the relationships between ACE, sleep quality, anxiety symptom, serum C-reactive protein (CRP) levels and suicide ideation. The mediating roles of sleep quality, anxiety symptoms, and CRP levels on the influence of ACE on suicide ideation were explored.Results: ACE was positively related to anxiety symptoms, CRP levels, and suicide ideation, and negatively related to sleep quality. Anxiety symptoms and CRP levels were positively related to suicide ideation, while sleep quality was negatively related to suicide ideation. Anxiety symptoms were positively related to CRP levels but negatively related to sleep quality. From these results, we found ACE affected suicide ideation directly and was mediated by roles sleep quality, anxiety symptom and CRP.Conclusion: ACE not only directly affected suicide ideation but also affected suicide ideation through sleep quality, anxiety symptoms, and inflammatory conditions in young cancer patients during the COVID-19 pandemic. Therefore, targeted intervention and help for cancer patients from the perspective of ACE should be put into practice.Keywords: coronavirus disease 2019, psychosocial oncology, adverse childhood experience, anxiety symptom, sleep quality, suicide ideation

Na Yang, Liyun He, Yuxiu Li, Lingling Xu, Fan Ping, Wei Li, Huabing Zhang Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Huabing ZhangPeking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaTel/ Fax +-86-010-69155073Email huabingzhangchn@163.comPurpose: High dietary magnesium intake may reduce insulin resistance (IR) and metabolic syndrome (MetS). The aim of the cross-sectional analysis was to evaluate the association between dietary magnesium intake, IR, and MetS using data from China Health and Nutrition Survey.Methods: Dietary magnesium intake was defined as daily dietary magnesium intake divided by body weight. Logistic regression analysis was used to calculate the odds ratio (OR) for IR and the prevalence of MetS across the quartile categories of dietary magnesium intake. In addition, we used the macro PROCESS to perform the mediation analyses.Results: A total of 8120 participants were included in the final analysis. We found a significant negative association between dietary magnesium intake and IR, the multivariable-adjusted OR for HOMA-IR comparing the highest to the lowest quartile of dietary magnesium intake was 0.435 (95% confidence intervals [CI] 0.376 to 0.502). The prevalence of the MetS was 38.6%, 28.9%, 22.5%, and 16.5% for increasing quartiles of dietary magnesium intake (p < 0.001). The mediation model analysis displayed that insulin resistance mediated the effect of dietary magnesium on MetS. The direct effect and indirect effect of dietary magnesium on MetS were found significant, and the calculated percentage of mediation by insulin resistance was 19.6%.Conclusion: Our study demonstrated a significant and independent negative relationship among weight-adjusted dietary magnesium intake, HOMA-IR, and MetS in a large Chinese population. IR partly mediated the relationship between dietary magnesium intake and MetS.Keywords: diet magnesium intake, metabolic syndrome, insulin resistance, Chinese population, mediation effect

Liang Zeng,1,2,* Yizhi Li,2,* Qinqin Xu,3,* Wenjuan Jiang,2 Analyn Lizaso,4 Xinru Mao,4 Yongchang Zhang,2 Nong Yang,2 Zhenxing Wang1 1Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, People’s Republic of China; 2Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, People’s Republic of China; 3Department of Medical Oncology, Qinghai Provincial People’s Hospital, Xining, People’s Republic of China; 4Department of Medical Affairs, Burning Rock Biotech, Guangzhou, 510300, People’s Republic of China*These authors contributed equally to this workCorrespondence: Nong YangDepartment of Medical Oncology,Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, People’s Republic of ChinaTel +86 73189762327Email yangnong0217@163.cnZhenxing WangDepartment of Medical Oncology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, People’s Republic of ChinaTel +86 73189762327Email zhenxw316@163.comIntroduction: Reliable diagnostic approaches to detect ALK rearrangement are critical for selecting patients eligible for crizotinib therapy. This study aimed to compare next-generation sequencing (NGS) and Ventana immunohistochemistry (IHC) in evaluating ALK rearrangements and evaluate their impact on first-line crizotinib efficacy.Patients and Methods: A total of 472 NSCLC patients were identified as ALK-positive by NGS and/or IHC between March 2014 and February 2020. The concordance of ALK detection, overall response rate (ORR), and progression-free survival (PFS) were analyzed for 319 patients who received front-line crizotinib.Results: First-line crizotinib (n=319) significantly prolonged PFS in comparison with chemotherapy (n=46; 12.0 vs 6.8 months; p< 0.0001). Of the 76 crizotinib-treated patients whose ALK status was assessed by both NGS and IHC, 78.9% of the patients had concordant ALK status (NGS-positive/IHC-positive), 18.4% patients were NGS-positive but IHC-negative, and 2 patients were IHC-positive but NGS-negative. Different detection assays confer no statistical difference in ORR and PFS with first-line crizotinib. The ORR in NGS only, IHC only, and both NGS and IHC was 84.3%, 90.1%, and 88.1%, respectively, while PFS was 11.4, 13.0, and 11.0 months, respectively. The ORR in NGS-positive/IHC-positive and NGS-positive/IHC-negative patients was 85.4% and 92.8%, respectively. Compared to NGS-positive/IHC-positive patients, those with NGS-positive/IHC-negative results had a trend of shorter PFS but statistical significance was not reached (mPFS, 5.9 months vs 11.5 months, p=0.43).Conclusion: Our results demonstrate that ALK status detected by NGS and/or IHC is reliable in identifying patients with ALK-positive NSCLC who will benefit from ALK inhibitor therapy.Keywords: ALK status evaluation, ALK IHC, ALK inhibitor

Huiling Ma,1,2 Xinyu Zhao,1 Longbing Yang,1 Peipei Su,1 Ping Fu,1,3 Jian Peng,1,3 Na Yang,4 Guo Guo1,3,4 1Key and Characteristic Laboratory of Modern Pathogen Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, People’s Republic of China; 2Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Sanquan College of Xinxiang Medical University, Xinxiang 453003, People’s Republic of China; 3Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang 550025, People’s Republic of China; 4School of Food Science, Guizhou Medical University, Guiyang 550025, People’s Republic of ChinaCorrespondence: Guo Guo Tel +86 13765024379Email guoguojsc@163.comBackground: Candida albicans is associated with high mortality among immunocompromised patients. Resistance to and toxic side effects of antifungal drugs require the development of alternative antifungal agents. AMP-17 is a novel antimicrobial peptide derived from Musca domestica that exerts excellent antifungal effects against the Candida species. In this article, we discuss the potential mechanism of AMP-17 against C. albicans from the perspective of affecting the latter’s cell external structure.Methods: Recombinant AMP-17 was prepared by prokaryotic expression system, and its anti-C. albicans activity was detected by microdilution method. Microscopy and scanning electron microscopy were used to examine morphological changes in C. albicans. Cell wall-specific staining method was used to detect the change of cell wall integrity of C. albicans after AMP-17 treatment. AMP-17-induced damage to the C. albicans cell membrane was analyzed by fluorescent probes and glycerol assay kit. The expression of genes related to fungal cell wall and cell-membrane synthesis was detected by qRT-PCR.Results: Morphological observations showed that the growth of C. albicans was significantly inhibited in AMP-17-treated cells; the cells appeared aggregated and dissolved, with severe irregularities in shape. Furthermore, AMP-17 damaged the integrity of C. albicans cell walls. The cell wall integrity rate of AMP-17-treated cells was only 21.7% compared to untreated cells. Moreover, the change of membrane dynamics and permeability suggested that the cell membrane was disrupted by AMP-17 treatment. Genetic analysis showed that after AMP-17 treatment, the cell wall synthesis-related gene FKS2 of C. albicans was up-regulated 3.46-fold, while the cell membrane ergosterol synthesis-related genes ERG1, ERG5, ERG6, and MET6 were down-regulated 5.88-, 17.54-, 13.33-, and 7.14-fold, respectively.Conclusion: AMP-17 treatment disrupted the cell wall integrity and membrane structure of C. albicans and is likely a novel therapeutic option for prevention and control of C. albicans infections.Keywords: AMP-17, C. albicans, cell wall, membrane dynamics and permeability

Jingyu Chen,1 Tianyi Liu,2 Hui Wang,3 Zhipeng Wang,1 Yanju Lv,4 Yuying Zhao,1 Ning Yang,1 Xueli Yuan1 1Department of Oncology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150001, People’s Republic of China; 2Department of Pathology, The Second Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, People’s Republic of China; 3Department of Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong Province 250117, People’s Republic of China; 4Department of Oncology, The Second Hospital of Harbin Medical University, Harbin, Heilongjiang Province 150086, People’s Republic of ChinaCorrespondence: Xueli YuanDepartment of Oncology, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, YiYuan Street, NanGang District, Harbin 150001, People’s Republic of ChinaTel +86-451-85939760Email hmu_yuanxueli@hotmail.comPurpose: Glioma (GM) usually presents with an aggressive behavior and has a poor survival outcome. The abnormal expression of circular RNAs (circRNAs) has already been detected in GM, and circ_0079586 was found to have an increased expression in GM tumors.Patients and Methods: We assessed the differences in the expression of circ_0079586 in GM tissues (N=60) and cell lines (N=5) using qRT-PCR. The clinical value of circ_0079586 was measured by Fisher’s exact test and Kaplan–Meier and Cox regression analyses. Circ_0079586 siRNA and vector were transfected into LN229 and U251 cells, respectively, and the transfection was verified by qRT-PCR. Cell growth was evaluated by cell counting kit-8 (CCK-8). Cell apoptosis was measured using flow cytometric assay. Cell metastatic properties were measured by wound scratch and transwell experiments. Subcellular fractionation was used to identify the location of circ_0079586. Dual-luciferase reporter test was utilized to confirm the interaction between miR-183-5p and circ_0079586/MDM4 3ʹ-UTR.Results: The expression of circ_0079586 was elevated in GM samples and cells and correlated with the clinical severity and unfavorable prognosis of the patients. The elevated expression of circ_0079586 led to an increase in cell growth, migration and invasion but inhibited apoptosis in U251 cells, whereas its down-regulation reversed these effects in the LN229 cells. Mechanistically, we found circ_0079586 to be primarily located in the cytoplasm of GM cells. Furthermore, circ_0079586 could act as a sponge for miR-183-5p and elevate MDM4 expression at the posttranscriptional level.Conclusion: In summary, circ_0079586 was found to be up-regulated in GM that increased the proliferation, migration and invasion in GM cells via interaction with the miR-183-5p/MDM4 axis. We anticipate that our study would provide newer insights into the mechanism and treatment of GM.Keywords: glioma, circular RNA, circ_0079586, miR-183-5p, MDM4 protein

Xianlin Xu,1,* Yan Zhang,2,* Wei Wang,3 Yin Zhang,1 Ningxi Yang2 1Department of Gastroenterology, Huiyang Sanhe Hospital, Huizhou, Guangdong, People’s Republic of China; 2College of Humanities and Social Sciences, Harbin Engineering University, Harbin, Heilongjiang, People’s Republic of China; 3School of Health Sciences, Wuhan University, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ningxi Yang 145 Nantong Road, Harbin, Heilongjiang, People’s Republic of ChinaTel +86045182569608Email yangningxi@bjmu.edu.cnYin Zhang 3 Kanghe Road, Huizhou, Guangdong, People’s Republic of ChinaTel +8607523800260Email zhang_yin_2008@126.comBackground: Physician–patient empathy is inextricably linked with outcomes of patients. The purpose of this study was to test whether anxiety, self-efficacy, and sleep quality played intermediary roles in relationships between patients’ perceptions of physician–patient relational empathy and an inflammation marker in Crohn’s disease patients.Methods: The study included 187 patients. At admission (T1) and 3 months after admission (T2), anxiety, self-efficacy, sleep, and the inflammatory marker IL6 of patients were tested and compared. Patients’ perceptions of physician–patient relational empathy (CARE scale) was measured at T2. Correlations among patients’ anxiety, self-efficacy, sleep quality, IL6, and CARE scores were explored by Pearson’s correlation analysis and a structural equation model.Results: Compared with T1, patients showed higher self-efficacy and sleep quality and lower anxiety and IL6 at T2. Patients’ perceptions of physician–patient relational empathy were negatively related to anxiety and IL6 and connected to self-efficacy and sleep quality positively. Patients’ anxiety, self-efficacy, and sleep quality played intermediary roles incorrelations between empathy and IL6.Conclusion: In correlations of patients’ perceptions of physician–patient relational empathy and IL6 in patients with Crohn’s disease, patients’ anxiety, self-efficacy, and sleep quality acted as intermediary effects. Therefore, medical staff should empathize with patients.Keywords: empathy, Crohn’s disease, physician–patient communication, mental health

Huiduo Wu,1,* Yan Zhang,2,* Shiyue Li,3 Qiaoyun Liu,1 Ningxi Yang2 1Education and Rehabilitation Department, Faculty of Education, East China Normal University, Shanghai, People’s Republic of China; 2College of Humanities and Social Sciences, Harbin Engineering University, Harbin, Heilongjiang, People’s Republic of China; 3School of Health Sciences, Wuhan University, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiaoyun LiuEducation and Rehabilitation Department, Faculty of Education, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, People’s Republic of ChinaTel +86 21 6223 2287Email qyliu@spe.ecnu.edu.cnNingxi YangCollege of Humanities and Social Sciences, Harbin Engineering University, No. 145 Nantong Road, Harbin, Heilongjiang, People’s Republic of ChinaTel +86 188 1926 8616Email yangningxi@bjmu.edu.cnBackground: To explore the impact of empathy between Chinese doctors and patients on anxiety, self-efficacy, sleep and IL-6 levels in hospitalized asthmatic patients.Methods: This study included 195 asthmatic patients and 30 respirologists in China. The Jefferson Empathy Scale (JSE) was used to measure the empathy level of doctors, and the consultation and relational empathy (CARE) scale was used to measure patients’ perception of empathy between themselves and their doctors. Doctors were divided into three groups, according to JSE scores. Data about anxiety, self-efficacy, sleep and IL-6 were collected and compared between patients in different JSE groups at admission (T1) and 3 months later (T2). The correlation between JSE scores and CARE scores was analyzed. Pearson correlation analysis along with a structural equation model was applied to explore the relevance among anxiety, self-efficacy, sleep, inflammatory factors (IL-6) and patients’ perception of empathy shown by their doctors.Results: There was no statistical difference between the indices of patients in three groups at admission. For all patients, the changes of indicators were statistically different from T1 to T2. Three months later, patients in high empathy scoring group showed lower anxiety and IL-6, and higher self-efficacy and sleep quality. There was a positive correlation between JSE and CARE scores. Patients’ perception of doctor-patient empathy was negatively correlated to anxiety levels and IL-6, and positively correlated to self-efficacy and sleep quality. Anxiety, self-efficacy and sleep quality were mediators in the relationship between patients’ perception of empathy and IL-6.Conclusion: In the Chinese sample, anxiety, self-efficacy, sleep, empathy between doctors and patients and IL-6 are closely correlated. Anxiety, self-efficacy and sleep may play additional roles in the influence of patients’ perception of empathy between doctors and patients on IL-6 in asthmatic patients.Keywords: doctor-patient relationship, empathy, asthmatic, self-efficacy, anxiety, sleep, IL-6, China

Yu Chen, 1–3,* Wei Zhu, 4,* Fan Shu, 5 Yan Fan, 1, 2 Ning Yang, 1, 2 Tao Wu, 1, 2 Le Ji, 1, 2 Wei Xie, 1, 2 Rengui Bade, 1, 2 Shuyuan Jiang, 1, 2 Xiaolei Liu, 1, 2 Guo Shao, 1–3 Gang Wu, 1, 2 Xiaoe Jia 1–3 1Biomedicine Research Center, Neuroscience Institute, Baotou Medical College, Baotou 014040, People’s Republic of China; 2Inner Mongolia Key Laboratory of Hypoxic Translational Medicine, Baotou Medical College, Baotou 014040, People’s Republic of China; 3Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 4School of Pharmacy, Baotou Medical College, Baotou 014040, People’s Republic of China; 5Third Hospital of Baotou, Baotou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoe Jia Email evangeline2004@163.comGang Wu Tel/Fax +86-472-7167830Email wugang0525@163.comIntroduction: Rare-earth nanoparticles in the environment and human body pose a potential threat to human health. Although toxic effects of rare-earth nanoparticles have been extensively studied, the effects on the early development are not well understood. In this study, we attempted to explain the toxic effects of neodymium oxide (Nd 2O 3) nanoparticles on early development.Methods: We added the Nd 2O 3 nanoparticles at different concentrations and recorded the mortality and malformation rate per 24 hrs under a microscope. The live embryos treated with Nd 2O 3 nanoparticles were imaged as movies and Z step lapses with a confocal microscope, and heart rates were counted for 30 s to measure the cardiac function. The live Tg (Flk1:EGFP) transgenic embryos exposed to Nd 2O 3 nanoparticles were observed under confocal microscope to measure the cerebrovascular development. Subsequently, we extracted the total protein for Western blot at 5 days post-fertilisation (dpf). Embryos were collected to undergo TUNEL staining for apoptosis detection.Results: Nd 2O 3 nanoparticles disturbed embryo development at high concentrations (> 200 μg/mL). The mortality and malformation rate gradually increased in a dose-dependent manner by morphological observation, while the Nd 2O 3 median lethal concentration (LD50) was 203.4 μg/mL at 120 hrs post-fertilisation (hpf). Furthermore, the Nd 2O 3-treated embryos showed severe arrhythmia and reduced heart rate. We also observed the markedly cerebrovascular disappearance at middle concentration (100 and 200 μg/mL). The downregulated autophagy flux in brain blood vessels and increased apoptosis level in neurons might affect vessels sprouting and contribute to the vanished cerebrovascular.Conclusion: The results suggested that the embryos exposed to Nd 2O 3 activated the apoptosis pathway and induced toxicity and abnormal cardiac/cerebrovascular development.Keywords: Nd 2O 3, zebrafish, toxicity, arrhythmias, cerebrovascular

Yin Zhang,1,* Bin Pi,2,* Xianlin Xu,1 Ying Li,3 Xiangfan Chen,3 Ningxi Yang4 1Department of Gastroenterology, Huiyang Sanhe Hospital, Huizhou, People’s Republic of China; 2Department of Orthopedics, Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 3School of Health Science, Wuhan University, Wuhan, Hubei, People’s Republic of China; 4College of Humanities and Social Sciences, Harbin Engineering University, Harbin, Heilongjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ningxi YangCollege of Humanities and Social Sciences, Harbin Engineering University, No. 145 Nantong Street, Harbin, Heilongjiang, People’s Republic of ChinaTel +86-18819268616Fax +86 451-82569608Email yangningxi@bjmu.edu.cnBackground: Inflammatory bowel disease arthritis (IBDA) threatens patients’ physical and mental health. Therefore, patients need not only physical therapy, but also adequate health education and psychological support. This study was designed to explore the effect of health education based on narrative medicine combined with an online patient mutual assistance group that was based on the physical and mental health of patients with IBDA.Methods: A total of 120 patients with IBDA were randomly divided into four groups (30 patients per group). Patients in the control group were given routine health education on the premise of routine treatment. The three treatment groups were given health education based on narrative medicine, online patient mutual assistance group intervention, or combined intervention. Depression, sleep, arthralgia, irritable bowel syndrome (IBS) symptoms, and inflammatory factors were measured and compared before and 1 month after the intervention.Results: Before the intervention, no significant differences were observed in baseline data between the four groups. However, after the intervention, the physical and mental health of patients who received health education based on narrative medicine or online patient mutual assistance groups was improved. Our data showed that patients in the combined intervention group experienced a better outcome.Conclusion: Narrative medicine-based health education combined with an online patient mutual assistance group is beneficial to the physical and mental health of IBDA patients. Taken together, this model needs to be further deepened and popularized in clinical practice.Keywords: IBDA, narrative medicine, online patient mutual assistance group, health education