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Xiying Zhang,1 Zhixia Jiang,2 Aiai Huang,3 Fuyan Zhang,4 Yuancheng Zhang,5 Fang Zhang,6 Lin Gao,7 Xiaoling Yang,8 Rujun Hu9 1Department of Intensive Care Unit, Jinsha County People’s Hospital, Bijie, Guizhou Province, 551800, People’s Republic of China; 2Office of the Director, Guizhou Nursing Vocational and Technical College, Guiyang, Guizhou Province, 550081, People’s Republic of China; 3Department of Nursing, Panyu Maternal and Child Care Service Center of Guangzhou, Guangzhou, Guangdong Province, 511400, People’s Republic of China; 4Department of Nursing, Jinsha County People’s Hospital, Bijie, Guizhou Province, 551800, People’s Republic of China; 5Department of Orthopaedics, Jinsha County People’s Hospital, Bijie, Guizhou Province, 551800, People’s Republic of China; 6Surgical Teaching and Research Office, Guizhou Nursing Vocational and Technical College, Guiyang, Guizhou Province, 550081, People’s Republic of China; 7Department of Endocrinology, Jinsha County People’s Hospital, Bijie, Guizhou Province, 551800, People’s Republic of China; 8Comprehensive Department of Nursing, Guizhou Nursing Vocational and Technical College, Guiyang, Guizhou Province, 550081, People’s Republic of China; 9Department of Intensive Care Unit, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou Province, 563000, People’s Republic of ChinaCorrespondence: Xiying Zhang, Department of Intensive Care Unit, Jinsha County People’s Hospital, Yangdeng Community, Xiluo Street, Jinsha County, Bijie City, Guizhou Province, People’s Republic of China, Tel +86 15285207705, Email zhang_xiying9@yeah.netObjective: To identify the latent trajectories of activities of daily living (ADL) disability and the influential factors among adults with post-intensive care syndrome (PICS).Methods: We evaluated five-time longitudinal data about PICS diagnosed in 434 of 593 assessed patients (73.19%). Disability was measured by the Barthel index scale, which grades individuals according to how difficult it is to carry out ADL. We utilized the growth mixture model (GMM) to identify latent trajectories and associated factors.Results: Two groups with distinct trajectories of ADL disability were identified, including the Severe Disability Sustained Group and the Disability Recovery Group. People who were of advanced age transferred to another hospital for treatment, or had cognitive impairment or depression were more likely to be classified into the Severe Disability Sustained Group (P < 005).Conclusion: There are two potential trajectories of ADL disability in patients with PICS, which are the severe disability persistence group and the disability recovery group. Improvement in cognitive impairment or depression may contribute to recovery from disability, transfer to hospital or advanced age may not be conducive to recovery of ADL ability, and disability may last longer.Keywords: activities of daily living, critical illness, disability, growth mixture model, post-intensive care syndrome

Kai Zhang,1 Yu Han,2 Yu Xuan Gao,1 Fang Ming Gu,1 Zhao Xuan Gu,1 Jia Ying Liang,1 Jia Yu Zhao,1 Tianqi Zhang,1 Min Gao,3 Tian Yi Cai,1 Rui Hu,1 Tian Zhou Liu,4 Bo Li,1 Yixin Zhang1 1Cardiovascular Surgery Department, Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Ophthalmology, First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 3Department of Cancer Center, First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 4Department of Gastrointestinal Surgery, Second Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of ChinaCorrespondence: Yixin Zhang, The Second Hospital, Jilin University, No. 218, Zi Qiang Street, Changchun, Jilin Province, People’s Republic of China, Email zyx900711@163.comBackground: There has been a growing body of research focusing on patients with Congestive Heart Failure (CHF) and chronic obstructive pulmonary disease (COPD) admitted to the intensive care unit (ICU). However, the optimal blood pressure (BP) level for such patients remains insufficiently explored. This study aimed to investigate the associations between systolic blood pressure (SBP) and in-hospital mortality among ICU patients with both CHF and COPD.Methods: This retrospective cohort study enrolled 6309 patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. SBP was examined as both a continuous and categorical variable, with the primary outcome being in-hospital mortality. The investigation involved multivariable logistic regression, restricted cubic spline regression, and subgroup analysis to determine the relationship between SBP and mortality.Results: The cohort consisted of 6309 patients with concurrent CHF and COPD (3246 females and 3063 males), with an average age of 73.0 ± 12.5 years. The multivariate analysis revealed an inverse association between SBP and in-hospital mortality, both as a continuous variable (odds ratio = 0.99 [95% CI, 0.99~1]) and as a categorical variable (divided into quintiles). Restricted cubic spline analysis demonstrated an L-shaped relationship between SBP and mortality risk (P nonlinearity < 0.001), with an inflection point at 99.479 mmHg. Stratified analyses further supported the robustness of this correlation.Conclusion: The relationship between SBP and in-hospital mortality in patients with both CHF and COPD follows an L-shaped pattern, with an inflection point at approximately 99.479 mmHg.Keywords: systolic blood pressure, in-hospital mortality, congestive heart failure, chronic obstructive pulmonary disease, generalized additive model

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

Yuxin Chen,1,2,&ast; Rui Hu,1,&ast; Xinmao Xu,1 Binxue Hong,1 Jinquan Zhang,1 Peng Jia,3,4 Li Zhao1,2,4 1West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, People’s Republic of China; 2China-PUMC C.C. Chen Institute of Health, Sichuan University, Chengdu, People’s Republic of China; 3School of Resource and Environmental Sciences, Wuhan University, Wuhan, People’s Republic of China; 4International Institute of Spatial Lifecourse Health (ISLE), Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Zhao, Email zhaoli@scu.edu.cnBackground: Nonsuicidal self-injury (NSSI) is an overwhelming social problem in children and adolescents. Focusing on the change of NSSI behavior, including onset, cessation, and maintenance, is crucial to developing effective prevention and intervention strategies. This study explored the effect of mental health status (depressive and anxiety symptoms) and family function on NSSI.Methods: The study sample comprised 7554 children and adolescents based on the first two rounds of the Chengdu Positive Child Development (CPCD) dataset in China. Depressive and anxiety symptoms measured mental health status. The self-reported questionnaires also assessed NSSI behaviors and family function. The interrelationship between NSSI behaviors, mental health status, and family function was evaluated. Logistic regression and linear regression were performed to examine the interrelationship between mental health status, family function and NSSI behaviors. Sensitivity analysis was performed.Results: In this study, 2167 (28.69%) participants reported NSSI at baseline and 2101 (27.81%) at follow-up. Depression, anxiety, and family function were salient influential factors in the prevalence, onset, and cessation of NSSI. Parents’ accompaniment showed a significant effect on the prevalence of NSSI.Conclusion: Depression, anxiety, family function, and parents’ accompaniment are all associated with NSSI behaviors. Strategies targeting mental health status and family function could effectively protect children and adolescents from NSSI behaviors.Keywords: nonsuicidal self-injury, NSSI, depression, anxiety, family function, children, adolescent

Xiaoyu He,1,2 Yu Luo,2 Jianan Hao,1,2 Rui Hu,1,2 Xiaoyue Yang,1,2 Luping Ren2 1Graduate School, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Luping Ren, Department of Endocrinology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, 050051, People’s Republic of China, Tel +86 311 859 889 75, Email renluping1122@163.comPurpose: Diabetes is an important contributor to the progression of atherosclerosis (AS). We aimed to investigate the correlation between ketosis episodes and lipid-related parameters in patients with new-onset ketosis-prone type 2 diabetes (KPT2D), further attempting to assess the impact of ketosis episodes on AS.Patients and Methods: A cross-sectional study of 147 subjects with new-onset diabetes was performed, including 65 KPT2D subjects (KPT2D group) and 82 non-ketotic type 2 diabetes (T2D) (T2D group) subjects. Anthropometric and biochemical parameters were measured in all subjects. Calculation of atherogenic index of plasma (AIP) by traditional lipid parameters.Results: The AIP (P = 0.008) level and the percentage of AIP ≥ 0.24 (P = 0.026) in subjects with KPT2D were higher than in subjects with T2D. The apoA1 (P = 0.001) levels were significantly lower in patients with KPT2D than in patients with T2D. In the KPT2D group, plasma ketones were positively correlated with AIP (P = 0.023) and negatively correlated with apoA1 (P = 0.002). Univariate logistic regression suggested that plasma ketone (OR = 1.704, P = 0.040) was an important related factor for the AS in subjects with KPT2D. Multiple linear regression suggested plasma ketone was significantly positive with AIP (β = 0.437, P = 0.020). In multiple linear regression analysis suggests that apolipoprotein A1 (β = – 0.335, P = 0.033) is strongly associated with ketotic episodes in newly diagnosed ketosis-prone type 2 diabetic patients.Conclusion: Ketosis episodes in patients with KPT2D were significantly and positively associated with elevated AIP levels and reduced apoA1 levels. Frequent ketosis episodes may accelerate the progression of AS.Keywords: ketosis onset, ketosis-prone type 2 diabetes, lipid metabolism, atherosclerosis, atherogenic index of plasma

Bin Wang,1,&ast; Xiao Zhong,2,&ast; Haojie Fu,3 Haobo Zhang,4 Ruilin Hu,1 Jufen Li,1 Changxia Chen,1 Kexin Wang5 1Southwest University of Science and Technology, Mianyang, Sichuan, People’s Republic of China; 2School of Psychology, Beijing University of Sports, Beijing, People’s Republic of China; 3Shanghai Research Institute for Intelligent Autonomous Systems, Tongji University, Shanghai, People’s Republic of China; 4College of Education Science, Guangxi University for Nationalities, Nanning, Guangxi, People’s Republic of China; 5College of Media and International Culture, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changxia Chen, Southwest University of Science and Technology, No. 59, Middle Section of Qinglong Avenue, Fucheng District, Fucheng District, Mianyang City, Sichuan Province, People’s Republic of China, Email Chenchangxia@swust.edu.cn Kexin Wang, College of Media and International Culture, Zhejiang University, No. 866 Yuhangtang Road, Xihu District, Hangzhou, Zhejiang, People’s Republic of China, Email wangkexin0809@zju.edu.cnPurpose: This study explores the status of pandemic fatigue, predictors, and their mechanisms of action based on a stress-response framework and a parallel model of future-oriented response.Patients and methods: Study 1 investigated 8426 Chinese adult residents’ understanding of and willingness to cooperate with the pandemic prevention and control policies and Study 2 surveyed 1635 Chinese residents on their activeness of pandemic prevention and control (APPC), pandemic risk perception, perceived stress, and future-oriented coping.Results: Study 1 found that public understanding of and willingness to cooperate with prevention policies were significantly lower in 2022 than in 2020 and 2021. Study 2 found that risk perception negatively predicted the APPC; perceived stress and preventive coping significantly mediated the relationship between risk perception and APPC; but perceived stress and proactive coping did not significantly mediate the relationship between risk perception and APPC.Conclusion: This revealed an increase in public fatigue in the third year of the pandemic. Pandemic fatigue can be predicted by pandemic risk perception, but the direct pathway of action is not significant and requires the mediation of perceived stress and preventive coping.Keywords: pandemic fatigue, risk perception, stress, proactive coping, preventive coping

Yaling Li,1,&ast; Kaiyang Shao,1,&ast; Ruyi Cai,1 Yi Liu,2 Xiaojing Liu,2,3 Feihua Ni,1 Huiyan Zheng,1 Ruying Hu,1 Ting Sun1 1Department of Health Management Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ting Sun, Department of Health Management Center, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, People’s Republic of China, Email 1195037@zju.edu.cnBackground: The coexistence of blaNDM-1 with other resistance determinants is rarely reported for Providencia rettgeri. Therefore, this study investigates the phenotypic and genetic characteristics of a multidrug-resistant P. rettgeri strain YQ150713.Methods: P. rettgeri YQ150713 was identified as carrying blaNDM-1. S1-pulsed-field gel electrophoresis (S1-PFGE), Southern blotting, and conjugation experiments were used to determine plasmid characteristics. An antimicrobial susceptibility test was conducted. The complete genomic sequence of YQ150713 was obtained using Illumina NovaSeq 6000 and Oxford nanopore platforms. To further characterize the phylogenetic structure of P. rettgeri YQ150713, average nucleotide identity (ANI) and phylogenetic analyses were conducted.Results: The S1-PFGE, Southern blot, and conjugation assays have confirmed that the isolate P. rettgeri YQ150713 contains the blaNDM-1 gene on a conjugative plasmid pYQ150713-NDM-1. Antimicrobial susceptibility testing has indicated that strain YQ150713 was resistant to various common antibiotics, except aztreonam and fosfomycin. Bioinformatics analysis has further shown that pYQ150713-NDM-1 was a novel plasmid with a size of 265,883 bp, and blaNDM-1 and blaOXA-10 were co-located on it. Phylogenetic analysis suggesting P. rettgeri has spread widely throughout the world.Conclusion: In this study, blaNDM-1 and blaOXA-10 were co-localized on a novel plasmid pYQ150713-NDM-1 with a horizontal transfer function. To reduce the risk of the dissemination of such P. rettgeri isolates in clinical settings, more surveillance will be required in the future.Keywords: antimicrobial resistance, blaNDM-1, blaOXA-10, Providencia rettgeri, carbapenemase-producing, average nucleotide identity, phylogenetic

To understand the health and ecological benefits of scenic recreational forests, we elucidated their spatial distribution characteristics, which can be used to create guidelines and reveal strategic issues regarding the spatial distribution of tree species. We randomly set up 900 m2 quadrats in scenic recreational forest communities in Guangzhou, Foshan, and Zhuhai, and surveyed each tree using LiDAR. We then calculated the living vegetation volume (LVV) and amount of recreational space on the forest floor (RSFF), and analyzed the differences in spatial distribution characteristics across cities, locations, and forest types. The spatial distribution characteristics of trees differed between different cities, but were similar among different locations and forest types. Urban scenic recreational forest areas are thus configured based on aesthetics, recreational functions, and the spatial distribution characteristics of different tree species. Additionally, the relationship between the tree crown LVV and the RSFF was generally synergistic, yet contradictory. Although an increase in LVV can effectively improve ecological benefits, it may also reduce RSFF and other benefits provided by tree crowns to urban residents.

Yanan Liu, Shuo Zhang, Rongrong Hu, Chao Li, Gang Chen, Xiaoxiao Shi, Yan Liu, Ke Zheng, Hang Li, Yubing Wen, Xuemei Li, Xuewang Li, Peng Xia, Yan Qin Department of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Peng Xia; Yan Qin, Department of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100730, People’s Republic of China, Tel +86 01069155058, Email 7-xp@163.com; qinyanbeijing@126.comPurpose: There are increasing reports of atypical membranous nephropathy (AMN) cases with similar pathological characteristics to secondary membranous nephropathy (SMN) without definite underlying causes. Although rituximab has become a first-line option in treating idiopathic membranous nephropathy (IMN), the efficacy and safety of rituximab-based regimen for AMN is not clear.Patients and Methods: This is a retrospective, single-center study. AMN patients who received rituximab-based therapy were included. IMN patients treated with rituximab during the same period were selected as the control group matched by gender, sex, baseline urinary protein and albumin levels. Baseline data and follow-up data were collected.Results: A total of 20 AMN patients and 40 IMN patients were included. The baseline levels of urinary protein were comparable between the two groups [6.77 (IQR 3.34, 11.49) g/24 h vs 6.47 (IQR 3.4, 10.76) g/24 h, P=0.944]. The baseline levels of serum albumin were 26.15± 6.71 g/L and 26.8± 5.54 g/L (P=0.689) respectively. The cumulative remission rate for rituximab-based treatment at the 12th month was lower in AMN group than IMN group [13 (65%) vs 36 (90%), P=0.045]. In AMN group, non-responders showed a higher level of proteinuria and a worse renal function at baseline than those of responders. There was no significant difference in the overall adverse events or serious adverse events between the two groups.Conclusion: In our study, AMN patients obtained proteinuria remission in a lower percentage compared with IMN patients. In general, rituximab-based therapy is effective in AMN patients with an acceptable safety profile.Keywords: rituximab, atypical membranous nephropathy, idiopathic membranous nephropathy, efficacy

Xiaoyue Yang,1 Rui Hu,1 Zhen Wang,1 Yilin Hou,1 Guangyao Song1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China; 2Endocrinology Department, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaCorrespondence: Guangyao Song, Endocrinology Department, Hebei General Hospital, 361 Zhongshan East Road, Shijiazhuang, People’s Republic of China, Tel +86 13930119808, Email sguangyao2@163.comBackground: Adequate intake of folic acid (FA) has been proven essential for metabolism, cellular homeostasis, and antioxidant effects in diabetic patients. Our aim was to evaluate the association between serum folate levels and the risk of insulin resistance in patients with type 2 diabetes mellitus (T2DM) and to provide new ideas and approaches for reducing the risk of T2DM.Methods: This was a case–control study involving 412 participants (206 with T2DM). Anthropometric parameters, islet function, biochemical parameters and body composition of T2DM group and control group were determined. Correlation analysis and logistic regression were used to evaluate the risk factors associated with the onset of insulin resistance in T2DM.Results: The folate levels in type 2 diabetic patients with insulin resistance were significantly lower than those in patients without insulin resistance. Logistic regression showed that FA and high-density lipoprotein were independent influencing factors for insulin resistance in diabetic patients (P < 0.05). After adjusting for confounding factors, the degree of insulin resistance in diabetic patients was in a significant inverse relationship with folate levels (P< 0.05). We also found that below the serum FA threshold of 7.09 ng/mL insulin resistance was significantly more elevated.Conclusion: Our findings suggest that the risk of insulin resistance increases with the decrease in serum FA levels in T2DM patients. Monitoring folate levels in these patients and FA supplementation are warranted preventive measures.Keywords: folic acid, type 2 diabetes mellitus, insulin resistance, Chinese

Mingqi Tu,1,&ast; Sangsang Xiong,1,&ast; Shengxia Lv,2,&ast; Xiaoting Wu,1 Hantong Hu,3 Renjie Hu,4 Jianqiao Fang,1 Xiaomei Shao1 1Key Laboratory for Research ofAcupuncture Treatment and Transformation of Emotional Diseases, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2The School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaomei Shao, Key Laboratory for Research of Acupuncture Treatment and Transformation of Emotional Diseases, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, The Third Clinical Medical College, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, Zhejiang Province, People’s Republic of China, Tel +86 189 5713 0287, Email 13185097375@163.comIntroduction: Acupuncture has a long history of treating major depressive disorder (MDD), yet the acupoint selection of acupuncture for MDD varies greatly. This study aimed to explore the characteristics and principles of acupuncture for MDD by analyzing clinical trials of acupuncture for MDD using data mining techniques.Methods: In this study, clinical trials of acupuncture for MDD were retrieved and relevant data were extracted, and then the data were analyzed by data mining techniques. In addition, association rule mining, network analysis and hierarchical cluster analysis were used to determine the correlation between different acupoints.Results: The results revealed that GV20, LR3, PC6, SP6 and GV29 were used most frequently; acupoints in the Yang meridian were used more often than those in the Yin meridian, with the most applied acupoints in the Governor Vessel; the percentage of specific acupoints applied was 69.39%, with the most applied being five-shu points; the frequency of acupoints used was highest in the lower limbs, while the head, face, and neck had the most acupoints used; GV29 combined with GV20 were the most used acupoint groups; the core acupoints used for MDD were GV20, PC6 and SP36; there were 5 acupoint groups according to the cluster analysis. The most used acupuncture method was manual acupuncture; the frequency of treatment was mostly 7 times per week and the duration of treatment was mostly 42 days.Discussion: We discussed the current character of acupuncture treatment on MDD, including the frequency used of acupoints, the property of used acupoints, the acupoint combination, the acupuncture method, and the frequency and duration of treatment. These findings may provide new ideas for the clinical treatment of MDD. However, further clinical/experimental studies are needed to demonstrate the significance of this concept and approach.Keywords: acupuncture treatment, data mining technology, association rule mining, network analysis, cluster analysis

Yilin Hou,1,2 Xiaoyu Hou,1,2 Qian Nie,3 Qiuyang Xia,1,2 Rui Hu,1,2 Xiaoyue Yang,1,2 Guangyao Song,2,4 Luping Ren2,4 1Graduate School, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 3Health Examination Center, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China; 4Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of ChinaCorrespondence: Guangyao Song; Luping Ren, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, 050051, People’s Republic of China, Email sguangyao2@163.com; renluping1122@163.comPurpose: The aim of this study was to evaluate the association of bone turnover markers (BTMs) with type 2 diabetes mellitus (T2DM) and microvascular complications.Methods: A total of 166 T2DM patients and 166 non-diabetic controls matched by gender and age were enrolled. T2DM patients were sub-classified into groups based on whether they had diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR), and diabetic kidney disease (DKD). Clinical data including demographic characteristics and blood test results [serum levels of osteocalcin (OC), N-terminal propeptide of type 1 procollagen (P1NP), and β-crosslaps (β-CTX)] were collected. Logistic regression and restrictive cubic spline curves were performed to examine the association of BTMs with the risk of T2DM and microvascular complications.Results: After adjusting for family history of diabetes, sex and age, an inverse association was observed between elevated serum OC levels [O, p < 0.001] and increased serum P1NP levels , p < 0.001] with the risk of T2DM. Moreover, there was an inverse linear association of serum OC and P1NP levels with the risk of T2DM. However, β-CTX was not associated with T2DM. Further analysis showed a nonlinear association between OC and the risk of DR, while P1NP and β-CTX were not correlated with DR. Serum concentrations of BTMs were not associated with the risks of DPN and DKD.Conclusion: Serum OC and P1NP levels were negatively correlated with T2DM risk. Particularly, serum OC levels were associated with DR risk. Given that BTMs are widely used as markers of bone remodeling, the present finding provides a new perspective for estimating the risk of diabetic microvascular complications.Keywords: bone turnover markers, type 2 diabetes mellitus, microvascular complications

Xiufang Wang,1,&ast; Jia Liu,1,&ast; Andong He,1 Zhiyong Dong,2– 4 Xiaomei Chen,2– 4 Shuqing Yu,2– 4 Lilian Gao,2– 4 Huaxi Wang,2– 4 Wenhui Chen,2– 4 Ruixiang Hu,2– 4 Shuwen Jiang,2– 4 Jianxue Wang,2– 4 Yuan Chen,2– 4 Cunchuan Wang,2– 4 Wah Yang,2– 4 Ruiman Li1 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 2Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Jinan University Institute of Obesity and Metabolic Disorders, Guangzhou, People’s Republic of China; 4Guangdong-Hong Kong-Macao Joint University Laboratory of Metabolic and Molecular Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruiman Li, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Avenue West, Guangzhou, People’s Republic of China, Email hqyyck@126.com Wah Yang, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, No. 613, Huangpu Avenue West, Guangzhou, People’s Republic of China, Email yangwah@qq.com; yangwah@connect.hku.hkBackground: Bariatric and metabolic surgery (BMS) is an effective treatment for obesity and its complications, but its effect on pregnancy outcomes is inconclusive. The present study aimed to investigate women’s pregnancy status and outcomes as well as the impact of pregnancy intervals after BMS.Methods: The menstrual cycle and fertility status of women who underwent BMS in our centre between July 2010 and January 2021 were retrospectively analyzed and followed up until one-year post-delivery. The pregnancy outcomes after BMS were observed, including changes in weight, pregnancy interval, pregnancy complications, weight and health status of the newborn (premature birth, admission to neonatology, or deformity).Results: We identified 31 women who were successfully conceived after BMS. There were statistical differences in weight and menstrual status before and post-operation (P < 0.05), and 77.97% of them had remission or recovery of obesity-related comorbidities. Eighteen patients delivered successfully after BMS, but there were still 12 cases of spontaneous abortion and 1 case of induced abortion. The abortion rate in pregnancy intervals less than 2 years was higher than those ≥ 2 years (P = 0.045). Of the women who delivered successfully, 5 had pregnancy-specific complications, including gestational diabetes mellitus and hypertensive disorder of pregnancy. However, the growth and development of the newborn are normal since the birth follow-up.Conclusion: The present results suggest that the abortion rate in pregnancy intervals less than 2 years was higher than those ≥ 2 years. It is recommended that postoperative patients avoid pregnancy until their weight is stable to reduce the risk of adverse pregnancy outcomes.Keywords: pregnancy, bariatric surgery, metabolic surgery, obesity

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

Xuebin Yan,1 Yi Liu,2 Shanzi Yu,1 Dong Huang,1 Rong Hu1 1Department of Pain, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 2Department of Anesthesia, The First Hospital of Changsha, Changsha, People’s Republic of ChinaCorrespondence: Rong Hu, Department of Pain, The Third Xiangya Hospital of Central South University, Changsha, People’s Republic of China, Tel +86 18973162969, Email vroro@126.comObjective: The current study investigated the effects of bone marrow mesenchymal stem cells (BMSCs) on pain behavior in rats with trigeminal neuralgia induced by infraorbital nerve chronic constriction injury (ION-CCI), and the repair effects of BMSCs on pathological changes in trigeminal ganglion demyelination.Methods: BMSCs or phosphate-buffered saline (PBS) alone were injected around trigeminal ganglion in ION-CCI rats via a rat brain stereotaxic apparatus. Mechanical pain threshold (von Frey test) and face grooming behavior were measured in each group. Recovery of demyelination of trigeminal ganglion was observed via electron microscopy 2 weeks later, and BMSC differentiation was observed via immunofluorescence.Results: Rats in the BMSC group exhibited significant improvements in mechanical pain threshold and face grooming behavior compared with the PBS group. BMSCs could repair demyelinating changes in trigeminal ganglion in ION-CCI rats. Only cells expressing GFAP, S-100, and p75 were observed via immunofluorescence, and no PKH67-labeled BMSCs were observed in the trigeminal ganglion. No BMSC differentiation was observed in the trigeminal ganglion.Conclusion: Injection of BMSCs around the trigeminal ganglion could relieve trigeminal neuralgia effectively and repair trigeminal ganglion demyelination. No differentiation of BMSCs injected around the trigeminal ganglion into Schwann cells was observed. The mechanism of trigeminal neuralgia demyelination repair requires further investigation.Keywords: bone marrow mesenchymal stem cells, demyelination, trigeminal neuralgia, treatment

Lingli Chen,1,&ast; Jianfeng Hong,2,&ast; Renjing Hu,3,&ast; Xiaomei Yu,1 Xindong Chen,1 Shaoxiong Zheng,1 Yuan Qin,1 Xiumei Zhou,1 Yigang Wang,1 Liping Zheng,2 Hongming Fang,2 Pengfei Liu,4 Biao Huang1 1Department of Immunoassay Laboratory, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, People’s Republic of China; 2Department of Laboratory, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, People’s Republic of China; 3Department of Laboratory, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 4Department of Gastroenterology, The Jiangyin Clinical College of Xuzhou Medical University, Wuxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Biao HuangImmunoassay Laboratory, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310016, People’s Republic of ChinaTel +86 571-86843187Email jswxhb@163.comHongming FangDepartment of Laboratory, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 310016, People’s Republic of ChinaTel +86 571 83865858Email 3295988078@qq.comPurpose: The present study aimed to evaluate the clinical value of the combined detection of soluble T cell immunoglobulinand mucin domain molecule 3 (sTim-3) and pepsinogen (PG) in sera for gastric cancer (GC) diagnosis.Patients and Methods: The double antibody sandwich method was used to establish a highly sensitive time-resolved fluorescence immunoassay for the detection of sTim-3. Serum sTim-3, PGI, and PGII levels in 149 GC patients (123 first-diagnosis GC patients and 26 post-GC patients), 81 patients with benign gastric disease (BGD), and 73 healthy controls were quantitatively detected. The clinical diagnostic value of the combined detection of sTim-3 and PG in GC was analyzed.Results: Serum sTim-3 levels in GC (20.41 ± 9.55 ng/mL) and BGD (16.50 ± 9.76 ng/mL) patients were significantly higher (P < 0.001) than those in healthy controls (9.22 ± 3.40 ng/mL). Combined detection of sTim-3 and PGI/PGII (AUC: 0.9330, sensitivity: 86.44%, and specificity: 91.78%) showed a high diagnostic value for GC. When the level of PGI/PGII was less than 12.11 and that of sTim-3 was greater than 14.30 ng/mL, the positive rate of the control group was reduced to 0%, and the positive detection rate of GC was 54.47%. In addition, in post-operative patients, serum sTim-3 levels in the recurrence group (33.56 ± 4.91 ng/mL) were significantly higher than those in the no recurrence group (11.95 ± 5.16 ng/mL).Conclusion: sTim-3 levels in BGD and GC sera were significantly higher than those in the control group sera. Additionally, sTim-3 serum levels can predict recurrence in post-operative patients. Compared with PG alone, the combined detection of serum PG and sTim-3 can significantly improve the detection sensitivity and specificity of BGD and GC.Keywords: T cell immunoglobulin and mucin domain molecule 3, time-resolved fluorescence immunoassay, biomarker, gastric cancer

Qin Li,1,&ast; Jie Ren,2,&ast; Wei Liu,3 Guoqin Jiang,2 Rongkuan Hu1 1GenePharma Co., Ltd., Suzhou, 215125, Jiangsu, People’s Republic of China; 2Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqin JiangDepartment of General Surgery, The Second Affiliated Hospital, Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu, People’s Republic of ChinaTel +86-512-67784797Email jiang_guoqin@163.comRongkuan HuGenePharma Co., Ltd., 199 Dongping Street, Suzhou, 215125, Jiangsu, People’s Republic of ChinaTel +86-512-86668828Email rkhu@mail.ustc.edu.cnPurpose: The purpose of our research was to identify and evaluate synthetic phosphorothioate-modified CPG oligodeoxynucleotides (CPG-ODNs) activating innate and adaptive immune responses. Furthermore, combined treatment with CpG and an mRNA cancer vaccine was evaluated in melanoma models as a therapeutic approach.Methods: A molecular assay was used to screen new CpG molecules; mouse modeling and pathological analysis were used to confirm the antitumor effect of CpG alone or in combination with an mRNA vaccine. Finally, safety was assessed by monitoring blood biochemistry.Results: We first screened and identified a new CpG-B class ODN (CpG2018B) that effectively stimulated type II interferons in both mouse plasmacytoid dendritic cells (pDCs) and human peripheral blood mononuclear cells (PBMCs). In addition, CpG2018B promoted cytokine production mainly via toll-like receptor 9 (TLR9) pathways. We further demonstrated that intratumoral (IT) injection of CpG2018B inhibited melanoma growth in syngeneic models and could turn “cold” tumors into “hot” tumors. Then, CpG2018B and an mRNA-based neoantigen cancer vaccine were encapsulated in lipid nanoparticles (LNPs) and intratumorally injected into melanoma mouse models. Interestingly, vaccination with CpG or the mRNA vaccine alone could inhibit tumor growth, while combination of CpG with the mRNA vaccine enhanced the antitumor effect. Finally, we described the long-term safety and tolerability of CpG2018B and mRNA therapy in mice model.Conclusion: We identified a novel CpG-B class ODN to promote the immune response, and CpG combined with mRNA cancer vaccines is an attractive candidate approach for immunostimulatory sequence (ISS)-based therapeutic strategies.Keywords: CpG, IFN-γ, TLR9, mRNA vaccine, neoantigen

Rong Hu,1– 3 Jintao Zhang,1,2,4 Xuemei Liu,1,2 Dong Huang,3 Yu-Qing Cao1,2 1Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA; 2Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA; 3Department of Pain Management, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Yu-Qing CaoDepartment of Anesthesiology, Washington University School of Medicine, 660 South Euclid, Box 8054, St. Louis, MO, 63110, USATel +1 314 362 8726Fax +1 314 362 8334Email caoy@anest.wustl.eduPurpose: Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known. In the present study, we addressed this knowledge gap by treating mice with low-dose interleukin-2 (ld-IL2) injections or adoptive transfer of Treg cells.Methods: Female Swiss Webster mice received daily injections of ld-IL2 (1 μg/mouse, intraperitoneally) either before or after unilateral spared nerve injury (SNI). Male C57BL/6J mice received adoptive transfer of 1 x 106 Treg cells 3 weeks post-SNI. The responses to punctate and dynamic mechanical stimuli on the hindpaw were monitored before and up to 4– 6 weeks post-SNI. We also compared the distribution of Treg cells and CD3+ total T cells after SNI and/or ld-IL2 treatment.Results: Ld-IL2 pretreatment in female Swiss Webster mice completely blocked the development of SNI-induced dynamic mechanical allodynia and reduced the magnitude of punctate allodynia. Delayed ld-IL2 treatment in female mice significantly attenuated the morphine-resistant punctate and dynamic allodynia at 3– 5 weeks post-SNI. Adoptive transfer of Treg cells to male C57BL/6J mice 3 weeks post-SNI effectively reversed the persistent punctate and dynamic allodynia, supporting that the effect of ld-IL2 is mediated through endogenous Treg cells, and is likely independent of mouse strain and sex. Neither ld-IL2 treatment nor Treg transfer affected the basal responses to punctate or brush stimuli. Ld-IL2 significantly increased the frequency of Treg cells among total CD3+ T cells in the injured sciatic nerves but not in the uninjured nerves or the dorsal root ganglia, suggesting the injured nerve as ld-IL2’s site of action.Conclusion: Collectively, results from the present study supports Treg as a cellular target and ld-IL2 as a potential therapeutic option for nerve injury-induced persistent punctate and dynamic mechanical allodynia.Keywords: spared nerve injury, chronic pain, punctate allodynia, dynamic allodynia, low-dose interleukin-2, regulatory T cell

Chao Zhang, Jun Zhong, Wei-Xiang Chen, Xu-Yang Zhang, Yu-Hong Li, Teng-Yuan Zhou, Yong-Jie Zou, Chuan Lan, Lan Li, Zhao-Pan Lai, Hua Feng, Rong Hu Department of Neurosurgery and Key Laboratory of Neurotrauma, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of ChinaCorrespondence: Rong Hu; Hua Feng Email huchrong@tmmu.edu.cn; fenghua8888@vip.163.comBackground: Inflammation plays an essential role in secondary brain injury after intracerebral hemorrhage (ICH). Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have been suggested to suppress neuroinflammation after central nervous system (CNS) damage in animal models. However, the role of ACEIs and ARBs in ICH patients with hypertension remains unresolved in clinic. The aim of the present study is to evaluate the effect of ACEIs/ARBs on ICH patients with hypertension using a retrospective, single-center data analysis.Methods: ICH patients diagnosed by computerized tomographic (CT) at Southwest Hospital, Third Military Medical University were included in the present research from January 2015 to December 2019. According to the medical history for the usage of antihypertensive drugs, patients were assigned into either ACEIs/ARBs group or non-ACEIs/ARBs group. Demographics, clinical baseline, radiological documents and treatments were collected and these data were statistically analyzed between the two groups.Results: A total of 635 ICH patients with hypertension were included and allocated into 2 groups according to the usage of antihypertensive drugs: 281 in the ACEIs/ARBs group and 354 in the non-ACEIs/ARBs group. The results presented that the 3-months mortality and prevalence of ICH-associated pneumonia were lower in ACEIs/ARBs group than that in non-ACEIs/ARBs group (5.0% vs 11.9%, p=0.002; 58.4% vs 66.7%, p=0.031). While, there was no significant difference in favorable outcome (40.2% vs 33.9%, p=0.101) between the two groups. Furthermore, patients in ACEIs/ARBs group exhibited significantly less perihematomal edema volume on days 3 (23.5 ± 14.4 versus 28.7 ± 20.1 mL, p=0.045) and 7 (21.0 ± 13.7 versus 25.7 ± 17.6 mL, p=0.044), compared to that in non- ACEIs/ARBs group.Conclusion: The usage of ACEIs/ARBs helps decrease mortality, perihematomal edema volume, and prevalence of ICH-associated pneumonia in ICH patients with hypertension.Keywords: angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, inflammation, intracerebral hemorrhage, ICH-associated pneumonia

Bo Zhao,1,* Renjing Hu,2,* Lei Gong,1 Xiaoyun Wang,1 Yingwei Zhu,1 Gaojue Wu1 1Department of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 2Department of Clinical Laboratory, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyun WangDepartment of Gastroenterology, The Affiliated Wuxi Second People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of ChinaTel +86 15061857125Fax +86 510 685662052Email xiaoyunwang68@aliyun.comRationale: Klebsiella pneumoniae (K. pneumoniae, KP) are divided into two types: classic K. pneumoniae (cKP) and hypervirulent K. pneumoniae (hvKP). hvKP causes liver abscess and metastatic infection. Here, we report one case with pyogenic liver abscess (PLA) and endogenous endophthalmitis (EE) due to a relatively rarely reported serotype of K. pneumoniae in China.Patient Concerns: An 80-year old man presented with nausea, vomiting, and epigastric discomfort for 2 weeks.Diagnoses: PLA was identified by CT scan and abdominal ultrasound. Urgent ophthalmologic consultation was performed. B-scan ocular ultrasound was done and he was diagnosed as EE.Interventions: Antibiotic treatment, intravitreal injection of eyes and eye drops were given. Percutaneous needle aspiration, evisceration, and drainage of the right eye were performed.Outcomes: Cultures of the blood, the aspirated pus from the liver abscess, and the contents of the eyeball all yielded K. pneumoniae with a positive string test. The capsular serotype was K64. According to the existence of multiple virulence genes and the severe invasive clinical manifestation, this strain is regarded as a hvKp strain. Multilocus sequence typing (MLST) revealed the sequence type (ST) of this strain was K64-ST1764. Antimicrobial resistance genes, blaNDM-1 and blaKPC-2, were not detected in the genome. The patient lost his eyesight but his symptoms subsided. During 15 months follow-up, the result was satisfactory.Lessons: Here, we report one case with PLA due to a relatively rarely reported serotype of K. pneumoniae in China. This K64 K. pneumoniae strain is confirmed as hvKp by multiple methods. It is noteworthy that the sequence type is K64-ST1764 instead of the commonest ST11. Moreover, this strain is not considered a K. pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) or a carbapenem-resistant K. pneumoniae (CRKP) as it is usually. Further follow-up and research are required to investigate this strain.Keywords: case report, hypervirulent Klebsiella pneumoniae, pyogenic liver abscess, antibiotic resistance, ultrasonography guided puncture aspiration

Yutong Xing,1,2,* Peng Luo,2,* Rui Hu,1 Duanduan Wang,1 Gang Zhou,2 Jie Jiang3 1Department of Cardiothoracic Surgery, The Fifth Hospital of Xiamen, Xiamen, People’s Republic of China; 2Department of Cardiothoracic Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, People’s Republic of China; 3Department of Thoracic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yutong Xing Department of Cardiothoracic SurgeryThe Fifth Hospital of Xiamen, Xiamen, Fujian 361101, People’s Republic of ChinaEmail xingyt2018@163.comBackground: The pseudokinase Tribbles 3 (TRIB3) is involved in many cellular processes and various cancers. In recent years, the importance of metabolic transformation in the maintenance of malignant tumors has become increasingly prominent. Abnormal metabolism of cancer cells is considered a hallmark of cancer. However, the exact role and molecular mechanism of TRIB3 in lung adenocarcinoma (LUAD) cell reprogramming is largely unknown.Methods: The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) of cells were examined with a Seahorse XF Extracellular Flux Analyzer. In vitro and in vivo RT-qPCR, Western blotting, and functional assays were performed to explore the functional roles of TRIB3 in LUAD.Results: In the present study, we demonstrated that TRIB3 is remarkably upregulated in LUAD cell lines as well as tissues. TRIB3 knockdown significantly inhibited LUAD cell growth and suppressed LUAD cell invasion, while TRIB3 overexpression conferred the opposite effects. Moreover, silencing TRIB3 suppressed the tumorigenesis and metastatic ability of LUAD cells. Mechanistically, we demonstrated that silencing TRIB3 significantly impaired aerobic glycolysis ability in LUAD cells. Furthermore, our data indicated that TRIB3 knockdown decreased hypoxia-inducible factor (HIF)1α levels and targeted the glycolytic genes regulated by HIF1α.Conclusion: Together, our findings revealed a previously unappreciated function of TRIB3 in cancer cell metabolism and tumor progression, illustrating that TRIB3 could be considered a valuable therapeutic target for LUAD patients.Keywords: TRIB3, LUAD, aerobic glycolysis, HIF1α

Wei Chang, Wen Xu, Rong Hu, Yunsong An Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, People’s Republic of ChinaCorrespondence: Wen Xu Email xuwendoc@126.comPurpose: Satisfactory quantitative diagnostic approaches to pharyngeal paresthesia patients with depression or anxiety remain to be explored. This study investigated the plausibility of current perception threshold (CPT) testing in diagnosing pharyngeal paresthesia in patients with depression or anxiety.Patients and Methods: A total of 41 patients with pharyngeal paresthesia with depression or anxiety were recruited as the study group. Additionally, 60 healthy volunteers constituted the control group. The CPT values associated with 5-, 250-, and 2000-Hz electrical stimulation frequencies were measured at the palatal lingual arch and posterior third of the lingual body (two sensory nerve distribution sites in the pharynx). The normal range of CPT values of the above three frequencies was analyzed. The differences in the CPT values for sensory nerves were compared.Results: There were no significant differences in age and sex between the study and control groups. The CPT values of the pharynx at the two tested sites were not significantly correlated with age and gender. The CPT value of the study group was significantly lower than that of the control group in the palatal lingual arch and posterior third of the lingual body at an electrical stimulation of 5 Hz (p< 0.05). No significant differences in the CPT values at other frequencies were found between the two groups.Conclusion: CPT testing is effective in determining pharyngeal paresthesia in patients with depression and anxiety. Paresthesia of the pharyngeal sensory nerve region is caused by damaged C fibers.Keywords: pharyngeal paresthesia, sensory nerve fibers, current perception threshold testing, reference values, depression, anxiety

Meng-Long Zhou,1,2,* Wang Yang,1,2,* Ya-Qi Wang,1,2,* Miao Mo,2,3 Ran Hu,1,2 Yan Wang,1,2 Jia-Ning Yang,1,2 Gui-Chao Li,1,2 Ya-Nong Wang,2,4 Zhen Zhang1,21Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Cancer Prevention, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China; 4Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workPurpose: N3 gastric cancer (GC) is characterized by a heavy burden of lymph node metastasis and a high postoperative recurrence rate. The role of radiotherapy in this group of patients remains undetermined. The purpose of this study was to compare the effectiveness of adjuvant chemoradiotherapy (CRT) and adjuvant chemotherapy (ChT) for N3 GC after D2/R0 resection.Patients and methods: From January 2004 to December 2015, patients with N3 GC in the database of Fudan University Shanghai Cancer Center were retrospectively reviewed. The eligible patients were enrolled in an adjuvant CRT group and an adjuvant ChT group. Four different methods based on a propensity score model were used to balance the baseline characteristics. Then, survival analyses between the two groups were performed in addition to patterns of recurrence and subgroup analyses.Results: In total, 175 and 365 eligible patients were enrolled into the CRT and ChT groups, respectively. After balancing, the disease-free survival (DFS) of patients in the CRT group was significantly better than that of patients in the ChT group (p=0.021). Subgroup analyses showed that patients with N3a GC benefitted from adjuvant CRT.Conclusion: Compared with adjuvant ChT, adjuvant CRT can further improve the DFS of patients with N3 GC after D2/R0 resection. Patients with lymph node metastases should be further stratified when selecting patients for adjuvant CRT.Keywords: stomach neoplasms, gastrectomy, chemoradiation, propensity score, survival analysis

Min Li,1 Rong Hu,2 Xiaoyang Liu,3 Shuping Tao,4 Biaoxue Rong1,5 1Department of Respiratory Medicine, Shenmu Hospital, Shenmu, Shaanxi, China; 2Department of Nursing, Shenmu Hospital, Shenmu, Shaanxi, China; 3Department of Surgery, Shenmu Hospital, Shenmu, Shaanxi, China; 4Department of Respiratory Medicine, Gansu Provincial Hospital, Lanzhou, Gansu, China; 5Department of Respiratory Medicine, First Affiliated Hospital, Xi’an Medical University, Xi’an, Shaanxi China Background: The aim of this study was to evaluate the efficacy of extended care in patients with COPD. Patients and methods: A total of 140 patients with GOLD-2 to -4 of COPD were included in final analysis. The care efficacy was evaluated by the St George’s Respiratory Questionnaire 12-item General Health Questionnaire (GHQ-12), pulmonary function test and blood gas analysis. Results: The extended care improved the activity ability of COPD patients, relieved the clinical symptoms as well as reduced the impact degree of COPD to daily life (P

Xin-lin Li,1,* Hui-juan Cao,1,* Ya-jing Zhang,1 Rui-xue Hu,1 Bao-yong Lai,1 Nan-qi Zhao,1 Hui Hu,2 Zhan-guo Xie,3 Jian-Ping Liu1 1Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 100029, China; 2The Department of Acupuncture and Metabolic Diseases, Eastern Hospital Affiliated to Beijing University of Chinese Medicine, Fengtai District, Beijing, China; 3The Department of Acupuncture and Moxibustion, First People’s Hospital of Dongcheng District, Beijing, China *These authors contributed equally to this work Objective: To explore the influence of patients’ participation in and completing the acupuncture clinical trials through a cross-sectional survey. In addition, we explored potential factors involved in improving patient’s compliance to treatment, thus enhancing the quality of acupuncture clinical studies.Methods: A survey was conducted at outpatient department of acupuncture and metabolic diseases in two hospitals in Beijing. The semi-structured questionnaire was designed based on literature review and Delphi methods. It contains 15 questions related to patients’ experience and attitude. SPSS 22.0 was used for analyses. OR and 95% CI were used for dichotomous outcomes. Logistic regression analysis (LRA) and multi-LRA were used to explore the factors influencing patients’ participation or completion and the relationship between demographic characteristics and potential factors.Results: A survey was conducted from April to September 2016. Five hundred patients were consecutively sampled to fill semi-structured questionnaires regardless of their types of disease. The participants (75.2% were female) were in the age range of 15–85 years and all of them completed the survey. The effect and safety of acupuncture therapy were considered to be the deciding factors by 92% and 96% of the respondents, respectively. Only 40 of the surveyed participants (8.0%) had previously participated in the clinical trials. The LRA showed they paid more attention to treatment regimen (frequency and session of treatment) when deciding whether or not to participate in the trials (OR 1.54, 95% CI 1.02–2.34). Multivariate LRA showed that elder people considered cost (OR 1.36, 95% CI 1.09–1.70) to be an important factor, while the participants having medical insurance (OR 1.45, 95% CI -0.20–0.93) thought informed consent was important. Meanwhile, participants with higher education preferred regular follow-up (OR 1.16, 95% CI 0.02–0.28).Conclusion: After providing adequate information regarding the potential benefits and harms of the acupuncture treatment, completion of the treatment within the specific time regimen was found to be the most important factor affecting patient’s compliance. Other factors, such as cost and regular follow-up, should also be given special consideration. Keywords: patient compliance, acupuncture, clinical trials, cross-sectional study

Yaqi Wang,1,2,* Lifeng Yang,1,2,* Menglong Zhou,1,2 Lijun Shen,1,2 Jing Zhang,1,2 Weijuan Deng,1,2 Liping Liang,1,2 Ran Hu,1,2 Wang Yang,1,2 Ye Yao,1,2 Zhen Zhang1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China *These authors contributed equally to this work Purpose: To investigate whether young patients exhibit different characteristics and survival according to tumor location and stage using data from the Surveillance, Epidemiology, and End Results (SEER) database.Patients and methods: Young patients (20–49 years old) with stage I–III colon cancers were identified from the SEER program from 1990 to 2014. Kaplan–Meier survival analysis and Cox proportional hazards regression were used to analyze the data. Subset analyses were also done among different age and stage subgroups.Results: Of 8197 patients, 3709 (45.2%) had right-sided colon cancers (RCCs). Patients with RCCs were more likely to be male, to be younger, and to have more poorly differentiated and more advanced tumors. The Kaplan–Meier survival curves and univariate survival models revealed that left-sided colon cancers (LCCs) had lower mortality for all stages combined and stage III, but higher mortality for stage II, compared with right-sided tumors. However, multivariate Cox regression models showed no significant survival differences by location for all patients (adjusted hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.86–1.05; P=0.34) or for stage I (adjusted HR, 1.47; 95% CI, 0.82–2.63; P=0.20). Stage II left-sided cancers had higher mortality (adjusted HR, 1.24; 95% CI, 1.00–1.54; P=0.048), whereas stage III left-sided cancers had lower mortality (adjusted HR, 0.86; 95% CI, 0.77–0.97; P=0.01). For 20- to 39-year-old patients, a significant difference was only found in stage II disease, with a higher mortality for left-sided tumors (adjusted HR, 1.82; 95% CI, 1.12–2.97; P=0.02). However, for 40- to 49-year-old patients, a significant difference was only found in stage III disease, with a lower mortality for left-sided tumors (adjusted HR, 0.83; 95% CI, 0.72–0.95; P=0.008).Conclusion: In patients younger than 50 years, there were no significant differences in mortality between RCCs and LCCs for all stages combined after adjusting for multiple clinicopathological features. However, RCCs had lower mortality in stage II (especially in 20- to 39-year-old patients) and higher mortality in stage III (especially in 40- to 49-year-old patients). Keywords: young patients, survival, right-sided colon cancers, left-sided colon cancers, stages, SEER

In recent years, there has been renewed interest in Molten Salter Reactors (MSRs) for their potential advantages compared to reactors that rely on solid fuel. In response to such interest, the System Analysis Module (SAM) was enhanced to include MSR-specific modeling features including a delayed neutron precursor drift model and a modified point kinetics model. This paper discusses the validation of these features using the experiments conducted in the Molten Salt Reactor Experiment (MSRE). These experiments include the pump start-up and coast-down tests at zero power and a thermal convection test. For the zero power tests, the change in pump speeds induces flow rate changes in the core that impact the precursor concentrations. This introduces a neutron imbalance and requires the adjustment of the control rods to counter-balance this effect. SAM was used to evaluate the precursor concentration in the core as a function of time, and the resulting changes in reactivity were evaluated through the modified point kinetics equation. The results show good agreement with the experimental data. It should be noted that the pump performance curve used in this analysis was re-constructed based on the initial water test data of the fuel pump. The steady-state pump curve is assumed to be applicable to transient flow operations. The thermal convection test was conducted by shutting off the pumps, reducing the inlet core temperature for 360 minutes, and allowing the power to be adjusted by the inherent feedbacks of the system. The power level during this transient was evaluated by SAM as a function of time.

Jia-Xin Shi,1 Jia-Shu Li,1 Rong Hu,1 Xiao-Min Li,2 Hong Wang3 1Department of Respiratory Medicine, Lianyungang First People’s Hospital, Affiliated Hospital of Xuzhou Medical University, Affiliated Hospital of the Clinical Medical School of Nanjing Medical University, Clinical Medical School of Jiangsu University, Lianyungang, 2Department of Critical Care Medicine, Lianyungang First People’s Hospital, Affiliated Hospital of Xuzhou Medical University, Affiliated Hospital of the Clinical Medical School of Nanjing Medical University, Clinical Medical School of Jiangsu University, Lianyungang, 3Department of Respiratory Medicine, Jiangsu Province Hospital, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China Abstract: The carbon catabolite repressor protein 4 (CCR4)–negative on TATA (NOT) complex includes multiple subunits and is conserved in the eukaryotic cells. The CCR4–NOT complex can regulate gene expression at different levels. Two subunits of the CCR4–NOT complex, CCR4 and CCR4-associated factor 1 (CAF1), possess deadenylase activity. In yeast, the deadenylase activity is mainly provided by the CCR4 subunit; however, the deadenylase activity is provided by both CCR4 and CAF1 in other eukaryotes. A previous study reported that CAF1 but not CCR4 is required for the decay of a reporter mRNA with AU-rich elements. Our previous study showed that CAF1 is involved in the regulation of intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8) expression. Both ICAM-1 and IL-8 play crucial roles in acute lung injury. In the present study, we examined the effects of CAF1 deficiency on IL-8 and ICAM-1 expression and acute lung injury in mice. Here we showed that there were no differences between the wild-type and CAF1-knockout mice on phenotypes. The lung histology and protein and mRNA levels of IL-8 and ICAM-1 in unstimulated wild-type mice were comparable to those in unstimulated CAF1-knockout mice. However, lipopolysaccharide stimulation led to more severe lung histological injury and greatly higher IL-8 and ICAM-1 expression in CAF1-knockout mice compared to the wild-type mice. These results, together with our previous study, suggest that CAF1 is involved in the regulation of lipopolysaccharide-stimulated IL-8 and ICAM-1 expression in vivo and affects the progression of acute lung injury. Keywords: CAF1, knockout, mice, acute lung injury, IL-8, ICAM-1

Qingjuan Shi,1 Hong Zheng,2 Rongdang Hu1 1Department of Orthodontics, Hospital of Stomatology, Wenzhou Medical University, 2Department of Stomatology, People Hospital of Wenzhou, Wenzhou, People’s Republic of China Background: Previous studies have reported some evaluation methods about profiles, but so far, they have no consistent agreement on the esthetic profiles of color images. Thus, the aim of this study was to determine whether the judges have different preferences about the color of the photograph and lip position for esthetic profiles when comparing a Chinese boy and girl.Methods: The photographic records of a Chinese boy and girl with a good balanced profile were randomly selected. The images of the patients’ profile were altered to produce silhouettes and black and white and color photographs (a total of six images). After evaluation by the judges, the best two photographs of the boy and girl were used to produce images of anterior–posterior lip positions with -6, -4, -2, 0, +2, +4, and +6 mm in relation to the esthetic plane, which was created by Ricketts. The judges were invited to enumerate the images in the order in which they considered the most attractive.Results: The chromophotograph was chosen as the best way to express the facial profile in both the boy and girl. The profiles with a deviation of -4 mm in the boy and a deviation of -2 mm in the girl from line E were considered as the most attractive, and the image with a deviation of +6 mm from the normal line E was considered the least attractive. There were statistically significant differences between the preferences of the profiles of the boy and girl; the same results were recorded in the variables educational background and clinic role of the judges.Conclusion: The chromophotograph was considered as the best way to evaluate the esthetic profiles, and the judges preferred the boy with a concave profile than the concave profile of the girl. Keywords: orthodontic, esthetic, chromophotograph

Li X, Cao H, Zhang Y, Hu R, Lai B, Zhao N, Hu H, Xie Z, Liu JP. Patient Prefer Adherence. 2019;13:53–61.Page 53, Abstract, Results section, the text “Multivariate LRA showed that elder people considered cost (OR 1.36, 95% CI 1.09–1.70) to be an important factor, while the participants having medical insurance (OR 1.45, 95% CI -0.20–0.93) thought informed consent was important. Meanwhile, participants with higher education preferred regular follow-up (OR 1.16, 95% CI 0.02–0.28).” should read “Multivariate LRA showed that elder people considered cost (OR 1.36, 95% CI 1.09–1.70) to be an important factor, while the participants having medical insurance (OR 1.45, 95% CI 0.82–2.54) thought informed consent was important. Meanwhile, participants with higher education preferred regular follow-up (OR 1.16, 95% CI 1.02–1.32). Read the original article

Xiaomin Liu,1,* Rui Hu,2,* Hongwei Lian,1,3 Yang Liu,4 Jing Liu,1 Jianwei Liu,1 Guimiao Lin,5 Liwei Liu,6 Xiaojian Duan,1 Ken-Tye Yong,2 Ling Ye1 1Institute of Gerontology and Geriatrics, Chinese PLA General Hospital, Beijing Key Lab of Aging and Geriatrics, Beijing, People’s Republic of China; 2School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore, Singapore; 3Department of Emergency Medicine, Peking University Third Hospital, Beijing, 4Department of Geriatric Nephrology, Chinese PLA General Hospital, Beijing, 5Key Lab of Biomedical Engineering, School of Medical Sciences, Shenzhen University, Shenzhen, 6School of Science, Changchun University of Science and Technology, Changchun, People’s Republic of China *These authors contributed equally to this work Abstract: Diabetes is one of the major chronic diseases diagnosed worldwide with a common complication of diabetic nephropathy (DN). There are multiple possible mechanisms associated with DN. Aldose reductase (AR) and Toll-like receptor 4 (TLR4) may be involved in the occurrence and development of DN. Here, we describe the distribution of AR and TLR4 in cells and renal tissues of diabetic rats through a quantum dot (QD)-based immunofluorescence technique and conventional immunohistochemistry. As a new type of nanosized fluorophore, QDs have been recognized in imaging applications and have broad prospects in biomedical research. The results of the reported study demonstrate that both the AR and the TLR4 proteins were upregulated in the renal tissues of diabetic rats. Further, to explore the relationship between AR and TLR4 in the pathogenesis of DN, a dual-color immunofluorescent labeling technique based on QDs was applied, where the expressions of AR and TLR4 in the renal tissues of diabetic rats were simultaneously observed – for the first time, as far as we are aware. The optimized QD-based immunofluorescence technique has not only shown a satisfying sensitivity and specificity for the detection of biomarkers in cells and tissues, but also is a valuable supplement of immunohistochemistry. The QD-based multiplexed imaging technology provides a new insight into the mechanistic study of the correlation among biological factors as well as having potential applications in the diagnosis and treatment of diseases. Keywords: diabetic nephropathy, TLR4, immunofluorescence, immunohistochemistry

Xiaomin He,1,* Bei Feng,1,2,* Chuanpei Huang,1 Hao Wang,1 Yang Ge,1 Renjie Hu,1 Meng Yin,1 Zhiwei Xu,1 Wei Wang,1 Wei Fu,1,2 Jinghao Zheng1 1Department of Pediatric Cardiothoracic Surgery, 2Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Electrospinning has recently received considerable attention, showing notable potential as a novel method of scaffold fabrication for cartilage engineering. The aim of this study was to use a coculture strategy of chondrocytes combined with electrospun gelatin/polycaprolactone (GT/PCL) membranes, instead of pure chondrocytes, to evaluate the formation of cartilaginous tissue. We prepared the GT/PCL membranes, seeded bone marrow stromal cell (BMSC)/chondrocyte cocultures (75% BMSCs and 25% chondrocytes) in a sandwich model in vitro, and then implanted the constructs subcutaneously into nude mice for 12 weeks. Gross observation, histological and immunohistological evaluation, glycosaminoglycan analyses, Young’s modulus measurement, and immunofluorescence staining were performed postimplantation. We found that the coculture group formed mature cartilage-like tissue, with no statistically significant difference from the chondrocyte group, and labeled BMSCs could differentiate into chondrocyte-like cells under the chondrogenic niche of chondrocytes. This entire strategy indicates that GT/PCL membranes are also a suitable scaffold for stem cell-based cartilage engineering and may provide a potentially clinically feasible approach for cartilage repairs. Keywords: electrospinning, nanocomposite, cartilage tissue engineering, nanomaterials, stem cells

Wei Fu,1,2,* Zhenling Liu,1,* Bei Feng,1,2 Renjie Hu,1 Xiaomin He,1 Hao Wang,1 Meng Yin,1 Huimin Huang,1 Haibo Zhang,1 Wei Wang11Department of Pediatric Cardiothoracic Surgery, 2Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China*These authors contributed equally to this workAbstract: Electrospun hybrid nanofibers prepared using combinations of natural and synthetic polymers have been widely investigated in cardiovascular tissue engineering. In this study, electrospun gelatin/polycaprolactone (PCL) and collagen/poly(l-lactic acid-co-ε-caprolactone) (PLCL) scaffolds were successfully produced. Scanning electron micrographs showed that fibers of both membranes were smooth and homogeneous. Water contact angle measurements further demonstrated that both scaffolds were hydrophilic. To determine cell attachment and migration on the scaffolds, both hybrid scaffolds were seeded with human umbilical arterial smooth muscle cells. Scanning electron micrographs and MTT assays showed that the cells grew and proliferated well on both hybrid scaffolds. Gross observation of the transplanted scaffolds revealed that the engineered collagen/PLCL scaffolds were smoother and brighter than the gelatin/PCL scaffolds. Hematoxylin and eosin staining showed that the engineered blood vessels constructed by collagen/PLCL electrospun membranes formed relatively homogenous vessel-like tissues. Interestingly, Young's modulus for the engineered collagen/PLCL scaffolds was greater than for the gelatin/PCL scaffolds. Together, these results indicate that nanofibrous collagen/PLCL membranes with favorable mechanical and biological properties may be a desirable scaffold for vascular tissue engineering.Keywords: electrospinning, gelatin, collagen, polycaprolactone, poly(l-lactic acid-co-ε-caprolactone)

Real-world data can be multimodal distributed, e.g., data describing the opinion divergence in a community, the interspike interval distribution of neurons, and the oscillators' natural frequencies. Generating multimodal distributed real-world data has become a challenge to existing generative adversarial networks (GANs). For example, it is often observed that Neural SDEs have only demonstrated successful performance mainly in generating unimodal time series datasets. In this paper, we propose a novel time series generator, named directed chain GANs (DC-GANs), which inserts a time series dataset (called a neighborhood process of the directed chain or input) into the drift and diffusion coefficients of the directed chain SDEs with distributional constraints. DC-GANs can generate new time series of the same distribution as the neighborhood process, and the neighborhood process will provide the key step in learning and generating multimodal distributed time series. The proposed DC-GANs are examined on four datasets, including two stochastic models from social sciences and computational neuroscience, and two real-world datasets on stock prices and energy consumption. To our best knowledge, DC-GANs are the first work that can generate multimodal time series data and consistently outperforms state-of-the-art benchmarks with respect to measures of distribution, data similarity, and predictive ability.