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Ruixue Zhang,1 Hui Xu,1 Xiaoxue Zhang,1 Hui Xiong,2 Fei Tang,3 Liping Lv,3 Xiangdong Mu,4 Wei Tian,5 Yueguang Cheng,6 JianRong Lu,6 Xiuhong Nie,7 Yang Guo,8 Yingying Liu,9 Zhi Zhang,10 Lianjun Lin1 1Department of Geriatrics, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Emergency, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Interventional Pulmonology, Anhui Province Chest Hospital, Hefei, People’s Republic of China; 4Department of Respiratory, Tsinghua Changgung Hospital, Beijing, People’s Republic of China; 5Department of Geriatrics, Jishuitan Hospital, Beijing, People’s Republic of China; 6Department of Emergency, Jingmei Group General Hospital, Beijing, People’s Republic of China; 7Department of Respiratory, Xuanwu Hospital, Beijing, People’s Republic of China; 8Department of Endoscopic Diagnosis &treatment, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 9CapitalBio Technology Co., Ltd, Beijing, People’s Republic of China; 10Bio Biological Group Co., Ltd, Beijing, People’s Republic of ChinaCorrespondence: Lianjun Lin, Department of Geriatrics, Peking University First Hospital, No. 8 Xishiku Avenue, Beijing, 100034, People’s Republic of China, Email 06474@pkufh.comPurpose: The detection of pathogenic microorganisms plays a significant role in the diagnosis and management of pneumonia that are responsible for a substantial number of deaths worldwide. However, conventional microbiological tests (CMT) have low accuracy and are time-consuming. In this study, we aim to evaluate the clinical value of Chips for Complicated Infection Detection (CCID) in detecting pneumonia pathogens.Patients and Methods: This study was conducted at nine hospitals in China from January 2021 to September 2022. Respiratory samples from adult pneumonia patients were collected from each patient. CMT and CCID were performed in parallel to identify the pathogens.Results: A total of 245 patients were included, with 73% being elderly. CCID identified pathogenic microbes in 78.0% of patients and conventional microbiological tests (CMT) in 57.1% of the patients (p< 0.001). The overall positive and negative percent agreements between CCID and CMT for pathogen detection were 90.07% and 38.46%, respectively. 38.8% of patients were diagnosed with mixed infections with at least two pathogens by CCID. Bacterial infections identified by CCID accounted for 60.0% of 245 patients, with the top 3 being Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterococcus faecium, respectively. K. pneumoniae was the most common pathogen in elderly patients, with a significantly higher prevalence compared to non-elderly patients (p = 0.0011). Among the 197 patients who had used antibiotics before sample collection, the positive rate of CCID was significantly higher than that of CMT (p < 0.001).Conclusion: This study indicates that compared to CMT, this novel chip has significant advantages in detecting pathogens in pneumonia patients, especially in the elderly.Keywords: pneumonia, elderly, pathogens, chip, LAMP

Xinyang Nie,1– 3,&ast; Jian Liu,1,2,&ast; Daohan Wang,1,2,&ast; Chuan Li,1,2 Yuxin Teng,1,2 Zhufeng Li,1,2 Yangpu Jia,1,2 Peiyao Wang,1,2 Jingyu Deng,2,3 Weidong Li,1,2 Li Lu1,2 1Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Tianjin Medical University, Tianjin, People’s Republic of China; 3Department of Gastric Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Lu; Weidong Li, Department of General surgery, Tianjin Medical University General Hospital, 154, Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China, Email luli_1989@126.com; tjmughgs_lwd@163.comBackground: Cisplatin (DDP) resistance in gastric cancer (GC) is likely to come from gastric cancer stem cells (GCSC). It is a new idea to study the mechanism of the DDP-resistance in GCSC from miRNA.Materials and Methods: CD44+ GCSCs and CD44- control cells were constructed based on the HGC27 gastric cancer cell line. DDP sensitivities in CD44+ and CD44- cells were detected via CCK-8 assay. The differential expression of miR-21-5p in these cell lines was detected by RT‒qPCR. The expression levels of downstream TGF-β 2, SMAD2 and SMAD3 were determined through RT‒PCR and Western blotting. A luciferase assay was used to detect the relationship between miR-21-5p and TGFB2, and the TCGA database, clinical data from our centre, and vivo experiment were used for validation. Finally, we knocked down miR-21-5p to detect changes in cisplatin resistance in GCSCs and to verify changes in the levels of downstream pathways in GCSCs.Results: CD44+ GCSCs induced cisplatin resistance compared with CD44- cells. miR-21-5p was highly expressed in GCSCs, and the TGF-β 2/SMAD pathway was also highly expressed. TGFB2 was proven to be a downstream target gene of miR-21-5p and had a positive relationship with it in phenotype. After knockdown of miR-21-5p, the TGF-β 2/SMAD pathway was also inhibited, and the resistance of GCSCs to cisplatin was specifically decreased.Conclusion: MiR-21-5p promotes cisplatin resistance in gastric cancer stem cells by regulating the TGF-β 2/SMAD signalling pathway.Keywords: miR-21-5p, cisplatin resistance, GCSCs, TGF-β 2 pathway

Zhiyuan Wang,1,&ast; Ruilin Wang,1,&ast; Xiaoyu Li,1,&ast; Lin Bai,1 Pingan Fan,1 Yuanyuan Tang,2 Xin Li,3 Yangmu Huang,4 Xiaoyan Nie,1,5 Sheng Han,1,5 Luwen Shi,1,5 Jing Chen1,5 1Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 2Bidding Management Office, Suqian First Hospital, Suqian, Jiangsu, People’s Republic of China; 3Department of Clinical Pharmacy, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 4School of Public Health, Peking University, Beijing, People’s Republic of China; 5International Research Center for Medicinal Administration, Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Chen, Email jingchen@bjmu.edu.cnBackground: Although affordable generics could probably contribute to the solution of rapidly increasing pharmaceutical expenditure, those drugs are prescribed at a lower rate in China. Physicians’ perception and knowledge of generics have a great influence on their prescribing behavior.Objective: This study aimed to identify factors that affect physicians’ generic prescribing behavior based on the theory of planned behaviors (TPB).Methods: Data were collected by both electronic and paper-based surveys from 1297 Chinese physicians, and 1047 surveys were retained. The structural equation model (SEM) was employed to investigate the relationship between four behavioral constructs, namely, attitudes, subjective norms, perceived control of behaviors, and intentions.Results: About 50% of Chinese physicians had a positive attitude towards generic drugs that had passed the “Consistency Evaluation of Quality and Efficacy of Generic Drugs” (high-quality generic drugs), but their knowledge of generic drugs was relatively inadequate. The path coefficients for the effect of attitudes, subjective norms, and perceived behavioral control on behavioral intention were 0.285, 0.366, and 0.322 respectively. The path coefficients for the effect of behavioral intention and perceived behavioral control on prescribing behavior were 0.009 and 0.410 respectively.Conclusion: Physicians’ attitudes, subjective norms, and perceived behavioral control were significant positive correlation predictors of behavioral intention. Subjective norms and perceived behavior control had a greater impact than attitude on physicians’ prescribing intention. However, the generic prescribing behavior is not under the volitional control of Chinese physicians. Physicians’ prescribing practice is likely affected by perceived strong control over prescribing generic drugs.Keywords: generic prescribing behavior, perception, structural equation model, theory of planned behaviors

Jie Liu,1,&ast; Xiajie Huang,1,&ast; Hongjie Su,1 Jie Yu,1 Xinyu Nie,1 Kaibing Liu,1 Wencong Qin,1 Yongxin Zhao,1 Yongfeng Su,1 Xiaocong Kuang,2 Di Chen,3 William W Lu,4 Yan Chen,1 Qikai Hua1 1Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 2Yulin Campus of Guangxi Medical University, Yulin, Guangxi, People’s Republic of China; 3Research Center for Computer-Aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China; 4Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong&ast;These authors contributed equally to this workCorrespondence: Yan Chen; Qikai Hua, Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China, Email cy003@connect.hku.hk; hqk100@yeah.netPurpose: Management of severe diabetic foot ulcers (DFUs) remains challenging. Tibial cortex transverse transport (TTT) facilitates healing and limb salvage in patients with recalcitrant DFUs. However, the underlying mechanism is largely unknown, necessitating the establishment of an animal model and mechanism exploration.Methods: Severe DFUs were induced in rats, then assigned to TTT, sham, or control groups (n=16/group). The TTT group underwent a tibial corticotomy, with 6 days each of medial and lateral transport; the sham group had a corticotomy without transport. Ulcer healing was assessed through Laser Doppler, CT angiography, histology, and immunohistochemistry. Serum HIF-1α, PDGF-BB, SDF-1, and VEGF levels were measured by ELISA.Results: The TTT group showed lower percentages of wound area, higher dermis thickness (all p < 0.001 expect for p = 0.001 for TTT vs Sham at day 6) and percentage of collagen content (all p < 0.001) than the other two groups. The TTT group had higher perfusion and vessel volume in the hindlimb (all p < 0.001). The number of CD31+ cells (all p < 0.001) and VEGFR2+ cells (at day 6, TTT vs Control, p = 0.001, TTT vs Sham, p = 0.006; at day 12, TTT vs Control, p = 0.003, TTT vs Sham, p = 0.01) were higher in the TTT group. The activity of HIF-1α, PDGF-BB, and SDF-1 was increased in the TTT group (all p < 0.001 except for SDF-1 at day 12, TTT vs Sham, p = 0.005). The TTT group had higher levels of HIF-1α, PDGF-BB, SDF-1, and VEGF in serum than the other groups (all p < 0.001).Conclusion: TTT enhanced neovascularization and perfusion at the hindlimb and accelerated healing of the severe DFUs. The underlying mechanism is related to HIF-1α-induced angiogenesis.Keywords: distraction osteogenesis, tibial cortex transverse transport, diabetic foot, HIF-1α, angiogenesis

Yanbei Duo,1 Shuoning Song,1 Xiaolin Qiao,2 Yuemei Zhang,3 Jiyu Xu,4 Jing Zhang,5 Zhenyao Peng,6 Yan Chen,2 Xiaorui Nie,2 Qiujin Sun,7 Xianchun Yang,7 Ailing Wang,8 Wei Sun,4 Yong Fu,1 Yingyue Dong,1 Zechun Lu,8 Tao Yuan,1,&ast; Weigang Zhao1,&ast; 1Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Obstetrics, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 3Department of Obstetrics, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 4Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 6Department of Dean’s Office, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 7Department of Clinical Laboratory, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 8National Center for Women and Children’s Health, China CDC, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Yuan; Weigang Zhao, Email t75y@sina.com; xiehezhaoweigang@163.comObjective: Gestational diabetes mellitus (GDM) is a condition of glucose intolerance, which may be accompanied with inflammation. The levels of hematological parameters during pregnancy can reflect inflammatory conditions in pregnant women. This study aims to describe the dynamic change of blood cell parameters from the first trimester (6– 12 weeks of gestation) to the second trimester (24– 28 weeks of gestation) and to investigate the associations of these biomarkers with the risk of GDM.Methods: This study was a prospective double-center study conducted in Beijing, China (clinical trial number: NCT03246295). Hematological parameters were tested four times during the follow-up. Logistic regression analysis and Receiver Operating Characteristic (ROC) curve analysis were used to explore the association and predictive ability of hematological parameters for GDM.Results: There were 258 of 1027 pregnant women in our study developed GDM. Among the 1027 pregnant women, white blood cells (WBC) gradually increased, and red blood cells (RBC), hemoglobin (HGB), and platelet (PLT) tended to decrease from the first trimester to second trimester. After adjusting for confounding factors, higher levels of RBC, HGB, and PLT in both early and middle pregnancy were positively associated with GDM risk, whereas the level of WBC was associated with GDM risk only in early pregnancy. WBC, RBC, HGB, and PLT in early and middle pregnancy were all correlated with fasting insulin (FINS) in early pregnancy.Conclusion: Higher levels of hematological parameters in early and middle pregnancy were associated with glucose metabolism in early pregnancy and the subsequent risk of GDM.Keywords: hematological parameters, gestational diabetes mellitus, inflammation, insulin resistance, prospective study

Yuling Liu,1,&ast; Xin Nie,2,3,&ast; Yihan Wu,2 Longfei Lin,1 Qian Liao,1 Jingjing Li,4 Simon Ming-Yuen Lee,3 Hui Li,1,5 Jinming Zhang2 1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macau, Macau Special Administrative Region, People’s Republic of China; 4Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China; 5Institute of Traditional Chinese Medicine Health Industry, China Academy of Chinese Medical Sciences, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Li, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Email lihuiyiren@163.com Jinming Zhang, State Key Laboratory of Southwestern Chinese Medicine Resource, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China, Email cdutcmzjm@126.comIntroduction: The insufficient targeting delivery of therapeutic agents greatly impeded the treatment outcomes of rheumatoid arthritis (RA). Despite the recognized therapeutic advantages of gambogic acid (GBA) in inflammatory diseases, its high delivery efficiency to inflammatory site still limits its clinical application. Self-assembly of drug dimers into carrier-free nanoparticles (NPs) has become a straightforward and attractive approach to develop nanomedicines for RA treatment. Herein, homodimers of GBA were designed to form the carrier-free NPs by self-assembly for RA treatment.Methods: The synthetic gambogic acid dimers (GBA2) were self-assembled into NPs using a one-step solvent evaporation method. The size distribution, morphology, drug-loading efficiency (DLE) and storage stability were evaluated. A molecular dynamic simulation was conducted to gain further insight into the self-assembly mechanisms of GBA2/NPs. Besides, we investigated the cytotoxicity, apoptosis and cellular uptake profiles of GBA2/NPs in macrophages and osteoclasts. Finally, the specific biodistribution on the ankles of adjuvant-induced arthritis (AIA) mice, and the anti-RA efficacy of the AIA rat model were assessed.Results: GBA2/NPs exhibited the uniform spherical structure, possessing excellent colloidal stability, high self-assembly stability, high drug loading and low hemolytic activity. Comparing with GBA, GBA2/NPs showed higher cytotoxicity, cellular uptake and apoptosis rate against osteoclasts. In addition, GBA2/NPs exhibited much higher accumulation in ankle joints in vivo. As expected, the systematic administration of GBA2/NPs resulted in the greater alleviation of arthritic symptoms, cartilage protection, and inflammation, notably the reduced systemic toxicity compared to free GBA.Conclusion: GBA2/NPs formed GBA dimers exhibited the superior accumulation in the inflamed joint and anti-RA activity, potentially attributing to the similar extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration (“ELVIS”) effects in inflamed joint and the enhanced cellular uptake in macrophages and osteoclasts. Our findings provide substantial evidence that self-assembly of GBA2/NPs would be a promising therapeutic alternative for RA treatment.Keywords: gambogic acid dimers, carrier-free nanoparticles, self-assembly, rheumatoid arthritis, macrophage, osteoclast

Xinyu Nie,1,2 Xinru Dong,1,2 Yuge Hu,1,2 Fangjun Xu,1 Cong Hu,2 Chang Shu1 1Obstetrics and Gynecology Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Reproductive Medicine Center, Prenatal Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Chang Shu, Email shu_chang@jlu.edu.cnAbstract: Female infertility and pregnancy maintenance are associate with various factors, including quantity and quality of oocytes, genital inflammation, endometriosis, and other diseases. Women are even diagnosed as unexplained infertility or unexplained recurrent spontaneous abortion when failed to achieve pregnancy with current treatment, which are urgent clinical issues need to be addressed. Coenzyme Q10 (CoQ10) is a lipid-soluble electron carrier in the mitochondrial electron transport chain. It is not only essential for the mitochondria to produce energy, but also function as an antioxidant to maintain redox homeostasis in the body. Recently, the capacity of CoQ10 to reduce oxidative stress (OS), enhance mitochondrial activity, regulate gene expression and inhibit inflammatory responses, has been discovered as a novel adjuvant in male reproductive performance enhancing in both animal and human studies. Furthermore, CoQ10 is also proved to regulate immune balance, antioxidant, promote glucose and lipid metabolism. These properties will bring highlight for ovarian dysfunction reversing, ovulation ameliorating, oocyte maturation/fertilization promoting, and embryonic development optimizing. In this review, we systematically discuss the pleiotropic effects of CoQ10 in female reproductive disorders to investigate the mechanism and therapeutic potential to provide a reference in subsequent studies.Keywords: coenzyme Q10, oxidative stress, reactive oxygen species, reproductive, oocyte, endometriosis

Zhengzheng Gao,1 Jianmin Zhang,1 Xiaolu Nie,2 Xiaohuan Cui1 1Department of Anesthesiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Center for Clinical Epidemiology and Evidence-based Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of ChinaCorrespondence: Jianmin Zhang, Department of Anesthesiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56 South Lishi Road, Xicheng District, Beijing, 100045, People’s Republic of China, Tel +86 10-59616415, Email sunbrighangel@sina.comBackground: Emergence agitation (EA) has a negative effect on the recovery from general anesthesia in children. This study aimed to evaluate the effectiveness of intravenous ibuprofen in reducing the incidence of EA in children.Methods: This randomized, double-blind, placebo-controlled, single-center study analyzed data from patients aged 3– 9 years undergoing tonsillectomy under general anesthesia with propofol and remifentanil. These patients were randomly assigned to receive either the ibuprofen or the placebo intraoperatively. The primary endpoint was a between-group difference in the incidence of EA at 15 min following extubation. EA was defined as Pediatric Anesthesia Emergence Delirium score ≥ 10. The secondary endpoint included the associated factors of EA.Results: Eighty-nine patients were included in the study. Ibuprofen decreased the incidence of EA at 15 min following extubation (8.9% in the treatment group vs 34.1% in the control group; odds ratio [OR], 0.261; 95% confidence interval [CI], 0.094– 0.724; P=0.004). Compared with the control group, there was a significant reduction in the number of rescue fentanyl doses (P=0.045), and fewer patients experienced moderate to severe pain at 15 min following extubation in the treatment group (P=0.048). Upon logistic regression analysis, high modified Pediatric Anesthesia Behavior and pain scores following surgery were considered the risk factors related to EA (OR, 8.07; 95% CI, 1.12– 58.07, P=0.038 and OR, 2.78; 95% CI, 1.60– 4.82, P< 0.001, respectively). Ibuprofen administration was the protective factor related to EA (OR, 0.05; 95% CI, 0.01– 0.67, P=0.023).Conclusion: Intraoperative ibuprofen infusion can significantly reduce the incidence of EA following general anesthesia with propofol and remifentanil in children.Trial Registration: The study was registered with the Chinese Clinical Trial Registry on 7 April 2021 (number: ChiCTR2100045128; https://www.chictr.org.cn/edit.aspx?pid=124595&htm=4).Keywords: emergence agitation, children, ibuprofen, general anesthesia, protective factor

Shuoning Song,1 Yuemei Zhang,2 Xiaolin Qiao,3 Yanbei Duo,1 Jiyu Xu,4 Zhenyao Peng,5 Jing Zhang,6 Yan Chen,3 Xiaorui Nie,3 Qiujin Sun,7 Xianchun Yang,7 Ailing Wang,8 Zechun Lu,8 Wei Sun,4 Yong Fu,1 Yingyue Dong,1 Tao Yuan,1 Weigang Zhao1 1Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Obstetrics, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 3Department of Obstetrics, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 4Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Dean’s Office, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 6Department of Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 7Department of Clinical Laboratory, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 8National Center for Women and Children’s Health, China CDC, Beijing, People’s Republic of ChinaCorrespondence: Tao Yuan; Weigang ZhaoDepartment of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel/Fax +86 1069155073Email t75y@sina.com; xiehezhaoweigang@163.comObjective: This study aimed to find the association between alanine transaminase-to-aspartate aminotransferase ratio (ALT/AST) and the incidence of gestational diabetes mellitus (GDM).Methods: A total of 1128 pregnant women were included in this prospective, double-center, observational cohort study. ALT, AST and total bilirubin (TBil) were tested during 6– 12 weeks of gestation and 75-g oral glucose tolerance test (OGTT) was conducted during 24– 28 weeks of gestation to screen GDM. The association between ALT/AST and glucose concentration during OGTT was analyzed by linear regression model. The OR with 95% CI for incidence of GDM associated with ALT/AST was estimated by binary logistic regression. The discriminatory values of ALT/AST and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) for GDM were calculated by the area under the receiver operating characteristic curve (ROC-AUC).Results: The incidence of GDM was 22.07% (249/1128). ALT/AST was higher in GDM group than in NGT group (0.92 [0.75, 1.18] vs 0.80[0.65, 1.02], P < 0.001). ALT/AST had positive correlations with fasting blood glucose, 1-hour and 2-hour blood glucose concentration during OGTT (0.089 [95% CI: 0.034, 0.163], 0.176 [95% CI: 0.052, 0.104], and 0.115 [95% CI: 0.199, 0.609], respectively). The OR of ALT/AST for incidence of GDM was 1.603 (95% CI:1.097, 2.344). The ROC-AUC of ALT/AST and TG/HDL-C reached 0.615 (95% CI: 0.575, 0.655) and 0.619 (95% CI: 0.580, 0.659), respectively.Conclusion: ALT/AST in early pregnancy was an independent risk factor of GDM. The predictive ability of ALT/AST was similar to TG/HDL-C for GDM.Keywords: gestational diabetes mellitus, type 2 diabetes mellitus, alanine transaminase, aspartate aminotransferase, triglyceride

Shuoning Song,1 Yanbei Duo,1 Yuemei Zhang,2 Xiaolin Qiao,3 Jiyu Xu,4 Jing Zhang,5 Zhenyao Peng,6 Yan Chen,3 Xiaorui Nie,3 Qiujin Sun,7 Xianchun Yang,7 Ailing Wang,8 Wei Sun,4 Yong Fu,1 Yingyue Dong,1 Zechun Lu,8 Tao Yuan,1 Weigang Zhao1 1Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Obstetrics, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 3Department of Obstetrics, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 4Core Facility of Instrument, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, People’s Republic of China; 5Department of Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 6Department of Dean’s Office, Haidian District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 7Department of Clinical Laboratory, Beijing Chaoyang District Maternal and Child Health Care Hospital, Beijing, People’s Republic of China; 8National Center for Women and Children’s Health, China CDC, Beijing, People’s Republic of ChinaCorrespondence: Tao Yuan; Weigang Zhao Email t75y@sina.com; xiehezhaoweigang@163.comObjective: To evaluate the association of hepatic steatosis index (HSI) in the first trimester and the risk of gestational diabetes mellitus (GDM) as well as large for gestational age (LGA) infant in Chinese women.Methods: A total of 1082 pregnant women were included in this study. Maternal basic laboratory data, including ALT, AST, FBG, insulin, TG, and HDL-C, were tested during 6– 12 weeks of gestation and anthropometric characteristics were monitored during gestation. A 75-g oral glucose tolerance test (OGTT) was conducted at 24– 28 weeks of gestation. HSI, nonalcoholic fatty liver disease (NAFLD) liver fat score, triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) and triglyceride-glucose (TyG) index were calculated. Odds ratio with 95% confidence interval for subsequent risk of GDM and LGA by HSI quartiles were assessed by binary logistic regression model. The predictive ability of HSI for GDM and LGA was evaluated by the receiver operating characteristic (ROC) curve analysis and was compared with other indices.Results: The incidence of GDM and LGA were 22.09% (239/1082) and 10.53% (87/826). HSI was higher in GDM group than in NGT group (median, interquartile range: 30.67, 27.20– 35.10 vs 27.98, 25.70– 30.82, P< 0.001). Incidence of GDM was gradually increased with increasing HSI values. Women in the highest HSI quartile had significantly higher risk of LGA delivery than those in the lowest HSI quartile (P< 0.05). The area under the ROC curves of HSI for GDM and LGA were higher than other indices, reaching 0.646 (95%CI: 0.605– 0.686) and 0.600 (95%CI: 0.541– 0.660), respectively.Conclusion: Higher HSI was independently associated with higher risk of GDM and LGA in Chinese women. HSI in the first trimester can predict the risk of GDM and LGA.Keywords: hepatic steatosis index, nonalcoholic fatty liver disease, gestational diabetes mellitus, large for gestational age infant

Zhangying Feng, Jinglin Gao, Xiaonan Gao, Li Hua, Xuyang Nie, Yaqi Sun, Mingxia Wang Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Mingxia WangDepartment of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of ChinaTel +86311-66696233Email mxia_wang@163.comPurpose: A simple, rapid and reliable method to quantify methotrexate (MTX) in human plasma by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) was established and validated in two laboratories.Patients and Methods: Sample separation was achieved on a Synergi Hydro-RP column (50 mm× 2.0 mm, 2.5 μm) with a gradient elution program in 3.5 min after a simple protein precipitation with methanol (MeOH) and acetonitrile (ACN) (1:1). About 5 mM ammonium formate aqueous solution with 0.2% formic acid and ACN were used as mobile phase with a flow rate of 0.5 mL/min at 40 °C. Mass spectrometry detection using AB Sciex Triple Quad 4500 mass spectrometer (4500 QQQ) and Qtrap 5500 mass spectrometer (5500 Q-trap) were both characterized by electrospray ionization (ESI) for positive ions in multiple reaction-monitoring (MRM) mode. Quantitative ion pairs were m/z 455.1→m/z 308.0 for MTX and m/z 248.1→m/z 121.0 for tinidazole (TNZ) used as internal standard (IS).Results: Linear calibration curves were generated over the range of 5– 1000 ng/mL (r2> 0.99) on both the 4500 QQQ and 5500 Q-trap, both of the intra- and inter-batch precision were less than 7.67% and accuracy ranged from 96.33% to 108.94%. The recovery and matrix effect were 82.20– 93.98% and 102.69– 105.28%, respectively.Conclusion: An analytical method transfer was achieved by re-verification in two laboratories to ensure stability and reproducibility and this method has been applied for therapeutic drug monitoring (TDM) successfully in children and adults with NHL, and during routine TDM, two delayed elimination of MTX cases were observed and analyzed.Keywords: methotrexate, therapeutic drug monitoring, non-Hodgkin lymphoma, children, adult

Ran An,1,2 Dong Li,1 Yingying Dong,1 Qiuyun She,1 Ting Zhou,1 Xiaoqi Nie,1 Ronghua Pan,1 Yunhua Deng1 1Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Department of Dermatology, Children’s Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Yunhua DengDepartment of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Qiaokou, Wuhan, Hubei, People’s Republic of ChinaTel +86 027 83663370Fax +86 027 83663625Email 820331158@qq.comPurpose: Oxidative stress is considered a major determinant in the pathogenesis of vitiligo. Methylcobalamin (MeCbl) is an activated form of vitamin B12 that regulates inflammatory factors, counters oxidative stress, and reduces apoptosis in many disease models. However, the specific mechanism of MeCbl repigmentation against vitiligo is unknown. In this study, we explored the effect of MeCbl on melanocytes following hydrogen peroxide (H2O2)-induced oxidative stress.Methods: We established an oxidative stress model using the immortalized human normal melanocyte cell line PIG1. We used a Cell Counting Kit-8 (CCK-8) to detect drug cytotoxicity, and we measured the melanin content of cells using the NaOH method. Intracellular oxidative damage was assessed by flow cytometry and antioxidant enzyme detection kits. In addition, we assessed the presence of apoptosis by flow cytometry and Western blots. We explored the underlying mechanisms of MeCbl during oxidative stress in melanocytes by analyzing the results of experiments based on real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, and laser scanning confocal immunofluorescence microscopy. Finally, we repeated the experiments after applying an inhibitor to block the Nrf2 pathway.Results: We found that MeCbl treatment enhanced cell viability, increased melanin content, reduced intracellular reactive oxygen species (ROS) accumulation, increased the activities of antioxidant enzyme superoxide dismutase (SOD) and catalase (CAT), reduced melanocyte apoptosis, and up-regulated the expression of the Nrf2/HO-1 pathway. Moreover, the protective effects of MeCbl were significantly weakened after inhibiting the Nrf2/HO-1 pathway.Conclusion: Our results indicate that MeCbl attenuated the H2O2-induced oxidative stress in melanocytes by activating the Nrf2/HO-1 pathway, this suggests that MeCbl may be an effective treatment against vitiligo.Keywords: methylcobalamin, vitiligo, oxidative stress, melanocytes, NF-E2-related factor 2

Jiaqi Xu, Kun Cheng, Hai Lin, Wei Han, Tieying He, Xiaohan Nie, Yonghui Sun, Sulidankazha Qiuman, Yilidan Reheman, Qilong Chen Department of Pancreatic Surgery, Centre of Digestive and Vascular Surgery, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, People’s Republic of ChinaCorrespondence: Qilong Chen Email chenqilong651003@sohu.comBackground: Pancreatic cancer (PC) presents a phenomenal disease burden worldwide. The GATA transcription factor family is associated with a variety of human malignancies. However, the relation between GATA family members (GATAs) and PC has not been elucidated.Methods: This study integrates large-scale bioinformatics database resources to analyze the expression patterns of GATAs in PC patients and explore their underlying function mechanism and relevance to immune infiltration and other different cell types in the tumor microenvironment in pancreatic cancer. First, the expression pattern of GATAs in pancreatic cancer was detected by the Oncomine database and the Gene Expression Profile Interaction Analysis (GEPIA2) database and verified through other datasets in the R2 platform. Then, we used the cBioPortal database and the Human Protein Atlas to assess the correlation between GATAs and clinicopathological features of PC. Then, survival analyses were performed to identify candidate prognostic factors in the GATA family in PC patients. Further, we performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction (PPI) network, immune-infiltration correlation analysis, and cell type analysis of the tumor microenvironment at the single-cell level to explain the function of GATAs in pancreatic cancer.Results: We found that GATA3 and GATA6 were highly expressed in pancreatic cancer, and the expression levels of GATA4 and GATA6 correlated with the pathological stage, differentiation grade, and molecular subtype of pancreatic cancer. The survival analysis revealed that lower GATA4 of PC patients was associated with better outcomes, and higher GATA6 might be associated with longer OS. In addition, GATA3 was associated with immune cell infiltration of PC, and GATA6 was mainly distributed in the epithelial cells with ductal phenotype.Conclusion: This work tentatively identified GATA3, GATA4, and GATA6 in the GATA family associated with pancreatic cancer. GATA4 may serve as a prognostic factor for PC patients, and GATA6 may act as a subtype marker for PC. In addition, GATA3 may reflect the immune-infiltration status of PC.Keywords: pancreatic cancer, GATA transcriptional factor, prognosis, tumor microenvironment, bioinformatics analysis

Xiaobo Nie,1 Huiyang Liu,1 Xiaoyun Wei,1 Lanqing Li,1 Linhua Lan,2 Lili Fan,1 Han Ma,1 Lei Liu,1 Yun Zhou,1 Ruifang Hou,1 Wei-Dong Chen1,3 1Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People’s Hospital of Hebi, Henan University, Kaifeng, People’s Republic of China; 2Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, People’s Republic of ChinaCorrespondence: Wei-Dong Chen Email wdchenmed@163.comBackground: The dysregulation of microRNAs (miRNAs) and hepatotoxicity due to the aberrant accumulation of bile acids (BAs) are notorious causes that predispose an individual to the development of hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), encoded by NR1H4 gene, has been identified as a crucial BA receptor to maintain the homeostasis of BA pool and its expression is decreased in HCC. miR-382-5p plays an important role in the pathogenesis of many human malignancies and was reported to promote the proliferation and differentiation of normal liver cells and liver regeneration. However, there is still some controversy about its role in HCC microenvironment. This study aims to explore the expression pattern of miR-382-5p in HCC and its role in regulating FXR during the development of HCC.Methods: Tissues collected from 30 HCC patients were subjected to extraction of total RNA and quantitative real-time PCR (qRT-PCR) for the analyses of miR-382-5p expression and NR1H4 mRNA levels, and their expressions were verified by analyzing the online HCC-related GSE datasets. The role of miR-382-5p in regulating cellular proliferation and expression of FXR in different HCC cell lines was analyzed by qRT-PCR, Western Blot, real-time cellular analysis (RTCA) and luciferase reporter assays. The role of miR-382-5p in regulating downstream genes of FXR in HCC cells was also analyzed.Results: miR-382-5p was upregulated in HCC tissues and inversely associated with the downregulation of NR1H4 mRNA levels. The luciferase reporter assay proved that miR-382-5p directly targeted the 3ʹ-untranslated region (3ʹ-UTR) of human NR1H4 mRNA. Overexpression of miR-382-5p led to a malignant proliferation of HCC cells by suppressing the expression of FXR. In contrast, blocking the endogenous miR-382-5p was sufficient to suppress the cellular proliferation rate of HCC through increasing FXR expression. Additionally, miR-382-5p inhibited the expression of some target genes of FXR, including SHP, FGF19 and SLC51A, and this inhibitory effect was FXR-dependent.Conclusion: Therefore, miR-382-5p promotes the progression of HCC in vitro by suppressing FXR and could serve as a valuable therapeutic target for HCC treatment.Keywords: hepatocellular carcinoma, miRNA-382-5p, FXR, proliferation

Junyu Deng,1 Ye Liu,1 Yiqiu Liu,1 Wei Li,1,2 Xuqiang Nie1– 4 1College of Pharmacy, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 2Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 3Key Laboratory of the Basic Pharmacology of the Ministry of Education, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 4Institute of Materia Medica, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, 400038, People’s Republic of ChinaCorrespondence: Xuqiang NieCollege of Pharmacy, Joint International Research Laboratory of Ethnomedicine of Chinese Ministry of Education, Zunyi Medical University, Zunyi, 563000, People’s Republic of ChinaTel +86-0851-2864-2516Email niexuqiang@zmu.edu.cnAbstract: Diabetic nephropathy (DN) is a common microvascular complication in the late stages of diabetes. Currently, the etiology and pathogenesis of DN are not well understood. Even so, available evidence shows its development is associated with metabolism, oxidative stress, cytokine interaction, genetic factors, and renal microvascular disease. Diabetic nephropathy can lead to proteinuria, edema and hypertension, among other complications. In severe cases, it can cause life-threatening complications such as renal failure. Patients with type 1 diabetes, hypertension, high protein intake, and smokers have a higher risk of developing DN. Fibroblast growth factor (FGF) regulates several human processes essential for normal development. Even though FGF has been implicated in the pathological development of DN, the underlying mechanisms are not well understood. This review summarizes the role of FGF in the development of DN. Moreover, the association of FGF with metabolism, inflammation, oxidative stress and fibrosis in the context of DN is discussed. Findings of this review are expected to deepen our understanding of DN and generate ideas for developing effective prevention and treatments for the disease.Keywords: fibroblast growth factor, diabetic nephropathy, signaling pathways, pharmacological action, renal fibrosis

Qilin Fan,1,* Fumei Shang,1,* Chen Chen,1 Hongxia Zhou,1 Jun Fan,2 Ming Yang,2 Xiu Nie,2 Li Liu,3 Kailin Cai,4 Hongli Liu1 1Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Epidemiology and Biostatistics, The Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongli LiuCancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of ChinaTel +86-27-85871962Fax +86-27-65650733Email hongli_liu@hust.edu.cnKailin CaiDepartment of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of ChinaTel +86-27-85871962Fax +86-27-65650733Email caikailin@hust.edu.cnBackground: Intestinal microbiota play a critical role in the development of colorectal cancer. However, little is known about the structure and characteristics of gut microbial in colorectal cancer, especially in locally advanced rectal cancer after neoadjuvant chemoradiation therapy.Methods: Here, we performed this study to evaluate microbial characteristics between pathologic complete response (pCR) (n=12) and non-pathological complete response (Non-pCR) (n=45) tumor tissues from patients with locally advanced rectal cancer after neoadjuvant chemoradiation therapy. In this study, 16S rRNA gene sequencing was used to detect the microbial diversity including Alpha diversity and Beta diversity. Moreover, we used PICRUSt from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database to predict the microbial metabolism functions.Results: There was significant statistical difference in PFS between pCR and Non-pCR group (p < 0.05). However, there was no significant difference in OS between pCR and Non-pCR group. The microbial compositions in the both groups were Proteobacteria, Actinobacteria, Firmicutes and Thermi and Bacteroidetes at the phylum level. The five most predominant genera in both pCR and Non-pCR tissue groups were Sphingobium, Acinetobacter, Cupriavidus, Thermi and Sphingomonas at the genus level. The key taxa identified in the pCR and Non-pCR tissues were Thermi and Sphingomonadaceae respectively. In addition, a series of human disease-related genes were also significantly different between pCR and Non-pCR group.Conclusion: In summary, we demonstrated the characteristic differences in microbial communities between pCR tissues and Non-pCR tumor tissues from locally advanced rectal cancer patients after neoadjuvant chemoradiation therapy. Our results present new alterations in the microbiome in locally advanced rectal cancer after neoadjuvant chemoradiation therapy, suggesting that it will provide a new perspective for the precise treatment of neoadjuvant rectal cancer by targeting specific microbial species in the future.Keywords: intestinal microbial, 16S rRNA gene sequencing, pathologic complete response, neoadjuvant chemoradiation therapy, colorectal cancer

Xin Nie,1 Zhejie Chen,2 Lan Pang,1 Lin Wang,1 Huajuan Jiang,1 Yi Chen,1 Zhen Zhang,1 Chaomei Fu,1 Bo Ren,1 Jinming Zhang1 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People’s Republic of China; 2State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999087, People’s Republic of ChinaCorrespondence: Jinming Zhang; Bo Ren Email cdutcmzjm@126.com; renbo@cdutcm.edu.cnAbstract: In view of the worldwide serious health threat of type 2 diabetes mellitus (T2DM), natural sources of chemotherapies have been corroborated as the promising alternatives, with the excellent antidiabetic activities, bio-safety, and more cost-effective properties. However, their clinical application is somewhat limited, because of the poor solubility, instability in the gastrointestinal tract (GIT), low bioavailability, and so on. Nowadays, to develop nanoscaled systems has become a prominent strategy to improve the drug delivery of phytochemicals. In this review, we primarily summarized the intervention mechanisms of phytocompounds against T2DM and presented the recent advances in various nanosystems of antidiabetic phytocompounds. Selected nanosystems were grouped depending on their classification and structures, including polymeric NPs, lipid-based nanosystems, vesicular systems, inorganic nanocarriers, and so on. Based on this review, the state-of-the-art nanosystems for phytocompounds in T2DM treatment have been presented, suggesting the preponderance and potential of nanotechnologies.Keywords: type 2 diabetes mellitus (T2DM), phytocompounds, drug delivery systems, nanoparticles (NPs), antidiabetic effects

Xiaoxiao Li,1,* Xueli Lv,1,* Zhenfei Jiang,1 Xinrui Nie,1 Xinghe Wang,1 Tong Li,1 Lianyi Zhang,2 Su Liu1,2 1Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Su Liu Department of AnesthesiologyThe Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, People’s Republic of ChinaTel +86 18118309692Fax +86 516-8346-9496Email liusu112277@gmail.comObjective: Propofol for procedural sedation and analgesia (PSA) for colonoscopy can result in a high prevalence of severe respiratory depression. Studies have shown that intravenous (IV) infusion of lidocaine can reduce propofol requirements significantly and increase the ventilatory response to carbon dioxide in humans. We tested the hypothesis that IV lidocaine could improve propofol-induced respiratory depression in obese patients during colonoscopy.Methods: Ninety obese patients scheduled for painless colonoscopy were randomized to receive lidocaine (1.5 mg/kg, then 2 mg/kg/h, IV) or the same volume of 0.9% saline. Intraoperative sedation was provided by propofol. The primary outcome was the number of oxygen-desaturation episodes. Secondary outcomes were: the number of apnea episodes; total propofol consumption; time to the first hypoxia episode; time to consciousness loss; intraoperative hemodynamic parameters; awakening time; adverse events; duration of post-anesthesia care unit (PACU) stay; satisfaction of endoscopists and patients.Results: Demographic characteristics between the two groups were comparable. The number of oxygen-desaturation episodes in group L (1.49± 1.12) decreased by 0.622 (P=0.018) compared with that in group N (2.11± 1.32), and the number of apnea episodes in group L decreased by 0.533 (P< 0.001). Kaplan–Meier curves showed that the median time to the first hypoxia episode was longer in group L (86.78 s) than that in group N (63.83 s) (Log rank P=0.0008). The total propofol consumption, awakening time, and duration of PACU stay were reduced in group L. There was no significant difference in the prevalence of adverse events (P> 0.05 for all). Satisfaction scores for endoscopists and patients in group L were higher than that in group N (P< 0.001).Conclusion: Intravenous infusion of lidocaine could significantly reduce the number of oxygen-desaturation and apnea episodes in obese patients during painless colonoscopy. This method is worthy of clinical promotion.Clinical Trials Registration: ChiCTR2000028937.Keywords: lidocaine, propofol, obese patients, colonoscopy

Xiaomin Nie,* Yun Shen,* Xiaojing Ma, Yiting Xu, Yufei Wang, Jian Zhou, Yuqian Bao Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Clinical Center for Diabetes; Shanghai Key Clinical Center for Metabolic Disease; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaojing Ma; Yuqian BaoDepartment of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes; Shanghai Key Clinical Center for Metabolic Disease; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus, 600 Yishan Road, Shanghai 200233, People’s Republic of ChinaTel +86-21-64369181Fax +86-21-64368031Email maxiaojing@sjtu.edu.cn; yqbao@sjtu.edu.cnPurpose: Although overt thyroid dysfunction has been found to influence the level of glycated albumin (GA), the associations between thyroid hormones and GA in individuals with euthyroidism and subclinical hypothyroidism (SHypo) are still unknown. The present study aimed to investigate whether thyroid hormones were related to GA in euthyroid and SHypo individuals.Methods: We recruited 685 euthyroid and 103 SHypo subjects with normal weight from communities in Shanghai. Electrochemiluminescence immunoassay was used to detect the serum levels of free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone. GA was detected by the enzymatic method. Glycated hemoglobin (HbA1c) was detected by high-performance liquid chromatography.Results: Among the 788 subjects (age range 31– 81 years old), 307 were men and 481 were women. In the Spearman correlation analysis and multiple stepwise regression analysis, FT3 was negatively correlated with both GA and GA/HbA1c in euthyroid subjects (all P < 0.05). The values of GA and GA/HbA1c were reduced by approximately 0.30 and 0.05, respectively, for each 0.50 pmol/L increment in FT3. In SHypo subjects, FT4 was negatively associated with both GA and GA/HbA1c (all P < 0.05). The values of GA and GA/HbA1c were reduced by approximately 0.23 and 0.03, respectively, for each 1.00 pmol/L increment in FT4.Conclusion: In euthyroid and SHypo subjects, more attention should be paid to the potential effects of individual differences in thyroid hormones on GA.Keywords: glycated albumin, glycated hemoglobin, free triiodothyronine, free thyroxine

Wan Xie,1,2 Shenyin Zhu,3 Biyong Yang,4 Chunyan Chen,1 Shuning Chen,1 Yujiao Liu,1 Xuyuan Nie,5 Lan Hao,2 Zhigang Wang,2 Jiangchuan Sun,1 Shufang Chang1 1Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 2Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, People’s Republic of China; 4Chongqing Institute for Food and Drug Control, Chongqing 401121, People’s Republic of China; 5School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, People’s Republic of ChinaCorrespondence: Shufang Chang; Jiangchuan SunDepartment of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjian Road, Yuzhong District, Chongqing 400010, People’s Republic of ChinaTel +86 023 6369 3279Fax +86 023 6510 4238Email shfch2018@hospital.cqmu.edu.cn; sunjiangchuan@126.comPurpose: Photodynamic therapy (PDT), sonodynamic therapy (SDT), and oxaliplatin (OXP) can induce immunogenic cell death (ICD) following damage-associated molecular patterns (DAMPs) exposure or release and can be united via the use of nanoplatforms to deliver drugs that can impart anti-tumor effects. The aim of this study was to develop phase-transition nanoparticles (OI_NPs) loaded with perfluoropentane (PFP), indocyanine green (ICG), and oxaliplatin (OXP), to augment anti-tumor efficacy and the immunological effects of chemotherapy, photodynamic therapy and sonodynamic therapy (PSDT).Methods: OI_NPs were fabricated by a double emulsion method and a range of physicochemical and dual-modal imaging features were characterized. Confocal microscopy and flow cytometry were used to determine the cellular uptake of OI_NPs by ID8 cells. The viability and apoptotic rate of ID8 cells were investigated using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry. Flow cytometry, Western blotting, and luminometric assays were then used to investigate the exposure or release of crucial DAMPs such as calreticulin (CRT), high mobility group box 1 (HMGB1), and adenosine-5ʹ-triphosphate (ATP). Tumor rechallenge experiments were then used to investigate whether treated ID8 cells underwent ICD. Finally, cytotoxic T lymphocyte (CTL) activity was determined by a lactate dehydrogenase (LDH) assay.Results: Spherical OI_NPs were able to carry OXP, ICG and PFP and were successfully internalized by ID8 cells. The application of OI_NPs significantly enhanced the phase shift ability of PFP and the optical characteristics of ICG, thus leading to a significant improvement in photoacoustic and ultrasonic imaging. When combined with near-infrared light and ultrasound, the application of OI_NPs led to improved anti-tumor effects on cancer cells, and significantly enhanced the expression of DAMPs, thus generating a long-term anti-tumor effect.Conclusion: The application of OI_NPs, loaded with appropriate cargo, may represent a novel strategy with which to increase anti-tumor effects, enhance immunological potency, and improve dual-mode imaging.Keywords: ovarian cancer, multifunctional nanoparticles, photo-sonodynamic therapy, immunogenic cell death, reactive oxygen species

Xin Nie,1,2 Cong Liu,3 Qian Guo,1,2 Ming-jun Zheng,1,2 Ling-ling Gao,1,2 Xiao Li,1,2 Da-wo Liu,1,2 Lian-cheng Zhu,1,2 Juan-juan Liu,1,2 Bei Lin1,2 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; 2Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China; 3Department of Obstetrics and Gynaecology, Wuxi Materal and Child Health Hospital, Jiangsu, China Background: Transmembrane protein with epidermal growth factor-like and two follistatin-like domains 1 (TMEFF1) has an anticarcinogenic effect in brain tumors. However, little is known about the role of TMEFF1 in epithelial ovarian cancer (EOC).Materials and methods: TMEFF1 expression in EOC was detected by immunohistochemistry; its relationship with clinical pathological parameters and its influence on prognosis were analyzed. The MTT, scratch, Transwell assays, and flow cytometry were used to assess the malignant behavior of ovarian cancer cell. Changes in node proteins in MAPK and PI3K/AKT signaling pathways and the expression of epithelial–mesenchymal transformation markers were measured by Western blot. The regulatory effect of p53 on TMEFF1 was verified by chromatin immunoprecipitation (ChIP) assay and Western blot.Results: TMEFF1 expression was higher in the EOC group than in the borderline and benign tumor groups and normal ovary group; its high expression was significantly related to International Federation of Gynecology and Obstetrics stage (P=0.024) and independently predicted shorter overall survival (P

Jingru Zhang,1,2 Yiwei Liu,1 Xiaolu Nie,1 Yuncui Yu,1 Jian Gu,3 Libo Zhao1 1Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, Beijing, China; 2Department of Pharmacy Administration and Clinical Pharmacy, Peking University School of Pharmaceutical Sciences, Beijing, China; 3Department of Pharmacy, Peking University People’s Hospital, Beijing, China Objectives: The optimum trough concentration of itraconazole for clinical response and safty is controversial. The objective of this systematic review and meta-analysis was to determine the optimum trough concentration of itraconazole and evaluate its relationship with efficacy and safety.Methods: We searched PubMed, EMBASE, Web of Science, the Cochrane Library, ClinicalTrials.gov, and three Chinese literature databases (CNKI, WanFang, and CBM). We included observational studies that compared clinical outcomes below or above the trough concentration cut-off value which we set as 0.25, 0.5, and 1.0 mg/L. The efficacy outcomes were rate of successful treatment, rate of prophylaxis failure and invasive fungal infection (IFI)-related mortality. The safety outcomes included incidents of hepatotoxicity and other adverse events.Results: The study included a total of 29 studies involving 2,346 patients. Our meta-analysis showed that compared with itraconazole trough concentrations (Ctrough) of ≥0.25 mg/L, levels of

Using first-principles calculations, site occupancy behaviors of transition elements in C15 NbCr2 Laves phase are systematically investigated. Elements Y, Sc, Zr, Hf, Cd, Ta, Ti and Ag prefer to occupy the Nb site, and elements Zn, Pt, Re, Tc, Ir, V, Os, Rh, Ru, Ni, Co, Mn, Fe and Cu favor to occupy the Cr site; whereas elements Mo, W, Pd and Au have weak site preference for Cr or Nb site. The present calculations agree well with the available experimental and previously calculated results. It was found that the site occupancy behavior of transition elements in NbCr2 is mainly affected by the radii of transition elements. The present calculations also propose the correlation between the site preference energy and radii of transition elements.

Xiao Nie,1,* Yi Shao,2,* Si-yu Liu,3 Hai-jun Li,1 Ai-lan Wan,4 Si Nie,1 De-chang Peng,1 Xi-jian Dai1,5 1Department of Radiology, The First Affiliated Hospital of Nanchang University, Nangchang, Jiangxi, People’s Republic of China; 2Department of Ophthalmology,The First Affiliated Hospital of Nanchang University, Nangchang, Jiangxi, People’s Republic of China; 3Medical College of Nanchang University, Nangchang, Jiangxi, People’s Republic of China; 4Department of Psychosomatic Medicine, The First Affiliated Hospital of Nanchang University, Nangchang, Jiangxi, People’s Republic of China; 5Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China *These authors contributed equally to this work Objective: The aim of this study is to explore the resting-state functional connectivity (FC) differences between the paired default mode network (DMN) subregions in patients with primary insomnia (PIs).Methods: Forty-two PIs and forty-two age- and sex-matched good sleepers (GSs) were recruited. All subjects underwent the resting-state functional magnetic resonance imaging scans. The seed-based region-to-region FC method was used to evaluate the abnormal connectivity within the DMN subregions between the PIs and the GSs. Pearson correlation analysis was used to investigate the relationships between the abnormal FC strength within the paired DMN subregions and the clinical features in PIs.Results: Compared with the GSs, the PIs showed higher Pittsburgh Sleep Quality Index score, Hamilton Anxiety Rating Scale score, Hamilton Depression Rating Scale score, Self-Rating Depression Scale score, Self Rating Anxiety Scale score, Self-Rating Scale of Sleep score, and Profile of Mood States score (P

Hai-Jun Li,1,* Xi-Jian Dai,1,2,* Hong-Han Gong,1 Xiao Nie,1 Wei Zhang,3 De-Chang Peng1 1Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, People’s Republic of China; 3Department of Pneumology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China *These authors contributed equally to this work Background: The majority of previous neuroimaging studies have demonstrated both structural and functional abnormalities in obstructive sleep apnea (OSA). However, few studies have focused on the regional intensity of spontaneous fluctuations during the resting state and the relationship between the abnormal properties and the behavioral performances. In the present study, we employed the amplitude of low-frequency fluctuation (ALFF) method to explore the local features of spontaneous brain activity in OSA patients (OSAs).Methods: Twenty-five untreated male severe OSAs and 25 age-matched and years-of-education-matched male good sleepers (GSs) were included in this study. The ALFF method was used to assess the local features of spontaneous brain activity. The mean signal values of the altered ALFF areas were analyzed with receiver operating characteristic curve. Partial correlation analysis was used to explore the relationship between the observed mean ALFF values of the different areas and the behavioral performances.Results: Compared with GSs, OSAs had significantly higher scores for body mass index, apnea–hypopnea index, arterial oxygen saturation

Xi-Jian Dai,1,2 De-Chang Peng,1 Hong-Han Gong,1 Ai-Lan Wan,3 Xiao Nie,1 Hai-Jun Li,1 Yi-Xiang J Wang2 1Department of Radiology, The First Affiliated Hospital of Nanchang University, Nangchang, Jiangxi, People’s Republic of China; 2Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong; 3Department of Psychosomatic Medicine, the First Affiliated Hospital of Nangchang University, Nangchang, Jiangxi, People’s Republic of China Study objective: To prospectively explore the underlying regional homogeneity (ReHo) brain-activity deficit in patients with chronic primary insomnia (PCPIs) and its relationship with clinical features.Design: The ReHo method and Statistical Parametric Mapping 8 software were used to evaluate whether resting-state localized brain activity was modulated between PCPIs and good sleepers (GSs), and correlation analysis between altered regional brain areas and clinical features was calculated. Patients and participants: Twenty-four PCPIs (17 females, seven males) and 24 (12 females, 12 males) age-, sex-, and education-matched GSs.Measurements and results: PCPIs disturbed subjective sleep quality, split positive mood, and exacerbated negative moods. Compared with GSs, PCPIs showed higher ReHo in left fusiform gyrus, and lower ReHo in bilateral cingulate gyrus and right cerebellum anterior lobe. Compared with female GSs, female PCPIs showed higher ReHo in the left fusiform gyrus and right posterior cingulate, and lower ReHo in the left cerebellum anterior lobe and left superior frontal gyrus. Compared with male GSs, male PCPIs showed higher ReHo in the right temporal lobe and lower ReHo in the bilateral frontal lobe. The fusiform gyrus showed strong positive correlations and the frontal lobe showed negative correlations with the clinical measurements.Conclusion: The ReHo analysis is a useful noninvasive imaging tool for the detection of cerebral changes and the indexing of clinical features. The abnormal spontaneous activity areas provided important information on the neural mechanisms underlying emotion and sleep-quality impairment in PCPIs. Keywords: insomnia, regional homogeneity, functional magnetic resonance imaging, sex difference, sleep disorder, blood oxygen level-dependent, mood disorder

De-Chang Peng,1 Xi-Jian Dai,1,2 Hong-Han Gong,1 Hai-Jun Li,1 Xiao Nie,1 Wei Zhang3 1Department of Radiology, The First Affiliated Hospital of Nanchang University, Jiangxi, 2Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region, 3Department of Pneumology, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China Background: Previous studies have demonstrated that obstructive sleep apnea (OSA) is associated with abnormal brain structural deficits. However, little is known about the changes in local synchronization of spontaneous activity in patients with OSA. The primary aim of the present study was to investigate spontaneous brain activity in patients with OSA compared with good sleepers (GSs) using regional homogeneity (ReHo) analysis based on resting-state ­functional magnetic resonance imaging (MRI). Methods: Twenty-five untreated male patients with severe OSA and 25 male GSs matched for age and years of education were included in this study. The ReHo method was calculated to assess the strength of local signal synchrony and was compared between the two groups. The observed mean ReHo values were entered into Statistical Package for the Social Sciences software to assess their correlation with behavioral performance. Results: Compared with GSs, patients with OSA showed significantly lower ReHo in the right medial frontal gyrus (BA11), right superior frontal gyrus (BA10), right cluster of the precuneus and angular gyrus (BA39), and left superior parietal lobule (BA7), and higher ReHo in the right posterior lobe of the cerebellum, right cingulate gyrus (BA23), and bilateral cluster covering the lentiform nucleus, putamen, and insula (BA13). The lower mean ReHo value in the right cluster of the precuneus and angular gyrus had a significant negative correlation with sleep time (r=-0.430, P=0.032), and higher ReHo in the right posterior lobe of the cerebellum showed a significant positive correlation with stage 3 sleep (r=0.458, P=0.021) and in the right cingulate gyrus showed a significant positive correlation with percent rapid eye movement sleep (r=0.405, P=0.045). Conclusion: Patients with OSA showed significant regional spontaneous activity deficits in default mode network areas. The ReHo method is a useful noninvasive imaging tool for detection of early changes in cerebral ReHo in patients with OSA. Keywords: obstructive sleep apnea, regional homogeneity, intermittent hypoxia, functional magnetic resonance imaging, resting state, spontaneous activity

This study investigates the 2014/15 failed El Niño using salinity from an ocean general circulation model. The results indicate that subsurface processes were especially strong in the summer of 2014 and they led to positive sea surface salinity anomalies in the central equatorial Pacific. The positive sea surface salinity anomalies induced a westward displacement of the sea surface salinity front that represents the eastern boundary of the western Pacific warm pool, preventing the warm surface water from shifting eastward as seen in a typical El Niño event. In the meantime, more salty water was transported equatorward by a strengthening subtropical cell in the South Pacific. The enhanced subsurface processes in the central equatorial Pacific conveyed the salinity anomalies of subtropical origin to the sea surface and were largely responsible for the sea surface salinity variability but had less impacts on sea surface temperature during the 2014/15 failed El Niño, suggesting some potential advantage of ocean salinity in the El Niño-Southern Oscillation prediction.

Identifying dangerous driving behaviors on urban roads is crucial for enhancing traffic safety, streamlining traffic management, and bolstering intelligent transportation systems. To address the limitations of traditional methods, such as high relative error rates, low identification rates, and prolonged processing times, a novel method based on the Hidden Markov Model (HMM) has been developed. This approach involves collecting urban road driving behavior data using smartphones, clustering the data via spectral clustering, and refining the clustering results with Box-Cox transformation. Subsequently, driving behavior features are extracted using HMM, selected through the application of random forests, and combined with a twin support vector machine to achieve accurate identification of dangerous driving behaviors. Experimental outcomes indicate that the proposed method yields a maximum relative error rate of 4.12% for feature extraction, attains a peak identification rate of 98.75%, and operates within an identification time frame of 0.16 to 0.38 seconds. [ABSTRACT FROM AUTHOR]