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Ya-Ya Bai,1 Rui Tian,1 Yan Qian,2 Qiao Zhang,1 Chong-Bo Zhao,1 Yong-Gang Yan,1 Li Zhang,3 Shi-Jun Yue,4 Yu-Ping Tang1 1Key Laboratory of Shaanxi Administration of Traditional Chinese Medicine for TCM Compatibility, and State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), and Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, and Shaanxi Traditional Chinese Medicine Processing Technology Heritage Base, Shaanxi University of Chinese Medicine, Xi’an, 712046, People’s Republic of China; 2Suzhou Institute for Drug Control, Suzhou, Jiangsu Province, 215000, People’s Republic of China; 3Hanlin College, Nanjing University of Chinese Medicine, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 4International Joint Research Center on Resource Utilization and Quality Evaluation of Traditional Chinese Medicine of Hebei Province, Hebei University of Chinese Medicine, Shijiazhuang, 050200, People’s Republic of ChinaCorrespondence: Qiao Zhang, Shaanxi University of Chinese Medicine, Shiji Avenue, Xi Xian New District, Xi’an, 712046, People’s Republic of China, Tel +86-15895973680, Fax: +86-02938185061, Email 18700081184@163.comBackground: Long-term use of rhubarb (RH) commonly leads to diarrhea, which can be alleviated by steaming with wine. However, the specific mechanism by which wine steaming alleviates RH-induced diarrhea remains unknown.Objective: This study aims to reveal the underlying mechanisms of wine steaming in alleviating RH-induced diarrhea by examining small intestinal flora and serum metabolomics.Methods: Major anthraquinone and anthrone components were detected using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Eighty-four ICR mice were randomly divided into control, RH, and RH steamed with wine (PRH) groups and were administered RH and PRH (1, 4, and 8 g/kg, i.g). for 14 consecutive days. Histopathological analysis was performed using hematoxylin-eosin staining. Levels of inflammatory factors and tight junction proteins, zonula occludens-1 (ZO-1) and occludin, in the small intestine were measured. The small intestine content was analyzed using 16S rRNA sequencing, and UPLC-MS was used to analyze endogenous metabolites.Results: Levels of major anthraquinone and anthrone components decreased in PRH. Both RH and PRH groups showed varying degrees of loose stools and increased fecal water rates; the RH group exhibited more severe effects. Compared with the control group, RH caused small intestine injuries, increased levels of inflammatory cytokines, downregulated the expression of ZO-1 and occludin, and induced gut microbiota (GM) imbalance. The relative abundance of Lactobacillus decreased, while the relative abundance of Shigella and Streptococcus increased. However, PRH had a milder impact than RH. The glycerophospholipid metabolic pathway was involved in this effect. The levels of inflammatory cytokines and potential metabolites (sn-glycero-3-phosphoethanolamine) were positively correlated with Streptococcus infection, while the levels of ZO-1 and occludin were negatively correlated with Streptococcus infection. GM imbalance and abnormal glycerophospholipid metabolism contributed to impaired intestinal barrier function and inflammatory factor release, which may underlie RH-induced diarrhea, though PRH had a weaker effect.Conclusion: PRH alleviated RH-induced diarrhea by recovering GM balance, reducing ZO-1 and occludin expression, and decreasing the release of inflammatory factors. This mechanism may be linked to the reduced anthraquinone content. This study is the first to explore the mechanism of wine steaming in alleviating RH-induced diarrhea through small intestinal flora and serum metabolomics. It provides data to support the broader clinical use of RH and its safer application. Keywords: gut microbiota, metabolomics, wine steaming, diarrhea, rhubarb

Fengting Wang,1,* Limin Rong,1,* Linlin Luo,2 Fuqin Mu,1 Liju Qian,3 Yandan Qian,4 Xinyao Zhang,1 Yuying Lang,1 Weijia Wang,1 Yan Liu,5,6 Ying Zhang,7 Jianli Wang1,8 1School of Mental Health, Jining Medical University, Jining, Shandong, People’s Republic of China; 2Department of Hematology, Tai’an Central Hospital, Tai’an, Shandong, People’s Republic of China; 3Shandong Daizhuang Hospital, Jining, Shandong, People’s Republic of China; 4The Third People’s Hospital of Jiashan County, Jiashan, Zhejiang, People’s Republic of China; 5School of Public Health, Jining Medical University, Jining, Shandong, People’s Republic of China; 6Center of Evidence-Based Medicine, Jining Medical University, Jining, Shandong, People’s Republic of China; 7School of Public Health, University of Sydney, Sydney, NSW, Australia; 8Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada*These authors contributed equally to this workCorrespondence: Fengting Wang, School of Mental Health, Jining Medical University, Jining, Shandong, 272013, People’s Republic of China, Email wft.0810@163.com Yan Liu, School of Public Health, Jining Medical University, Jining, Shandong, 272013, People’s Republic of China, Email hakunaly@163.comBackground: Youth and young adults have a high prevalence of major depressive disorder (MDD). Limited longitudinal research has explored the relationship between different dimensions of psychological stress and MDD. This study aimed to estimate the effect of psychological stress on the risk of first onset MDD in a sample of Chinese freshmen.Methods: Using a longitudinal design, 8079 Chinese first-year students were recruited at baseline, and 6985 were followed up one year later. The Psychological Stress Scale for College Students was utilized to evaluate the levels of psychological stress. MDD was evaluated using the Chinese version of the Composite International Diagnostic Interview (CIDI-3.0). Logistic regression modeling was utilized to estimate the associations between dimensions of psychological stress and the risk of MDD.Results: Two dimensions of psychological stress, namely learning stress (OR=1.05, 95% CI:1.01– 1.09, P=0.017) and economic stress (OR=1.11, 95% CI:1.04– 1.19, P=0.001), were significantly associated with the risk of MDD. Other dimensions of psychological stress (specify family stress, interpersonal stress, intimate relationship stress, employment stress and appearance stress) were not associated with MDD.Conclusion: Psychological stress, especially learning and economic stresses, could increase the risk of MDD in university students. These factors should be incorporated into mental health prevention and intervention programs at universities to reduce the risks of MDD.Keywords: major depressive disorder, psychological stress, longitudinal study, freshmen

Fengsong Chen,1 Yanhua Huang,1 Yayun Qian,2 Ya Zhao,2 Chiwen Bu,3 Dong Zhang3 1Department of Gastroenterology, Haimen People’s Hospital, Nantong, 226000, People’s Republic of China; 2Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, People’s Republic of China; 3Institute of Surgery, Guanyun People’s Hospital, Guanyun, 222200, People’s Republic of ChinaCorrespondence: Dong Zhang; Chiwen Bu, Email gyxrmyykjk@163.com; gyxrmyybcw@163.comBackground: Gastric lesions pose significant clinical challenges due to their varying degrees of malignancy and difficulty in early diagnosis. Early and accurate detection of these lesions is crucial for effective treatment and improved patient outcomes.Methods: This paper proposed a label-free and highly sensitive classification method for serum of patients with different degrees of gastric lesions by combining surface-enhanced Raman scattering (SERS) and machine learning analysis. Specifically, we prepared Au lotus-shaped (AuLS) nanoarrays substrates using seed-mediated and liquid–liquid interface self-assembly method for measuring SERS spectra of serum, and then the collected spectra were processed by principal component analysis (PCA) - multi-local means based nearest neighbor (MLMNN) model to achieve differentiation.Results: By employing this pattern analysis, AuLS nanoarray substrates can achieve fast, sensitive, and label-free serum spectral detection. The classification accuracy can reach 97.5%, the sensitivity is higher than 96.7%, and the specificity is higher than 95.0%. Moreover, by analyzing the PCs loading plots, the most critical spectral features distinguishing different degrees of gastric lesions were successfully captured.Conclusion: This discovery lays the foundation for combining SERS with machine learning for real-time diagnosis and recognition of gastric lesions.Keywords: surface-enhanced Raman scattering, gastric lesions, Au lotus-shaped nanoarrays, principal component analysis, multi-local means based nearest neighbor

Liang Liu,1 Yan Qian,2 Yanhua Chen1 1Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2School of Social and Public Administration, East China University of Science and Technology, Shanghai, People’s Republic of ChinaCorrespondence: Yanhua Chen, Email chenyh@shspdjw.comBackground: After acute treatment, patients with schizophrenia return to their original living environment for further rehabilitation, which not only determines the quality of life of the patients and their families but also has an important impact on society. However, patients often find it difficult to adapt to changes in the environment when they are discharged from the hospital. This may be related to the incompleteness of China’s mental health service system, as many services for schizophrenia patients are only in the treatment stage. In China, schizophrenia is traditionally associated with poor moral quality, and patients find it difficult to obtain support. Many patients have trouble reintegrating into the community after treatment. Schizophrenic multifamily teams gather families affected by the same illness and pain together to promote healing together in an environment that allows mutual sharing, understanding and transparency, maximizes the use of family resources for support, improves discharge readiness, and better deals with post-discharge recovery.Methods: The multifamily group intervention method was used to improve the motivation of the patients’ family motivation as well as the discharge readiness and self-efficacy of the patient.Results: After the intervention, the motivation of the family and discharge readiness of the patient were improved compared with that of the baseline period; however, the improvement was not significant. The self-efficacy of the patients was significantly improved (P=0.042).Conclusions: In the discharge preparation of schizophrenia patients, multifamily teams can be used to help patients and their families share resources, enhance support and prepare for discharge. Patients will have better support following discharge for recovery in the community. Additional consideration should be given to the impact of the environment on patient services, and the evaluation of the service process is key to continuously improving the service effect.Keywords: schizophrenia multifamily discharge group

Wenbin Zou,1,&ast; Wan Kuang,2,&ast; Chun Cai,1 Yan Qian1 1Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Qian, Tongji Hospital, Tongji Medical College, 1095 Jiefang Avenue, Qiaokou District, Wuhan, Hubei Province, 430000, People’s Republic of China, Tel +86-27-83665211, Email qianyan@tjh.tjmu.edu.cnBackground & Aims: The objective of this study was to evaluate the prognostic nutritional index (PNI) as a predictor of short-term postoperative complications in esophageal squamous cell carcinoma patients undergoing neoadjuvant immunochemotherapy.Methods: Clinical data were collected from 77 patients undergoing radical esophageal cancer surgery after neoadjuvant immunochemotherapy at Tongji Hospital from January 2022 to January 2023. The receiver operating characteristic curve (ROC) was utilized to establish the optimal cut-off point for the PNI. Subsequently, patients were stratified into low and high PNI groups according to this cut-off point, and comparisons were made between the two groups in terms of clinical data and postoperative complications.Results: Out of the 77 patients included in the study, 31 were categorized in the low PNI group and 46 in the high PNI group, with a defined cutoff point of 47.38. Significant statistical variances were noted in the occurrence rates of general complications (P < 0.001), pulmonary infections (P < 0.001), and anastomotic fistula (P = 0.034) between the two groups. The low PNI group displayed elevated rates of these complications in comparison to the high PNI group.Conclusion: The research findings indicate that preoperative nutritional assessment using the PNI can effectively predict short-term postoperative complications in esophageal squamous cell carcinoma patients who have undergone neoadjuvant therapy. Furthermore, the results suggest that implementing nutritional interventions for patients with moderate-to-severe malnutrition, as indicated by preoperative PNI evaluation, may help reduce the incidence of postoperative complications.Keywords: prognostic nutritional index, neoadjuvant immunochemotherapy, postoperative complications, esophageal squamous cell carcinoma

Guang-Hong Xie,1,&ast; Jun Shen,2,&ast; Fan Li,2 Huan-Huan Yan,2 Ying Qian3 1Department of Operating Room, The First People’s Hospital of Lianyungang, The Affiliated Hospital of XuZhou Medical University, Lianyungang, Jiangsu, 222002, People’s Republic of China; 2Department of Breast Surgery, The First People’s Hospital of Lianyungang, The Affiliated Hospital of XuZhou Medical University, Lianyungang, Jiangsu, 222002, People’s Republic of China; 3Department of Operating Room, Wuxi People’s Hospital, Wuxi, Jiangsu, 214063, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Qian Department of Operating Room, Wuxi People’s Hospital, No. 299 Qingyang Road, Liangxi District, Wuxi, 214063, Jiangsu, People’s Republic of China, Tel +8615190209358, Email qianying_q06@126.comObjective: We aimed to analyze the factors related to delay in transfer of patients in the post-anesthesia care unit (PACU) and to develop and validate a prediction model for understanding these factors to guide precise clinical intervention.Methods: We collected data from two cohorts of 1153 and 297 patients who underwent surgery and were treated in the PACU at two time points. We examined their clinical features and anesthesia care data using analytical methods such as logistic regression, Random Forest, and eXtreme Gradient Boosting (Xgboost) to screen out variables and establish a prediction model. We then validated and simplified the model and plotted a nomogram. Using LASSO regression, we reduced the dimensionality of the data. We developed multiple models and plotted receiver operating characteristic (ROC) and calibration curves. We then constructed a simplified model by pooling the identified variables, which included hemoglobin (HB), alanine transaminase (ALT), glucose levels, duration of anesthesia, and the minimum bispectral index value (BIS_min).Results: The model had good prediction performance parameters in the training and validation sets, with an AUC of 0.909 (0.887– 0.932) in the training set and 0.939 (0.919– 0.959) in the validation set. When we compared model 6 with other models, the net reclassification index (NRI) and the integrated discriminant improvement (IDI) index indicated that it did not differ significantly from the other models. We developed a scoring system, and it showed good prediction performance when verified with the training and validation sets as well as external data. Additionally, both the decision curve analysis (DCA) and clinical impact curve (CIC) demonstrated the potential clinical efficacy of the model in guiding patient interventions.Conclusion: Predicting transfer delays in the post-anesthesia care unit using predictive models is feasible; however, this merits further exploration.Keywords: delayed transfer, machine learning, nomogram, post-anesthesia care unit, predictive model

Renzhe Tang,1,&ast; Chong Li,2,&ast; Dongmei Di,1 Lin Zhou,2 Yongxiang Qian,1 Chaohua Qiang,3 Chao Ma,1 Rui Zhou,1 Bin Wang,1 Min Wang1 1Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, 213003, People’s Republic of China; 2Department of Respiratory Medicine, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, 213003, People’s Republic of China; 3Department of Echocardiography, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, 213003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Wang; Bin Wang, Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, No. 185 of Juqian Street, Changzhou, Jiangsu Province, 213003, People’s Republic of China, Email wangmin80808@163.com; wangbin1987@suda.edu.cnObjective: Obstructive sleep apnea (OSA) is a disorder characterized by disruption in breathing and hypoventilation. In parallel, metabolic syndrome (MetS) mainly co-occur with OSA, however, their association has not been fully elucidated. Therefore, this study aimed to reveal the relationship between OSA and MetS using data from the National Health And Nutrition Examination Survey (NHANES) database and pooled data from Genome-Wide Association Studies (GWAS).Material and Methods: Data from the National Health and Nutrition Examination Survey and pooled data from genome-wide association analysis (GWAS) were used univariate and multivariate logistic regression analyses were carried out to evaluate the correlation between OSA and MetS, and multivariate logistic regression models were utilized for adjusting for potential confounders. Two-sample Mendelian randomization (MR) was used to assess the causal relationship between OSA and MetS. The variance-weighted inverse method was employed as the main method of analysis.Results: A positive relationship of OSA with Mets was evidenced by multivariate logistic regression analysis, and OSA was associated with higher incidence rates of all-cause and cardiovascular mortality. OSA is strongly associated with abdominal obesity, hypertension, hyperglycemia, high triglycerides, and low HDL. Furthermore, except for hypertriglyceridemia, MR analysis indicated that genetically driven OSA was causally associated with a higher risk of MetS.Conclusion: The positive relationship of OSA with Mets was revealed, and higher incidence rates of all-cause mortality and cardiovascular mortality were noted to be correlated with OSA. MR analysis further confirmed the causal relationship of OSA with MetS and cardiovascular disease.Keywords: obstructive sleep apnea, metabolic syndrome, cardiovascular disease, NHANES, Mendelian randomization

Chunmei Yang,1,2 Tingwan Du,1 Yueying Zhao,1 Youhui Qian,1 Jiashi Tang,1 Xiaohong Li,2,&ast; Ling Ma1,3,&ast; 1Department of Nutrition and Food Hygiene, School of Public Health, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Health Management Center, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohong Li; Ling Ma, Email 1848922774@qq.com; xjml@swmu.edu.cnPurpose: To construct and validate a precise and personalized predictive model for non-alcoholic fatty liver disease (NAFLD) to enhance NAFLD screening and healthcare administration.Patients and Methods: A total of 730 participants’ clinical information and outcome measurements were gathered and randomly divided into training and validation sets in a ratio of 3:7. Using the least absolute shrinkage and selection operator (LASSO) regression and multiple logistic regression, a nomogram was established to select risk predictor variables. The NAFLD prediction model was validated through the receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis (DCA).Results: After random grouping, the cohort comprised 517 in the training set and 213 in the validation set. The prediction model employed nine of the 20 selected variables, namely gender, hypertension, waist circumference, body mass index, blood platelet, triglycerides, high-density lipoprotein cholesterol, plasma glucose, and alanine aminotransferase. ROC curve analysis yielded an area under the curve values of 0.877 (95% Confidence Interval [CI]: 0.848– 0.907) for the training set and 0.871 (95% CI: 0.825– 0.917) for the validation set. Optimal critical values were determined as 0.472 (0.786, 0.825) in the training set and 0.457 (0.743, 0.839) in the validation set. Calibration curves for both sets showed proximity to the ideal diagonal, with P-values of 0.972 and 0.370 for the training and validation sets, respectively (P > 0.05). DCA indicated favorable clinical applicability of the model.Conclusion: We constructed a nomogram model that could complement traditional NAFLD detection methods, aiding in individualized risk assessment for NAFLD.Keywords: non-alcoholic fatty liver disease, nomogram, prediction model, LASSO

Zheng-Dao Mao,1,&ast; Zhi-Guang Liu,1,&ast; Yan Qian,1 Yu-Jia Shi,1 Lian-Zheng Zhou,1 Qian Zhang,1 Chun-Jian Qi2 1Department of Respiratory and Critical Care Medicine, Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China; 2Central Laboratory, Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chun-Jian Qi, Laboratory of Oncology, Changzhou Second People’s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, People’s Republic of China, Tel +86-519-81087391, Email qichunjian@njmu.edu.cn Qian Zhang, Department of Respiratory and Critical Care Medicine, Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, No. 29 Xinlong Road, Changzhou, 213003, People’s Republic of China, Tel +86-519-81087391, Email qianzhang@njmu.edu.cnIntroduction: Combined allergic rhinitis and asthma syndrome (CARAS) is a concurrent clinical or subclinical allergic symptom of diseases of the upper and lower respiratory tract. This study is the first to explore the expression profiles of mRNA, lncRNA, and circRNA in CARAS using RNA sequencing, which may provide insight into the mechanisms underlying CARAS.Material and Methods: Whole blood samples from nine participants (three CARAS patients, three AR patients, and three normal control participants) were subjected to perform RNA sequencing, followed by identification of differentially expressed lncRNAs (DElncRNAs), circRNAs (DEcircRNAs) and mRNAs (DEmRNAs). Then, lncRNA/circRNA-mRNA regulatory pairs were constructed, followed by functional analysis, immune infiltration analysis, drug prediction, and expression validation with RT-qPCR and ELISA.Results: The results showed that 61 DEmRNAs, 23 DElncRNAs and 3 DEcircRNAs may be related to the occurrence and development of CARAS. KRT8 may be implicated in the development of AR into CARAS. Three immunity-related mRNAs (IDO1, CYSLTR2, and TEC) and two hypoxia-related mRNAs (TKTL1 and VLDLR) were associated with the occurrence and development of CARAS. TEC may be considered a drug target for Dasatinib in treating CARAS. Several lncRNA/circRNA-mRNA regulatory pairs were identified in CARAS, including LINC00452/MIR4280HG/hsa_circ_0007272/hsa_circ_0070934-CLC, HEATR6-DT/LINC00639/LINC01783/hsa_circ_0008903-TEC, RP11-71L14.3-IDO1/SMPD3, RP11-178F10.2-IDO1/HRH4, and hsa_circ_0008903-CYSLTR2, which may indicate potential regulatory effects of lncRNAs/circRNAs in CARAS. Dysregulated levels of immune cell infiltration may be closely related to CARAS.Conclusion: The regulating effect of lncRNA/circRNA-immunity/hypoxia-related mRNA regulatory pairs may be involved in the occurrence and development of CARAS.Keywords: combined allergic rhinitis and asthma syndrome, lncRNA, circRNA, immunity, hypoxia

Qingjian Li,1,&ast; Kunhuan Yang,2– 5,&ast; Qianlin Ji,1,&ast; Jing Jiang,1 Rongrong Zong,2– 5 Yu Zhang,1 Yiwen Qian,1 Xin Che,1 Jinshan Suo,1 Zhiliang Wang1 1Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian, People’s Republic of China; 3Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen, Fujian, People’s Republic of China; 4Eye Institute of Xiamen University, Xiamen, Fujian, People’s Republic of China; 5Xiamen University School of Medicine, Xiamen, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinshan Suo; Zhiliang Wang, Email ammy_suo@163.com; ophwzl@163.comPurpose: To evaluate the efficacy and safety of idiopathic epiretinal membrane (ERM) surgery in patients aged over 80 years.Methods: Consecutive patients who underwent pars plana vitrectomy (PPV) combined with ERM and internal limiting membrane (ILM) peeling with retrobulbar anesthesia were recruited. Based on age, the patients were divided into the elderly group (≥ 80 years of age) and the control group (< 80 years of age). The best-corrected visual acuity (BCVA) and surgical complications were regarded as the main measurement indicators.Results: This study included 43 eyes from 43 patients aged 80 to 91 years and 86 eyes from 86 patients aged 54 to 79 years. Surgical intervention substantially improved BCVA both in the elderly and control groups (p = 0.005 and p < 0.001, respectively). Statistical analyses showed no significant difference in the incidence of surgical complications between the two groups (p = 0.631). The operations in either group were not delayed or canceled for the reason of complications of retrobulbar anesthesia, severe anxiety, or physical discomfort in the perioperative period. Moreover, no patient required a second operation. Also, no stroke, myocardial infarction, or death occurred during the follow-up period. All the surgical complications were treated satisfactorily.Conclusion: Our outcomes indicate that PPV combined with ERM and ILM peeling with retrobulbar anesthesia is effective and safe in elderly patients aged 80 years or older. Based on age alone, we believe that advancing age should not be the risk factor for idiopathic ERM surgery.Keywords: idiopathic epiretinal membrane, elderly, pars plana vitrectomy, complication, safety

Xiaoyu Zhang,1– 3,&ast; Lan Ding,1– 3,&ast; Ling Sun,1– 3 Bingqing Sun,1– 3 Yangyi Huang,1– 3 Yishan Qian,1– 3,&ast; Xingtao Zhou1– 3,&ast; 1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China; 2Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, People’s Republic of China; 3Shanghai Research Center of Ophthalmology and Optometry, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yishan Qian; Xingtao Zhou, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China, Tel +86-21-64377134, Fax +86-21-64377151, Email thronebird31@hotmail.com; doctzhouxingtao@163.comPurpose: To investigate the relationship between corneal tomographic or biomechanical parameters and risk of keratoconus in very asymmetric ectasia (VAE).Methods: This retrospective case-control single-centre study included patients with VAE and normal controls. The VAE group had clinical ectasia in one eye and normal topography (VAE-NT) in the fellow eye; VAE-NT eyes were selected for analysis. The control group was selected from corneal refractive surgery candidates; the right eye was enrolled. Scheimpflug-based corneal tomography (Pentacam) and corneal biomechanical assessment (Corvis ST) were performed. Univariate and multivariable logistic regression were performed using Cox proportional hazards models to evaluate keratoconus-associated risk factors. A two-piecewise linear regression model was applied to examine the threshold effect of selected vital paragmeters on the risk of keratoconus according to a smoothing plot.Results: Threshold effect between tomographic integration and risk of keratoconus was observed. Discrepancy between the central corneal thickness and thinnest corneal thickness (discrepancy CCT vs TCT) greater than 5 μm, discrepancy between the apex corneal thickness and thinnest corneal thickness (discrepancy ACT vs TCT) greater than 3 μm, vector distance between CCT and TCT (distance CCT vs TCT) greater than 0.65 mm indicated a significant increased risk of keratoconus. Risk of keratoconus decreased when distance CCT vs TCT was less than 0.65 mm.Conclusion: Discrepancy CCT vs TCT, discrepancy ACT vs TCT, and distance CCT vs TCT can be used as indicators for risk assessment of early keratoconus.Keywords: keratoconus, corneal tomographic, corneal biomechanical, very asymmetric ectasia

Yang Qian, Chenting Cai, Mengqing Sun, Dan Lv, Yun Zhao The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Dan Lv, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, People’s Republic of China, Email fylvdan@nbu.edu.cnAbstract: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is the exacerbation of a range of respiratory symptoms during the stable phase of chronic obstructive pulmonary disease (COPD). AECOPD is thus a dangerous stage and key event in the course of COPD, as its deterioration and frequency seriously affects the quality of life of patients and shortens their survival. Acute exacerbations occur and develop due to many factors such as infection, tobacco smoke inhalation, air pollution, comorbidities, airflow limitation, various biomarkers, history of previous deterioration, natural killer cell abnormalities, immunoglobulin G deficiency, genetics, abnormal muscle and nutritional status, negative psychology, and seasonal temperature changes. There is relatively limited research on the impact of the role of standardized management on the alleviation of AECOPD. However, with the establishment of relevant prevention and management systems and the promotion of artificial intelligence technology and Internet medical approaches, long-term effective and standardized management of COPD patients may help to achieve the quality of life and disease prognosis in COPD patients and reduce the risk of AE.Keywords: chronic obstructive pulmonary disease, acute exacerbation, related risk factors

Xu Yang,1 Mi Yao,2 Delu Yin,3 Na Zhang,1 Jing Li,1 Yan Jiang,1 Rundong Fu,1 Yi Qian1 1Department of General Practice, Donghuashi Community Health Service Center, Beijing, People’s Republic of China; 2Department of General Practice, Peking University Health Science Center, Beijing, People’s Republic of China; 3Department of Health Development, Capital Institute of Pediatrics, Beijing, People’s Republic of ChinaCorrespondence: Xu Yang, Department of General Practice, Donghuashi Community Health Service Center, 33 Donghuashi Street, Dongcheng District, Beijing, 100062, People’s Republic of China, Tel +86 13693088802, Fax +86 1067120077, Email xuyang8799@163.comBackground: Chronic obstructive pulmonary disease (COPD) has a high incidence rate in China, but the diagnosis rate remains insufficient. This study aimed to explore and compare COPD screening tools for primary healthcare institutions in China.Purpose: Exploring COPD Screening Tools and Their Combined Use for Primary Healthcare Institutions in China.Patients and Methods: From September 2022 to March 2023, a screening for COPD was conducted among residents aged 35 years and above in primary healthcare institutions in Beijing, China. The screening involved the use of the CAPTURE scale, COPD-SQ scale, and peak expiratory flow rate test. Any positive results from these screening tests were followed by further pulmonary function testing to confirm the diagnosis. Sensitivity, specificity, positive predictive value, negative predictive value, and receiver operating characteristic (ROC) curves were calculated for each screening tool alone and in combination.Results: A total of 986 individuals completed the screening tests. The positive rates for the CAPTURE scale, COPD-SQ scale, and peak flow meter screening were 41.78%, 29.11%, and 52.03%, respectively. Of the participants, 166 (24.09%) underwent pulmonary function tests, with an average age of 61.69± 13.68 years. The peak flow meter screening showed the highest sensitivity (83.78%) when used alone, while the COPD-SQ scale exhibited the best specificity (59.69%), positive predictive value (31.58%), and negative predictive value (58.56%). Significant differences (P< 0.05) were observed between any two of the three screening tools. Among the combinations, the peak flow meter screening + COPD-SQ scale showed the highest accuracy, with a Youden index of 0.277 and an AUC of 0.638.Conclusion: There is variation in the accuracy of existing screening tools for COPD when used alone. For primary healthcare institutions, the optimal COPD screening tool is the combination of peak flow meter screening and the COPD-SQ questionnaire. If limited by screening equipment conditions, the COPD-SQ questionnaire can be used alone for screening.Keywords: primary health care institutions, chronic obstructive pulmonary disease, COPD, screening questionnaire, peak flow rate test, pulmonary function tests

Ying Qian,1,&ast; Zhuohang Che,1,&ast; Chuanwen Fu,1,&ast; Xinqiang Chen,1 Jia Zeng,1 Xuehui Zhang,1 Yongli Zeng,2 Jianzhong Yin1,3 1School of Public Health, Kunming Medical University, Kunming, 650500, People’s Republic of China; 2Department of Cardiology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China; 3Baoshan College of Traditional Chinese Medicine, Baoshan, 678000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianzhong Yin, Baoshan College of Traditional Chinese Medicine, Longyang District, Baoshan City, Yunnan Province, 678000, People’s Republic of China, Tel +86 13987645337, Email yinjianzhong2005@sina.com Yongli Zeng, Department of Cardiology, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, People’s Republic of China, Tel +86 13888931757, Email zyluh@126.comBackground: In recent years, with the rapidly development of economic globalization, residents’ dietary structure has undergone major changes, and diet have emerged as an important environmental factors linked to the increased incidence of obesity. Therefore, evaluating the overall dietary quality and structure of residents, further clarifying the main dietary factors that lead to disease occurrence, is of great practical significance for disease prevention and control.Methods: Baseline data from the China Multi-Ethnic Cohort study (CMEC), Han people living in high-altitude and cold regions of Yunnan Province, which was 1518 participants. In this study, the dietary balance index (DBI-16) was used (i) To evaluate the dietary quality of Han nationality residents 30– 79 years old in the Yunnan plateau; (ii) To analyze the correlation between the dietary quality and overweight/obesity; (iii) And to provide reference basis of nutritional intervention for local residents and explore the main dietary factors affecting their health status.Results: The dietary structure of the Han nationality residents in the cold regions of Yunnan plateau is unreasonable. Firstly, the intake of cereals, fruits, dairy, eggs and fishes is insufficient to varying degrees, while the intake of beans, poultry, and cooking oil is relatively high. Secondly, the dietary patterns of normal groups, the overweight and obese groups obeyed the A, E, H and I dietary patterns, and the serum Leptin and adipocyte fatty acid binding protein (A-FABP) levels of the overweight and obese group were higher than the normal group between the different dietary patterns (P < 0.05, r > 0). Additionally, excessive dietary intake was positively correlated with a higher serum UCP1 level (P < 0.05, r > 0). In comparison, insufficient dietary intake was positively correlated with a higher serum A-FABP level (P < 0.05, r > 0).Conclusion: Through the DBI-16, it is found that the dietary structure of the Han nationality residents in the cold regions of Yunnan plateau was in a serious imbalance state, and nutritional guidance and intervention should be further strengthened.Keywords: plateau Han nationality, dietary balance index-16, dietary quality, dietary evaluation, dietary pattern

Yayun Qian,1 Yuexing Gu,2 Jialin Deng,3 Zhaoying Cai,3 Yang Wang,3 Ruoyu Zhou,3 Dongxu Zhu,3 Hongmei Lu,4 Zheng Wang1 1Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, People’s Republic of China; 2Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 3Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, People’s Republic of China; 4Department of Pathology, Yangzhou Maternal and Child Health Hospital, Yangzhou, People’s Republic of ChinaCorrespondence: Zheng Wang; Yayun Qian, Email yzdxfsyywz@163.com; yyqian@yzu.edu.cnIntroduction: As the most common malignant tumor in the world, the prognosis of patients with advanced lung cancer remains poor even after treatment. There are many prognostic marker assays available, but there is still more room for the development of high-throughput and sensitive detection of circulating tumor DNA (ctDNA). Surface-enhanced Raman spectroscopy (SERS), a spectroscopic detection method that has received wide attention in recent years, can achieve exponential amplification of Raman signals by using different metallic nanomaterials. Integrating SERS with signal amplification strategy into the microfluidic chip and applying it to ctDNA detection is expected to be an effective tool for the prognosis of lung cancer treatment effect in the future.Methods: To construct a high-throughput SERS microfluidic chip integrated with enzyme-assisted signal amplification (EASA) and catalytic hairpin self-assembly (CHA) signal amplification strategies, using hpDNA-functionalized Au nanocone arrays (AuNCAs) as capture substrates and cisplatin-treated lung cancer mice to simulate the detection environment for sensitive detection of ctDNA in serum of lung cancer patients after treatment.Results: The SERS microfluidic chip constructed by this scheme, with two reaction zones, can simultaneously and sensitively detect the concentrations of four prognostic ctDNAs in the serum of three lung cancer patients with a limit of detection (LOD) as low as the aM level. The results of the ELISA assay are consistent with this scheme, and its accuracy is guaranteed.Conclusion: This high-throughput SERS microfluidic chip has high sensitivity and specificity in the detection of ctDNA. This could be a potential tool for prognostic assessment of lung cancer treatment efficacy in future clinical applications.Keywords: circulating tumor DNA, surface-enhanced Raman scattering, lung cancer, AuNCAs, prognostic assessment

Yezhou Qian,1 Zhangli Fei,2 Feige Nian2 1Department of Cardiology, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of China; 2Department of Rheumatology, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, Jiaxing, People’s Republic of ChinaCorrespondence: Feige Nian, Department of Rheumatology, The First Hospital of Jiaxing, The Affiliated Hospital of Jiaxing University, No. 1882 Zhong Huan Road, Jiaxing, 314000, People’s Republic of China, Tel +8619884323170, Email 00192649@zjxu.edu.cnAbstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia with a significant increase in morbidity and mortality worldwide. Rheumatoid arthritis (RA), as a systemic inflammatory disease, affecting 0.5– 1.0% of the adult population, is associated with increased incidence of cardiac arrhythmias such as AF. Several epidemiologic studies find that the risk of AF is increased in RA when compared with the general population. Other studies are inconsistent. Considering that inflammation plays an important role in AF, RA may be involved in the occurrence and development of AF. This review summarizes the epidemiology, pathophysiology, and management of AF in patients with RA.Keywords: atrial fibrillation, rheumatoid arthritis, epidemiology, pathophysiology, management

Yuexing Gu,1,2,&ast; Yan Li,3,&ast; Shengjie Ge,1,2 Wenbo Lu,4 Yu Mao,1,2 Miao Chen,1,2 Yayun Qian1,2 1Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, People’s Republic of China; 2Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, People’s Republic of China; 3Department of Obstetrics and Gynecology, The Second People’s Hospital of Taizhou City, Taizhou, People’s Republic of China; 4Shanxi Normal University, College of Chemistry and Material Science, Linfen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yayun Qian, Email yyqian@yzu.edu.cnPurpose: This paper aims to construct a surface-enhanced Raman spectroscopy (SERS) biosensor based on functionalized Au-Si nanocone arrays (Au-SiNCA) using a dual signal amplification strategy (SDA-CHA) to evaluate telomerase activity during epithelial-mesenchymal transition (EMT) in laryngeal carcinoma (LC).Methods: A SERS biosensor based on functionalized Au-SiNCA was designed with an integrated dual-signal amplification strategy to achieve ultrasensitive detection of telomerase activity during EMT in LC patients.Results: Labeled probes (Au-AgNRs@4-MBA@H1) and capture substrates (Au-SiNCA@H2) were prepared by modifying hairpin DNA and Raman signal molecules. Using this scheme, telomerase activity in peripheral mononuclear cells (PMNC) could be successfully detected with a limit of detection (LOD) as low as 10− 6 IU/mL. In addition, biological experiments using BLM treatment of TU686 effectively mimicked the EMT process. The results of this scheme were highly consistent with the ELISA scheme, confirming its accuracy.Conclusion: This scheme provides a reproducible, selective, and ultrasensitive assay for telomerase activity, which is expected to be a potential tool for the early screening of LC in future clinical applications.Keywords: surface-enhanced Raman scattering, telomerase, laryngeal carcinoma, epithelial-mesenchymal transition, Au-SiNCA

Haochen Jiang,1,2,&ast; Zhi Shang,2,&ast; Liping You,1,2,&ast; Jinghao Zhang,1 Junzhe Jiao,2 Yihan Qian,2 Jiacheng Lin,2 Fang Wang,2 Yueqiu Gao,1 Xiaoni Kong,2 Xuehua Sun1 1Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuehua Sun, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Email susan_sxh@shutcm.edu.cn Xiaoni Kong, Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Email xiaonikong@shutcm.edu.cnBackground and Purpose: Current pharmacological approaches to prevent hepatic ischemia/reperfusion injury (IRI) are limited. To mitigate hepatic injury, more research is needed to improve the understanding of hepatic IRI. Depending on traditional Chinese medicine (TCM) theory, acupuncture therapy has been used for the treatment of ischemic diseases with good efficacy. However, the efficacy and mechanism of acupuncture for hepatic IRI are still unclear.Methods: Blood provided to the left and middle lobe of mice livers was blocked with a non-invasive clamp and then the clamps were removed for reperfusion to establish a liver IRI model. Quantitative proteomics approach was used to evaluate the impact of EA pretreatment on liver tissue proteome in the IRI group. Serum biochemistry was used to detect liver injury, inflammation, and oxidative stress levels. H&E staining and TUNEL staining were used to detect hepatocyte injury and apoptosis. Immunohistochemistry and ELISA were used to detect the degree of inflammatory cell infiltration and the level of inflammation. The anti-inflammatory and antioxidant capacities were detected by Quantitative RT-PCR and Western blotting.Results: We found that EA at Zusanli (ST36) has a protective effect on hepatic IRI in mice by alleviating oxidative stress, hepatocyte death, and inflammation response. Nuclear factor E2-related factor 2 (Nrf2) as a crucial target was regulated by EA and was then successfully validated. The Nrf2 inhibitor ML385 and cervical vagotomy eliminated the protective effect in the EA treatment group.Conclusion: This study firstly demonstrated that EA pretreatment at ST36 significantly ameliorates hepatic IRI in mice by inhibiting oxidative stress via activating the Nrf2 signal pathway, which was vagus nerve-dependent.Keywords: inflammation, liver, proteomics

Haipeng Yao,1 Zhen Sun,1 Wei Yuan,1 Chen Shao,1 Honghua Cai,2 Lihua Li,3 Yongjiang Qian,1 Zhongqun Wang1 1Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 2Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 3Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of ChinaCorrespondence: Zhongqun Wang, Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212000, People’s Republic of China, Email wangtsmc@126.comPurpose: The research explores the relationship between the triglyceride-glucose index (TyG index) and the macroangiopathy risk in single-center hospitalized type 2 diabetes mellitus (T2DM) patients and develops a risk prediction nomogram model.Patients and Methods: A total of 858 patients with T2DM were studied retrospectively. Lasso regression was used to eliminate unimportant factors, and multivariate logistic regression analysis was used to investigate the association between the TyG index and macrovascular disease in T2DM. A nomogram model was constructed to predict macrovascular disease in T2DM and tested using the bootstrap technique, and the efficacy of the nomogram model was investigated using ROC curves. The multivariate Cox proportional hazards model estimated the association between the TyG index and all-cause mortality.Results: TyG index, high-density lipoprotein, red blood cell count, hypertension, history of taking ACEI/ARB drugs, and aortic calcification were closely related to macrovascular complications. In Cox proportional hazard model, the HRs of TyG index were 1.89 (95% confidence interval (CI) 1.29– 2.76, p < 0.001) after adjusting for covariates. The risk of all-cause mortality in T2DM with macrovascular complications was significantly higher than in diabetic patients without vascular disease. In the ROC curve analysis, the cut-off value of the TyG index for macrovascular complications of T2DM was 9.31 (AUC: 0.702, 95% CI 0.67– 0.74, p < 0.001).Conclusion: TyG index predicts future macrovascular disease in diabetic patients independently of known cardiovascular risk factors, suggesting that TyG index may be a useful marker for prognosis in diabetic patients.Keywords: diabetes, cardiovascular events, vascular complications, risk factors, triglyceride-glucose index

Long Yan,1,2 Yulin Qian,1 Hong Li1,2 1First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300380, People’s Republic of China; 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300380, People’s Republic of ChinaCorrespondence: Hong Li, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 88, Changling Road, Liqizhuang Street, Xiqing District, Tianjin, People’s Republic of China, Email 15222817069@163.comIntroduction: Stroke often leaves behind a wide range of functional impairments, of which limb movement disorders are more common. Approximately 85% of patients have varying degrees of upper limb motor impairment. In recent years, transcutaneous vagus nerve stimulation combined with rehabilitation training has been gradually used in the rehabilitation of upper limb motor dysfunction after stroke and appears to have some therapeutic benefits.Purpose: We conducted the systematic review to evaluate the efficacy and safety of transcutaneous vagus nerve stimulation combined with rehabilitation training in the rehabilitation of upper limb motor dysfunction after stroke.Methods: Six databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure Database (CNKI), Wanfang Database, and China Science and Technology Journal Database (VIP), were searched for January 1, 2016 to January 30, 2022. Randomized controlled trials using TVNS combined with rehabilitation training to intervene in upper limb motor dysfunction after stroke were included, and meta-analysis was performed using Review Manager 5.4.1 software.Results: Total of 101 participants from 4 studies were included in this systematic review. These studies were evaluated using the Cochrane Review’s Handbook 5.1 evaluation criteria and PEDro scores, and meta-analysis was performed on the collected data. The systematic review shows a significant effect of TVNS combined with rehabilitation training on the Upper Extremity Fugl-Meyer Score (MD=3.58, 95% CI [2.34, 4.82], P< 0.00001, I2=0%), Function Independent Measure Score (MD=3.86, 95% CI [0.45, 7.27], P=0.03, I2=0%) and the Wolf Motor Function Test Score (MD=3.58, 95% CI [1.97, 5.18], P< 0.0001, I2=0%).Conclusion: Based on UE-FM, FIM, and WMFT scores, TVNS combined with rehabilitation training showed some improvement in upper limb motor dysfunction in post-stroke patients, but its long-term effects, stimulation sites, stimulation parameters, combined mode with rehabilitation training, and adverse effects still need further observation.Registration: PROSPERO: CRD42022312453 (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022312453).Keywords: TVNS, stroke, motor function, systematic review, meta-analysis

Aiyun Li,1,&ast; Ming Fang,2,&ast; Dongjie Hao,1 Qiaoai Wu,1 Yaqi Qian,1 Hao Xu,3,4 Bo Zhu1 1Department of Clinical Medicine, The Women’s Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Institute of Infection Disease Control, Shandong Center for Disease Control and Prevention, Jinan, People’s Republic of China; 3State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Department of Structure and Morphology, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Xu; Bo Zhu, Email xuhao0523@zju.edu.cn; 5202054@zju.edu.cnBackground: Late-onset group B Streptococcus (LOGBS) sepsis is a cause of infection and death in infants. Infected breast milk has been considered a source of neonatal GBS infection and invasive infection. However, mother-to-infant transmission of GBS detected by the high-resolution diagnostic method is rarely reported.Methods: This study describes a low-weight premature infant who developed late-onset GBS septicemia 21 days after birth. GBS strains isolated from the mother’s cervical secretion, the mother’s milk, and the baby’s blood were cultured to identify the source of GBS infection. We further confirmed the GBS isolates through matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Finally, we performed whole-genome sequencing (WGS) and phylogenetic analyses on the GBS strains recovered.Results: GBS isolates were cultured from the bloodstream of the premature infant and the mother’s milk, respectively. Subsequently, WGS and phylogenetic analyses on three GBS isolates demonstrated that the GBS strain from the infant’s bloodstream was 100% homologous to that from the mother’s breast milk, which had some different gene fragments from the GBS strain from the mother’s cervical secretion. It provided evidence that this infant’s late-onset GBS septicemia originated from his mother’s breast milk instead of the vertical mother-to-infant transmission.Conclusion: Through WGS and phylogenetic analysis of the GBS strains, we proved in this study that the late-onset GBS sepsis in a premature infant was derived from his mother’s breast milk. It indicated that WGS diagnosis is an effective tool for infection tracing. Furthermore, this report provides direction for preventing late-onset GBS infection.Keywords: group B Streptococcus, late-onset GBS sepsis, breast milk, whole-genome sequencing, phylogenetic analysis

Wei Zhang,1 Yue Qian,1 Xue Jin,2 Yixian Wang,1 Lili Mu,1 Zhixia Jiang2 1Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, People’s Republic of China; 2Guizhou Nursing Vocational College, Guiyang, People’s Republic of ChinaCorrespondence: Wei Zhang, Department of Pathogen Biology, Guizhou Nursing Vocational College, Guiyang, 550000, Guizhou, People’s Republic of China, Email lawrence2013@163.comBackground: SIRT7 has been shown to be expressed in many cancer types, including clear cell renal cell carcinoma (KIRC), but its functional role in this oncogenic context remains to be firmly defined. This study was designed to explore correlations between SIRT7 and KIRC characteristics using the TCGA database.Methods: Relationships between SIRT7 expression and KIRC patient clinicopathological characteristics were assessed through Kruskal–Wallis tests, Wilcoxon signed-rank tests, and logistic regression analyses. Area under the ROC curve (AUC) values were used to assess the prognostic value of SIRT7 as a means of classifying clear cell renal cell carcinoma patients. The functional role of SIRT7 in this cancer type was assessed through GO/KEGG enrichment analyses and immune cell infiltration analyses.Results: In KIRC patients, higher levels of SIRT7 expression were associated with Race, M stage, T stage (all P < 0.05). SIRT7 offered significant diagnostic value in ROC curve analyses (AUC = 0.912), and elevated SIRT7 levels were linked to worse patient overall survival (OS; P < 0.001). The expression of SIRT7 was independently related with KIRC patient OS (HR: 1.827; 95% CI: 1.346– 2.481; P< 0.001). In GO/KEGG analyses, SIRT7 was found to be associated with ubiquitin-mediated proteolysis and nucleotide excision repair. Higher SIRT7 expression was related to the enhanced infiltration of certain immune cells.Conclusion: Increased SIRT7 expression was associated with a worse KIRC patient prognosis, and immune infiltrates, suggesting it may offer value as a prognostic biomarker for this cancer type.Keywords: SIRT7, biomarker, KIRC, prognosis, tumor-immune infiltration

Yiguan Qian,&ast; Yang Li,&ast; Ke Chen,&ast; Ning Liu, Xi Hong, Di Wu, Zheng Xu, Liuhua Zhou, Luwei Xu, Ruipeng Jia, Yu-Zheng Ge Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruipeng Jia; Yu-Zheng Ge, Department of Urology, Nanjing First Hospital, Nanjing Medical University Nanjing, Jiangsu, People’s Republic of China, Tel +86-15850675660, Email ruipengj@163.com; geyuzheng@njmu.edu.cnBackground: Polo-like kinase 1 (PLK1) belongs to polo-like kinases family and affects cell cycles. However, the role of PLK1 in some malignant tumors remains unclear.Methods: To obtain a comprehensive view of PLK1 expression patterns, public databases including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, the Genotype-Tissue Expression, and human cell landscape databases were employed. The correlation of PLK1 expression with prognosis, immune infiltrations, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methylation was examined. Besides, we validated the results of clear cell renal cell carcinoma (ccRCC) in two cohorts, with quantitative real-time PCR, Western blot, and loss-of-function experiments.Results: By mining public datasets, we discovered that PLK1 expression in tumor tissues and cancer cell lines displayed heterogeneity compared to normal controls across different cancers. Besides, high expression of PLK1 results in shorter survival time in 15 cancer types, especially in ccRCC. PLK1 expression showed strong association with immune cell infiltration and immune checkpoint genes across cancer types. Moreover, we identified a strong association between PLK1 expression and TMB, MSI MMR, and DNA methylation. PLK1 was validated to be highly expressed in ccRCC tissues and promote ccRCC cell proliferation, migration, invasion, and cell cycle. Mechanistically, PLK1 could regulate forkhead box protein M1 and target cell cycle-associated genes to participate in cell cycle control.Conclusion: PLK1 has important prognostic value and is associated with tumor immunity across cancer types including ccRCC.Keywords: PLK1, pan-cancer analysis, ccRCC, biomarker, tumor immunity

Peng Feng,1,&ast; Yuchen Li,2,&ast; Zhijie Tian,1,&ast; Yuan Qian,1 Xingyu Miao,1 Yuelin Zhang3 1Neurosurgery, Shaanxi Provincial People’s Hospital, Xian, 710068, People’s Republic of China; 2Hengyang Medical School, University of South China, Hengyang, 421001, People’s Republic of China; 3Xi’an Medical University, Xian, 710021, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingyu Miao; Yuelin Zhang, Email miaoxyu@163.com; xyyxyfp@163.comBackground: High-grade glioma is a type of heterogeneous lethal brain tumor most common in adults. At present, immune checkpoint inhibitors (ICIs) are being considered for first-line therapeutics for malignant GBM. Nonetheless, molecular markers for malignant GBM are unavailable at present. As a result, it is important to explore molecular markers related to immunity for GBM.Materials and Methods: The present study adopted a deconvolution algorithm for quantifying immunocyte composition and measuring gene expression, and used weighted gene co-expression network analysis (WGCNA) to analyze GBM expression data obtained from Gene Expression Omnibus (GEO), Chinese Glioma Genome Atlas (CGGA), and the Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) databases. Thereafter, key CD8+ T cell infiltration-related genes and modules were identified, and database analysis was conducted to verify the therapeutic and immune features of the selected genes.Results: From this study, CD8+ T cell-related modules were identified. By using consistent clustering analysis, two panels of genes (red and green) with the highest correlation with CD8+ T cells infiltration were used to construct high-, low-expression groups, silent and/or mixed group of T cell infiltrations. In the high and low CD8+ T cell infiltration groups, a total of 535 differential genes were obtained, of which ten genes (RPS5, RPS6, FAU, RPS19, RPS23, RPS15A, RPS29, RPS14, RPS16, RPS27A) were identified through protein–protein interactions and co-expression network analysis. Post Cox regression and Kaplan–Meier (K-M) survival analysis, RPS5, RPS6, and RPS16 were selected as candidate prognostic biomarkers related to CD8+ T cells.Conclusion: The three associated genes RPS5, RPS6, and RPS16 were markedly related to degree of T cell infiltration and immune-related activated. We identified their potential biomarkers and therapeutic targets associated with the extent of CD8+ T cell infiltration in GBM.Keywords: prognosis, mutation, glioblastoma, gene, WGCNA

Yao Wang,1,&ast; Jingjing Sun,1,&ast; Yang Yang,1,&ast; Sonia Zebaze Dongmo,2 Yeben Qian,1 Zhen Wang3 1Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Department of General Surgery, Feixi County People’s Hospital, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yeben QianDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of ChinaEmail qinayeben123@hotmail.comZhen WangDepartment of General Surgery, Feixi County People’s Hospital, Hefei, 231200, People’s Republic of ChinaEmail 1593824167@qq.comPurpose: Hypoxia and immune cell infiltration play an important role in the progression and metastasis of gastric cancer. However, the molecular classification of gastric cancer combined with hypoxia and immune cell infiltration remains unknown.Materials and Methods: ssGSEA was used to evaluate the hypoxic state and immune cell infiltration of 1059 gastric cancer samples collected from the GEO and TCGA database. Based on the results, unsupervised clustering was performed to obtain different gastric cancer subtypes. The differentially expressed genes related to OS between these subtypes were utilized for LASSO analysis to construct a prognostic signature (HIscore). Subsequently, small-molecule drugs were predicted using the Connectivity Map (CMAP) database.Results: We obtained three hypoxic-immune infiltration patterns (HIcluster A-C) with different prognoses and classified them as low hypoxic/low immune, high hypoxic/high immune, and low hypoxic/high immune subtypes. Based on the differential genes between HIclusters, we have also obtained other three gastric cancer subtypes (genecluster A-C) and a 13-gene signature (HIscore). At the same time, we extensively explored the clinical and transcriptome traits in different clusters and groups with high or low HIscore. We proved that HIscore is an independent prognostic biomarker and an indicator of genome stability and EMT. Using the CMAP database, we found 96 small-molecule drugs that could reverse the poor prognosis and could serve as therapeutic drugs, especially for gastric cancer patients with high HIscore.Conclusion: Our study evaluated the hypoxic state and immune cell infiltration in gastric tumors, and identified different gastric cancer subtypes. In addition, we established a hypoxia-immune signature to predict prognosis which is tightly linked to tumor EMT and genomic stability. Based on HIscore, we used the CMAP database to explore small-molecule drugs that may have the potential in serving as therapeutic drugs.Keywords: hypoxia, tumor microenvironment, genome instability, microsatellites, mutation burden

Zhimin Zha,1,&ast; Yujia Cheng,2,3,&ast; Lu Cao,2 Yanxia Qian,2 Xinjian Liu,3,4 Yan Guo,1 Junhong Wang2 1Department of Gerontology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China; 3Key Laboratory of Antibody Techniques of National Health Commission, Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Pathogen Biology, Nanjing Medical University, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Guo; Junhong WangDepartment of Gerontology, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing City, Jiangsu Province, 210009, People’s Republic of ChinaTel +86-25-68305083; +86-25-68308273Email guoyan51@hotmail.com; wangjunhong@jsph.org.cnObjective: A polarized macrophage response plays a critical role in the pathophysiological process of myocardial infarction (MI). Several studies have shown a pro-inflammatory role for monomeric C-reactive protein (mCRP) in cardiovascular disease. However, the mechanism of how mCRP regulates macrophage phenotype switching remains unknown. In the present study, the effect of mCRP on macrophage polarization and its pathological function in myocardial repair after myocardial infarction was investigated.Methods: MI was induced by permanent ligation of the left anterior descending coronary artery in ICR mice. Adult mice were injected with mCRP (2.5 mg/kg) with or without SP600125 (15 mg/kg, JNK inhibitor) 45 min before MI. The cardiac function, scar size as well as cardiac fibrosis, infiltration of inflammatory cells, and the level of proteins in the JNK signaling pathway in infarcted myocardium were assessed. In addition, the phenotypic characterization of macrophages was further measured by ELISA, flow cytometry and quantitative RT-PCR in cultured THP-1 cells or peritoneal macrophages.Results: Cardiac function deterioration, ventricular dilatation and fibrosis were exacerbated in mice pretreatment with mCRP following MI. Meanwhile, an increased accumulation of infiltrated inflammatory cells in infarcted myocardium was observed in the mCRP group. Moreover, activation of the JNK signaling pathway was markedly elevated in mCRP treated animals post-MI. In contrast, pharmacological inhibition of JNK phosphorylation activity by SP600125 muted the detrimental effects of mCRP in MI mice. Furthermore, in vitro and in vivo co-culture experiments showed that mCRP shifted macrophage polarization towards pro-inflammatory phenotypes, and this polarization could be abolished by sp600125.Conclusion: Taken together, our results imply that mCRP impairs myocardial repair after myocardial infarction by polarizing the macrophages into the pro-inflammatory M1 phenotype via the JNK-dependent pathway.Keywords: myocardial infarction, monomeric CRP, inflammation, macrophage polarization, JNK pathway

Fang Chen,1,2,&ast; Han Zhong,1,&ast; Tengjiao Yang,3 Chuan Shen,2 Yuxiao Deng,4 Longzhi Han,2 Xiaosong Chen,2 Haomin Zhang,5 Yongbing Qian2 1Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Pharmacy, The Third People’s Hospital of Henan Province, Zhengzhou, People’s Republic of China; 4Department of Critical Care Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 5Department of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haomin ZhangDepartment of Laboratory Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86-21-68383715Email zhanghaomin@renji.comYongbing QianDepartment of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86-21-68383715Email qianyb79@hotmail.comBackground: Ceftazidime-avibactam (CZA) has been approved in vitro activity against carbapenem-resistant K. pneumoniae (CRKP), but the experience for the treatment of CRKP in liver transplantation (LT) recipients was limited, and previous data on its efficacy in this setting are lacking.Methods: LT recipients with CRKP infection who received CZA treatment were reviewed retrospectively, microbiological and clinical response, adverse events were also assessed. The primary outcome was 30-day mortality after CZA administration.Results: CZA was used in 21 LT recipients (including 4 pediatric patients) with CRKP infections after failure with other antimicrobials. CZA was administered as monotherapy in 4 patients. Median time from the onset of CRKP infection until the initiation of CZA treatment was 2 days (IQR, 1– 6.5), and the median treatment duration was 12 days (IQR, 8.5– 18.5). The mortality at 14 days, 30 days and all-cause was 28.6%, 38.1% and 42.9%, respectively. In adult patients, clinical response of 14 days and 30 days was 70.6% (12/17) and 58.8% (10/17), respectively, while in pediatric patients the 14-day and 30-day clinical response were both 75%, respectively. The relapse rate during the treatment developed in 3 patients after 30 days with the cessation of CZA monotherapy. CZA resistance was not detected in any case and 3 (3/21, 14.3%) patients developed acute kidney injury related to uncontrolled infection.Conclusion: CZA shows promising results, even in monotherapy, for the treatment of patients with severe infections due to carbapenem-resistant K. pneumoniae among LT recipients. The emergence of resistance to CZA was not observed.Keywords: carbapenem-resistant Klebsiella pneumoniae, ceftazidime-avibactam, liver transplantation, intra-abdominal infection, pneumonia

Yanxiong Mao,1,&ast; Yuanyuan Qian,2,&ast; Xiaoyan Sun,3 Na Li,1 Huaqiong Huang1 1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Haining People’s Hospital, Haining Branch, The First Affiliated Hospital, Zhejiang University, Haining, Zhejiang, People’s Republic of China; 3Department of Gynecology, Women’s Hospital School of Medicine Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huaqiong HuangKey Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of ChinaTel/Fax +86-571-87783552Email zr_hhq@zju.edu.cnBackground: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) could be triggered by community-acquired pneumonia (CAP). Peripheral blood eosinopenia are strongly associated with increased mortality. In hospitalized AECOPD patients with CAP, eosinopenia may be used to identify patients with high risk of death on admission.Methods: We conducted a retrospective cohort study in 82 hospitalized AECOPD patients with CAP. Patients who had received systemic corticosteroids preadmission were excluded. The patients were identified by individual case file review. According to blood eosinophil count, patients were grouped as eosinopenia (< 50/μL) and non-eosinopenia (≥ 50/μL). Association of eosinopenia with infection and 18-month survival were analyzed using appropriate statistical methods.Results: Baseline demographic, comorbidity, CURB65 and Pneumonia Severity Index scores were similar between two groups. The eosinopenia group had significantly higher pro-brain natriuretic peptide, D-dimer, neutrophil percentage, and lower lymphocyte count and lymphocyte percentage. The eosinopenia group had significantly higher C-reactive protein (median 77.30 vs 16.55, p=0.008) and procalcitonin (median 0.32 vs 0.12, p=0.001). Survival at 18 months after hospital discharge was significantly lower in the eosinopenia group vs non-eosinopenia group (log rank, p=0.002).Conclusion: Eosinopenia (< 50/μL) was a strong predictor of 18-month mortality and associated with more severe infection in hospitalized AECOPD patients with CAP. Eosinophil count at admission can be used as a prognosis marker of mortality in those population.Keywords: eosinopenia, chronic obstructive pulmonary disease, community-acquired pneumonia, mortality

Di He,1,2,&ast; Yuanyi Qian,1,2,&ast; Limei Zhou,3 Haozhao Qi,1,2 Yanming Liu1,2 1Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, People’s Republic of China; 2Clinical Research Center for Oral Diseases of Zhejiang Province, Hangzhou, 310020, People’s Republic of China; 3Hangzhou Dental Hospital, Hangzhou, 310002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanming LiuDepartment of Oral and Maxillofacial Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Shangcheng District, Hangzhou, Zhejiang, People’s Republic of ChinaTel/Fax +86571-87783741Email liuyanming@zju.edu.cnPurpose: Odontogenic deep fascial space infection in the head and neck is a common potentially fatal clinical problem. Traditional drainage method is considered laborious and gravity-dependent. In this study, we aimed to evaluate the clinical effect of a modified multifunctional irrigation-assisted vacuum drainage (MIVD) by comparing it with the traditional drainage method in the treatment of odontogenic deep fascial infection.Patients and Methods: Patients diagnosed with odontogenic deep fascial space infection in the Second Affiliated Hospital, Zhejiang University School of Medicine, China between March 2018 and March 2021 were studied. We divided the patients into two groups based on the drainage method they received: patients with the MIVD device were included in the MIVD group, patients with traditional drainage were included in the traditional group. Data were collected retrospectively including baseline characteristics and treatment outcome variables.Results: A total of 65 patients were included. All the patients were eventually cured. There were no significant differences in age, gender, diabetes, end stage renal disease, autoimmune diseases, other systemic diseases, tobacco use, number of the infected spaces, preoperative white blood cell count and C-reactive protein between the two groups. The number and frequency of manual irrigation by clinicians (MIC), time required for white blood cell count to return to normal levels (TWBC), time required for C-reactive protein to return to normal levels (TCRP), the length of hospitalization and the length and total cost of antibiotics use were significantly less in the MIVD group. There was no significant difference in the cost of hospitalization between the 2 groups.Conclusion: The MIVD device significantly reduced the number and frequency of MIC, TWBC, TCRP, the length of hospitalization and the length and total cost of antibiotics use in comparison with the traditional drainage method. It provided a favorable treatment method for patients with odontogenic deep fascial space infection in the head and neck.Keywords: deep fascial space infection, odontogenic infection, irrigation, vacuum drainage, head and neck

Shujuan Chu,1 Zhilin Wu,1 Zhouyang Wu,1 Jing Wu,1 Yue Qian2 1Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 2Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of ChinaCorrespondence: Jing Wu; Yue Qian Email tounj_002@163.com; qianyue011@sohu.comBackground: The causal relationship between insomnia and migraine is contradictory and no study has been carried out among the Chinese population to date.Methods: In this case, we conducted a case–control study and a bidirectional mendelian randomization (MR) analysis to determine whether insomnia is causally related to the development of migraine. The instrumental variables for insomnia were derived from the largest genome-wide association study of 1,331,010 participants, while the genetic instruments for migraine were available from the largest meta-analysis of migraine with 59,674 cases and 316,078 controls.Results: In case–control study, subjects with insomnia have significantly higher risk of migraine (OR=4.29, 95% CI: 3.21– 5.74, P< 0.001), compared with those without insomnia. The bidirectional two-sample MR analysis revealed that insomnia was significantly associated with higher risk of migraine (OR=1.24, 95% CI: 1.11– 1.38, P=1.01× 10-4), and the results were validated in the UK Biobank data. The results showed no indication for directional pleiotropy effects as assessed by the MR-Egger intercept (P> 0.05).Conclusion: Conclusively, our study highlighted that increased migraine risk was confined to subjects with a genetic pre-disposition to insomnia, and these findings had potential implications for improving the sleep quality to reduce the burden of migraine.Keywords: mendelian randomization, insomnia, migraine, case–control

Haiyan Ge,1,&ast; Xuanqi Liu,1,&ast; Wenchao Gu,2 Xiumin Feng,3,4 Fengying Zhang,5 Fengfeng Han,6 Yechang Qian,7 Xiaoyan Jin,8 Beilan Gao,9 Li Yu,10 Hong Bao,11 Min Zhou,12 Shengqing Li,13 Zhijun Jie,14 Jian Wang,15 Zhihong Chen,16 Jingqing Hang,5 Jingxi Zhang,3 Huili Zhu1 1Department of Respiratory and Critical Care Medicine, Huadong Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Respiratory Medicine, Pudong New District People’s Hospital, Shanghai, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Changhai Hospital Affiliated to Navy Military Medical University, Shanghai, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Changji Branch of First Affiliated Hospital of Xinjiang Medical University, Xinjiang, People’s Republic of China; 5Department of Respiratory Medicine, Putuo District People’s Hospital, Shanghai, People’s Republic of China; 6Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 7Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, People’s Republic of China; 8Department of Respiratory Medicine, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 9Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University, Shanghai, People’s Republic of China; 10Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 11Department of Respiratory Medicine Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, People’s Republic of China; 12Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 13Department of Respiratory and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 14Department of Respiratory Medicine, Shanghai Fifth’s Hospital, Fudan University, Shanghai, People’s Republic of China; 15Department of Respiratory Medicine, Shanghai Ninth’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 16Department of Respiratory and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huili Zhu Email zhuhuili001@126.comJingxi Zhang Email jingxizhang2000@126.comBackground: Chronic obstructive pulmonary disease (COPD) often coexists with multiple comorbidities which may have a significant impact on acute exacerbations of patients. At present, what kind of comorbidities affects acute exacerbations and how comorbidities lead to poor prognosis are still controversial. The purpose of our study is to determine the impact of comorbidities on COPD exacerbation and establish an acute exacerbation risk assessment system related to comorbidities.Methods: A total of 742 COPD patients participated in the Shanghai COPD Investigation on Comorbidity Program (SCICP, ChiCTR2000030911). Finally, the baseline information of 415 participants and one-year follow-up data were involved in the analysis. We collected hemogram indices, pulmonary function tests and acute exacerbation of COPD with regular medical follow-up. Q-type cluster analysis was used to determine the clusters of participants. Receiver operating characteristic (ROC) analysis was constructed to assess the ability of indicators in predicting acute exacerbations.Results: Almost 65% of the population we investigated had at least one comorbidity. The distribution and incidence of comorbidities differed between exacerbation group and non-exacerbation group. Three comorbidity clusters were identified: (1) respiratory, metabolic, immune and psychologic disease (non-severe cases); (2) cardiovascular and neoplastic disease (severe cases); (3) less comorbidity. Different sub-phenotypes of COPD patients showed significant distinction in health status. Anxiety (OR=5.936, P=0.001), angina (OR=10.155, P=0.025) and hypertension (OR=3.142, P=0.001) were found to be independent risk factors of exacerbation in a year. The novel risk score containing BODEx and four diseases showed great prognostic value of COPD exacerbation in developing sample.Conclusion: Our study detailed the major interaction between comorbidities and exacerbation in COPD. Noteworthily, a novel risk score using comprehensive index – BODEx – and comorbidity parameters can identify patients at high risk of acute exacerbation.Keywords: chronic obstructive pulmonary disease, exacerbation, comorbidity, risk score

Intense ion beam production is of high importance for various versatile applications from accelerator injectors to secondary ion mass spectrometry (SIMS). For these purposes, different types of ion beams are needed and, accordingly, the optimum plasma to produce the desired ion beams. RF-type plasma features a simple structure, high plasma density and low plasma temperature, which is essential for negative ion beam production. A very compact RF-type ion source using a planar coil antenna has been developed at IMP for negative molecular oxygen ion beam production. In terms of high-intensity positive ion beam production, 2.45 GHz microwave power-excited plasma has been widely used. At IMP, we developed a 2.45 GHz plasma source with both ridged waveguide and coaxial antenna coupling schemes, tested successfully with intense beam production. Thanks to the plasma built with an external planar coil antenna, high O2− production efficiency has been achieved, i.e., up to 43%. With 2.45 GHz microwave plasma, the ridged waveguide can support a higher power coupling of high efficiency that leads to the production of intense hydrogen beams up to 90 emA, whereas the coaxial antenna is less efficient in power coupling to plasma but can lead to attractive ion source compactness, with a reasonable beam extraction of several emA.

Jing Xiong,1,* Yunyun Qian,1,* Shikai Yu,1 HongWei Ji,1 Jiadela Teliewubai,1 Chen Chi,1 YuYan Lu,1 YiWu Zhou,1 XiMin Fan,1 Jue Li,2 Jacques Blacher,3 Yi Zhang,1 YaWei Xu1 1Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2The Research Institute of Clinical Epidemiology, Tongji University School of Medicine, Shanghai, People’s Republic of China; 3Paris Descartes University, AP-HP, Diagnosis and Therapeutic Center, Hôtel-Dieu, Paris, France*These authors contributed equally to this workCorrespondence: Yi Zhang; Yawei XuDepartment of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, ChinaTel +86-21-66308182Fax +86-21-66301051Email yizshcn@gmail.com; xuyawei@tongji.edu.cnObjective: To investigate the relationship between asymptomatic target organ damage (TOD) and different somatotypes in a population of elderly from Chinese community-dwelling.Methods: A total of 2098 Chinese senior residents from northern Shanghai older than 65 years were recruited in the research. The following somatotype parameters were recorded and analyzed: body mass index, waist circumference, hip circumference, and waist-hip ratio were recorded and calculated. Asymptomatic TOD, including urine albumin/creatinine ratio, estimated glomerular filtration rate (eGFR), intima-media thickness (IMT), left ventricular mass index (LVMI), left ventricular diastolic function, and carotid-femoral pulse wave velocity (PWV) was recorded using the MyLab30 Gold CV system and SphygmoCor.Results: Of all 2098 residents, 817 (38.9%) were overweight and 289 (13.8%) were obese. All somatotype measures were significantly correlated with TOD parameters (p< 0.05). After adjustment for age and male gender, in total population, LVMI (p< 0.001), cardiac diastolic function (E/Ea, p< 0.001), PWV (p< 0.001), eGFR (p=0.03), and urine albumin/creatinine ratio (p< 0.001) changed gradually and significantly correlated with increasing BMI values. Obesity and overweight were independently related to the incidence of LVH, LVDD, artery stiffness, carotid arterial plaque, and microalbuminuria.Conclusion: The incidence of asymptomatic TOD was significantly correlated with overweight and obesity, especially in women, whereas the underweight may favor in the prevention of TOD.Keywords: Chinese elderly cardiovascular risk

Li Zhang, Xiaoping Li, Jiang Lu, Yi Qian, Tao Qian, Xing Wu, Qinghua Xu Department of Hepatobiliary and Pancreatic Surgery, LiYang People’s Hospital, LiYang, 213300, Jiangsu, People’s Republic of ChinaCorrespondence: Qinghua Xu; Xing WuDepartment of Hepatobiliary and Pancreatic Surgery, LiYang People’s Hospital, 70# JianShe West Road, LiYang, 213300, Jiangsu, People’s Republic of ChinaTel/Fax +86-519-68091108Email xqh7888882@163.com; sxj6628@126.comBackground: Previous studies have shown that epidermal growth factor receptor (EGFR) promotes cell proliferation through the PI3K-Akt-mTOR signaling pathway and participates in the occurrence and development of hepatocellular carcinoma (HCC). Here, we focused on the functional polymorphism of EGFR in the 3ʹ-untranslated region (UTR), aiming to reveal the potential mechanisms by which functional polymorphism is associated with the risk and development of HCC in the Han Chinese population.Methods: This study was a hospital-based case-control study. A total of 600 patients were enrolled, and another 600 healthy volunteers served as controls. The miR-associated SNPs in EGFR were screened, and genotyping was performed by TaqMan allele differential analysis. In this study, genotyping, real-time PCR, cell transfection and double luciferase reporter gene were used for subsequent analysis.Results: HBV/HCV infection instead of alcohol exposure, smoking exposure, hypertension or diabetes mellitus was associated with an increased risk of HCC. Compared with TT genotypes, TG and GG genotypes of EGFR rs884225 were significantly associated with reduced HCC risk. The stratified analysis of association between rs884225 and HCC subgroup feature reveal a highly correlation with tumor size. Furthermore, qRT-PCR confirmed that EGFR rs884225, TG and GG genotypes were more likely to bind to miR-3196 and down-regulate EGFR level in cells, thereby inhibiting cell proliferation.Conclusion: This study suggested that EGFR rs884225 is associated with a reduced risk of liver cancer and may be a developing biomarker.Keywords: miR-3196, polymorphism, proliferation, hepatocellular carcinoma, HCC, epidermal growth factor receptor, EGFR

Ding Ye,1 Bin Liu,1 Zhixing He,2 Lin Huang,2 Yu Qian,1 Keding Shao,2 Chengping Wen,2 Yingying Mao1 1Department of Epidemiology and Biostatistics, Zhejiang Chinese Medical University School of Public Health, Hangzhou, Zhejiang, 310053, People’s Republic of China; 2Institute of Basic Research in Clinical Medicine, Zhejiang Chinese Medical University School of Basic Medical Sciences, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaCorrespondence: Yingying MaoDepartment of Epidemiology and Biostatistics, Zhejiang Chinese Medical University School of Public Health, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaTel +86-571-8661-3536Email myy@zcmu.edu.cnChengping WenInstitute of Basic Research in Clinical Medicine, Zhejiang Chinese Medical University School of Basic Medical Sciences, Hangzhou, Zhejiang, 310053, People’s Republic of ChinaTel +86-571-8663-3377Email wengcp@163.comObjective: To investigate the potential causal associations of circulating levels of growth differentiation factor 15 (GDF-15) with the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) using a Mendelian randomization (MR) design.Methods: A genome-wide association study (GWAS) of GDF-15 among 5,440 individuals of European ancestry was used to identify genetic instruments. Summary statistics of SLE, RA and IBD were obtained from publicly available GWASs. We conducted an MR study using the inverse-variance weighted (IVW) method, supplemented with simple-median and weighted-median methods. Cochran Q test and MR-Egger regression were used to detect potential heterogeneity and directional pleiotropy. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.Results: We found that genetically predicted high circulating GDF-15 levels were associated with a decreased risk of SLE (OR 0.80, 95% CI 0.68– 0.92 by IVW), with similar results in sensitivity analyses. In replication analysis using summary data from another SLE GWAS, the results were consistent (OR 0.82, 95% CI 0.71– 0.93 by IVW). Moreover, no evidence of heterogeneity or pleiotropy was detected. However, genetically determined circulating levels of GDF-15 were not associated with risk of RA or IBD in the primary analysis and subsequent sensitivity analyses.Conclusions: Our study suggested an inverse association between circulating GDF-15 levels and risk of SLE, and further studies are warranted to elucidate the underlying biological mechanisms. There was limited evidence supporting a causal association of circulating GDF-15 levels with risk of RA and IBD.Keywords: growth differentiation factor 15, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Mendelian randomization, single nucleotide polymorphism

Xiaozhuo Chen,1– 7 Nigel A Daniels,1,4,5,8 David Cottrill,2,3 Yanyang Cao,2,3 Xuan Wang,2,3 Yunsheng Li,2 Pratik Shriwas,2,3 Yanrong Qian,2 Michael W Archer,1,4 Nicholas B Whitticar,4,9 Ishrat Jahan,1,4 Craig S Nunemaker,1,3– 5 Aili Guo10 1The Diabetes Institute at Ohio University, Athens, OH, 45701, USA; 2The Edison Biotechnology Institute, Athens, OH, 45701, USA; 3Department of Biological Sciences, Athens, OH, 45701, USA; 4Department of Biomedical Sciences, Athens, OH, 45701, USA; 5Heritage College of Osteopathic Medicine, Athens, OH, 45701, USA; 6Interdisciplinary Graduate Program in Molecular and Cellular Biology, Athens, OH, 45701, USA; 7Department of Chemistry and Biochemistry, Athens, OH, 45701, USA; 8Department of Specialty Medicine, Athens, OH, 45701, USA; 9Translational Biomedical Sciences Program, Ohio University, Athens, OH, 45701, USA; 10Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of California at Davis (UC Davis) School of Medicine, UC Davis Health Science, Sacramento, CA, 95817, USACorrespondence: Aili GuoDepartment of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of California at Davis (UC Davis) School of Medicine, UC Davis Health Science, PSSB, G400, 4150 V St., Sacramento, CA, 95817, USATel +1 916-734-3730Fax +1 916-734-2292Email alguo@ucdavis.eduCraig S NunemakerDepartment of Biomedical Sciences, 1 Ohio University, Athens, OH, 45701, USATel +1 740-593-2387Fax +1 740-593-4795Email nunemake@ohio.eduPurpose: Previously we showed that natural compound α-penta-galloyl-glucose (α-PGG) and its synthetic derivative 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ) act to improve insulin signaling in adipocytes by increasing glucose transport. In this study, we investigated the mechanism of actions of α-PGG and 6Cl-TGQ on insulin secretion.Methods: Mouse islets and/or INS-1832/13 beta-cells were used to test the effects of our compounds on glucose-stimulated insulin secretion (GSIS), intracellular calcium [Ca2+]i using fura-2AM, glucose transport activity via a radioactive glucose uptake assay, intracellular ATP/ADP, and extracellular acidification (ECAR) and mitochondrial oxygen consumption rates (OCAR) using Seahorse metabolic analysis.Results: Both compounds reduced GSIS in beta-cells without negatively affecting cell viability. The compounds primarily diminished glucose uptake into islets and beta-cells. Despite insulin-like effects in the peripheral tissues, these compounds do not act through the insulin receptor in islets. Further interrogation of the stimulus-secretion pathway showed that all the key metabolic factors involved in GSIS including ECAR, OCAR, ATP/ADP ratios, and [Ca2+]i of INS-1832/13 cells were diminished after the compound treatment.Conclusion: The compounds suppress glucose uptake of the beta-cells, which consequently slows down the rates of glycolysis and ATP synthesis, leading to decrease in [Ca2+]i and GSIS. The difference between adipocytes and beta-cells in effects on glucose uptake is of great interest. Further structural and functional modifications could produce new compounds with optimized therapeutic potentials for different target cells. The higher potency of synthetic 6Cl-TGQ in enhancing insulin signaling in adipocytes but lower potency in reducing glucose uptake in beta-cells compared to α-PGG suggests the feasibility of such an approach.Keywords: glucose-stimulated insulin secretion, calcium influx, glucose transporter, α-PGG, 6Cl-TGQ

Shengming Deng,1– 4,* Zhiyao Fan,1– 4,* Huanyu Xia,1– 4,* Yitao Gong,1– 4 Yunzhen Qian,1– 4 Qiuyi Huang,1– 4 He Cheng,1– 4 Kaizhou Jin,1– 4 Zhiwen Xiao,1– 4 Guopei Luo,1– 4 Xianjun Yu,1– 4 Chen Liu1– 4 1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Pancreatic Cancer Institute, Shanghai, People’s Republic of China; 4Pancreatic Cancer Institute, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chen Liu; Xianjun YuShanghai Pancreatic Cancer Institute, 270 Dong an Road, Shanghai 200032, People’s Republic of ChinaTel/Fax +86-21-6403-1446Email liuchen@fudanpci.org; yuxianjun@fudanpci.orgBackground: The fibrinogen/albumin ratio (FAR) has been widely reported to be a possible biomarker for predicting prognosis in several types of tumors, but the prognostic value of the FAR in pancreatic neuroendocrine neoplasms (Pan-NENs) has not been systematically studied.Patients and Methods: In total, 324 patients with Pan-NENs were recruited. The patients were divided into 2 subgroups according to the FAR cutoff value, and clinicopathological characteristics of the 2 subgroups were compared. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The prognostic value of the FAR was analyzed in univariate and multivariate analyses.Results: The optimal cutoff value for the FAR was calculated to be 0.08 for OS. The patients with a FAR ≥ 0.08 had higher proportions of nonfunctioning tumors, Pan-NECs, grade 3 tumors, and stage IV tumors than those with a FAR < 0.08. In the univariate analysis, a FAR ≥ 0.08 was associated with poor OS (hazard ratio (HR) = 2.37, P < 0.001) and PFS (HR = 2.37, P < 0.001). In the multivariate analysis, a FAR ≥ 0.08 was an independent risk factor for poor OS (HR = 4.70, P < 0.001) and PFS (HR = 1.80, P = 0.006).Conclusion: The pretreatment FAR, which includes fibrinogen and albumin, was a feasible and predictive biomarker for prognosis in patients with Pan-NENs. An elevated FAR, based on a cutoff value of 0.08, was an independent risk factor for poor OS and PFS.Keywords: pancreatic neuroendocrine neoplasms, survival, fibrinogen/albumin ratio

Lingying Dai,1,* Dan Zhang,2,* Yunzhi Qian,2 Yemin Wan,2 Shuchen Chang,2 Haihua Qian2 1No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, People’s Republic of China; 2Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haihua Qian Tel +86-025-86617141Fax +86-025-86617141Email zyqianhaihua@sina.comIntroduction: Phosphorylation of signal transducer and activator of transcription 6 (STAT6) in the colonic epithelium is elevated in ulcerative colitis (UC) patients, and its inhibition prevents IL-13-associated apoptosis and barrier disruption. Recently, the STAT6 rs324015 polymorphism was reported to be related to genetic susceptibility to UC.Methods: We examined STAT6 rs324015 using the PCR–RFLP method in 268 UC cases and 357 controls. STAT6 expression was determined by quantitative reverse-transcription PCR. The gene–environment interactions were addressed by cross-over analysis.Results: We found that the STAT6 rs324015 polymorphism enhanced the risk of UC under the homozygous, dominant, and allelic models. Further subgroup analyses indicated that this relationship was more evident in alcohol users, smokers, and those younger than 40 years. Cross-over analysis showed strong interactions of STAT6 rs324015 with smoking/alcohol use. In addition, this polymorphism was associated with the severity, and location of UC. The GG genotype was significantly associated with increased STAT6 gene levels.Conclusion: In summary, the STAT6 rs324015 polymorphism is related with predisposition to UC in a Chinese Han population.Keywords: STAT6, ulcerative colitis, case–control study, rs324015 polymorphism

Jin Wang,1,2 Ye Qian,2 Xuemin Gao,3 Na Mao,3 Yucong Geng,4 Gaojie Lin,3 Guibin Zhang,2 Han Li,3 Fang Yang,3 Hong Xu3 1Department of Clinical Laboratory, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, People’s Republic of China; 2Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, Hebei 063210, People’s Republic of China; 3Medical Research Center, International Science and Technology Cooperation Base of Geriatric Medicine, North China University of Science and Technology, Tangshan, Hebei 063210, People’s Republic of China; 4Department of Pathology, Haigang Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People’s Republic of ChinaCorrespondence: Hong XuMedical Research Center, International Science and Technology Cooperation Base of Geriatric Medicine, North China University of Science and Technology, Tangshan, Hebei 063210, People’s Republic of ChinaTel +86-315-8816236Fax +86-315-8816238; Email xuhong@ncst.edu.cnBackground: N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a short peptide with an anti-silicosis effect. However, the short biological half-life and low plasma concentration of Ac-SDKP hamper discovery of specific targets in organisms and reduce the anti-silicosis effect. A novel peptide, Ac-SDK (biotin) proline, termed “Ac-B”, with anti-fibrotic properties was synthesized.Methods: Ac-B was detected quantitatively by high-performance liquid chromatography. Phagocytosis of Ac-B by the alveolar epithelial cell line A549 was investigated by confocal laser scanning microscopy and flow cytometry. To further elucidate the cellular-uptake mechanism of Ac-B, chemical inhibitors of specific uptake pathways were used. After stimulation with transforming growth factor-β 1, the effects of Ac-B on expression of the myofibroblast marker vimentin and accumulation of collagen type I in A549 cells were analyzed by Western blotting. Sirius Red staining and immunohistochemical analyses of the effect of Ac-B on expression of α-smooth muscle actin (SMA) in a rat model of silicosis were undertaken.Results: Ac-B had good traceability during the uptake, entry, and distribution in cells. Ac-B treatment prevented an increase in α-SMA expression in vivo and in vitro and was superior to that of Ac-SDKP. Caveolae-mediated uptake of Ac-B by A549 cells led to achieving anti-epithelial–mesenchymal transformation (EMT) effects.Conclusion: Ac-B had an anti-fibrotic effect and could be a promising agent for the fibrosis observed in silicosis in the future.Keywords: Ac-SDKP, biotin, epithelial–mesenchymal transformation, phagocytosis, anti-fibrotic function

Peng Sun,1,2 Qichang Yang,1 Yanben Wang,2 Jiaxuan Peng,3 Kangxian Zhao,1 Yewei Jia,2 Tan Zhang,2 Xuanyuan Lu,2 Weiqi Han,2 Yu Qian1,2 1The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 2Department of Orthopedics, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang 312000, People’s Republic of China; 3Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaCorrespondence: Yu QianThe Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, No. 109, XueYuan Road, Wenzhou, Zhejiang 325000, People’s Republic of ChinaEmail doctor120@hotmail.comIntroduction: Osteoporosis is a metabolic bone disease characterized by reduced bone quantity and microstructure, typically owing to increased osteoclastogenesis and/or enhanced osteoclastic bone resorption, resulting in uncontrolled bone loss, which primarily affects postmenopausal women. In consideration of the severe side effects of current drugs for osteoporosis, new safe and effective medications are necessary. Pristimerin (Pri), a quinone methide triterpene extracted from Celastraceae and Hippocrateaceae members, exhibits potent antineoplastic and anti-inflammatory effects. However, its effect on osteoclasts remains unknown.Materials and Methods: We evaluated the anti-osteoclastogenic and anti-resorptive effect of Pri on bone marrow-derived osteoclasts and its underlying mechanism in vitro. In addition, the protective effect of Pri on ovariectomy model was also explored in vivo.Results: In vitro, Pri inhibited osteoclast differentiation and mature osteoclastic bone resorption in a time- and dose-dependent manner. Further, Pri suppressed the expression of osteoclast-related genes and the activation of key proteins. Pri also inhibited the early activation of ERK, JNK MAPK, and AKT signaling pathways in bone marrow-derived macrophages (BMMs), ultimately inhibiting the induction and activation of the crucial osteoclast transcriptional factor nuclear factor of activated T‐cell cytoplasmic 1 (NFATc1). In vivo, consistent with our in vitro data, Pri clearly prevented ovariectomy-induced bone loss.Conclusion: Our data showed that Pri inhibits the differentiation and activation of osteoclasts in vitro and in vivo, and could be a promising candidate for treating osteoporosis.Keywords: osteoclast, osteoporosis, ERK, JNK, AKT, Pri

Jidi Zhao,1 Jianguo Jia,2 Ying Qian,3 Lumin Zhong,4 Jiancong Wang,5 Yuyang Cai4,6 1Faculty of Economics and Management, East China Normal University, Shanghai, People’s Republic of China; 2System Dynamics Chapter, Systems Engineering Society of China, Beijing, People’s Republic of China; 3School of Management, Shanghai University, Shanghai, People’s Republic of China; 4School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Institute of Global Health, University of Geneva, Geneva, Switzerland; 6China Institute for Urban Governance, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Yuyang Cai; Ying Qian Email caiyuyang@sjtu.edu.cn; qian.ying@t.shu.edu.cnPurpose: It is unclear how and to what extent various infection prevention and control (IPC) policies affect the spread of an epidemic during work resumption. In order to assess the impact of IPC policies, this research addresses the results of a policy simulation in Shanghai, China, which estimates the transmission dynamics of COVID-19 under various IPC policies and offers evidence-based outcomes of work resumption policies for the world.Materials and Methods: This simulation research is based on a system dynamics (SD) model that integrates IPC work resumption policies implemented in Shanghai into the classical susceptible-exposed-infected-removed (SEIR) epidemiological model. Input data were obtained from official websites, the Baidu migration index and published literature. The SD model was validated by comparing results with real-world data.Results: The simulations show that a non-quarantined and non-staged approach to work resumption (Policy 1) would bring a small secondary outbreak of COVID-19. The quarantined but non-staged approach (Policy 2) and the non-quarantined but staged approach (Policy 3) would not bring a secondary outbreak of COVID-19. However, they both would generate more newly confirmed cases than the staged and quarantined approach (Policy 4). Moreover, the 14-day quarantine policy alone appears to be more effective in reducing transmission risk than the staged work resumption policy alone. The combined staged and quarantined IPC policy led to the fewest confirmed cases caused by work resumption in Shanghai, and the spread of COVID-19 stopped (ie, the number of newly confirmed cases reduced to zero) at the earliest date.Conclusion: Conservative IPC policies can prevent a second outbreak of COVID-19 during work resumption. The dynamic systems model designed in this study can serve as a tool to test various IPC work resumption policies, facilitating decision-making in responses to combating the COVID-19 pandemic.Keywords: IPC policies, work resumption, COVID-19, system dynamics, SEIR

Yifeng Qian,1– 3,* Huiting Yu,4,* Weijun Yuan,1– 3,* Jiaqing Wu,5 Qingyu Xu,5 Nianrou Mei,5 Xudong Wang,1– 3 Chunfang Wang4 1Department of Oral and Craniomaxillofacial Surgery, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 2National Clinical Research Center for Oral Diseases, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, People’s Republic of China; 4Shanghai Municipal Center for Disease Control and Prevention, Shanghai, People’s Republic of China; 5College of Stomatology, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xudong Wang; Chunfang Wang Email xudongwang70@hotmail.com; qyf208@163.comPurpose: There has been growing interest in the association between periodontitis and systemic disease. In recent years, however, inconsistent results have also been found by case–control studies for the role of periodontitis in the development of oral cancer. This study aimed to examine whether periodontitis was an independent risk factor for oral cancer with a ≥ 75-year age group cohort.Materials and Methods: Between January 2010 and December 2014, 1385 patients aged ≥ 75 years who underwent radiographic examination were included in this retrospective cohort study. We collected demographic information and comorbid health conditions from local health authorities. Participants were followed up until either the occurrence of mortality, or the end of the study on December 31, 2018. Cox proportional hazards regression and competing risk hazard models were used to examine the association between periodontitis and oral cancer mortality.Results: Periodontitis and loss of teeth were significantly associated with oral cancer mortality. Compared to oral cancer mortality in healthy subjects, the HR and 95% CI in patients with mild, moderate, and severe periodontitis were 4.46 (0.94– 21.06), 5.16 (1.14– 23.39), and 6.65 (1.51– 29.36), respectively. The HR (95% CI) was 1.05 (1.01– 1.09) for tooth loss after controlling for potential confounding factors. All the increases in risk persisted in patients aged ≥ 80 years.Conclusion: The present study provides substantial evidence that poor periodontal health is associated with oral cancer mortality. It is necessary to underline the importance of considering periodontitis in the prevention of oral cancer, particularly in the older patients.Keywords: periodontitis, alveolar bone loss, tooth loss, oral cancer, prevention

Jiaxuan Peng,1,* Kangxian Zhao,2,* Jiling Zhu,3,* Yanben Wang,4,5 Peng Sun,2 Qichang Yang,2 Tan Zhang,4 Weiqi Han,4 Wenjun Hu,4 Wanlei Yang,4 Jianwei Ruan,6 Yu Qian1,2,4 1Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, People’s Republic of China; 2The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 3Department of Clinical Medicine, Medical College of Shaoxing University, Shaoxing, Zhejiang 312000, People’s Republic of China; 4Department of Orthopaedics, Shaoxing People’s Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang, People’s Republic of China; 5Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 6Department of Orthopaedics, Taizhou Municipal Hospital, Taizhou 318000, Zhejiang, Republic of China*These authors contributed equally to this workCorrespondence: Yu QianDepartment of Orthopaedics, Shaoxing People’s Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang, People’s Republic of ChinaEmail doctor120@hotmail.comIntroduction: Osteoclasts are giant polynuclear cells; their main function is bone resorption. An increased number of osteoclasts and enhanced bone resorption exert significant effects on osteoclast-related bone-lytic diseases, including osteoporosis. Given the limitations of current therapies for osteolytic diseases, it is urgently required to develop safer and more effective alternatives. Sarsasapogenin, a major sapogenin from Anemarrhena asphodeloides Bunge, possesses potent antitumor effects and inhibits NF-κB and MAPK signaling. However, the manner in which it affects osteoclasts is unclear.Methods: We investigated the effects of anti-osteoclastogenic and anti-resorptive of sarsasapogenin on bone marrow-derived osteoclasts.Results: Sarsasapogenin inhibited multiple RANKL-induced signaling cascades, thereby inhibiting the induction of key osteoclast transcription factor NFATc1. The in vivo and in vitro results were consistent: sarsasapogenin treatment protected against bone loss in a mouse osteolysis model induced by lipopolysaccharide.Conclusion: Our research confirms that sarsasapogenin can be used as a new treatment for osteoclast-related osteolytic diseases.Keywords: sarsasapogenin, osteoclast, osteoclastogenesis, NF-κB, MAPK, NFATc1, therapeutics

Yitao Gong,1– 4,* Zhiyao Fan,1– 4,* Guopei Luo,1– 4,* Qiuyi Huang,1– 4 Yunzhen Qian,1– 4 He Cheng,1– 4 Kaizhou Jin,1– 4 Quanxing Ni,1– 4 Xianjun Yu,1– 4 Chen Liu1– 4 1Department of Pancreatic Surgery, 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; 3Shanghai Pancreatic Cancer Institute, Shanghai 200032, People’s Republic of China; 4Pancreatic Cancer Institute, Fudan University, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xianjun Yu; Chen LiuDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai 200032, People’s Republic of ChinaTel + 86 21-64175590 ext 1307Fax + 86 21-64031446Email yuxianjun@fudanpci.org; liuchen@fudanpci.orgPurpose: Pancreatic neuroendocrine tumours (panNETs) are rare tumours of pancreas. Lymphocyte subsets in the peripheral blood are reported to reflect tumour prognosis and progression. The objective of the study is to investigate the hypotheses that the levels of peripheral lymphocytes may reflect tumour progression and may predict the prognosis of pancreatic neuroendocrine tumours (panNETs).Patients and Methods: A retrospective cohort study consisting of 73 patients diagnosed with panNETs was conducted. Kaplan–Meier methods and Log rank tests were used to compare the survival rates, and a Cox regression model was used to perform multivariate analyses.Results: panNET patients with distant metastasis were associated with lower peripheral total T cell (p = 0.039) and CD4+ T cell (p = 0.006) counts. Lower peripheral B cells (p = 0.007) and higher peripheral NK cell (p = 0.001) counts indicated worse progression-free survival (PFS) in Log rank tests. In multivariate analyses, low B cell count (hazard ratio (HR): 6.769, 95% confidence interval (CI): 2.158 to 21.228, p = 0.001) and high NK cell count (HR: 3.715, 95% CI: 1.164 to 11.855, p = 0.027) were independent risk factors for progression. NK cells and B cells were also significantly associated with PFS following radical surgical resection.Conclusion: Peripheral total T cell and CD4+ T cell counts may reflect the distant metastasis status in panNET patients. The absolute count of peripheral B cells and NK cells may independently predict the progression of panNET patients, making them promising prognostic indicators and potential targets for treatment of panNETs.Keywords: pancreatic neuroendocrine tumours, panNETs, lymphocyte subsets, progression-free survival, B cells

Zhixiao Yao,1,* Juehong Li,1,* Xu Wang,1 Shiqiao Peng,2 Jiexin Ning,3 Yun Qian,1 Cunyi Fan1 1Department of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, People’s Republic of China; 2Department of Endocrinology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, People’s Republic of China; 3Department of Plastics, Binzhou People’s Hospital, Binzhou 256610, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Qian; Cunyi FanDepartment of Orthopaedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, People’s Republic of ChinaTel +86 21-64369181Email lollipopcloudland@foxmail.com; cyfan@sjtu.edu.cnPurpose: As a common complication of tendon injury, tendon adhesion is an unresolved problem in clinical work. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cell-derived exosomes (HUMSC-Exos), one of the most promising new-generation cell-free therapeutic agents, can improve tendon adhesion and explore potential-related mechanisms.Methods: The rat Achilles tendon injury adhesion model was constructed in vivo, and the localization of HUMSC-Exos was used to evaluate the tendon adhesion. Rat fibroblast cell lines were treated with transforming growth factor β 1 (TGF-β 1) and/or HUMSC-Exos in vitro, and cell proliferation, apoptosis and gene expression were measured. MicroRNA (miRNA) sequencing and quantitative PCR (qPCR) analysis confirmed differential miRNAs. A specific miRNA antagonist (antagomir-21a-5p) was used to transform HUMSC-Exos and obtain modified exosomes to verify its efficacy and related mechanism of action.Results: In this study, we found HUMSC-Exos reduced rat fibroblast proliferation and inhibited the expression of fibrosis genes: collagen III (COL III) and α-smooth muscle actin (α-SMA) in vitro. In the rat tendon adhesion model, topical application of HUMSC-Exos contributed to relief of tendon adhesion. Specifically, the fibrosis and inflammation-related genes were simultaneously inhibited by HUMSC-Exos. Further, miRNA sequencing of HUMSCs and HUMSC-Exos showed that miR-21a-3p was expressed at low abundance in HUMSC-Exos. The antagonist targeting miR-21a-3p was recruited for treatment of HUMSCs, and harvested HUMSC-Exos, which expressed low levels of miR-21a-3p, and expanded the inhibition of tendon adhesion in subsequent in vitro experiments.Conclusion: Our results indicate that HUMSC-Exos may manipulate p65 activity by delivering low-abundance miR-21a-3p, ultimately inhibiting tendon adhesion. The findings may be promising for dealing with tendon adhesion.Keywords: HUMSC, exosome, tendon adhesion, TGF-β 1, p65, miR-21a-3p, NF-κB

Weiwei Wang,1 Junting Fan,2 Guang Zhu,1 Jing Wang,1 Yumei Qian,1 Hongxia Li,1 Jianming Ju,3 Lingling Shan1 1Institute of Pharmaceutical Biotechnology, School of Biology and Food Engineering, Key Laboratory of Spin Electron and Nanomaterials of Anhui Higher Education Institutes, Suzhou University, Suzhou 234000, People’s Republic of China; 2Department of Pharmaceutical Analysis, School of Pharmacy, Nanjing Medical University, Nanjing 211166, People’s Republic of China; 3Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, People’s Republic of ChinaCorrespondence: Lingling Shan; Junting Fan Email ntlinger-300@163.com; Juntingfan@njmu.edu.cnBackground: Targeted prodrug has various applications as drug formulation for tumor therapy. Therefore, amphoteric small-molecule prodrug combined with nanoscale characteristics for the self-assembly of the nano-drug delivery system (DDS) is a highly interesting research topic.Methods and Results: In this study, we developed a prodrug self-assembled nanoplatform, 2-glucosamine-fluorescein-5(6)-isothiocyanate-glutamic acid-paclitaxel (2DA-FITC-PTX NPs) by integration of targeted small molecule and nano-DDS with regular structure and perfect targeting ability. 2-glucosamine (DA) and paclitaxel were conjugated as the targeted ligand and anti-tumor chemotherapy drug by amino acid group. 2-DA molecular structure can enhance the targeting ability of prodrug-based 2DA-FITC-PTX NPs and prolong retention time, thereby reducing the toxicity of normal cell/tissue. The fluorescent dye FITC or near-infrared fluorescent dye ICG in prodrug-based DDS was attractive for in vivo optical imaging to study the behavior of 2DA-FITC-PTX NPs. In vitro and in vivo results proved that 2DA-FITC-PTX NPs exhibited excellent targeting ability, anticancer activity, and weak side effects.Conclusion: This work demonstrates a new combination of nanomaterials for chemotherapy and may promote prodrug-based DDS clinical applications in the future.Keywords: targeted prodrug, nanoplatform, NIR imaging, chemotherapy

Aiyun Li,1,* Hao Xu,2,* Xiaoyu Li,3 Hong Ye,1 Donghao Shan,1 Nan Feng,1 Yaqi Qian,1 Xiangzhe Huang,1 Dongjie Hao,1 Xiaoxiao Zhang,1 Bo Zhu,1 Beiwen Zheng2 1Department of Clinical Medicine, The Women’s Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3Department of Clinical Medicine, Hangzhou Children’s Hospital, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Beiwen Zheng; Bo Zhu Email zhengbw@zju.edu.cn; 5202054@zju.edu.cnIntroduction: There are few investigations describing the pregnancy-associated listeriosis in China, and the molecular characteristics of Listeria monocytogenes causing such infections remain largely unknown. We aim to investigate the phenotypic and genomic profiles of pregnancy-associated L. monocytogenes isolates and their association with isolates recovered from human and non-human in China.Materials and Methods: In this study, we conducted a 3-year surveillance of listeriosis in a women’s hospital in Zhejiang province, using whole genome sequencing and bioinformatics tools.Results: From 2016 to 2018, we identified 13 clinical L. monocytogenes isolates. Among these pregnancy-associated isolates, we found seven sequence types (STs), with the prevalent STs of ST87 and ST7. Serotyping divided the strains into four serotypes, including serotype 1/2a, 1/2b, 3a, and 4b. Antimicrobial resistance testing showed that all the isolates were susceptible to 10 antibiotics. Comparative genomics analysis clearly classified our genome collection into four distinct evolutionary lineages with most isolates grouping into lineages I and II. Interestingly, we found three pairs of isolates with high identity, although no evident epidemiological association was observed.Conclusion: This study reports for the first time the surveillance of pregnancy-associated listeriosis in Zhejiang province, China, which indicates that the infection rate is low in this region. Our findings provide insight into the evolution and genetic diversity of pregnancy-associated L. monocytogenes from Zhejiang province. Additional investigations involving more human and non-human isolates with a “one health” strategy are needed for prediction of the listeriosis risk associated with a typical prevalent clone in Zhejiang province, such as ST87.Keywords: Listeria monocytogenses, pregnancy-associated, ST87, whole genome sequencing, comparative genomics analysis

Yewei Jia,1,* Wei He,1,* Hanxiao Zhang,2 Lei He,1 Yanben Wang,1 Tan Zhang,1 Jiaxuan Peng,3 Peng Sun,2 Yu Qian1 1Department of Orthopaedics, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, People’s Republic of China; 2The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 3Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Guangxi 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu QianDepartment of Orthopaedics, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, Zhejiang 312000, People’s Republic of ChinaTel +86 13905754033Email doctor120@hotmail.comPurpose: Osteoarthritis (OA) is one of the most common degenerative joint diseases in the world, characterized primarily by the progressive degradation of articular cartilage. Accumulating evidence has shown that Morusin, a flavonoid derived from the root bark of Morus alba (mulberry) plants, exerts unique protective properties in several diseases. However, its effects on OA, specifically, have not yet been characterized.Methods: In this study, we evaluated the anti-inflammatory effect of Morusin on mouse chondrocytes and its underlying mechanism in vitro. In addition, the protective effect of Morusin on destabilization of the medial meniscus (DMM) model was also explored in vivo.Results: In vitro, IL-1β-induced activation of inflammatory factors (TNF-α, IL-6, INOS and COX2) was dramatically suppressed by Morusin. Further, Morusin treatment inhibited the expression of ADAMTS5 and metalloproteinase (MMPs), both of which regulate extracellular matrix degradation. Morusin also decreased IL-1β-induced p65 phosphorylation and IκBα degradation. In vivo, degradation of the articular cartilage following surgical DMM, which mimicked OA pathology, was abrogated following treatment with Morusin, thus demonstrating a protective effect in the DMM model.Conclusion: Herein, we demonstrate that Morusin reduces the OA inflammatory response in vitro and protects against articular cartilage degradation in vivo potentially via regulation of the NF-κB pathway. Hence, Morusin may prove to be an effective candidate for novel OA therapeutic strategies.Keywords: osteoarthritis, chondrocytes, Morusin, IL-1β, NF-κB pathway

Yu Qian,1,2,* Yuan Wu,3,* Zilong Yuan,4 Xiaohui Niu,5 Yaoyao He,4 Jun Peng,6 Fuxiang Zhou,1 Shaozhong Wei,7 Desheng Hu,3 Yunfeng Zhou1 1Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Medical Oncology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China; 3Department of Radiation Oncology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China; 4Department of Radiology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China; 5College of Informatics, Huazhong Agricultural University, Wuhan, Hubei, People’s Republic of China; 6Department of Pathology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China; 7Department of Surgery, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunfeng ZhouDepartment of Radiation and Medical Oncology, Zhongnan Hospital, 169 Donghu Road, Wuhan, Hubei, People’s Republic of ChinaTel +86 139 0715 4247Fax +86 27 6781 2892Email yfzhouwhu@163.comDesheng HuDepartment of Radiation Oncology, Hubei Cancer Hospital, 16 Zhuodaoquan S Road, Wuhan, Hubei, People’s Republic of ChinaTel +86 27 8767 0318Fax +86 27 8767 0151Email hds13907174495@163.comPurpose: Circulating tumour cells (CTCs) have been found to correlate with treatment response and prognosis in some cancers; however, such correlations have not been reported in nasopharyngeal carcinoma (NPC). We aimed to determine the relationship between CTCs and the treatment response in NPC.Patients and methods: In this prospective study, we ascertained the karyotype of CTCs and identified a possible correlation between karyotype and treatment response in locally advanced NPC (LANPC). We prospectively collected peripheral blood from LANPC patients. CTCs were measured by negative enrichment with immunofluorescence in situ hybridization (imFISH) and a centromere of chromosome 8 (CEP8) probe. Chromosome 8 was karyotyped in CTCs, which were identified as triploid, tetraploid or multiploid. Patients were then treated with platinum-based induction chemotherapy followed by concurrent chemoradiotherapy. CTCs were measured before and after treatment.Results: We detected CTCs in 27 of 50 (54%) patients, which served as a baseline value. The results were independent of age, smoking history and NPC clinical stage. All of the 27 evaluable enrolled patients with detectable CTCs showed decreases in both total CTCs and CTCs of different ploidies after treatment (P

Yu Qian,1,* Ding Ye,1,* David JH Wu,1,2 Chen Feng,3 Zhen Zeng,1 Lihong Ye,1 Rui Zhu,4 Zhenyu Zhang,5 Yingying Mao11School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 2University of Minnesota Medical School, Minneapolis, MN 55455, USA; 3The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 4College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People’s Republic of China; 5Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA*These authors contributed equally to this workPurpose: Numerous studies have indicated that smokers have an increased risk of developing ischemic stroke. However, less is known about the causal relationship between cigarette smoking and ischemic stroke subtypes. In the present study, we aim to determine whether genetically predicted cigarette smoking was associated with subtypes of ischemic stroke using Mendelian randomization (MR).Patients and methods: We used summary-level genetic association data from the MEGASTROKE consortium, including 438,847 individuals of European ancestry (34,217 cases of ischemic stroke and 404,630 controls). We used 176 single nucleotide polymorphisms as instrumental variables, which were previously identified to be associated with smoking in the Study of the Social Science Genetic Association Consortium (n=518,633). MR analyses were performed using inverse-variance-weighted method, weighted-median method, and MR-Egger regression.Results: We found that genetically predicted smoking was associated with a higher risk of ischemic stroke (odds ratio (OR): 1.24, 95% CI: 1.10–1.39) and large artery ischemic stroke (OR: 1.52, 95% CI: 1.14–2.02), but not with risk of cardioembolic ischemic stroke or small vessel ischemic stroke. Sensitivity analyses using alternative MR approaches produced similar results.Conclusion: Genetic predisposition toward smoking is causally associated with a higher incidence of large artery ischemic stroke. Further work is warranted to clarify the underlying mechanism of smoking in the development of large artery ischemic stroke.Keywords: ischemic stroke, Mendelian randomization, polymorphism, single nucleotide, smoking