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Min Gu,1,2,&ast; Xiaohui Zhang,1,2,&ast; Fang Ni,1,2 Jue Wang,1,2 Wenying Xia,1,2 Yanfei Lu1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfei Lu; Wenying Xia, Department of Laboratory Medicine, Jiangsu Province Hospital, Street No. 300, Guangzhou, 210029, People’s Republic of China, Tel +8625-6830-6287, Email 549793546@qq.com; xiawenying21106891@163.comPurpose: To explore the characteristics of the pathogen distribution and drug resistance in bloodstream infections (BSIs) during the COVID-19 pandemic in a tertiary hospital in eastern China, and to compare them with those before the pandemic.Patients and Methods: Non-repetitive strain data of BSIs were retrospectively obtained before the COVID-19 pandemic (Pre-Pandemic, n=2698) and during the COVID-19 pandemic (Pandemic, n=2922), the distribution of pathogens and drug resistance were compared between the two groups.Results: The main pathogens of BSIs were Gram-negative bacteria (57.91%), followed by Gram-positive bacteria (32.58%), fungi and anaerobic bacteria accounting for 5.48% and 3.39%, respectively. Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus were the top 3 isolates. The proportion of Serratia marcescens, Enterobacter aerogenes, Enterococcus faecium, Enterococcus faecalis and Candida tropicalis were significantly increased, while those of Pseudomonas aeruginosa, Streptococcus sanguinis and Streptococcus pneumoniae were significantly decreased when compared to the Pre-Pandemic (P< 0.05). Carbapenem-resistant Enterobacterales (CRE) significantly elevated during the Pandemic (17.4% vs 14.4%, P=0.041); the detection of carbapenem-resistant Pseudomonas aeruginosa (CRPA) significantly ascended (39.0% vs 24.4%, P=0.016); and the proportion of carbapenem-resistant Acinetobacter baumannii (CRAB) maintained stable (78.8%). Gram-positive bacteria had the lowest resistance to linezolid, vancomycin and tigecycline, which remained a stable trend with the Pre-Pandemic (< 5.0%). The isolate rates of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) were 38.9% and 1.0%, respectively. Staphylococcus aureus showed a decrease in the isolation rate of vancomycin minimum inhibitory concentration (MIC) ≤ 0.5 μg/mL (χ 2=7.676, P=0.006) and an increase with vancomycin MIC=1 μg/mL (χ 2=9.008, P=0.003).Conclusion: The pathogen distribution and drug resistance of BSIs during the COVID-19 pandemic were transformed from Pre-Pandemic and accompanied by increasing bacterial resistance. Clinical management of antibiotic application and infection control should be strengthened.Keywords: COVID-19 pandemic, bloodstream infection, pathogen distribution, antibiotic resistance

Weixin Bei,1,2,&ast; Shuhui Dong,1,2,&ast; Guoying Liu,1,3,4,&ast; Lanfeng Lin,2,5,&ast; Yaofei Jiang,1,2 Nian Lu,1,2 Wangzhong Li,1,2 Hu Liang,1,2 Yanqun Xiang,1,2 Weixiong Xia1,2 1Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 5Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanqun Xiang; Weixiong Xia, Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China, Tel +86-20-87343643, Fax +86-20-87343392, Email xiangyq@sysucc.org.cn; xiawx@sysucc.org.cnBackground: We aim to evaluate the efficacy and safety of anti-PD1 rechallenge in combination with chemotherapy in patients with metastatic nasopharyngeal carcinoma (mNPC) who have progressed on prior anti-PD1 therapy.Patients and Methods: We enrolled patients with mNPC who received chemotherapy combined with PD-1 immune-checkpoint inhibitors (ICIs) or chemotherapy alone after prior progression of anti-PD1 therapy. The primary endpoint was progress-free survival (PFS), and the secondary endpoints included overall survival (OS), disease control rate (DCR) and objective response rate (ORR).Results: A total of 96 patients were eligible between January 2015 and December 2020. Thirty-seven (38.5%) were in the PD-1 ICIs re-challenge group, while the remaining 59 patients (61.5%) were in the chemotherapy group. The ORR and DCR of PD-1 ICIs group and chemotherapy group were 37.8% vs 23.7% and 86.5% vs.74.5%, respectively. After a median follow-up period of 21.1 months (IQR 16.1– 28.7), the log-rank analysis demonstrated a significantly improved PFS in the PD-1 ICIs re-challenge group compared to the chemotherapy group (8.4 months [95% CI 4.3– 14.0] vs 5.0 months [95% CI 2.8– 7.2], P = 0.03). However, no significant difference in OS was observed between the two groups (28.3 vs 24.1 months, P = 0.09). The two groups had similar adverse reactions, but the incidence of grade 3 or 4 thrombocytopenia was significantly higher in the PD-1 ICIs re-challenge group (18.9% vs 3.4%, P = 0.025).Conclusion: mNPC patients who progressed from prior anti-PD1 therapy could benefit from the anti-PD1 rechallenge in combination with chemotherapy. However, further validation is needed.Keywords: metastatic nasopharyngeal carcinoma, chemotherapy, PD-1 immune checkpoint inhibitors, second-line treatment strategies

Wennuo Huang,1,&ast; Yuanzhe Li,2,&ast; Zhuqing Bao,3,&ast; Jing Ye,1 Wei Xia,1 Yan Lv,1 Jiahui Lu,4 Chao Wang,1 Xi Zhu1 1Department of Radiology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, 225002, People’s Republic of China; 2Department of CT/MRI, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 3Department of Emergency, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, 225002, People’s Republic of China; 4School of Medical Imaging, Hangzhou Medical College, Hangzhou, Zhejiang, 310053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xi Zhu, Department of Radiology, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, 225002, Jiangsu, People’s Republic of China, Tel +8618051062318, Email yzdxlcyxyzhuxi@qq.comPurpose: This study aimed to investigate the knowledge, attitudes, and practice (KAP) of radiologists regarding artificial intelligence (AI) in medical imaging in the southeast of China.Methods: This cross-sectional study was conducted among radiologists in the Jiangsu, Zhejiang, and Fujian regions from October to December 2022. A self-administered questionnaire was used to collect demographic data and assess the KAP of participants towards AI in medical imaging. A structural equation model (SEM) was used to analyze the relationships between KAP.Results: The study included 452 valid questionnaires. The mean knowledge score was 9.01± 4.87, the attitude score was 48.96± 4.90, and 75.22% of participants actively engaged in AI-related practices. Having a master’s degree or above (OR=1.877, P=0.024), 5– 10 years of radiology experience (OR=3.481, P=0.010), AI diagnosis-related training (OR=2.915, P< 0.001), and engaging in AI diagnosis-related research (OR=3.178, P< 0.001) were associated with sufficient knowledge. Participants with a junior college degree (OR=2.139, P=0.028), 5– 10 years of radiology experience (OR=2.462, P=0.047), and AI diagnosis-related training (OR=2.264, P< 0.001) were associated with a positive attitude. Higher knowledge scores (OR=5.240, P< 0.001), an associate senior professional title (OR=4.267, P=0.026), 5– 10 years of radiology experience (OR=0.344, P=0.044), utilizing AI diagnosis (OR=3.643, P=0.001), and engaging in AI diagnosis-related research (OR=6.382, P< 0.001) were associated with proactive practice. The SEM showed that knowledge had a direct effect on attitude (β=0.481, P< 0.001) and practice (β=0.412, P< 0.001), and attitude had a direct effect on practice (β=0.135, P< 0.001).Conclusion: Radiologists in southeastern China hold a favorable outlook on AI-assisted medical imaging, showing solid understanding and enthusiasm for its adoption, despite half lacking relevant training. There is a need for more AI diagnosis-related training, an efficient standardized AI database for medical imaging, and active promotion of AI-assisted imaging in clinical practice. Further research with larger sample sizes and more regions is necessary.Keywords: artificial intelligence, medical imaging, knowledge, attitude, practice, radiologists, cross-sectional study

Yingzi Zhang,1 Xiajuan Yao,1 Yaoquan Zhang,1 Zhuyun Chen,1 Zhongke Qin,1 Ying Cai,2 Wenkai Xia,1 Hong Hu1 1Department of Nephrology, Jiangyin People’s Hospital Affiliated to Nantong University, Jiangyin, Jiangsu, 214400, People’s Republic of China; 2Department of Hematology, Jiangyin People’s Hospital Affiliated to Nantong University, Jiangyin, Jiangsu, 214400, People’s Republic of ChinaCorrespondence: Wenkai Xia; Hong Hu, Department of Nephrology, Jiangyin People’s Hospital Affiliated to Nantong University, 3 Yingrui Road, Jiangyin, Jiangsu, 214400, People’s Republic of China, Email xiawenkai.xia@gmail.com; huhong1523@163.comBackground: The albumin-to-globulin ratio (AGR) and neutrophil-to-lymphocyte ratio (NLR) have been recently regarded as promising prognostic factors in various malignancies. The present study investigated the prognostic value of combining the AGR and NLR (ANS) for risk assessments in multiple myeloma (MM) with renal impairment (RI).Methods: From 2011 to 2018, 79 patients with MM and RI were enrolled in this study. Receiver operating curves (ROCs) were constructed to determine optimal AGR and NLR thresholds for predicting overall survival (OS) and progression-free survival (PFS) during follow up. The prognostic values of AGR, NLR, and ANS were evaluated with Cox regression and Kaplan-Meier methods. We also created a predictive nomogram for prognostic evaluations of OS and PFS, and the predictive accuracy was assessed with a concordance index (c-index).Results: The ROC curves analyses showed that the optimal cut-off levels were 2.27 for NLR and 1.57 for AGR. A high NLR and a high ANS were significantly associated with worse OS and PFS. However, a high NLR combined with a low AGR was associated with worse OS. Multivariate analyses demonstrated that both the NLR and ANS were independent predictors for both OS and PFS and that a low AGR was an independent predictor of a reduced OS. The nomogram accurately predicted OS (c-index: 0.785) and PFS (c-index: 0.786) in patients with MM and RI.Conclusion: ANS may serve as a potential prognostic biomarker in patients with MM and RI. The proposed nomograms may facilitate prognostic predictions for patients with MM and RI.Keywords: multiple myeloma, renal impairment, neutrophil–lymphocyte ratio, albumin-to-globulin ratio, prognosis

Sifan Ji,1,2,&ast; Hang Qi,1,2,&ast; Li Yan,1,2,&ast; Duo Zhang,1,2 Yang Wang,1,2 HaLiSai MuDanLiFu,1,2 Chuqing He,1,2 Wei Xia,1,2 Qian Zhu,1,2 Yan Liang,1,2 Jian Zhang1,2 1Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Zhang, Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Tel +86 18017316017, Email zhangjian_ipmch@sjtu.edu.cnIntroduction: Endometriosis (EM) is an estrogen-dependent benign gynecologic disease affecting approximately 10% of reproductive-age women with a high recurrence rate, but lacks reliable biomarkers. No previous studies have investigated the possible use of extracellular vesicle (EV)-associated micro RNAs (miRNAs) from menstrual blood (MB) as candidate diagnostic or prognostic markers of EM.Methods: Specimens were obtained from endometriosis and non-endometriosis patients at the International Peace Maternity and Child Health Hospital in Shanghai. Microarray was used to screen differentially expressed miRNAs among peritoneal fluid (PF), fallopian tube fluid (FF), and MB. Dual-luciferase reporter gene assay was carried out to verify the relationship between miR-4443 and ACSS2. Cell proliferation and Transwell invasion assays were performed in vitro after intervention on miR-4443 and ACSS2 in hEM15A human endometrial stromal cells and primary human endometrial stromal cells (hESCs). Spearman correlation analysis, receiver operating characteristic (ROC) curve analysis, and survival analysis were applied to clinical data, including severity of symptoms and relapse of EM among EM patients.Results: EV-associated miR-4443 was abundant in MB of endometriosis patients. ACSS2 knockdown and miR-4443 overexpression promoted cell proliferation and migration via the PI3K/AKT pathway. miR-4443 levels in MB-EVs were positively correlated with the degree of dyspareunia (r=0.64; P< 0.0001) and dysmenorrhea (r=0.42; P< 0.01) in the endometriosis group. ROC curve analyses showed an area under the curve (AUC) of 0.741 (95% CI 0.624– 0.858; P< 0.05) for miR-4443 and an AUC of 0.929 (95% CI 0.880– 0.978; P< 0.05) for the combination of miR-4443 and dysmenorrhea.Conclusion: MB-derived EV-associated miR-4443 might participate in endometriosis development, thus providing a new candidate biomarker for the noninvasive prediction of endometriosis recurrence. Keywords: endometriosis, menstrual blood, biomarker, extracellular vesicles, miR-4443

Tongchao Jiang,1,&ast; Haishuang Sun,2,&ast; Tiankai Xu,1 Shuyu Xue,1 Wen Xia,2 Xiang Xiao,1 Ying Wang,1 Ling Guo,3 Huanxin Lin1 1Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 3Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huanxin Lin, Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China, Email linhx@sysucc.org.cn Ling Guo, Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China, Email guoling@sysucc.org.cnBackground: The C-reactive protein-albumin-lymphocyte (CALLY) score is a novel indicator associated with inflammation, immunity, and nutrition, utilized for cancer prognostic stratification. This study aimed to evaluate the integrated prognostic significance of the pre-treatment CALLY score and Epstein-Barr virus (EBV) DNA levels in nasopharyngeal carcinoma (NPC) patients and to develop prognostic models.Patients and Methods: A total of 1707 NPC patients from September 2015 to December 2017 were retrospectively enrolled. The cut-off point for the CALLY score, determined by maximum selected rank statistics, integrates with the published cut-off point for pre-EBV DNA to develop a comprehensive index. Subsequently, patients were randomly allocated in a 1:1 ratio into training and validation cohorts. Survival analysis was conducted using the Kaplan-Meier method with Log rank tests, and the Cox proportional hazards model was applied to identify independent prognostic factors for constructing predictive nomograms. The predictive ability of the nomograms were assessed through the concordance index (C-index), calibration curves, and decision curve analysis.Results: By integrating CALLY scores and EBV-DNA levels, patients were categorized into three risk clusters. Kaplan-Meier curves reveal significant differences in overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) outcomes among different risk groups (all P values < 0.05). Multivariate analysis revealed that CALLY-EBV DNA index serves as an independent prognostic factor for the OS, DMFS, and LRRFS. The prognostic nomograms based on the CALLY-EBV DNA index provided accurate predictions for 1-year, 3-year, and 5-year OS, DMFS, and LRRFS. Additionally, compared to the traditional TNM staging system, the nomograms exhibited enhanced discriminatory power, calibration capability, and clinical applicability. All results were in agreement with the validation cohort.Conclusion: The CALLY-EBV DNA index is an independent prognostic biomarker. The nomogram prediction models, constructed based on the CALLY-EBV DNA index, demonstrates superior predictive performance compared to the traditional TNM staging.Keywords: CALLY score, EBV DNA, nasopharyngeal carcinoma, biomarker, prognostic model

Ying Chen,1,2,&ast; Wen-Xia Li,1,2,&ast; Jia-Hua Wu,1,2 Geng-Hang Chen,2 Chun-Min Yang,1,2 Hai Lu,1,2 Xi Wang,3 Shu-Sen Wang,4 Heng Huang,5 Li Cai,6 Li Zhao,7 Rou-Jun Peng,8 Ying Lin,9 Jun Tang,3 Jian Zeng,10 Le-Hong Zhang,11 Yong-Li Ke,12 Xian-Ming Wang,13 Xin-Mei Liu,14 An-Qin Zhang,15 Fei Xu,4 Xi-Wen Bi,4 Jia-Jia Huang,4 Ji-Bin Li,16 Dan-Mei Pang,17 Cong Xue,4 Yan-Xia Shi,4 Zhen-Yu He,18 Huan-Xin Lin,18 Xin An,4 Wen Xia,4 Ye Cao,16 Ying Guo,16 Ruo-Xi Hong,4 Kui-Kui Jiang,4 Yong-Yi Zhong,4 Ge Zhang,19 Piyawan Tienchaiananda,20 Masahiro Oikawa,21 Zhong-Yu Yuan,4 Qian-Jun Chen22,23 1Department of Breast Surgery, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Breast Surgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Breast Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4Department of Medical Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 5Department of Breast Oncology, Lianjiang People’s Hospital, Lianjiang, People’s Republic of China; 6Department of Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, People’s Republic of China; 7Department of Breast Oncology, Guangzhou First People Hospital, Guangzhou, People’s Republic of China; 8Department of Integrated Therapy in Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 9Department of Breast Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 10Department of Breast Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 11Department of Breast Oncology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 12Department of Breast Oncology, General Hospital of PLA Guangzhou Military Area, Guangzhou, People’s Republic of China; 13Department of Breast Oncology, Shenzhen Second People’s Hospital, Shenzhen, People’s Republic of China; 14Department of Breast Oncology, Haikou People’s Hospital, Haikou, People’s Republic of China; 15Department of Breast Oncology, Maternal and Child Health Care Hospital of Guangdong Province, Guangzhou, People’s Republic of China; 16Department of Good Clinical Practice, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 17Department of Medical Oncology, Foshan First People’s Hospital, Foshan, People’s Republic of China; 18Department of Radiotherapy, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 19Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong; 20Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Rangsit University, Rajavithi Hospital, Bangkok, Thailand; 21The Department of Breast Surgery, New-wa-kai Oikawa Hospital, Fukuoka, Japan; 22State Key Laboratory of Traditional Chinese Medicine Syndrome/Departments of Gynecologic Oncology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 23State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian-Jun Chen, 55N, Neihuanxi Road, Guangzhou, Guangdong, 510006, People’s Republic of China, Tel +86 1868883505, Email cqj55@163.com Zhong-Yu Yuan, 651 Dongfeng Road, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +86 13798027658, Email yuanzhy@sysucc.org.cnPurpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not.Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into “consistent” (standard acceptable dose) and “inconsistent” (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes.Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the “inconsistent” dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the “inconsistent” dose of anthracycline and taxane did not affect DFS compared with the “consistent” dose. Moreover, in the capecitabine group, the “inconsistent” anthracycline dose did not affect DFS compared with the “consistent” dose. However, patients with “consistent” taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06).Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.Keywords: adjuvant chemotherapy, capecitabine, SYSUCC-001, triple-negative breast cancer, TNBC

Zixia Wu,1,&ast; Weibo Xia,1,&ast; Liling Ou,1 Ling Zheng,1 Bingying Hou,1 Tonghe Pan,2 Wenjie Sun,1 Leo H Koole,1 Yongqing Shao,2 Lei Qi1 1National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People’s Republic of China; 2Ningbo Eye Hospital, Affiliated to Wenzhou Medical University, Ningbo, Zhejiang, 310000, the People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongqing Shao, Ningbo Eye Hospital, Affiliated to Wenzhou Medical University, Ningbo, Zhejiang, 310000, the People’s Republic of China, Tel +86-574 87862193, Email sunniesyq@163.com Lei Qi, School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, the People’s Republic of China, 325027, Tel +86-577-88067973, Email imdoll@163.comPurpose: Patients afflicted with dry eye disease (DED) experience significant discomfort. The underlying cause of DED is the excessive accumulation of ROS on the ocular surface. Here, we investigated the nitrogen doped-graphene quantum dots (NGQDs), known for their ROS-scavenging capabilities, as a treatment for DED.Methods: NGQDs were prepared by using citric acid and urea as precursors through hydrothermal method. The antioxidant abilities of NGQDs were evaluated through: scavenging the ROS both extracellular and intracellular, regulating the nuclear factor-erythroid 2-related factor (Nrf2) antioxidant pathway of human corneal epithelial cells (HCECs) and their transcription of inflammation related genes. Furthermore, NGQDs were modified by Arg-Gly-Asp-Ser (RGDS) peptides to obtain RGDS@NGQDs. In vivo, both the NGQDs and RGDS@NGQDs were suspended in 0.1% Pluronic F127 (w/v) and delivered as eye drops in the scopolamine hydrobromide-induced DED mouse model. Preclinical efficacy was compared to the healthy and DPBS treated DED mice.Results: These NGQDs demonstrated pronounced antioxidant properties, efficiently neutralizing free radicals and activating the intracellular Nrf2 pathway. In vitro studies revealed that treatment of H2O2-exposed HCECs with NGQDs induced a preservation in cell viability. Additionally, there was a reduction in the transcription of inflammation-associated genes. To prolong the corneal residence time of NGQDs, they were further modified with RGDS peptides and suspended in 0.1% Pluronic F127 (w/v) to create RGDS@NGQDs F127 eye drops. RGDS@NGQDs exhibited superior intracellular antioxidant activity even at low concentrations (10 μg/mL). Subsequent in vivo studies revealed that RGDS@NGQDs F127 eye drops notably mitigated the symptoms of DED mouse model, primarily by reducing ocular ROS levels.Conclusion: Our findings underscore the enhanced antioxidant benefits achieved by modifying GQDs through nitrogen doping and RGDS peptide tethering. Importantly, in a mouse model, our novel eye drops formulation effectively ameliorated DED symptoms, thereby representing a novel therapeutic pathway for DED management.Keywords: dry eye disease, antioxidant, nitrogen doped graphene quantum dots, Nrf2 antioxidant pathway

Weiping Xia,1,2 Yanbo Wang,1 Xiaoning Wu,1 Xiaojie Yang3 1Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, 200124, People’s Republic of China; 2Department of Surgical Inpatient, United Family Hospital, Shanghai, 200335, People’s Republic of China; 3Department of Orthopedics, Jiangyin Hospital Affiliated to Nantong University, Jiang Yin, 214400, People’s Republic of ChinaCorrespondence: Yanbo Wang, Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center Sciences, School of Medicine, Tongji University, Shanghai, 200124, People’s Republic of China, Email wang_yb@tongji.edu.cnPurpose: To develop a new questionnaire for assessing nurses’ current situation of knowledge, attitude and practice related to trauma-informed care (TIC) for patients with traumatic injury.Methods: By literature review, qualitative interview and Delphi consultation, the 46 preliminary items about trauma-informed care of nurses working with traumatically injured patients were selected. After that, the preliminary questionnaire was distributed to 293 Chinese nurses in relevant departments. The collected data were analyzed by internal reliability, split-half reliability, structural validity and content validity.Results: The questionnaire was developed with a total of 30 items in 3 dimensions: 8 items in the TIC knowledge dimension, 10 items in the TIC attitude dimension and 12 items in the TIC practice dimension. The Cronbach’s alpha coefficient was 0.939, and the content validity was 0.971.Conclusion: This designed questionnaire shews receptable reliability and validity, which could be used to assess the knowledge, attitude and practice of nurses in application of trauma-informed care for traumatically injured patients.Keywords: trauma-informed care, traumatic injury, nurse, questionnaire

Huangqi Duan,&ast; Yu Shen,&ast; Chen Wang, Weimin Xia, Shun Zhang, Shenggen Yu, Ding Xu, Qifeng Cao, Hailong Liu, Haibo Shen Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hailong Liu; Haibo Shen, Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China, Email liuhailong@xinhuamed.com.cn; shenhaibo@xinhuamed.com.cnBackground: Cuproptosis-related gene and long non-coding RNA (lncRNA) modulation of cancer regulation is well-established. This investigation aimed to elucidate the prognostic implications of cuproptosis-associated lncRNAs in muscle-invasive bladder cancer (MIBC).Methods: Employing the Cancer Genome Atlas (TCGA) and IMvigor210 cohorts, bioinformatics and statistical analyses probed the prognostic relevance of cuproptosis-related lncRNAs.Results: Co-expression analysis revealed tight associations between lncRNA expression and cuproptosis-linked genes, with 13 cuproptosis-related lncRNAs found to correlate with MIBC prognosis. Lasso regression identified a six-lncRNA prognostic signature, enabling patient stratification into high- and low-risk categories. Tissue validation substantiated differential expression of FAM13A-AS1, GHRLOS, LINC00456, OPA1-AS1, RAP2C-AS1, and UBE2Q1-AS1 between MIBC tumor and normal tissues. Comparative analyses of tumor microenvironments and immune profiles between risk groups disclosed elevated immunosuppressive molecule expression, including programmed cell death-1 (PD-L1) and T-cell immunoglobulin-3 (TIM-3), in high-risk individuals.Conclusion: These findings suggest that cuproptosis-related lncRNAs may modulate the expression of immunosuppressive molecules, thereby influencing MIBC tumorigenesis and progression. Further exploration is warranted to unveil novel therapeutic targets for MIBC based on the expression patterns of cuproptosis-related lncRNAs and their impact on immune responses in the tumor microenvironment.Keywords: cuproptosis-related lncRNAs, immunosuppressive molecules, MIBC, prognostic, risk scores

Rong Li,1 Jing Liu,2 Weidong Xia,3 Jingdong Ma1,4 1School of Medicine and Health Management, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Administrative Office, Yuebei People’s Hospital, Shaoguan, People’s Republic of China; 3Department of Information Systems and Business Analytics, College of Business, Florida International University, Miami, FL, USA; 4Institute for Smart Health Research, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Jingdong Ma, School of Medicine and Health Management, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China, Tel +8613098807808, Email jdma@hust.edu.cnPurpose: In the complex and rapidly changing healthcare environment, the dynamic capabilities of frontline employees (FLEs) to integrate resources and adapt to environmental changes are crucial. This study aims to investigate the relationship between FLEs’ self-efficacy, dynamic capabilities (including sensing capability and reconfiguring capability), and their impact on service performance.Methods: Data were collected from a matched sample of 123 doctors and 762 corresponding consumers from two medical aesthetic hospitals in China. SPSS and SmartPLS are used to test the proposed model.Results: The findings indicate that FLEs’ self-efficacy positively influences their service performance through the mediation of dynamic capabilities. Moreover, while the direct impact of FLEs’ sensing capabilities on service performance was found to be insignificant, it was observed that these capabilities indirectly affect service performance through reconfiguring capabilities.Conclusion: This study presents theories and arguments on the role of self-efficacy and dynamic capabilities in improving service performance. These findings contribute to a deeper understanding of how FLEs cultivate the dynamic capability of resource integration, offering valuable insights for the attainment of sustainable competitive advantages.Keywords: dynamic environment, frontline employee, self-efficacy, dynamic capability, service performance

Xinrui Feng,1,2,&ast; Yan Liu,1,&ast; Yang Zhao,3 Zhe Sun,1,4 Ning Xu,5 Chen Zhao,1 Wei Xia4 1College of Public Health, Jilin Medical University, Jilin, 132013, People’s Republic of China; 2Medical College, Yanbian University, Yanji, 136200, People’s Republic of China; 3Department of Emergency and Intensive Medicine, No. 965 Hospital of PLA Joint Logistic Support Force, Jilin, 132013, People’s Republic of China; 4College of Medical Technology, Beihua University, Jilin, 132013, People’s Republic of China; 5State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chen Zhao; Wei Xia, Email zhaochen0115@jlmu.edu.cn; xiawei4016@126.comAbstract: Recent, outbreaks of new emergency zoonotic diseases have prompted an urgent need to develop fast, accurate, and portable screening assays for pathogen infections. Recombinase polymerase amplification (RPA) is sensitive and specific and can be conducted at a constant low temperature with a short response time, making it especially suitable for on-site screening and making it a powerful tool for preventing or controlling the spread of zoonoses. This review summarizes the design principles of RPA-based biosensors as well as various signal output or readout technologies involved in fluorescence detection, lateral flow assays, enzymatic catalytic reactions, spectroscopic techniques, electrochemical techniques, chemiluminescence, nanopore sequencing technologies, microfluidic digital RPA, and clustered regularly interspaced short palindromic repeats/CRISPR-associated systems. The current status and prospects of the application of RPA-based biosensors in zoonoses screening are highlighted. RPA-based biosensors demonstrate the advantages of rapid response, easy-to-read result output, and easy implementation for on-site detection, enabling development toward greater portability, automation, and miniaturization. Although there are still problems such as high cost with unstable signal output, RPA-based biosensors are increasingly becoming one of the most important means of on-site pathogen screening in complex samples involving environmental, water, food, animal, and human samples for controlling the spread of zoonotic diseases. Keywords: recombinase polymerase amplification, biosensor, zoonoses, rapid detection, nanomaterials

Yanfei Lu,1,2,&ast; Wenying Xia,1,2,&ast; Shuxian Miao,1,2 Min Wang,1,2 Lei Wu,1,2 Ting Xu,1,2 Fang Wang,1,2 Jian Xu,1,2 Yuan Mu,1,2 Bingfeng Zhang,1,2 Shiyang Pan1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shiyang Pan, Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Guangzhou Street No. 300, Nanjing, 210029, People’s Republic of China, Tel +8625-6830-6287, Fax +8625-8372-4440, Email sypan@njmu.edu.cnObjective: This study aimed to investigate the clinical characteristics and risk factors of death in severe coronavirus disease 2019 (COVID-19) during the epidemic of Omicron variants, assess the clinical value of plasma cell-free DNA (cfDNA), and construct a prediction nomogram for patient mortality.Methods: The study included 282 patients with severe COVID-19 from December 2022 to January 2023. Patients were divided into survival and death groups based on 60-day prognosis. We compared the clinical characteristics, traditional laboratory indicators, and cfDNA concentrations at admission of the two groups. Univariate and multivariate logistic analyses were performed to identify independent risk factors for death in patients with severe COVID-19. A prediction nomogram for patient mortality was constructed using R software, and an internal validation was performed.Results: The median age of the patients included was 80.0 (71.0, 86.0) years, and 67.7% (191/282) were male. The mortality rate was 55.7% (157/282). Age, tracheal intubation, shock, cfDNA, and urea nitrogen (BUN) were the independent risk factors for death in patients with severe COVID-19, and the area under the curve (AUC) for cfDNA in predicting patient mortality was 0.805 (95% confidence interval [CI]: 0.713– 0.898, sensitivity 81.4%, specificity 75.6%, and cut-off value 97.67 ng/mL). These factors were used to construct a prediction nomogram for patient mortality (AUC = 0.856, 95% CI: 0.814– 0.899, sensitivity 78.3%, and specificity 78.4%), C-index was 0.856 (95% CI: 0.832– 0.918), mean absolute error of the calibration curve was 0.007 between actual and predicted probabilities, and Hosmer-Lemeshow test showed no statistical difference (χ 2=6.085, P=0.638).Conclusion: There was a high mortality rate among patients with severe COVID-19. cfDNA levels ≥ 97.67 ng/mg can significantly increase mortality. When predicting mortality in patients with severe COVID-19, a nomogram based on age, tracheal intubation, shock, cfDNA, and BUN showed high accuracy and consistency.Keywords: severe COVID-19, Omicron, clinical characteristics, mortality, CfDNA, predicting nomogram

Chen Wang,1,2 Qifeng Cao,2,&ast; Shun Zhang,2,&ast; Hailong Liu,2 Huangqi Duan,2 Weimin Xia,2 Haibo Shen,2 Cheng Wang1 1Department of Urology, The People’s Hospital of SND, Suzhou, People’s Republic of China; 2Department of Urology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cheng Wang, Department of Urology, The People’s Hospital of SND, Suzhou, People’s Republic of China, Tel +86-15050163288, Email 15050163288@163.com Haibo Shen, Department of Urology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China, Tel +86-18601712802, Email shenhaibo@xinhuamed.com.cnIntroduction and Objective: The mitogen-activated protein kinase (MAPK) pathway is inhibited by the pan-target inhibitor Anlotinib, which induces tumor cell death. In addition to the common apoptosis and necrosis, there is also a pyroptosis mode of cancer cell death in recent years, which is mainly manifested by the cleavage of gasdermin proteins (GSDMs). Gasdermin B (GSDMB) participates in the progression and outcome of bladder cancer. The efficacy and mechanism of Anlotinib in the treatment of GSDMB-positive bladder tumors have not been studied to date.Methods: The relationship between GSDMB expression and tumor stage, overall survival rate, immunotherapy response, tumor recurrence and progression rate was analyzed from the TCGA bladder cancer database. Anlotinib was used to treat GSDMB-positive bladder cancer in mice followed by flow analysis of the secretion of inflammatory factors related to pyroptosis and the level of anti-tumor factors. Western blot analysis detected which MAPK and MEK signal transduction pathways.Results: TCGA data analysis showed that the overall survival rate of bladder cancer patients with high GSDMB expression was better than that of patients with low GSDMB expression. In vivo experiments showed that Anlotinib was more effective in the treatment of GSDMB-positive bladder cancer than GSDMB-negative bladder cancer. Anlotinib can increase the secretion of antitumor-related factors in GSDMB-positive bladder cancer such as TNF-a and CD107a. In addition, Anlotinib also induced an increase in GSDMB protein expression. Anlotinib treatment of GSDMB-positive bladder cancer decreased AKT and MEK protein expression, which were involved in Anlotinib signal transduction pathway.Conclusion: Anlotinib has a strong antitumor effect on GSDMB-positive bladder tumors. This effect is mainly achieved by anlotinib stimulating the secretion of relevant antitumor factors by lymphocytes. The PI3K/AKT and MEK signal transduction pathways were inhibited by Anlotinib in bladder cancer expressing GSDMB protein.Keywords: bladder cancer, Anlotinib, GSDMB, targeted therapy, pyroptosis

Li Ding,1,&ast; Xiaobin Deng,2,&ast; Kun Wang,1,&ast; Wentao Xia,1,&ast; Yang Zhang,1 Yan Zhang,1 Xianfeng Shao,1 Junqi Wang1 1Department of Urology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 2Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junqi Wang, Email wangjq_68@163.comIntroduction: Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and lymphocyte/monocyte ratio (LMR) have been widely proposed to have predictive value for the patient prognosis of many malignancies, including bladder cancer. However, the predictive value of their combination in non-muscle-invasive bladder cancer (NMIBC) is unclear.Methods: Cases of NMIBC patients who underwent transurethral resection of the bladder tumor were recruited from two tertiary public medical centers. A systemic inflammatory marker (SIM) score was calculated based on comprehensive consideration of NLR, PLR, and LMR. Recurrence-free survival (RFS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. The Log rank test was used to compare differences between the groups. Cox regression was used to screen risk factors affecting RFS and PFS. Nomogram models were established and validated, and patients were stratified based on the model scores.Results: The study dataset was grouped according to a 7:3 randomization, with the training cohort consisting of 292 cases and the validation cohort consisting of 124 cases. Cox regression analysis showed that SIM score is an independent predictor of RFS and PFS in NMIBC patients. The novel models were established based on the SIM score and other statistically significant clinicopathological features. The area under the curve (AUC) for predicting 1-, 2-, and 3-year RFS was 0.667, 0.689, and 0.713, respectively. The AUC for predicting 1-, 2-, and 3-year PFS was 0.807, 0.775, and 0.862, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. The established models were applied to the patient evaluation of the validation cohort, which proved the great performance of the novel models.Conclusion: The novel models based on the SIM score and clinicopathological characteristics can accurately predict the survival prognosis of NMIBC patients, and the models can be used by clinicians for individualized patient assessment and to assist in clinical decision-making.Keywords: systemic inflammatory markers, risk factor, bladder cancer, NMIBC, tumor recurrence, nomogram

Hu L, Wang H, Rao M, et al. Int J Nanomedicine. 2014;9(1):1127–1138. We, the Editors and Publisher of International Journal of Nanomedicine, have retracted the following article. Following publication, the authors raised concerns about the duplication of images within the article. Specifically, The images for Figure 4C and 4F have been duplicated, as have the images for Figure 4D and 4E. The images for Figure 6A and 6B have been duplicated, as have the images for Figure 6C and 6D. It was noted that some images for Figures 2 and 10 may have duplicated regions, however, this was caused by an error during the publication process. When approached for an explanation, the authors were cooperative but wereg unable to provide an adequate explanation for the duplicated images and not all the original data for the study was available. As verifying the validity of published work is core to the integrity of the scholarly record, we are therefore retracting the article and the authors agreed with this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Xiaohui Zhang,1,2,&ast; Fei Jin,1,2,&ast; Yanfei Lu,1,2 Fang Ni,1,2 Yuqiao Xu,1,2 Wenying Xia1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuqiao Xu; Wenying Xia, Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Street No. 300, Guangzhou, 210029, People’s Republic of China, Tel +8625-6830-6146 ; +8625-6830-6287, Fax +8625-8372-4440, Email joe8165@163.com; xiawenying21106891@163.comPurpose: This study aimed (i) to investigate the clinical characteristics and risk factors related to in-hospital mortality in patients with infective endocarditis (IE) and (ii) to compare the differences in three age groups.Methods: A total of 240 IE cases diagnosed using the modified Duke criteria between January 2016 and December 2019 were included and retrospectively studied. Patients were stratified into three age groups: < 50 y, 50– 65 y, and > 65 y.Results: The mean age of the patients was 51 ± 14 y, and 154 patients (64.2%) were male. In addition, 136 (56.7%) patients with IE had no previous cardiac disease. Congenital heart disease (CHD, 21.3%) was the most common underlying heart disease, followed by rheumatic heart disease (RHD, 8.8%). Streptococcus was found in 55 (22.9%) patients and was the most common causative pathogen, comprising 52.9% of all positive blood cultures. Echocardiography showed the presence of vegetations in 88.3% of cases and the predominant involvement of the left heart valves. Fever and cardiac murmur were the most frequent presentations, with no significant differences among age groups. Compared with younger patients, elderly patients had a lower operation rate and higher in-hospital mortality. The independent risk factors of in-hospital mortality were age > 65 y, intracranial infection, splenic embolization, cerebral hemorrhage, NYHA class III–IV, and prosthetic valve infection.Conclusion: CHD replaces RHD as the most common underlying heart disease in IE patients. Patients without previous cardiac disease are at increased risk of IE. Streptococcus is still the primary causative pathogen of IE. Elderly patients present with more comorbidities and complications, in addition to a more severe prognosis than younger patients. Age older than 65 y, intracranial infection, splenic embolization, cerebral hemorrhage, NYHA class III–IV, and prosthetic valve infection showed poorer in-hospital outcomes.Keywords: infective endocarditis, clinical characteristics, risk factors, elderly patients

Hongxin Shen,1– 3 Yuzhi Fu,1– 3 Ying Chen,1– 3 Wenxing Xia,1– 3 Zhi-Jun Jia,1– 4 Qin Yu,3,5 Lingli Zhang,1– 3 Lu Han1– 3 1Department of Pharmacy, West China Second University Hospital of Sichuan University, Chengdu, People’s Republic of China; 2Evidence-Based Pharmacy Center, West China Second University Hospital of Sichuan University, Chengdu, People’s Republic of China; 3Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, People’s Republic of China; 4West China School of Pharmacy, Sichuan University, Chengdu, People’s Republic of China; 5Institute of Drug Clinical Trial GCP, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Lu Han, West China Second University Hospital, Sichuan University, No. 20, Third Section, Renmin South Road, Chengdu, Sichuan, 610041, People’s Republic of China, Email luhan830301@sina.comObjective: Pediatric electrolyte supplements injection is mainly used to supplement heat and body fluid, and commonly used in pediatrics. Its compatibility and stability with common clinical drugs such as antibiotics was rarely reported to ensure the children’s safety and the rational use of drugs. The aim of the present study was to investigate physical and chemical stability of pediatric electrolyte supplements injection mixed with ten commonly used clinical drugs.Methods: According to clinical drug concentration, we mix the pediatric electrolyte supplements injection mixed with ten drugs. The compatible solutions were withdrawn at certain time intervals (0, 0.5, 1, 2, 4, 6 hours) after mixing and tested by description, insoluble particles detection, pH determination and high performance liquid chromatography (HPLC) assay of active ingredient as measures of physicochemical compatibility.Results: No obvious appearance changes were observed when mixing. Furthermore, over the 6 hours post-preparation period the pH values were within the requirements of each drug quality standard and the number of insoluble particles (≥ 10 and ≥ 25μm) met requirements of Chinese Pharmacopeia (Edition 2020) except for mezlocillin sodium for injection. The percentages of the initial concentrations maintained at a minimum of 97% in the mixtures within 6 hours.Conclusions: Nine commonly used clinical drugs remained stable in the pediatric electrolyte supplements injection for 6 hours at 25°C and avoiding from light. Mezlocillin sodium for injection was not recommended to be combined with electrolyte supplement injection for children because its insoluble particles exceed the standard.Keywords: compatibility, stability, pediatric electrolyte supplements injection

Yanfei Lu,1,2,&ast; Wenying Xia,1,2,&ast; Fang Ni,1,2 Yuqiao Xu1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2Branch of National Clinical Research Center for Laboratory Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuqiao Xu, Department of Laboratory Medicine, Jiangsu Province Hospital, Guangzhou Street No. 300, Nanjing, 210029, People’s Republic of China, Tel + 8625-6830-6287, Fax + 8625-8372-4440, Email joe8165@163.comAbstract: Peptoniphilus asaccharolyticus is a Gram-positive anaerobic coccus, which forms part of the normal flora and the human commensals of the skin, genitourinary system, and gut. It can cause opportunistic infections in immunocompromised patients and is frequently isolated as part of polymicrobial spectra. Severe monomicrobial infections caused by the genus rarely occur. In this study, we report on septic shock, renal abscess, and bacteremia due to P. asaccharolyticus in a woman with nephrosis and diabetes mellitus. To the best of our knowledge, this report is the first to describe P. asaccharolyticus isolated from both renal abscess and blood cultures purely. The underlying diseases of the host and the removal of the double J tube were significant predisposing factors in this infection.Keywords: Peptoniphilus asaccharolyticus, septic shock, renal abscess, bacteremia, immunocompromised

Liying Zhan,1,&ast; Kai Huang,2,&ast; Wenfang Xia,1 Jingdi Chen,3 Lu Wang,1 Jiaming Lu,4 Jing Wang,4 Jun Lin,2,4 Wei Wu1 1Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 3Department of Orthopedics, The Airborne Military Hospital, Wuhan, Hubei, People’s Republic of China; 4Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wu; Jun Lin Email weiwu2012@whu.edu.cn; linjun64@126.comBackground: Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease caused by a bunyaviridae virus. Its main clinical manifestation is fever with thrombocytopenia, which may be accompanied by other clinical symptoms. Here, we report a patient diagnosed with SFTS using metagenomic next‑generation sequencing (mNGS).Case Presentation: A 56-year-old female patient was hospitalized with intermittent diarrhea and fever. She visited a local clinic for treatment, but instead of improving, the symptoms progressed to unconsciousness.Diagnosis: Using mNGS, we isolated the bunyaviridae virus and several other pathogens from the patient’s blood samples to confirm the diagnosis.Interventions: The patient was treated with symptomatic and supportive therapy, including intravenous human γ-globulin (20 g/d), platelet transfusion, platelet elevation (subcutaneous injection of recombinant human thrombopoietin, 15,000 IU), white blood cell elevation (subcutaneous injection of recombinant human granulocyte colony-stimulating factor, 200 ug, qd); and antibiotic (cefoperazone sodium and tazobactam sodium, 2 g, q8h), antiviral (ganciclovir, 250 mg, q12h), and antifungal therapy (voriconazole for injection, 0.2 g, q12h). After ten days of treatment, the patient’s condition gradually improved.Conclusion: Compared to traditional detection methods, mNGS has many advantages. It can quickly identify the pathogen when the patient’s clinical manifestations are complex and difficult to diagnose, resulting in the formulation of an effective treatment.Keywords: severe fever with thrombocytopenia syndrome, metagenomic next‑generation sequencing, bunyaviridae virus

Binbin Zhang,1,&ast; Aiqun Xu,2,&ast; Dong Wu,1,&ast; Wanli Xia,3,&ast; Pulin Li,1 Enze Wang,1 Rui Han,1 Peng Sun,1 Sijing Zhou,4,5 Ran Wang1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China; 2Department of General Medicine, Hefei Second People’s Hospital, Hefei, Anhui Province, People’s Republic of China; 3Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China; 4Hefei Third Clinical College of Anhui Medical University, Hefei, Anhui Province, People’s Republic of China; 5Hefei Prevention and Treatment Center for Occupational Diseases, Hefei, Anhui Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sijing ZhouHefei Prevention and Treatment Center for Occupational Diseases, Hefei, 230022, People’s Republic of ChinaTel/Fax +86 551-63672040Email zhousijing@yeah.netRan WangDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China, Tel/Fax +86-551-6292-2914Email ranwangtjmu@hotmail.comPurpose: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The mechanisms underlying NSCLC initiation and progression require further investigation. The purpose of this study was to investigate the role of ADP ribosylation factor-like GTPase 14 (ARL14) related to the progression of NSCLC.Patients and Methods: We analyzed the correlation between clinical characteristics and ARL14 expression using data from The Cancer Genome Atlas (TCGA). Kaplan–Meier analysis was conducted to evaluate the prognostic value of ARL14 in NSCLC. Functions of ARL14 were identified by enrichment analysis. The relationship between ARL14 expression and immune cell infiltration was also studied. Furthermore, ARL14 expression was examined using immunohistochemistry, and its clinical significance was analyzed in 120 patients with NSCLC.Results: Our study revealed that the expression level of ARL14 in patients with NSCLC was higher than that in normal tissues. Using TCGA data, higher ARL14 expression in lung adenocarcinoma was associated with residual tumor (P = 0.017), while it was associated with age (P = 0.003) and N stage (P = 0.009) in lung squamous cell carcinoma. Similar results were obtained from 120 patients with NSCLC. High ARL14 expression was associated with poor overall survival and progression-free survival in NSCLC. Multivariate analysis revealed that ARL14 was an independent risk factor for patients with NSCLC. Functional enrichment analysis indicated that ARL14 was related to the occurrence and development of tumors.Conclusion: Increased ARL14 expression was considerably correlated with poor survival in NSCLC, and it might be a promising prognostic biomarker for NSCLC.Keywords: ADP ribosylation factor-like GTPase 14, non-small cell lung cancer, prognosis, immunohistochemistry, bioinformatics

Jing Yuan,1,&ast; Fangfang Duan,2,&ast; Wenyu Zhai,3,&ast; Chenge Song,2 Li Wang,2 Wen Xia,2 Xin Hua,2 Zhongyu Yuan,2 Xiwen Bi,2 Jiajia Huang2 1Departments of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Departments of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Departments of Thoracic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiajia Huang; Xiwen BiDepartment of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaEmail huangjiaj@sysucc.org.cn; bixw@sysucc.org.cnBackground: Aging, an inevitable process characterized by functional decline over time, is a significant risk factor for various tumors. However, little is known about aging-related genes (ARGs) in breast cancer (BC). We aimed to explore the potential prognostic role of ARGs and to develop an ARG-based prognosis signature for BC.Methods: RNA-sequencing expression profiles and corresponding clinicopathological data of female patients with BC were obtained from public databases in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). An ARG-based risk signature was constructed in the TCGA cohort based on results of least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, and its prognostic value was further validated in the GSE20685 cohort.Results: A six ARG-based signature, including CLU, DGAT1, MXI1, NFKBI, PIK3CA and PLAU, was developed in the TCGA cohort and significantly stratified patients into low- and high-risk groups. Patients in the former group showed significantly better prognosis than those in the latter. Multivariate Cox regression analysis demonstrated that the ARG risk score was an independent prognostic factor for BC. A predictive nomogram integrating the ARG risk score and three identified factors (age, N- and M-classification) was established in the TCGA cohort and validated in the GSE20685 cohort. Calibration plots showed good consistency between predicted survival probabilities and actual observations.Conclusion: A novel ARG-based risk signature was developed for patients with BC, which can be used for individual prognosis prediction and promoting personalized treatment.Keywords: breast cancer, aging, prognostic signature, risk stratification

Shun Zhang,&ast; Cheng Wang,&ast; Weimin Xia, Huangqi Duan, Subo Qian, Haibo Shen Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haibo Shen;Subo Qian Tel +86-13651698392; +86-13761020575Fax +86-21-25078095Email shenhaibo@xinhuamed.com.cn; qiansubo@xinhuamed.com.cnObjective: Bladder cancer contributes to a serious disease burden in clinical settings. The characteristics and prognosis of patients with muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) are distinctly different. The study aims to figure out the respective role of ferroptosis in MIBC and NMIBC and to construct ferroptosis-related gene signatures that could predict patients’ prognoses.Methods: A total of 608 MIBC and 414 NMIBC RNA-seq transcriptome data with intact clinical and follow-up information were downloaded from The Cancer Genome Atlas (TCGA), ArrayExpress, and Gene expression omnibus (GEO) database. Ferroptosis-related multigene prognostic models were constructed and externally validated, respectively, in MIBC and NMIBC. Further functional enrichment analyses were also performed to explicate the underlying mechanisms and the differences between the two bladder cancer subtypes.Results: In MIBC, a 7-gene signature for prognostic prediction was constructed. Patients were then divided into high-risk and low-risk groups according to the risk scores calculated by the 7-gene prognostic model. Patients in the high-risk group presented an impaired OS when compared with patients in the low-risk group both in the training cohort and validation cohort. Further functional analyses revealed distinctly different immune statuses between the two risk-stratification groups, speculating that exhausted immune cell function was a cause of the worst OS in the high-risk group. In NMIBC, 6 ferroptosis-related genes were identified that were significantly correlated with recurrence-free survival (RFS). Similarly, a 6-gene prognostic model was constructed and verified as an independent prognostic predictor for RFS. Functional analyses revealed significant differences in the expressions of nuclear division genes between the high-risk group and low-risk group.Conclusion: Two novel ferroptosis-related multigene prognostic models for, respectively, predicting OS in MIBC and RFS in NMIBC were identified in this study, which indicated ferroptosis played vital roles in the oncogenesis and development of MIBC and NMIBC.Keywords: ferroptosis, bladder cancer, MIBC, NMIBC, prognosis, gene signature

Fangfang Duan,&ast; Chenge Song,&ast; Yuyu Ma, Kuikui Jiang, Fei Xu, Xiwen Bi, Jiajia Huang, Ruoxi Hong, Zhangzan Huang, Qianyi Lu, Zhongyu Yuan, Shusen Wang, Wen Xia Departments of Medical Oncology, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen XiaDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People’s Republic of ChinaEmail xiawen@sysucc.org.cnBackground: There are no clinically available prognostic models for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer treated with everolimus. We aimed to develop a tool to predict the progression-free survival (PFS) and overall survival (OS) of these patients and to identify optimal candidates who would benefit from everolimus-based treatment in this heterogeneous patient population.Methods: The clinical data of patients with HR+, HER2- metastatic breast cancer receiving everolimus between May 2012 and January 2018 at Sun Yat-sen University Cancer Center were retrospectively retrieved. Based on potential prognostic factors derived from multivariate Cox analysis, we established predictive nomogram models for PFS and OS and evaluated their predictive values by means of the concordance index (C-index). Calibration curves were used to estimate the consistency between the actual observations and the nomogram-predicted probabilities.Results: A total of 116 patients with HR+, HER2- metastatic breast cancer were enrolled in this study. Three independent prognostic factors, including the line of everolimus in the metastatic setting, everolimus clinical benefit rate and number of liver metastatic lesions, were identified from the multivariate Cox analysis. Prognostic models for individual survival prediction were established and graphically presented as nomograms. The C-index was 0.738 (95% confidence interval [CI]: 0.710– 0.767) for the PFS nomogram and 0.752 (95% CI: 0.717– 0.788) for the OS nomogram, which showed favourable discrimination. The calibration curves for the probabilities of 6-, 9-, and 12-month PFS and 1-, 2-, and 3-year OS suggested satisfactory consistency between the actual observations and the predicted probabilities.Conclusion: We constructed convenient nomogram models for patients with HR+, HER2- metastatic breast cancer to individually predict their potential benefits from everolimus in the metastatic setting. The models showed good performance in terms of accuracy, discrimination capacity and clinical application value.Keywords: prognostic nomogram, metastatic breast cancer, everolimus, progression-free survival, overall survival

Yanfei Lu,1,2,&ast; Xiaohui Zhang,1,2,&ast; Fang Ni,1,2 Wenying Xia1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenying XiaDepartment of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Street No. 300, Guangzhou, 210029, People’s Republic of ChinaTel +8625-6830-6287Fax +8625- 8372-4440Email xiawenying21106891@163.comAbstract: Human protothecosis is a rare infection caused by Prototheca spp., which are environmental achloric algae ubiquitously existing in nature. Members of the genus of Prototheca usually cause localized infection that affects the skin or wounds. Systemic infection is extremely rare and tends to occur in immunocompromised patients. Here, we report a case of cutaneous protothecosis and meningitis due to Prototheca wickerhamii in an immunocompetent teenager who obtained full-body tattoos at the time of infection. To the best of our knowledge, this is the first description of P. wickerhamii isolated from both skin tissue and cerebrospinal fluid. The data contained in this report will increase our understanding of this pathogen and elucidate the most optimal treatment.Keywords: Prototheca wickerhamii, cutaneous protothecosis, meningitis, immunocompetent

Huajun Yu,1 Yingbao Huang,2 Lifang Chen,2 Liuzhi Shi,3 Yunjun Yang,2 Weizhi Xia4 1Department of Pancreatitis Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 3Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Radiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Weizhi XiaDepartment of Radiology, The Second Affiliated Hospital of Wenzhou Medical University, Xue Yuan Xi Lu 109, Lucheng District, Wenzhou, 325000, People’s Republic of ChinaEmail kumamon1115@163.comBackground: Analytic morphometric assessment has recently been proposed to be applied to the study of acute pancreatitis (AP). However, the relationship between body composition and the outcomes of hypertriglyceridemic pancreatitis (HTGP) is still unclear. The aim of this study was to evaluate body composition in relation to the length of hospital stay (LOS) and recurrence of HTGP.Methods: Patient characteristics, admission examination data, body composition parameters, LOS, and recurrence within 1 year were collected from the institutional pancreatitis database and follow-up records. Logistic regression analysis was used to identify risk factors for LOS and recurrence of HTGP.Results: Of the 196 included patients, 158 (80.6%) were men and 53 (27.0%) were sarcopenic. The average LOS was 15.83± 10.02 days. The recurrence rate of HTGP was 36.7%. Multivariate analysis with multiple linear regression suggested that subcutaneous adipose tissue (SAT) area (p=0.019) and high-density lipoprotein-cholesterol (HDL-C) (p=0.001) were independently associated with the LOS for HTGP after adjusting for age and sex. The multivariate adjusted hazard ratios for SAT area and HDL-C, with respect to the relationship between body parameters and LOS, were 1.008 (95% confidence interval [CI], 1.001– 1.015) and 0.090 (95% CI, 0.022– 0.361), respectively. No significant differences were observed between the AP and recurrent AP (RAP) groups in terms of characteristics, admission examination data, and body composition parameters.Conclusion: SAT area and HDL-C are associated with LOS in patients with HTGP. The body composition of patients at the first symptom onset of HTGP cannot predict recurrence.Keywords: hypertriglyceridemic pancreatitis, recurrent pancreatitis, length of hospital stay, body composition, subcutaneous adipose tissue

Zhao Wang,1 Xiaoxia Song,2 Qingbo Fang,3 Weige Xia,1 Aihua Luo2 1Department of Orthopedics, The Second Poverty Relief Hospital of Xinjiang Uygur Autonomous Region (The Fifth People′s Hospital of Xinjiang Uygur Autonomous Region), Urumqi, Xinjiang, People’s Republic of China; 2Department of Critical Care Medicine, The Second Poverty Relief Hospital of Xinjiang Uygur Autonomous Region (The Fifth People′s Hospital of Xinjiang Uygur Autonomous Region), Urumqi, Xinjiang, People’s Republic of China; 3Department of Vascular Surgery, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, People’s Republic of ChinaCorrespondence: Aihua LuoDepartment of Critical Care Medicine, The Second Poverty Relief Hospital of Xinjiang Uygur Autonomous Region (The Fifth People′s Hospital of Xinjiang Uygur Autonomous Region), No. 159, West Kashi Road, Urumqi, 830000, People’s Republic of ChinaTel +86-18116803983Email 33180536@qq.comPurpose: To investigate the association of polymorphism of IL-1β rs16944(T/C) with intervertebral disk degeneration (IDD), explore the possible mechanism and evaluate the predictive value of IL-1β for IDD.Patients and Methods: A total of 196 consecutive patients with IDD were recruited, and 196 healthy controls were matched to these patients based on sex and age (± 3 years). The polymorphisms of IL-1β rs16944(T/C), rs1143623(G/C), rs10490571(T/C) and rs2853550(A/G) were determined, and serum IL-1β, MMP-1, MMP-3, MMP-9 and a disintegrin-like and metalloproteinase with thrombospondin motif-4 (ADAMTS-4) levels were measured. Univariate analysis was performed with Student t-test or one-way ANOVA followed by post hoc and Chi-square test. Variables with two-sided P< 0.10 were included in multivariate analysis, which employed a backward stepwise logistic regression model. Receiver operating characteristic (ROC) curve was used to evaluate the predictive value.Results: Multivariate analysis showed that the polymorphism of IL-1β rs16944(T/C) was independently associated with IDD. The risk for IDD was significantly increased in TT and TC genotype compared with CC genotype, and the OR of TT genotype was higher than that of TC genotype. ANOVA analysis showed that serum concentration of IL-1β was highest in IL-1β rs16944 TT genotype, intermediate in TC genotype, and lowest in CC genotype. Similarly, serum concentrations of MMP-3 and ADAMTS-4 demonstrated the same tendency of TT > TC > CC genotype. Serum concentrations of MMP-1 and MMP-9 were higher in TT genotype than in TC and CC genotype. The area under curve (AUC) of IL-1β levels in predicting IDD was 0.788 (SE: 0.023, P=0.001, 95% CI: 0.742– 0.834), and the predictive value was modest with a sensitivity of 77.0% and a specificity of 75%.Conclusion: Polymorphism of IL-1β rs16944(T/C) affected IDD susceptibility through upregulation of serum levels of IL-1β and subsequent stimulation of ECM degradation. IL-1β levels could be applied in predicting IDD.Keywords: intervertebral disk degeneration, single-nucleotide polymorphisms, IL-1β, susceptibility, predictive value

Yaping Han,1,2 Lei Huang,1,2 Chengcheng Liu,1,2 Xu Huang,3 Ruiying Zheng,1,2 Yanfei Lu,1,2 Wenying Xia,1,2 Fang Ni,1,2 Yaning Mei,1,2 Genyan Liu1,2 1Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Jiangsu Province Hospital, Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People’s Republic of China; 3Department of Laboratory Medicine, Children’s Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People’s Republic of ChinaCorrespondence: Genyan LiuDepartment of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People’s Republic of ChinaTel +86 25-6830-3453Fax +86 25- 8372-4440Email liugenyan@njmu.edu.cnObjective: Nosocomial infection caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is a great threat to severely ill patients. Here we report an outbreak of K. pneumoniae ST15 isolates co-producing KPC-2, CTX-M-15, and SHV-28 in the cardiac surgery intensive care unit (CSICU) of a tertiary hospital.Materials and Methods: From November 2019 to August 2020, all non-duplicated CRKP isolates were collected from the CSICU. The VITEK-2 compact system was used for bacterial identification and antimicrobial susceptibility testing. Clinical data were retrieved from electronic case records. All strains were also subjected to antibiotic resistance genes detection. Clonal relationships were analyzed by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE).Results: A total of 28 non-duplicated CRKP isolates were collected, including 23 strains belonging to ST15 and 5 strains belonging to ST11. All ST15 isolates were susceptible to amikacin, tigecycline, polymyxin B and ceftazidime/avibactam, but resistant to carbapenems, cephalosporins, quinolones, tobramycin and gentamicin. The detection of resistant determinants showed that 21 strains of ST15 CRKP co-harboured blaKPC-2, blaCTX-M-15, blaSHV-28, blaTEM-1, blaOXA-1 and aac(6ʹ)-Ib-cr. All the 28 CRKP isolates were classified into five PFGE patterns (A, B, C, D and E), of which type A and B belonged to ST15 and type C, D and E belonged to ST11. PFGE type A was the predominant clonotype of this nosocomial infection and belonged to ST15.Conclusion: K. pneumoniae ST15 co-producing KPC-2, CTX-M-15, SHV-28, TEM-1, OXA-1 and aac(6ʹ)-Ib-cr is the predominant clone spread in the CSICU. Surveillance and comprehensive infection control measures should be strengthened in clinical practice.Keywords: Klebsiella pneumoniae ST15, carbapenem-resistant, KPC-2, multidrug resistance, resistance gene

Liping Zou, Guiping Cheng, Chengcheng Xu, Heyu Liu, Yingying Wang, Nianyu Li, Xiaorong Fan, Changhong Zhu, Wei Xia Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Wei XiaInstitute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of ChinaTel/Fax +86 27 8369 2651Email tjxiawei@hust.edu.cnPurpose: The toxicity of copper nanoparticle (CuNP) exposure in the ovaries has attracted attention recently, but the precise molecular mechanism involved requires further investigation. We investigated the cytotoxicity of CuNPs in ovarian granulosa cells and the protective effect of heme oxygenase 1 (HO-1) against CuNP-induced damage.Methods: Human ovarian granulosa cells (COV434) were treated with CuNPs, and cytotoxicity was evaluated using Cell Counting Kit-8 and flow cytometry assays. Oxidative stress was identified using biochemical markers of oxidation and anti-oxidation. The protein levels of mitogen-activated protein kinase 14 (MAPK14), phospho-MAPK14, nuclear factor erythroid 2-related factor 2 (Nrf2), and HO-1 were measured by immunoblotting. Subsequently, for oxidative stress parameter detection, the cells were pre-treated with hemin to induce HO-1 expression prior to CuNP treatment.Results: Exposure to CuNPs decreased cell viability and the mitochondrial membrane potential, increased the apoptosis rate, and induced oxidative stress. Furthermore, hemin pretreatment induced HO-1 expression in cells, which partially reduced the accumulation of reactive oxygen species induced by CuNPs and increased the levels of antioxidant enzymes.Conclusion: CuNPs exert cytotoxic effects on human ovarian granulosa cells by inducing oxidative stress, and may induce HO-1 expression via the MAPK14-Nrf2 signaling pathway. Moreover, HO-1 protects against oxidative stress induced by CuNPs.Keywords: copper nanoparticles, cytotoxicity, oxidative stress, heme oxygenase 1

Tao Yang,1,2 Raymond W Lam,2 Jia Huang,1 Yousong Su,1 Jing Liu,2 Xiaorui Yang,1 Lu Yang,1 Na Zhu,3 Guoqing Zhao,4 Ruizhi Mao,1 Rubai Zhou,1 Weiping Xia,5 Hongmei Liu,1 Zuowei Wang,6 Jun Chen,1 Yiru Fang1,7,8 1Clinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada; 3Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Department of Psychology, Provincial Hospital Affiliated to Shandong University, Jinan, People’s Republic of China; 5Department of Medical Psychology, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, People’s Republic of China; 6Division of Mood Disorders, Shanghai Hongkou District Mental Health Center, Shanghai, People’s Republic of China; 7CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, People’s Republic of China; 8Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of ChinaCorrespondence: Yiru FangClinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Room B2409, Building 2, 600 South Wan Ping Road, Shanghai 200030, People’s Republic of ChinaTel +86 139 0199 7089Email yirufang@aliyun.comJun ChenClinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Room B2411, Building 2, 600 South Wan Ping Road, Shanghai 200030, People’s Republic of ChinaTel +86 180 1731 1373Email doctorcj2010@gmail.comBackground: Patients with bipolar disorder (BD) and patients with major depressive disorder (MDD) have relatively specific temperament and structural abnormalities of brain regions related to emotion and cognition. However, the effects of temperament factors on the structure of frontal and temporal cortex is still unclear. The aims of this study were to explore the differences and relationships between temperament characteristics and the gray matter volume of frontal and temporal cortex in patients with BD or MDD.Methods: T1-weighted magnetic resonance imaging (MRI) data, demographic and clinical information were obtained from 279 depressed patients (90 patients with BD, 189 patients with MDD) and 162 healthy controls (HC). Temperament was assessed with the Chinese short version of Temperament Evaluation of Memphis, Pisa and San Diego – Auto questionnaire (TEMPS-A). The Desikan-Killiany atlas was used for yielding gray matter volume by FreeSurfer 6.0 software suite. A total of 22 frontal and temporal regions were chosen as regions of interest (ROIs).Results: Compared with patients with MDD, patients with BD had higher TEMPS-A total scores and scores on cyclothymic, irritable and hyperthymic subscales. The gray matter volume in bilateral rostral middle frontal gyrus (RMFG), left temporal pole and right superior frontal gyrus were reduced in patients with BD. Patients with MDD only had lower gray matter volume in bilateral temporal pole. In the pooled patients, there were negative associations between hyperthymia and gray matter volume in right RMFG.Conclusion: Patients with BD and MDD had different temperament characteristics. The prominent temperament subscales in patients with BD were cyclothymia, irritable and hyperthymia. Patients with greater hyperthymia had lower gray matter volume in right frontal gyrus. Temperament may reflect an endophenotype in patients with mood disorders, especially in BD.Keywords: bipolar disorder, major depressive disorder, temperament, gray matter volume

The sulfur in coal not only influences the coke quality but also pollutes the environment during the combustion. The desulfurization of high organic sulfur coal is a key issue in coal cleaning science. As the pyrolysis has been used in low-rank coal conversion to obtain gas/liquid products and coal char, the desulfurization effects of pyrolysis on the low-rank coal with high organic sulfur requires further studies. This study investigated the desulfurization performance of high organic sulfur low-rank coal by the pyrolysis and the changes in the coal calorific value and sulfur forms during the pyrolysis. The XPS was applied to analyze the changing regulation of sulfur that forms on coal surface. The results indicated certain amount of FeS was newly created during the pyrolysis and high amounts of sulfate sulfur was transferred to pyrite sulfur and formed more FeS2 when compared to the distribution of raw coal. The total sulfur content of coal was reduced from 2.32% for raw coal to 1.68% for 700 °C pyrolysis coal and then the pyrolysis temperature had little effect on the sulfur content. The net calorific value (at constant volume and air-dry basis) was increased from 17.38 kJ for raw coal to 24.35 kJ for 700 °C pyrolysis coal. The pyrolysis temperature of 700 °C may be the best pyrolysis temperature for both low sulfur content and high calorific value.

Yuqiao Xu,1,2 Wenying Xia,1,2 Fang Ni1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of ChinaCorrespondence: Wenying Xia; Fang NiDepartment of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Guangzhou Street No. 300, 210029, People’s Republic of ChinaTel + 86 25-6830-6287Fax + 86 25- 8372-4440Email xiawenying21106891@163.com; 13813972378@163.comAbstract: Cryptococcus neoformans (C. neoformans) is an opportunistic fungal pathogen to humans, which can be acquired from environmental sources. Its most important virulence factor is its polysaccharide capsule, which can be used for diagnostic tests that identify the cryptococcal antigen (CrAg). The CrAg lateral flow assay (LFA) is a dipstick immunochromatographic assay with high sensitivity and specificity; however, several false-negative cases have been reported. Here, we present a case of a false-negative serum CrAg LFA, in which the blood culture from a matched sample was positive for C. neoformans, thus demonstrating the postzone phenomenon.Keywords: Cryptococcus neoformans, lateral flow immunoassay, postzone phenomenon

Huili Bai,1,* Rong Wang,1,2,* Wei Cheng,1 Yifan Shen,1 Haijun Li,2 Wei Xia,1 Zhenglin Ding,3,* Yuhong Zhang1,* 1The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Laboratory Medicine, Guangyuan Central Hospital, Guangyuan, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, The People’s Hospital of Nanchuan, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuhong Zhang; Zhenglin Ding Email zhangyuhong0730@126.com; 782829997@qq.comBackground: Microsatellite instability (MSI) is one of the most important molecular characteristics of colorectal cancer (CRC), which mainly results from defective DNA mismatch repair (MMR). This study was performed to investigate the concordance between deficient MMR and MSI testing, and to evaluate the association of these two results with clinicopathological characteristics in Chinese CRC patients.Methods: A total of 738 CRC patients were included. Tumor tissues and paired peripheral blood specimens were obtained. Screening for MMR was investigated using immunohistochemical (IHC) technique, and multiple polymerase chain reaction-capillary electrophoresis (PCR-CE) method was performed to detect the MSI status. All clinicopathological data, immunohistochemistry and microsatellite instability analyses were then statistically analyzed.Results: Of the 738 (17.75%) CRC patients, 131 expressed as deficient mismatch repair (dMMR) status, and postmeiotic segregation increased 2 (PMS2) deficiency was the most frequent deficiency among these four MMR proteins. MSI-high (MSI-H) status occurred in 74 of the 738 (10.03%) CRC patients, 55 of whom showed instability at all six mononucleotides repeat markers. dMMR was significantly associated with MSI-H and moderate concordance was observed between IHC and PCR-CE in evaluating deficient MMR/MSI through Kappa test. Statistically, dMMR was significantly associated with younger age, right-sided colon and poor differentiation. MSI-H was associated with younger age, right-sided colon, poor differentiation, mucinous type and tumor, node, metastasis (TNM) stage II.Conclusion: A moderate concordance between deficient MMR and MSI testing indicates that both IHC and PCR-CE methods should be routinely tested to provide reliable data for clinical treatment decisions.Keywords: deficient mismatch repair, microsatellite instability, clinicopathological features, colorectal cancer

Xiaohui Zhang,1,2,* Yanfei Lu,1,2,* Huimin Qian,3 Genyan Liu,1,2 Yaning Mei,1,2 Fei Jin,1,2 Wenying Xia,1,2 Fang Ni1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China; 3Key Laboratory of Enteric Pathogenic Microbiology of Ministry of Health, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenying Xia; Fang NiDepartment of Laboratory Medicine, Jiangsu Province Hospital, Guangzhou Street No. 300, 210029, People’s Republic of ChinaTel +8625-6830-6287Fax +8625-8372-4440Email xiawenying21106891@163.com; 13813972378@163.comAbstract: Non-O1, non-O139 Vibrio cholerae (NOVC) does not agglutinate with O1 and O139 antisera and can cause intestinal and extraintestinal infections in immunocompromised individuals. NOVC bacteremia has the highest mortality among NOVC infections, and the number of reports has increased in recent years. Nevertheless, some clinicians are poorly informed about this disease. Herein, we describe a documented case of NOVC bacteremia in a male patient with impaired liver function. Blood cultures revealed the presence of V. cholerae, but this strain showed self-coagulation on the serum agglutination test. To our knowledge, this phenomenon is unreported among cases of NOVC infections. This pathogen was finally confirmed as NOVC via PCR. Because the patient worked as a garbage transporter, he was likely infected after contact with contaminated water through a foot wound. The patient developed septic shock shortly after admission and ultimately died from the illness. This paper reviews 23 cases of NOVC bacteremia from 2015 to 2019. To improve the accuracy of identifying NOVC and analyze its virulence factors, relevant detection methods were reviewed and analyzed.Keywords: bacteremia, non-O1/non-O139 Vibrio cholerae, V. cholerae, virulence factors

Yanfei Lu, 1, 2,* Wenying Xia, 1, 2,* Xiaohui Zhang, 1, 2,* Fang Ni, 1, 2 Yaning Mei 1, 2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fang Ni; Yaning MeiDepartment of Laboratory Medicine, Jiangsu Province Hospital, Guangzhou Street No. 300, Nanjing 210029, People’s Republic of ChinaTel +86 25-6830-6287Fax +86 25- 8372-4440Email 13813972378@163.com; myn303@163.comAbstract: The genus Myroides are gram-negative bacilli which are completely aerobic, non-motile, non-fermenting and yellow-pigmented with a characteristic fruity odor. Myroides species are widely found in the environment, especially in water and soil, and are considered as low-grade opportunistic pathogens for humans. Myroides infections are most commonly seen in immunocompromised patients and only rarely occur in immunocompetent patients. We here report the first confirmed catheter-related bloodstream infection (CRBSI) due to Myroides odoratimimus in an immunocompetent patient. We also review the literature related to Myroides infections.Keywords: Myroides odoratimimus, CRBSI, immunocompetent patient

Pengfei Sun,1,2,* Wenying Xia,1,2,* Genyan Liu,1,2 Xu Huang,1,2 Chenjie Tang,1,2 Chengcheng Liu,1,2 Yuqiao Xu,1,2 Fang Ni,1,2 Yaning Mei,1,2 Shiyang Pan1,2 1Department of Laboratory Medicine, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China; 2National Key Clinical Department of Laboratory Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Genyan LiuDepartment of Laboratory Medicine, Jiangsu Province Hospital, Guangzhou Street No. 300, Nanjing 210029, People’s Republic of ChinaTel +8625 6830 7332Fax +8625 8372 4440Email liugenyan@njmu.edu.cnPurpose: The emergence and spread of carbapenem-resistant Enterobacteriaceae deserves special concern worldwide. Unlike the epidemiological characteristics reported in other studies, we found that the production of New Delhi metallo-β-lactamase 5 was the main mechanism for the resistance of Escherichia coli to carbapenems.Methods: All carbapenem-resistant strains were collected from July 2017 to July 2018 of the First Affiliated Hospital of Nanjing Medical University. The presence of carbapenemase-encoding genes was detected using PCR and gene sequencing. Genetic relatedness of the blaNDM-5-positive E. coli strains was determined with PFGE and MLST. Susceptibility profiles were measured with broth microdilution method and E-test strips. Transferability features of blaNDM-5 gene were assessed by conjugation experiments, S1-PFGE, southern blotting and PCR-based replicon typing methods. The genetic structures surrounding blaNDM-5 were acquired by whole genome sequencing and PCR mapping.Results: Among the 28 carbapenem-resistant E. coli strains, 18 (64%) were verified as NDM-5 producers. The 18 blaNDM-5-positive E. coli strains showed high resistance to most antibiotics, but 100% were sensitive to colistin and tigecycline. In addition, the 18 blaNDM-5-positive E. coli strains belonged to eight STs, among which ST167, ST410 and ST101 were found to cause clonal spread in the hospital. Further studies found that the blaNDM-5 gene was located on an IncX3-type plasmid, and all plasmids harbored an IS3000-ΔISAba125-IS5-blaNDM-5-bleMBL-trpF-dsbC-IS26 structure.Conclusion: The clonal spread of blaNDM-5-positive E. coli strains and horizontal dissemination via the pNDM-MGR 194-like plasmids should draw more attention. Appropriate infection control operations should be performed to prevent the further spread of blaNDM-5.Keywords: Escherichia coli, carbapenem-resistant Enterobacteriaceae, New Delhi metallo-β-lactamase, blaNDM-5, IncX3 type plasmid

Mengchun Chen,1,2 Ledan Wang,1 Fang Wang,1 Fan Li,3 Weiliang Xia,3 Hongchen Gu,3 Yijie Chen11Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 3State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200032, People’s Republic of ChinaPurpose: Combining siRNA and other chemotherapeutic agents into one nanocarrier can overcome the multidrug resistance (MDR) phenomenon by synergistically MDR relative genes silencing and elevated chemotherapeutic activity. Most of these systems are typically fabricated through complicated procedures, which involves materials preparation, drug loading and modifications. Herein, the purpose of this study is to develop a new and fast co-delivery system of siRNA and doxorubicin for potentially synergistic cancer treatment.Methods: The co-delivery system is constructed conveniently by a stable complex consisting of doxorubicin bound to siRNA via intercalation firstly, followed by interacting with (3-Aminopropyl)triethoxysilane (APTES) electrostatically and Tetraethyl orthosilicate (TEOS) co-condensed, and the characterizations of the resultant nanocarrier are also investigated. Furthermore, this study evaluates the synergistic anti-cancer efficacy in MCF-7/MDR cells after treatment of siRNA and doxorubicin ‘two in one’ nanocarriers.Results: We establish a new and fast method to craft a co-delivery system of siRNA and doxorubicin with controllable and nearly uniform size, and the entire fabrication process only costs in about 10 minutes. The resultant co-delivery system presents high loading capacities of siRNA and doxorubicin, and the encapsulated doxorubicin plays a pH-responsive control release. Further, biological functionality tests of the synthesized co-delivery nanocarriers show high inhibition of P-gp protein encoded by MDR-1 gene in MCF-7/MDR cells (a variant of human breast cancer cell line with drug resistance) after transfection of these nanocarriers carrying MDR-1 siRNA and doxorubicin simultaneously, which sensitize the MCF-7/MDR cells to doxorubicin, overall leading to improved cell suppression.Conclusion: Collectively, this co-delivery system not only serves as potent therapeutics for synergistic cancer therapy, it also may facilitate the bench-to-bedside translation of combinatorial delivery system as a robust drug nanocarrier by allowing for fabricating a simply and fast nanocarrier for co-delivery of siRNA and doxorubicin with predictable high production rate.Keywords: siRNA, doxorubicin, codelivery system, multidrug resistance, cancer therapy

Yichun Wang,1 Liyang Zhu,1 Wanli Xia,2 Fan Wang1 1Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P.R. China; 2Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, P.R. China Abstract: The lymphatic drainage of the inner layers (mucosa and submucosa) and the outer layers (muscularispropria and adventitia) of the thoracic esophagus is different. Longitudinal lymphatic vessels and long drainage territory in the submucosa and lamina propria should be the bases for bidirectional drainage and direct drainage to thoracic duct and extramural lymph nodes (LN). The submucosal vessels for direct extramural drainage are usually thick while lymphatic communication between the submucosa and intermuscular area is usually not clearly found, which does not facilitate transversal drainage to paraesophageal LN from submucosa. The right paratracheal lymphatic chain (PLC) is well developed while the left PLC is poorly developed. Direct drainage to the right recurrent laryngeal nerve LN and subcarinal LN from submucosa has been verified. Clinical data show that lymph node metastasis (LNM) is frequently present in the lower neck, upper mediastinum, and perigastric area, even for early-stage thoracic esophageal cancer (EC). The lymph node metastasis rate (LNMR) varies mainly according to the tumor location and depth of tumor invasion. However, there are some crucial LN for extramural relay which have a high LNMR, such as cervical paraesophageal LN, recurrent laryngeal nerve LN, subcarinal LN, LN along the left gastric artery, lesser curvature LN, and paracardial LN. Metastasis of thoracic paraesophageal LN seems to be a sign of more advanced EC. This review gives us a better understanding about the LNM and provides more information for treatments of thoracic EC. Keywords: esophageal carcinoma, lymphatic, lymph node metastasis,lymphadenectomy, radiotherapy

Yu-Chen Chen,1,2 Huiyou Chen,2 Fan Bo,2 Jin-Jing Xu,3 Yi Deng,3 Han Lv,4 Yuexin Cai,5 Wenqing Xia,6 Xindao Yin,2 Jian-Ping Gu,2 Guangming Lu1 1Department of Medical Imaging, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China; 2Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; 3Department of Otolaryngology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; 4Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China; 5Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; 6Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China Purpose: The default mode network (DMN) has been confirmed to be involved in chronic tinnitus perception. Tinnitus distress may be associated with abnormal functional connectivity (FC) within the DMN regions. The goal of this study was to determine whether tinnitus disrupted the FC patterns within the DMN as measured by using resting-state functional magnetic resonance imaging approach. Patients and methods: Resting-state functional magnetic resonance imaging scans were acquired from 40 chronic bilateral tinnitus patients and 41 healthy controls. Both were age, sex, and education well-matched with normal hearing. Two important DMN regions, the anterior cingulate cortex and posterior cingulate cortex, were chosen as seed regions to detect the FC patterns within the DMN and then determine whether these changes were linked to clinical measures of tinnitus such as tinnitus duration and tinnitus severity. Results: Compared with healthy controls, chronic tinnitus patients manifested significantly enhanced FC between the anterior cingulate cortex and left precuneus, which was correlated with the tinnitus duration (r=0.451, p=0.007). Moreover, enhanced FC between the posterior cingulate cortex and right medial prefrontal cortex in tinnitus patients was positively correlated with the tinnitus distress (r=0.411, p=0.014). Conclusion: Chronic tinnitus patients showed disrupted FC patterns within the DMN regions which are correlated with tinnitus distress. Increased resting-state connectivity pattern of the DMN may play a pivotal role in neuropathological features underlying chronic tinnitus. Keywords: tinnitus, anterior cingulate cortex, posterior cingulate cortex, default mode network, resting-state fMRI

Li-Xia Hu,1,* Shi-Fu Hu,2,* Meng Rao,2,3 Jing Yang,2,4 Hui Lei,2,5 Zhuo Duan,6 Wei Xia,2,7 Changhong Zhu2,7 1Department of Histology and Embryology, Preclinical Medicine College, Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China; 2Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 3Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 4Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 5Department of Gynaecology and Obstetrics, Taikang Tongji Hospital, Wuhan, Hubei, People’s Republic of China; 6Dayu Medical Devices Co., Ltd., Jingzhou, Hubei, People’s Republic of China; 7Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Introduction: The physiologic safety of devices and materials intended for clinical implantation should be evaluated. This study, a logical extension of our previous work, aimed to investigate the safety of a novel contraceptive device, the copper/low-density polyethylene nanocomposite intrauterine device (nano-Cu/LDPE IUD), through studies of its potential toxicity after acute and subchronic administration in mice and rats. Methods: For the acute toxicity study, single 50 mL/kg doses of nano-Cu/LDPE IUD extracts were administered to mice via intravenous or intraperitoneal injection. General behavioral adverse effects, mortality, and body weights were evaluated for up to 72 hours. In the 13-week subchronic toxicity study, the nano-Cu/LDPE composite with 10-fold higher than the standard clinical dose was implanted subcutaneously into the dorsal skin of Wistar rats. The control group underwent a sham procedure without material insertion. Results: During all acute study observation times, the biologic reactions of the mice in the nano-Cu/LDPE group did not differ from those observed in the control group. The groups did not differ statistically in terms of body weight gain, and no macroscopic changes were observed in any organs. In the subchronic study, no clinical signs of toxicity or mortality were observed in either the nano-Cu/LDPE or control group during the 13-week period. The nano-Cu/LDPE composite did not cause any alterations in body weight, food consumption, hematologic and biochemical parameters, or organ weight relative to the control for any observed sample group. Histopathologic examinations of the organs revealed normal architecture, indicating that the inserted material did not cause morphologic disturbances in the rats. Conclusion: Overall, the results indicate that the nano-Cu/LDPE IUD did not induce systemic toxicity under experimental conditions of the recommended standard practices, suggesting that the novel material IUD is safe and feasible for future contraceptive applications. Keywords: intrauterine device, copper/low-density polyethylene nanocomposite intrauterine device, acute toxicity, subchronic toxicity

Weiping Xia,1,2 Rubai Zhou,1 Guoqing Zhao,1 Fan Wang,1 Ruizhi Mao,1 Daihui Peng,1 Tao Yang,1 Zuowei Wang,1,3 Jun Chen,1 Yiru Fang1,4,5 1Division of Mood Disorders, Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Medical Psychology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Mood Disorder Department, Hongkou District Mental Health Center of Shanghai, Shanghai, People’s Republic of China; 4State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, CAS, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China Background: Almost half of patients with major depressive disorder (MDD) also have clinically meaningful levels of anxiety. Anxious depression is a distinct clinical subtype of MDD, which has poor response to pharmacotherapy; however, the neural mechanisms behind are largely unknown. In the present study, we explored the white matter (WM) integrity traits of anxious depression in first-episode and medication-free (medication-naïve and medication washout) Chinese young adult patients by detecting differences in diffusion tensor imaging (DTI) with the tract-based spatial statistics (TBSS) method.Subjects and methods: DTI was obtained from 39 first-episode, medication-free anxious depressive patients, 45 nonanxious depressive patients, and 50 demographically similar healthy controls. All subjects underwent clinical assessments. TBSS was carried out to investigate the difference in WM integrity among three groups within DTI parameter maps. WM integrity was measured using fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD). The correlations between WM integrity and clinical features were also computed.Results: When compared with nonanxious patients, lower FA values in anxious depressive patients were found in multiple regions of the brain, mainly involving left uncinate fasciculus (UF), superior longitudinal fasciculus (SLF), and forceps major and minor. Higher RD in forceps major and minor and SLF were also detected. The decreased FA values and increased RD values correlated with both anxiety level and depression level in the pooled depressive group.Conclusion: The anxious depressive patients had more abnormalities in WM integrity at the early phase than the nonanxious group. Alternations in WM integrity in fiber pathways, including SLF, UF, and forceps major and minor, may play a critical role in the neuropathology of anxious depression and might help to identify anxious MDD from nonanxious MDD. Further study with larger sample size, larger age range, and longitudinal design is needed to confer a robust inference to better understand the dynamic neurological change and neuropathology of WM integrity in anxious MDD. Keywords: diffusion tensor imaging, anxious depression, tract-based spatial statistics, micro-structure of whiter matter

Kai Zhang,* Ruoxi Hong,* Fei Xu, Wen Xia, Lee Kaping, Ge Qin, Qiufan Zheng, Qianyi Lu, Yan Xia Shi, Zhong Yu Yuan, Shusen Wang Sun Yat-Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Background: The clinical implication of plasma ESR1 mutations in the estrogen receptor (ER)-positive metastatic breast cancer (MBC) patients who had progressed after prior aromatase inhibitor (AI)-based therapy remains controversial. We conducted the first meta-analysis to investigate the prognostic significance and predictive role of plasma ESR1 mutations in MBC patients with prior exposure to AI therapy. Materials and methods: We searched PubMed, Embase, and Cochrane Library databases for eligible studies. Meta-analysis was conducted to calculate combined hazard ratios (HRs) with 95% CIs for progression-free survival (PFS) and overall survival (OS). Subgroup and sensitivity analyses were also performed. Results: This study enrolled a total of 1,530 patients with ER-positive MBC cases from six articles, including 429 ESR1 mutation carriers (28.04%). Meta-analysis demonstrated that plasma ESR1 mutation carriers had significantly worse PFS (HR: 1.40, 95% CI: 1.17–1.66; P

Qixing Mao,1–4,* Louqian Zhang,1–3,* Yi Zhang,1,* Gaochao Dong,1,3 Yao Yang,4 Wenjie Xia,1–4 Bing Chen,1–3 Weidong Ma,1–3 Jianzhong Hu,4 Feng Jiang,1,3 Lin Xu1,3 1Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China; 2The Fourth Clinical College of Nanjing Medical University, Nanjing, China; 3Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China; 4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA *These authors contributed equally to this work Background: A substantial increase in the number of non-smoking lung adenocarcinoma (LAC) patients has been drawing extensive attention in the past decade. However, effective biomarkers, which could guide the precise treatment, are still limited for identifying high-risk patients. Here, we provide a network-based signature to predict the survival of non-smoking LAC.Materials and methods: Gene expression profiles were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus. Significant gene co-expression networks and hub genes were identified by Weighted Gene Co-expression Network Analysis. Potential mechanisms and pathways of co-expression networks were analyzed by Gene Ontology. The predictive signature was constructed by penalized Cox regression analysis and tested in two independent datasets.Results: Two distinct co-expression modules were significantly correlated with the non-smoking status across 4 Gene Expression Omnibus datasets. Gene Ontology revealed that nuclear division and cell cycle pathways were main mechanisms of the blue module and that genes in the turquoise module were involved in lymphocyte activation and cell adhesion pathways. Seventeen genes were selected from hub genes at an optimal lambda value and built the prognostic signature. The prognostic signature distinguished the survival of non-smoking LAC (training: hazard ratio [HR]=3.696, 95% CI: 2.025–6.748, P

Yahui Yu,1–3,* Liangru Ke,1,4,* Xing Lv,1,2 Yi hong Ling,1,5 Jiabin Lu,1,5 Hu Liang,1,2 Wenze Qiu,1,2 Xinjun Huang,1,2 Guoying Liu,1,2 Wangzhong Li,1,2 Xiang Guo,1,2 Weixiong Xia,1,2 Yanqun Xiang1,2 1Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, Guangdong, People’s Republic of China; 2Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 3Department of Radiation Oncology, Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Diagnostic Radiology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 5Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Purpose: Tumor stroma cells play an important role in the carcinogenesis and progression of cancer. The aim of the present investigation was to explore the predictive role of carcinoma-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in nasopharyngeal carcinoma (NPC). Patients and methods: The densities of CAFs and TAMs were measured by immunohistochemistry staining for α-smooth muscle actin (α-SMA), CD68, and CD163 in two sets of tissue microarrays including 260 pretreatment NPC tissues, that is, a training test comprising of 152 patients and a validation set comprising of 108 patients. Chi-square tests were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan–Meier method and compared with log-rank tests. Cox proportional hazards models were used to identify significant independent variables. Results: Patients older than 50 years showed a lower expression of CD68, and there was a positive relationship between the densities of CAFs and CD163+ TAMs (p=0.001). In the multivariate analysis of the training test, both α-SMA and CD163 were independent prognostic factors for overall survival and progression-free survival (all p

Wenjie Xia,1,2,* Anpeng Wang,1,2,* Meng Jin,3,* Qixing Mao,1,2 Wenying Xia,4 Gaochao Dong,1 Bing Chen,1,2 Weidong Ma,1,2 Lin Xu,1 Feng Jiang1 1Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, 2Department of Oncology, Fourth Clinical College of Nanjing Medical University, Nanjing, 3Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 4Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Non-small cell lung cancer (NSCLC) prognosis and risk of lymph node positivity (LN+) are reference points for reasonable treatments. The aim of the current study was to investigate the effect of age on LN+ and NSCLC death. Data from the Surveillance, Epidemiology, and End Results (SEER) registry were used to identify 82,253 patients with NSCLC diagnosed between 1988 and 2008. All the patients underwent standard lung cancer surgery with lymph node examination. Demographic and clinicopathological parameters were extracted and compared among each age group. Impact of age on LN+ and NSCLC death was evaluated by the Cochran–Armitage trend test and logistic univariate and multivariate analyses for all T stages. Overall, 22,711 (27.60%) patients of the entirety had lymph node metastasis and 28,968 (35.22%) patients died of NSCLC within 5 years. With the increase in age, LN+ rates decreased regardless of T stages (P

Jing Yang,1,* Shifu Hu,1,* Meng Rao,1 Lixia Hu,2 Hui Lei,1 Yanqing Wu,1 Yingying Wang,1 Dandan Ke,1 Wei Xia,1,3 Chang-hong Zhu1,3 1Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 2Department of Histology and Embryology, Preclinical Medicine College, Xinxiang Medical University, Henan Province, Xinxiang, 3Reproductive Medicine Center, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work Abstract: Numerous studies have reported the accumulation of copper nanoparticles (Cu NPs) in organs and the corresponding damage, although whether Cu NPs can be translocated to the ovaries and their ovarian toxicity are still unknown. In this study, three groups of female rats were injected with 3.12, 6.25, or 12.5 mg/kg Cu NPs for 14 consecutive days. The pathological changes, hormone levels, apoptosis and apoptotic proteins, oxidative stress, and gene expression characteristics in the ovaries were then investigated. The results demonstrated that the Cu NPs exhibited obvious accumulation in the rat ovaries, leading to ovarian injury, an imbalance of sex hormones, and ovarian cell apoptosis. Cu NP exposure activated caspase 3, caspase 8, caspase 9, and tBid, decreased the protein levels of Bcl-2, increased the expression levels of the proteins Bax and cytochrome c, and promoted malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) reduction. Furthermore, gene microarray analysis showed that Cu NPs (12.5 mg/kg/d) caused 321 differentially expressed genes. Of these, 180 and 141 genes were upregulated and downregulated, respectively. Hsd17b1, Hsd3b1, Hsd3b6, and Hsd3b were involved in steroid and hormone metabolism, whereas Mt3 and Cebpb were associated with apoptosis. Overall, these findings provide strong evidence that Cu NPs trigger both intrinsic and extrinsic apoptotic pathways and regulate key ovarian genes in oxidative stress-mediated ovarian dysfunction. Keywords: Cu NPs, apoptosis, oxidative stress, microarray

Si-Si Zhang,1,* Wei-Ting Xia,1,* Jie Xu,2 He-Lin Xu,2 Cui-Tao Lu,2 Ying-Zheng Zhao,2,* Xue-Qing Wu1,* 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang, People’s Republic of China *These authors contributed equally to this work Abstract: Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E2) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat’s endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E2-HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E2-HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E2-HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E2-HP hydrogel showed a prolonged release of E2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E2-HP hydrogel group. We also demonstrated that E2-HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E2 into the injured endometrium. Therapeutic strategies targeting ER stress using E2-HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions. Keywords: intrauterine adhesions, 17β-estradiol, heparin-poloxamer hydrogel, endometrium regeneration, endoplasmic reticulum stress

Yi Qing,1,* Qing Li,1,* Tao Ren,1 Wei Xia,1 Yu Peng,1 Gao-Lei Liu,2 Hao Luo,1 Yu-Xin Yang,1 Xiao-Yan Dai,1 Shu-Feng Zhou,3 Dong Wang1 1Cancer Center, 2Urological Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China; 3Department of pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA *These authors contributed equally to this work Introduction: Gastric cancer is a fatal malignancy with a rising incidence rate. Effective methods for early diagnosis, monitoring metastasis, and prognosis are currently unavailable for gastric cancer. In this study, we examined the association of programmed death ligand-1 (PD-L1) and apurinic/apyrimidinic endonuclease 1 (APE1) expression with the prognosis of gastric cancer. Methods: The expressions of PD-L1 and APE1 were detected by immunohistochemistry in 107 cases of human gastric carcinoma. The correlation of PD-L1 and APE1 expression with the clinicopathologic features of gastric carcinoma was analyzed by SPSS version 19.0. Results: The positive expression rates of PD-L1 and APE1 in gastric cancer tissues were 50.5% (54/107) and 86.9% (93/107), respectively. PD-L1 and APE1 positive expressions were significantly associated with depth of invasion, lymph node metastasis, pathological type, overall survival, and higher T stage. Furthermore, the expression of PD-L1 in highly differentiated gastric cancers was higher than that in poorly differentiated cancers (P=0.008). Moreover, the expression of APE1 and PD-L1 in gastric cancers was positively correlated (r=0.336, P