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Liping Chen,1 Tongwei Xiang,2 Jing Xing,2 Xinan Lu,2 Shan Wei,2 Huaying Wang,2 Jipeng Li,1 Wanjun Yu2 1Department of Central Laboratory, The Affiliated People’s Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated People’s Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Liping Chen; Wanjun Yu, Email Chenliliy@outlook.com; nbyuwanjun@163.comBackground: It has been increasingly recognized that circular RNAs (circRNAs) act as a pivotal factor in the onset and progression of human malignancies. Yet, the specific activities and mechanistic roles of these RNAs in the context of lung adenocarcinoma (LUAD) are not fully understood.Methods: Microarray analysis identified a novel LUAD-associated circular RNA, termed hsa_circ_0006357 (also referred to as circEZH2). Reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was utilized for the analysis of circEZH2 expression in tissues and cell lines. The characteristics of circEZH2 were verified by RNase R treatment and fluorescence in situ hybridization (FISH) assays. The functions of circEZH2 were detected by Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays. The molecular mechanism of circEZH2 was clarified through bioinformatics analysis as well as RNA pulldown, dual-luciferase reporter, RT-qPCR, and immunoblotting assays. The role of circEZH2 in vivo was investigated using a xenograft model.Results: This investigation revealed that circEZH2 expression was elevated in LUAD cell lines and tumor samples. This elevation was associated with enhanced cell proliferation, migratory capacity, epithelial–mesenchymal transition (EMT), and invasion in vitro. Conversely, silencing of circEZH2 in vivo resulted in a notable decrease in LUAD tumorigenesis, whereas its overexpression led to the opposite effects. Mechanistically, circEZH2 appeared to act as a sponge for miR-495-3p, facilitating the upregulation of tumor protein D52 (TPD52) and triggering the nuclear factor kappa B (NF-κB) signaling pathway, thus contributing to the progression of LUAD.Conclusion: These findings indicate that circEZH2 may function as a competitive endogenous RNA (ceRNA), driving the progression of LUAD by manipulating the miR-495-3p/TPD52 axis and activating the NF-κB pathway.Keywords: lung adenocarcinoma, circular RNA, nuclear factor kappa B, tumor protein D52, miR-495-3p

Na Chen,1,2 Xuben Yu,3 Lu Li,1 Ping Yang,1 Rong Dong,1,4 Yizhen Huang,1,5 Xiao Ling,1,6 Qiaoqiao Shentu,1,7 Wenqiao Yu,8 Saiping Jiang1 1Department of Clinical Pharmaceutical, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou, People’s Republic of China; 3Department of Pharmacy, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Department of Pharmacy, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 6Department of Pharmacy, The People’s Hospital of Yuhuan, Taizhou, People’s Republic of China; 7Department of Pharmacy, Dongyang Red Cross Hospital, Jinhua, People’s Republic of China; 8Department of Hepatobiliary and Pancreatic Surgery and Intensive Care Unit, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Saiping Jiang; Wenqiao Yu, Email j5145@zju.edu.cn; yuwenqiao1980@zju.edu.cnBackground: The population pharmacokinetics of nirmatrelvir/ritonavir (NIR/RIT) has not yet been described for critically ill adult patient.Purpose: This was a prospective observational population pharmacokinetic study of nirmatrelvir/ritonavir (NIR/RIT) in critically ill adult patients and identify optimal dosing regimens.Patients and Methods: The prescription of NIR/RIT is determined by the attending physician and ranges from 150mg/100mg to 300mg/100mg twice a day. Two to three serial blood samples were collected for each patient after the second doses. We developed and validated PK model for plasma NIR and plasma RIT. Monte Carlo dosing simulations were performed to assess target attainment.Results: We analyzed 89 plasma samples from 31 adult patients. The data were best described by a one-compartment model. Among the covariates tested on pharmacokinetic parameters, creatinine clearance (CrCL) and area under curve (AUC) of RIT had a significant effect on apparent clearance (CL/F) of NIR. Mean (SD) parameters estimates for the absorption rate constant (Ka), apparent distribution (V/F) and CL/F were 0.42 (0.10) h− 1. 36.5 (8.5) L, 3.6 (0.26) L/h, respectively. Dosing simulations showed that the target in vitro 90% effective concentration (EC90) was more likely to be achieved twice a day than once a day at the same daily dose of NIR. High CrCL, low AUC of RIT were associated with a reduced likelihood of NIR reaching the target EC90.Conclusion: Based on our dosing simulations, the initial dosage of NIR/RIT was 300mg/100mg twice a day in critically ill patients with CrCL> 45 mL/min; When CrCL in critically ill patients is between 15 and 45 mL/min, NIR/RIT is 150mg/100mg twice a day. The maintenance dose is adjusted according to CrCL and AUC of RIT, with the dosages varying between 75mg/100mg and 300mg/100mg.Keywords: nirmatrelvir, ritonavir, pharmacokinetics, critically ill, creatinine clearance

Kaifei Chu,1,2,* Jie Liu,2,* Xu Zhang,1,2 Minran Wang,1 Wanping Yu,1 Yuyue Chen,1 Lingling Xu,2 Geng Yang,1 Naru Zhang,1 Tiejun Zhao1,2 1Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, People’s Republic of China; 2College of Life Sciences, Zhejiang Normal University, Jinhua, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tiejun Zhao; Naru Zhang, Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, Zhejiang, 310015, People’s Republic of China, Email tjzhao@hzcu.edu.cn; zhangnr@hzcu.edu.cnAbstract: Plant-derived exosome-like nanovesicles (PDNVs) are small nanoscale vesicles containing lipids, RNAs, proteins and some plant natural products secreted by plant cells. Over the last decade, PDNVs have garnered significant interest due to its exceptional therapeutic benefits in the treatment of various diseases. Herbal medicine, as a medicinal plant, plays an important role in the treatment of diseases including cancer. Especially in recent years, the function of herbal medicine derived exosome-like nanovesicles (HMDNVs) in the treatment of cancer has been widely concerned, and has become a research hotspot of nanomedicine. In this review, the biological characteristics, functions and the therapeutic advantages of PDNVs are reviewed, as well as the recent achievements and research progress of HMDNVs in cancer treatment, demonstrating its enormous promise as a cancer therapy, and new insights are provided for future research and development of anti-tumor drugs.Keywords: herbal medicine, plant-derived exosome-like nanovesicles, extracellular vesicles, cancer treatment, nanomedicine

Yanmeng Sun,1,2,* Zheng Li,1,2,* Yanfang Li,3 Chunyan Zhang,1,2 Mengyuan Wang,1,2 Wenwen Yu,1,2 Guohua Liu,2,3 Shifu Wang1,2 1Department of Microbiology Laboratory, Children’s Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Microbiology Laboratory, Shandong Provincial Clinical Research Center for Children’s Health and Disease, Jinan, Shandong, People’s Republic of China; 3Department of Neonatology, Children’s Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shifu Wang, Email wshfu709@163.comAbstract: Anaerobic bacterial meningitis is a serious infection of the central nervous system (CNS) that leads to severe neurological complications, resulting in high levels of disability and mortality worldwide. However, accurately diagnosing and isolating the responsible pathogens remains challenging due to the difficulty in culturing anaerobic bacteria, as they require harsh anaerobic culture conditions. Anaerobic bacteria have rarely been reported in meningitis, especially in children. This report details the first infant with anaerobic meningitis caused by Prevotella bivia. Additionally, we present a case of infant anaerobic meningitis caused by P. bivia, detected using metagenomics next-generation sequencing (mNGS). Our clinical experience highlights the importance of early identification of Prevotella spp. through mNGS and anaerobic culture, the effectiveness of antimicrobial medications, and the timely implementation of carefully planned precision therapeutic regimens. Furthermore, we have conducted a comprehensive review of 10 cases of Prevotella spp. infection, summarized their clinical and laboratory examination characteristics, and identified their commonalities.Keywords: Prevotella bivia, anaerobic meningitis, infant

Weifei Yu,1,&ast; Jingxia Qiu,2,&ast; Ximing Jiang,2 Haofen Xie,2 Zejun Cai,2 Bin Yang2 1Ningbo Hospital of Traditional Chinese Medicine, Ningbo, 315000, People’s Republic of China; 2The First Affiliated Hospital of Ningbo University(Yuehu Courtyard), Ningbo, 315000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haofen Xie, The First Affiliated Hospital of Ningbo University(Yuehu Courtyard), No. 59 of Liuting Street, Haishu District, Ningbo, 315010, People’s Republic of China, Tel +86 13867889859, Email xihfff2022@126.comAim: To investigate the grip strength of older patients with gastrointestinal tumours and analyse its explanatory factors.Methods: A total of 170 older patients with gastrointestinal tumours admitted to the Gastrointestinal Surgery Department of a Grade-III hospital in the Zhejiang province from January 2022 to December 2022 were selected as the investigation participants. Among them, there were 102 cases of gastric cancer (60.0%) and 68 cases of colon cancer (40.0%). There were 110 male patients (64.7%) and 60 female patients (35.3%), with patient ages ranging between 64 and 82 years old. A cross-sectional survey was conducted using a general data questionnaire, grip apparatus and the Nutritional Risk Screening 2002 (NRS-2002) score. Multiple linear regression was used to analyse the explanatory factors on the grip strength of older patients with gastrointestinal tumours.Results: The grip strength of older patients with gastrointestinal tumours was 25.3± 5.3 kg. Multiple linear regression analysis showed that gender, age, disease, body mass index (BMI), albumin concentration and the NRS-2002 score were the main explanatory factors on grip strength (P< 0.05).Conclusion: Grip strength was lower in older patients with gastrointestinal tumours and was lower in females, those aged ≥ 70 years, patients with colorectal cancer, individuals with a BMI of < 18.5, those with an albumin concentration of < 35g/l and those with an NRS2002 score of ≥ 3. Clinical staff should dynamically evaluate the level of grip strength in patients with gastrointestinal tumors and develop individualized interventions based on the related explanatory factors.Keywords: gastrointestinal tumour, grip strength, analysis of explanatory factors, nursing

Weihua Yu,&ast; Jionghuang Chen,&ast; Shengxi Jin, Xiaoxiao Fan, Xiujun Cai Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiujun Cai, Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, People’s Republic of China, Tel/Fax +86-571-86006617, Email srrsh_cxj@zju.edu.cnBackground: Obesity is reaching epidemic proportions in the developed world. The biosynthesis and degradation of human glycoproteins take place at the highest level in the liver. However, the association between glycosylation and the factors affecting obesity and metabolism-associated steatohepatitis (MASH) is still unclear.Materials and Methods: Gene expression data of liver samples from obese patients were retrieved from GSE83452 and GSE89632 databases. Difference analysis and machine learning were used to identify hub genes involved in glycosylation and associated with the response of weight loss treatment. A total of 7 glycosylation-related hub genes were identified and then subjected to correlation analysis, immune cells infiltration analysis and ROC (Receiver Operating Characteristic) analysis. We also evaluated the potential function of 7 hub genes in obesity patients. MASH mice were used to validate the glycosylation-related hub genes.Results: A total of 25 overlapped glycosylation-related genes were identified by DEGs analysis. ACER2, STX17, ARF5, GPC4, ENTPD5, NANP, and DPY19L2 were identified as hub genes. Among these hub genes, ACER2, STX17, ARF5, and ENTPD5 were also differential expressed in MASH patients. ENTPD5 showed increased transcription in obese MASH mice.Conclusion: The current study identified seven glycosylation-related genes, ACER2, STX17, ARF5, GPC4, ENTPD5, NANP, and DPY19L2, that might play key roles in the development of obesity. ENTPD5 might play a key role in the development of MASH. These findings provide fresh perspectives for expanding the investigation of obesity and MASH.Keywords: obesity, MASH, glycosylation, machine learning

Jian Zhou,1,2,&ast; Housheng Zheng,1,&ast; Huiru Zhang,1 Wenqiang Yu,1 Baoer Li,1 Liang Ye,1 Lu Wang1 1Hyperbaric Oxygen Department, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Medical School, Shenzhen, 518055, People’s Republic of China; 2Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518060, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lu Wang, Hyperbaric oxygen department, Shenzhen University General Hospital, Shenzhen University Medical School, Shenzhen, 518055, People’s Republic of China, Tel +86-0755-21839715, Email luwangszu@163.com Liang Ye, International Cancer Center, Shenzhen University Medical School, Shenzhen, 518055, People’s Republic of China, Tel +86-0755-26631420, Fax +86-0755-86671943, Email liangyeszu@163.comObjective: MCM5 is a DNA licensing factor involved in cell proliferation and has been previously established as an excellent biomarker in a number of malignancies. Nevertheless, the role of MCM5 in GBM has not been fully clarified. The present study aimed to investigate the potential roles of MCM5 in the treatment of GBM and to elucidate its underlying mechanism, which is beneficial for developing new therapeutic strategies and predicting prognosis.Methods: Firstly, we obtained transcriptomic and proteomic data from the TCGA and CPTAC databases on glioma patients. Employing the DeSeq2 R package, we then identified genes with joint differential expression in GBM tissues subjected to chemotherapy. To develop a prognostic risk score model, we performed univariate and multivariate Cox regression analyses. In vitro knockdown and overexpression of MCM5 were used to further investigate the biological functions of GBM cells. Additionally, we also delved into the upstream regulation of MCM5, revealing associations with several transcription factors. Finally, we investigated differences in immune cell infiltration and drug sensitivity across diverse risk groups identified in the prognostic risk model.Results: In this study, the chemotherapy-treated GBM samples exhibited consistent alterations in 46 upregulated and 94 downregulated genes at both the mRNA and protein levels. Notably, MCM5 emerged as a gene with prognostic significance as well as potential therapeutic relevance. In vitro experiments subsequently validated the role of increased MCM5 expression in promoting GBM cell proliferation and resistance to TMZ. Correlations with transcription factors such as CREB1, CTCF, NFYB, NRF1, PBX1, TEAD1, and USF1 were discovered during upstream regulatory analysis, enriching our understanding of MCM5 regulatory mechanisms. The study additionally delves into immune cell infiltration and drug sensitivity, providing valuable insights for personalized treatment approaches.Conclusion: This study identifies MCM5 as a key player in GBM, demonstrating its prognostic significance and potential therapeutic relevance by elucidating its role in promoting cell proliferation and resistance to chemotherapy.Keywords: glioblastoma, minichromosome maintenance protein 5, chemotherapeutic drug resistance

Likui Fang, Fangming Zhong, Wenfeng Yu, Pengfei Zhu, Guocan Yu Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of ChinaCorrespondence: Likui Fang, Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of China, Email 21618100@zju.edu.cnBackground: The impact of coagulation indicators on postoperative outcomes of patients with constrictive pericarditis undergoing pericardiectomy has been poorly investigated. This study aimed to assess the prognostic role of preoperative coagulation indicators in these patients.Methods: We retrospectively included 158 patients with constrictive pericarditis undergoing pericardiectomy. The diagnostic values of coagulation indicators for postoperative complications were evaluated by ROC curves. Patients were divided into two groups according to the cutoff value calculated by ROC curve. Postoperative outcomes were compared between the two groups. Logistic regression analysis was performed to identify risk factors of postoperative complications.Results: ROC curve showed that among different coagulation indicators, preoperative D-dimer (DD) level could effectively identify patients with postoperative complications (AUC 0.771, 95% CI 0.696– 0.847, P < 0.001). Patients were divided into the low DD group and the high DD group. The comparison of postoperative outcomes suggested that high preoperative DD level was significantly associated with longer durations of vasoactive agents using (P = 0.018), intubation (P = 0.020), ICU stay (P = 0.008), chest drainage (P=0.004) and hospital stay (P = 0.002). Multivariable analysis showed that high preoperative DD level was the independent risk factor of postoperative complications (OR 6.892, 95% CI 2.604– 18.235, P < 0.001).Conclusion: High preoperative DD level was significantly linked to poor postoperative outcomes and could provide an effective prediction ability for postoperative complications in patients with constrictive pericarditis.Keywords: constrictive pericarditis, D-dimer, postoperative complications, outcomes

Wenhui Guo,1,&ast; Xiang Lian,2,&ast; Hong Li,2 Lushun Jiang,1 Yingsha Chen,3 Ping Shen,1 Wei Yu1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Infectious Diseases, The Affiliated Xiangshan Hospital of Wenzhou Medical University; Xiangshan First People’s Hospital Medical and Health Group; Ningbo Fourth Hospital, Ningbo, People’s Republic of China; 3Department of Infectious Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Shen; Wei Yu, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Tel/Fax +86 571 87236421, Email shenping123451@126.com; wyu@zju.edu.cnObjective: To evaluate the characteristics of immunocytes and cytokines associated with bloodstream infections (BSIs) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP).Methods: Patients with BSIs K. pneumoniae (BSIs-Kpn) were enrolled in our hospital between 2015 and 2022. Whole blood and serum samples were collected on the first day after diagnosis. Immunocytes and cytokines profiles were assessed using multicolor flow cytometry and multiplex immunoassays, respectively. The test cytokines included interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17A.Results: A total of 313 patients had BSIs-Kpn, including 145 with CRKP, 43 with extended-spectrum β-lactamases (ESBL) producing Kpn (ESBL-Kpn) and 125 with non-CRKP or non-ESBL-Kpn (susceptible Kpn, S-Kpn). Absolute number of leukomonocyte (CD45+) in CRKP, ESBL-Kpn and S-Kpn were 280.0 (138.0– 523.0) cells/μL, 354.5 (150.3– 737.3) cells/μL, and 637.0 (245.0– 996.5) cells/μL, respectively. Compared with S-Kpn group, the absolute numbers of leukomonocyte (including T lymphocytes, B lymphocytes and natural killer cells) in patients with CRKP were significantly lower than that in patients with S-Kpn (P

Wenhua Yu,1,&ast; Shuodi Zhou,1,&ast; Yu Zhou2 1School of Mathematics and Statistics, Shandong Normal University, Jinan, Shandong, 250014, People’s Republic of China; 2Department of Mathematics, London School of Economics and Political Science, London, WC2A 2AE, UK&ast;These authors contributed equally to this workCorrespondence: Shuodi Zhou, School of Mathematics and Statistics, Shandong Normal University, Jinan, Shandong, People’s Republic of China, Email shuodzhou123@163.comPurpose: Research has demonstrated a strong correlation between mathematics self-efficacy and math performance. Middle school children are increasingly receiving solution-focused brief therapy (SFBT), which is a type of psychotherapy. The study intends to use SFBT intervention to improve mathematics self-efficacy of students and to determine whether SFBT intervention was effective. To examine whether Rasch model can be used to evaluate students’ mathematics self-efficacy.Methods: This study intends to use Radar chart, Rasch model, Line chart to measure the variations of mathematics self-efficacy of three 8th graders (n=3) during SFBT intervention.Results: Radar chart and Rasch model demonstrated a general increment in the mathematics self-efficacy of two pupils, while another one decreased. Additionally, three students showed a decline in their mathematics self-efficacy on particular mathematical problems using a line chart.Conclusion: Overall, students with varied degrees of self-efficacy in math benefited from SFBT interventions, which partially supports the usefulness of SFBT as a tool for assessing students’ mathematics self-efficacy. It supported that Rasch model can reflected the changes in students’ mathematics self-efficacy. This study provides guidance for measuring the improvement of students’ academic self-efficacy through SFBT intervention using Rasch model.Keywords: mathematics self-efficacy, solution-focused brief therapy intervention, radar chart, wright map

Zhengyu Fang,1,&ast; Peihong Lin,1,&ast; Rui Gao,1,&ast; Wenjing Yang,1 Aizhen Zhou,2 Wenying Yu1,3 1School of Pharmacy, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China; 2Department of Traditional Chinese Medicine, Zhejiang Pharmaceutical University, Ningbo, 315500, People’s Republic of China; 3Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aizhen Zhou; Wenying Yu, Tel +86 571 88215623, Email zhouaz@zjpc.net.cn; zjyuwenying@163.comBackground: Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, is a potential candidate for cancer chemotherapy. However, Tet has poor aqueous solubility and a short half-life, which limits its bioavailability and efficacy. Liposomes have been widely utilized to enhance the bioavailability and efficacy of drugs.Methods: In this study, Tet-loaded stealth liposomes (S-LPs@Tet) were prepared by ethanol injection method. Furthermore, physicochemical characterisation, biopharmaceutical behaviour, therapeutic efficacy, and biocompatibility of S-LPs@Tet were assessed.Results: The prepared S-LPs@Tet had an average particle size of 65.57 ± 1.60 nm, a surface charge of − 0.61 ± 0.10 mV, and an encapsulation efficiency of 87.20% ± 1.30%. The S-LPs@Tet released Tet in a sustained manner, and the results demonstrated that the formulation remained stable for one month. More importantly, S-LPs significantly enhanced the inhibitory ability of Tet on the proliferation and migration of lung cancer cells, and enabled Tet to escape phagocytosis by immune cells. Furthermore, in vivo studies confirmed the potential for long-circulation and potent tumor-suppressive effects of S-LPs@Tet. Moreover, ex vivo and in vivo safety experiments demonstrated that the carrier material S-LPs exhibited superior biocompatibility.Conclusion: Our research suggested that S-LPs@Tet has potential applications in lung cancer treatment.Keywords: tetrandrine, S-LPs, lung cancer, immune escape, in vivo imaging

Wenpeng Yu,1– 4,&ast; Jingli Ding,5,&ast; Jianfeng Chen,1– 3,&ast; Ying Jiang,4 Jinping Zhao,1– 3 Jichun Liu,4,6 Jianliang Zhou,1– 3 Jinping Liu1– 3 1Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China; 2Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, 430071, People’s Republic of China; 3Wuhan Clinical Research Center for Minimally Invasive Treatment of Structural Heart Disease, Wuhan, 430071, People’s Republic of China; 4Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 5Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, People’s Republic of China; 6Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianliang Zhou; Jinping Liu, Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People’s Republic of China, Tel +86 13767117511 ; +86 27-67812888, Email zjl20210802@whu.edu.cn; liujinping@znhospital.cnIntroduction: Excessive generation of reactive oxygen species (ROS) following myocardial ischemia-reperfusion (I/R) can result in additional death of myocardial cells. The rapid clearance of ROS after reperfusion injury and intervention during subsequent cardiac repair stages are crucial for the ultimate recovery of cardiac function.Methods: Magnesium-doped mesoporous bioactive glasses were prepared and loaded with the antioxidant drug gallic acid into MgNPs by sol-gel method. The antioxidant effects of MgNPs/GA were tested for their pro-angiogenic and anti-inflammatory effects based on the release characteristics of GA and Mg2+ from MgNPs/GA. Later, we confirmed in our in vivo tests through immunofluorescence staining of tissue sections at various time points that MgNPs/GA exhibited initial antioxidant effects and had both pro-angiogenic and anti-inflammatory effects during the cardiac repair phase. Finally, we evaluated the cardiac function in mice treated with MgNPs/GA.Results: We provide evidence that GA released by MgNPs/GA can effectively eliminate ROS in the early stage, decreasing myocardial cell apoptosis. During the subsequent cardiac repair phase, the gradual release of Mg2+ from MgNPs/GA stimulated angiogenesis and promoted M2 macrophage polarization, thereby reducing the release of inflammatory factors.Conclusion: MgNPs/GA acting on multiple cell types is an integrated solution for comprehensive attenuation of myocardial ischaemia-reperfusion injury and cardiac function protection.Keywords: myocardial ischemia/reperfusion injury, mesoporous bioactive glass, gallic acid, magnesium ion, macrophage polarization

Likui Fang, Wenfeng Yu, Guocan Yu, Gang Chen, Bo Ye Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of ChinaCorrespondence: Likui Fang, Department of Thoracic Surgery, Hangzhou Red Cross Hospital, Hangzhou, 310003, People’s Republic of China, Email 21618100@zju.edu.cnBackground: Tuberculous constrictive pericarditis (TCP) is recommended to be treated with anti-tuberculosis (TB) therapy before pericardiectomy. Whether different preoperative anti-TB regimens may lead to different outcomes is unclear.Methods: We retrospectively collected patients diagnosed as TCP and received pericardiectomy from April 2016 to June 2023. The study patients were assigned into the active TCP (A-TCP) group and the inactive TCP (IA-TCP) group according to the results of Mycobacterium tuberculosis (MTB) culture and MTB RNA assay. Baseline characteristics including anti-TB regimens and surgical outcomes were compared between the two groups. Logistic regression analysis and subgroup analysis were conducted to identify the protective factors of A-TCP.Results: Of the 102 study patients, 24 was in the A-TCP group and 78 was in the IA-TCP group. The rate of preoperative anti-TB regimen containing pyrazinamide was 37.5% in the A-TCP group, as compared with 74.4% in the IA-TCP group (P = 0.001). Multivariate analysis showed that preoperative use of pyrazinamide was the protective factor of A-TCP (OR 0.194, 95% CI 0.053– 0.703, P = 0.013). Subgroup analysis based on age also showed consistent findings. In the analyses of surgical outcomes, A-TCP was the independent risk factor of postoperative cardiac complications (OR 4.231, 95% CI 1.317– 13.593, P = 0.015) and associated with longer hospital stay (P = 0.004) and higher hospitalization cost (P = 0.001).Conclusion: A strategy involving anti-TB regimen containing pyrazinamide before pericardiectomy was superior to that without pyrazinamide in the patients with TCP. The strategy was associated with lower risk of A-TCP and might lead to better postoperative recovery and cost-effectiveness.Keywords: tuberculous constrictive pericarditis, pericardiectomy, pyrazinamide, outcomes

Wenhua Yu,1 Bo Yang,1 Siting Xu,1 Yun Gao,2 Yan Huang,3 Zhongqun Wang1 1Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 3Department of Ophthalmology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of ChinaCorrespondence: Zhongqun Wang; Yan Huang, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China, Tel +86-15262919468, Email wangtsmc@126.com; wangzhongqun@ujs.edu.cn; 0511syj@163.comAbstract: Diabetic complications can be divided into macrovascular complications such as cardiovascular disease and cerebrovascular disease and microvascular complications such as diabetic retinopathy, diabetic nephropathy and diabetic neuropathy. Among them, cardiovascular disease (CVD) is an important cause of death in diabetic patients. Diabetes retinopathy (DR) is one of the main reasons for the increasing disability rate of diabetes. In recent years, some studies have found that because DR and CVD have a common pathophysiological basis, the occurrence of DR and CVD are inseparable, and to a certain extent, DR can predict the occurrence of CVD. With the development of technology, the fundus parameters of DR can be quantitatively analyzed as an independent risk factor of CVD. In addition, the cytokines related to DR can also be used for early screening of DR. Although many advances have been made in the treatment of CVD, its situation of prevention and treatment is still not optimistic. This review hopes to discuss the feasibility of DR in predicting CVD from the common pathophysiological mechanism of DR and CVD, the new progress of diagnostic techniques for DR, and the biomarkers for early screening of DR.Keywords: diabetic retinopathy, cardiovascular disease, pathophysiological mechanism, optical coherence tomography angiography, biomarkers

Jiajia Wu,1,2,&ast; Shuangyu Qi,1,2,&ast; Wei Yu,3,&ast; Yujun Gao,4 Jun Ma1,2,4 1Department of Psychiatry, Wuhan Mental Health Center, Wuhan, People’s Republic of China; 2Wuhan Hospital for Psychotherapy, Wuhan, People’s Republic of China; 3Department of Psychiatry, Xianning Bode Mental Hospital, Xianning, People’s Republic of China; 4Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Ma, Department of Psychiatry, Wuhan Mental Health Center, No. 89, Gongnongbing Road, Wuhan, Hubei Province, People’s Republic of China, Email majun0313@wo.cn; Yujun Gao, Department of Psychiatry, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, Hubei Province, People’s Republic of China, Email Gaoyujun19820214@163.comIntroduction: Abnormal brain networks with emotional response in bipolar disorder (BD). However, there have been few studies on the local consistency between manic episodes in drug-naive first-episode BD patients and healthy controls (HCs). The purpose of this study is to evaluate the utility of neural activity values analyzed by Regional Homogeneity (ReHo).Methods: Thirty-seven manic episodes in first-episode, drug-naive BD patients and 37 HCs participated in resting-state functional magnetic resonance rescanning and scale estimation. Reho and receiver operating characteristic (ROC) curve methods were used to analyze the imaging data. Support vector machine (SVM) method was used to analyze ReHo in different brain regions.Results: Compared to HCs, ReHo increased in the left middle temporal gyrus (MTG.L), posterior cingulate gyrus (PCG), inferior parietal gyrus, and bilateral angular gyrus, and decreased in the left dorsolateral superior frontal gyrus in target group. The ROC results showed that the ReHo value of the left PCG could discriminate the target group from the HCs, and the AUC was 0.8766. In addition, the results of the support vector machine show that the increase in ReHo value in the left PCG can effectively discriminate the patients from the controls, with accuracy, sensitivity, and specificity of 86.02%, 86.49%, and 81.08%, respectively.Conclusion: The increased activity of the left PCG may contribute new evidence of participation in the pathophysiology of manic episodes in first-episode, drug-naive BD patients. The Reho value of the left posterior cingulate gyrus may be a potential neuroimaging biomarker to discriminate target group from HCs.Keywords: bipolar disorder, first-episode, drug-naïve, manic episode, left posterior cingulate gyrus, regional homogeneity

Decheng Meng,1 Fengxia Zhang,2 Wenfei Yu,1 Xin Zhang,1 Guoliang Yin,1 Pengpeng Liang,3 Yanan Feng,1 Suwen Chen,1 Hongshuai Liu1 1The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China; 3Shenzhen Hospital, Shanghai University of Traditional Chinese Medicine, Shenzhen, 518001, People’s Republic of ChinaCorrespondence: Fengxia Zhang, Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People’s Republic of China, Tel +86-131-5317-5246, Email fxzhang0987@163.comAbstract: Non-alcoholic fatty liver disease(NAFLD) is an umbrella term for a range of diseases ranging from hepatic fat accumulation and steatosis to non-alcoholic steatohepatitis (NASH) in the absence of excessive alcohol consumption and other definite liver damage factors. The incidence of NAFLD has increased significantly in recent years and will continue to grow in the coming decades. NAFLD has become a huge health problem and economic burden. SIRT1 is a member of Sirtuins, a group of highly conserved histone deacetylases regulated by NAD+, and plays a vital role in regulating cholesterol and lipid metabolism, improving oxidative stress, inflammation, and insulin resistance through deacetylating some downstream transcription factors and thus improving NAFLD. Although there are no currently approved drugs for treating NAFLD and some unresolved limitations in developing SIRT1 activators, SIRT1 holds promise as a proper therapeutic target for NAFLD and other metabolic diseases. In recent years, natural products have played an increasingly important role in drug development due to their safety and efficacy. It has been discovered that some natural products may be able to prevent and treat NAFLD by targeting SIRT1 and its related pathways. This paper reviews the mechanism of SIRT1 in the improvement of NALFD and the natural products that regulate NAFLD through SIRT1 and its associated pathways, and discusses the potential of SIRT1 as a therapeutic target for treating NAFLD and the effectiveness of these related natural products as clinical drugs or dietary supplements. These works may provide some new ideas and directions for finding new therapeutic targets for NAFLD and the development of anti-NAFLD drugs with good pharmacodynamic properties. Keywords: NAFLD, SIRT1, natural products, FFA, TG

Wu J, Li W, Ning J, Yu W, Rao T, Cheng F. Onco Targets Ther. 2019;12:495–508. At the authors request, the Editor and Publisher of the journal OncoTargets and Therapy have retracted the published article. Following publication of the article, the authors raised concerns about the duplication of images from Figure 6 with those from unrelated articles. Specifically, Images for Figure 6F, shRNA scramble, PCNA and UCA1 shRNA, Ki67, have been duplicated with images for Figure 4E, MCCK1+TMZ, Caspase-3 and Figure 5E, IM+Tan, Ki67, from Liu T, Li A, Xu Y, Xin Y. MCCK1 enhances the anticancer effect of temozolomide in attenuating the invasion, migration and epithelial-mesenchymal transition of glioblastoma cells in vitro and in vivo. Cancer Med. 2019;8:751–760. https://doi.org/10.1002/cam4.1951 and Teng Z, Xu S, Lei Q. Tanshinone IIA enhances the inhibitory effect of imatinib on proliferation and motility of acute leukemia cell line TIB‑152 in vivo and in vitro by inhibiting the PI3K/AKT/mTOR signaling pathway [Retracted]. Oncology Reports. 2020;43:503-515. https://doi.org/10.3892/or.2019.7453, respectively. The corresponding author was cooperative and responded to our queries but was unable to provide a satisfactory explanation for how the images came to be duplicated or provide satisfactory original data for the study. As verifying the validity of published work is core to the integrity of the scholarly record, the authors requested to retract the article and the Publisher and Editor 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”.

Chunxiang He,1,2 Ze Li,1,2 Miao Yang,1,2 Wenjing Yu,1,2 Rongsiqing Luo,1,2 Jinyong Zhou,1,2 Jiawei He,1,2 Qi Chen,1,2 Zhenyan Song,1,2 Shaowu Cheng1,2 1School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Zhenyan Song; Shaowu Cheng, Tel +86 073188458257, Email songzhenyan2013@hnucm.edu.cn; scheng@hnucm.edu.cnAbstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by complex pathophysiological features. Amyloid plaques resulting from extracellular amyloid deposition and neurofibrillary tangles formed by intracellular hyperphosphorylated tau accumulation serve as primary neuropathological criteria for AD diagnosis. The activation of microglia has been closely associated with these pathological manifestations. Non-coding RNA (ncRNA), a versatile molecule involved in various cellular functions such as genetic information storage and transport, as well as catalysis of biochemical reactions, plays a crucial role in microglial activation. This review aims to investigate the regulatory role of ncRNAs in protein expression by directly targeting genes, proteins, and interactions. Furthermore, it explores the ability of ncRNAs to modulate inflammatory pathways, influence the expression of inflammatory factors, and regulate microglia activation, all of which contribute to neuroinflammation and AD. However, there are still significant controversies surrounding microglial activation and polarization. The categorization into M1 and M2 phenotypes may oversimplify the intricate and multifaceted regulatory processes in microglial response to neuroinflammation. Limited research has been conducted on the role of ncRNAs in regulating microglial activation and inducing distinct polarization states in the context of neuroinflammation. Moreover, the regulatory mechanisms through which ncRNAs govern microglial function continue to be refined. The current understanding of ncRNA regulatory pathways involved in microglial activation remains incomplete and may be influenced by spatial, temporal, and tissue-specific factors. Therefore, further in-depth investigations are warranted. In conclusion, there are ongoing debates and uncertainties regarding the activation and polarization of microglial cells, particularly concerning the categorization into M1 and M2 phenotypes. The study of ncRNA regulation in microglial activation and polarization, as well as its mechanisms, is still in its early stages and requires further investigation. However, this review offers new insights and opportunities for therapeutic approaches in AD. The development of ncRNA-based drugs may hold promise as a new direction in AD treatment.Keywords: Alzheimer’s disease, non-coding RNA, neuroinflammation, microglia activation, miRNA, circRNA, lncRNA

Fengqin Zhu,1,2 Zongjing Hu,1 Wei Yu,1 Fengxian Dai,1 Dehuai Jing,1 Guangxi Zhou1 1Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People’s Republic of China; 2Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, People’s Republic of ChinaCorrespondence: Guangxi Zhou, Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong, 272000, People’s Republic of China, Email zgx_viola@126.comBackground: Ulcerative colitis (UC) is a chronic, relapsing progressive inflammatory immune disease. There is still no cure for it. Even worse, UC may predispose patients to opportunistic infections, and several extra-intestinal manifestations (EIMs) and comorbidities may antedate, occur with, or postdate the onset of UC, which may increase the mortality risk. But case reports of UC patients simultaneously concomitant with opportunistic infection, EIM, and comorbidity are extremely rare.Case Presentation: We report a case of 51-year-old male patient with incipient UC accompanied by cytomegalovirus (CMV) infection and bullous Sweet’s syndrome (bSS, a cutaneous EIM of UC) after treatment with oral mesalazine and prednisolone for 3 weeks. After clearance of the CMV infection by using ganciclovir, the patient was administered two cycles of infliximab to cure UC and bSS; however, he developed acute myeloid leukemia (AML) a month later and died after two cycles of chemotherapy.Conclusion: Based on this rare case of UC concomitant with CMV infection, bSS and AML, we recommend that it is important to distinguish between an acute UC flare and opportunistic infections, especially in patients receiving immunosuppressive therapy, and monitor EIMs and comorbidities timely. Particular attention should be paid to cancer surveillance. Clinicians should be mindful of these facts to adopt optimal therapeutic options to address all aspects of UC. Early initiation of biological therapy may be of benefit to patients with newly diagnosed severe UC.Keywords: ulcerative colitis, cytomegalovirus, bullous Sweet’s syndrome, acute myeloid leukemia

Wenhua Yu, Zhongqun Wang Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of ChinaCorrespondence: Zhongqun Wang, Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China, Email wangtsmc@126.com

JinJian Yao,1,2,&ast; Xiaochun Mao,3,&ast; Qigang Sun,4,&ast; Biao Wu,5 Weiling Yu,6 Yanjing Huang,7 Shuai Luo,1 Jia Zeng,1 Jusheng Lin2 1Department of Emergency, Hainan General Hospital, Haikou, Hainan, People’s Republic of China; 2Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Ophthalmology, Xiangyang Central Hospital Affiliated to Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of China; 4Department of Hepatobiliary and Pancreatic Surgery, Hainan General Hospital, Haikou, Hainan, People’s Republic of China; 5Infectious Disease, Hainan General Hospital, Haikou, Hainan, People’s Republic of China; 6Oncology Department, Haikou City People’s Hospital, Haikou, Hainan, People’s Republic of China; 7Oncology Department of Hainan General Hospital, Haikou, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: JinJian Yao; Jusheng Lin, Email 114715854@qq.com; jslin2005@163.comPurpose: Liver cirrhosis (LC) and hepatocellular carcinoma (HCC) are progressions affected by genetic predispositions, and persistent hepatitis B virus infection also demonstrates genetic susceptibility. All HBV-related outcomes have been compared in parallel to identify risk polymorphism in HBV progression.Methods: The multiple-stage association study filtered and validated the risk SNPs for HBV progression and explored their association with persistent infection, with a total of 8906 subjects in China from three sites. Cox proportional hazards models and Kaplan–Meier Log rank tests were used to determine the time to the progressive event in relation to the risk SNPs.Results: Rs3825214 in TBX5 replicated a specific association with LC and HCC in 4 progression cohorts and was not related to persistent infection, naivety to HBV infection and natural clearance in 3 persistent cohorts. In combined samples, rs3825214 was associated with an increased risk of LC (P< 0.001; OR = 1.98) and HCC (P< 0.001; OR = 1.68). The results of bioinformatics analysis indicated that rs3825214 genotypes change RNA structure and intron excision ratio. In the follow-up of 571 hospital-based persistent HBV infection patients, ninety-three (16.29%) developed LC, and seventy-four (12.96%) progressed to HCC at a median follow-up of 5.1 years. Rs3825214 was associated with HCC and LC events in Cox proportional hazards models (P< 0.001).Conclusion: We identified and confirmed that genetic variants in TBX5 are significantly associated with susceptibility to and the incidence of LC and HCC.Keywords: TBX5, polymorphism, liver cirrhosis, hepatocellular carcinoma, follow-up, hepatitis B virus

Xiaoyu Wu,1,&ast; Danfei Ji,1,&ast; Zefan Wang,1,&ast; Wenhua Yu,2 Quan Du,2 Wei Hu,3 Yongke Zheng,3 Xiaoqiao Dong,2 Fanghui Chen4 1The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Intensive Care Unit, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4Emergency Department, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoqiao Dong; Fanghui Chen, Email dxqhyy@163.com; wangxiaoleihzsy@163.comBackground: NADPH oxidase 2 (NOX2) is highly expressed in injured brain tissues. We determined serum NOX2 levels of aneurysmal subarachnoid hemorrhage (aSAH) patients and further investigated correlation of serum NOX2 levels with disease severity, delayed cerebral ischemia (DCI) plus prognosis after aSAH.Methods: Serum NOX2 levels were measured in 123 aSAH patients and 123 healthy controls. World Federation of Neurological Surgeons scale (WFNS) score and modified Fisher (mFisher) score were utilized to assess disease severity. Modified Rankin scale (mRS) score was used to evaluate the clinical prognosis at 90 days after aSAH. Relations of serum NOX2 levels to DCI and 90-day poor prognosis (mRS score of 3– 6) were analyzed using multivariate analysis. Receiver operating characteristic curve (ROC) was built to evaluate the prognostic predictive capability.Results: Serum NOX2 levels in aSAH patients, compared with healthy controls, were significantly increased, and were independently correlated with WFNS score, mFisher score and post-stroke 90-day mRS score. Patients with poor prognosis or DCI had significantly higher serum NOX2 levels than other remainders, and serum NOX2 levels independently predicted 90-day poor prognosis and DCI. Serum NOX2 had high prognosis and DCI predictive abilities, and their areas under ROC curve were similar to those of WFNS score and mFisher score.Conclusion: Serum NOX2 levels are significantly associated with hemorrhage severity, poor 90-day prognosis and DCI in aSAH patients. Hence, complement NOX2 may serve as a potential prognostic biomarker after aSAH.Keywords: NADPH oxidase 2, biomarker, aneurysmal subarachnoid hemorrhage, disease severity, delayed cerebral ischemia, prognosis

Wenmei Zhou,1 Tao Tao,1 Wenfeng Yu,2 Wanfu Wu,3 Zhirong Hui,1 Hongliang Xu,1 Yaqi Li,4 Ying Zhang,5 Xiaohui Yang1,6 1Department of Rehabilitation Medicine, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China; 2Department of Human Anatomy, Basic Medical College, Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China; 3Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA; 4Emergency Department, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, 550002, People’s Republic of China; 5Department of Chinese Traditional Medicine, Zunyi Medical and Pharmaceutical College, Zunyi, Guizhou, 563006, People’s Republic of China; 6Department of Rehabilitation Medicine, The Affiliated Hospital Guizhou Medical University, Guiyang, Guizhou, 550001, People’s Republic of ChinaCorrespondence: Tao Tao, Tel +86 13985162824, Email ttdoc915@sina.comBackground: Hypoxia inducible factor-1α (HIF-1α) regulates glucose metabolism during ischemia. This study investigated the effect of recombinant adenovirus HIF-1ɑ on neurological function and energy metabolism in a rat cerebral ischemia-reperfusion model.Methods: Rats were divided into four groups: sham-operated (Sham) group, cerebral ischemia-reperfusion (CIR) group, recombinant adenovirus empty vector (Ad) group, and recombinant adenovirus-mediated HIF-1α (AdHIF-1α) group. The AdHIF-1α group and the Ad group were injected with AdHIF-1α and Ad in the lateral ventricle. The mNSS was performed at post-ischemia day 0 (P0) and P1, P14 and P28. At P14, the cerebral infarct volume was compared. At P28, HE staining, Nissl stains and TUNEL staining were performed. The expression of HIF-1α, GLUT1 and PFKFB3 were evaluated by Western Blot and immunohistochemistry. High performance liquid chromatography (HPLC) was used to determine the expression of GLUT1 and PFKFB3, and the level of energy metabolites: ATP, ADP and AMP.Results: mNSS scores in the AdHIF-1α group were consistently lower than those in the CIR and Ad groups from P14 (P < 0.05) and Ad groups (P < 0.05). The cerebral infarct volume was reduced in the AdHIF-1α group compared with that in CIR group and Ad group (P < 0.05). At P28, HE showed better pathological changes in AdHIF-1α group. The number of Nissl bodies was increased in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The number of apoptotic cells in the AdHIF-1α group was fewer than that in the CIR and Ad groups (P < 0.05). The expression of HIF-1α, GLUT1 and PFKFB3 was significantly higher in the AdHIF-1α group compared with the CIR and Ad groups (P < 0.05). The ATP, ADP and AMP in the ischemic penumbra were also higher in the AdHIF-1α group (P < 0.05).Conclusion: HIF-lα promoted neurological function recovery and decreased cerebral infarct volume in rats after cerebral ischemia-reperfusion injury by improving energy metabolism.Keywords: cerebral ischemia-reperfusion injury, HIF-lα, energy metabolism, glucose transporter protein-1, GLUT1, 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3, PFKFB3

Yukun He,1,&ast; Yifan Wang,1,&ast; Xinqian Ma,1 Lili Zhao,1 Jie Guan,2 Jin Zhao,3 Wenyi Yu,1 Yanjun Li,4 Wentao Ni,1 Zhancheng Gao1 1Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China; 2Clinical Laboratory, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Respiratory Diseases, Air Force Medical Center, Chinese People’s Liberation Army, Beijing, People’s Republic of China; 4Clinical Laboratory, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wentao Ni; Zhancheng Gao, Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China, Email wentao.qingdao@163.com; zcgao@bjmu.edu.cnBackground: Cefiderocol (CFDC) is a promising antimicrobial agent against multidrug resistant Gram-negative bacteria. However, CFDC resistance has emerged in carbapenem-resistant Acinetobacter baumannii (CR-AB) but the underlying mechanisms remain unclear.Methods: Whole-genome sequencing and transcriptome sequencing were performed on CFDC-non-susceptible and CFDC-susceptible isolates. Two different recombinant plasmids was electro-transformed into the E. coli BL21 strain to determine the impact of blaPER and the combined impact of blaPER-1 and blaOXA-23 on CFDC resistance.Results: Fifty-five CR-AB isolates with minimum inhibitory concentrations (MICs) ranged from 0.06 mg/L to > 256 mg/L were sequenced, including 47 CFDC-non-susceptible and eight CFDC-susceptible isolates. Two CFDC-non-susceptible isolates belonged to ST104 whereas the remaining isolates belonged to ST2, and blaPER-1 was present only in CFDC-non-susceptible isolates. Amino acid substitutions were noted in penicillin-binding proteins (PBPs) in four CFDC-susceptible isolates, with slightly elevated MICs. The MICs of recombinant E. coli BL21 carrying the blaPER-1 gene increased 64-fold and recombinant E. coli BL21 carrying both the blaPER-1 and blaOXA-23 genes increased 8-fold but both remained within the susceptibility range. Transcriptome sequencing of 17 CFDC-non-susceptible isolates and eight CFDC-susceptible isolates revealed that transcriptional levels of various iron transport proteins, such as fiu, feoA, and feoB, and the energy transduction system, TonB-ExbB-ExbD, were relatively downregulated in CFDC-non-susceptible isolates. GO enrichment analysis revealed that the upregulated genes in CFDC-non-susceptible isolates were mainly associated with redox homeostasis and stress response. Besides, the expression levels of the blaOXA-23 and exbD genes were negatively correlated with the MICs.Conclusion: PER-1 production, iron transport system downregulation, and mutations in PBPs may synergistically impart high-level resistance to CFDC in CR-AB.Keywords: carbapenem-resistant Acinetobacter baumannii, cefiderocol resistance, blaPER-1, iron transporter systems

Poyu Chen1– 3&ast;, Chuangwei Zhang1– 3&ast;, Ping He,4 Shengyuan Pan,1– 3 Wenjie Zhong,1– 3 Yue Wang,1– 3 Qingyue Xiao,1– 3 Xinyan Wang,1– 3 Wenliang Yu,1– 3 Zhangmin He,1– 3 Xiang Gao,1– 3 Jinlin Song1– 3 1College of Stomatology, Chongqing Medical University, Chongqing, 401147, People’s Republic of China; 2Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, 401147, People’s Republic of China; 3Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, 401147, People’s Republic of China; 4Department of Stomatology, Dazhou Central Hospital, Dazhou, SiChuan, 635000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiang Gao; Jinlin Song, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, 401147, People’s Republic of China, Tel/Fax +86 23 88860105 ; Tel/Fax +86 23 88860026, Email xiangg@hospital.cqmu.edu.cn; songjinlin@hospital.cqmu.edu.cnIntroduction: The functional reconstruction of periodontal tissue defects remains a clinical challenge due to excessive and prolonged host response to various endogenous and exogenous pro-inflammatory stimuli. Thus, a biomimetic nanoplatform with the capability of modulating inflammatory response in a microenvironment-responsive manner is attractive for regenerative therapy of periodontal tissue.Methods: Herein, a facile and green design of engineered bone graft materials was developed by integrating a biomimetic apatite nanocomposite with a smart-release coating, which could realize inflammatory modulation by “on-demand” delivery of the anti-inflammatory agent through a pH-sensing mechanism.Results: In vitro and in vivo experiments demonstrated that this biocompatible nanoplatform could facilitate the clearance of reactive oxygen species in human periodontal ligament stem cells under inflammatory conditions via inhibiting the production of endogenous proinflammatory mediators, in turn contributing to the enhanced healing efficacy of periodontal tissue. Moreover, this system exhibited effective antimicrobial activity against common pathogenic bacteria in the oral cavity, which is beneficial for the elimination of exogenous pro-inflammatory factors from bacterial infection during healing of periodontal tissue.Conclusion: The proposed strategy provides a versatile apatite nanocomposite as a promising “inflammation scavenger” and propels the development of intelligent bone graft materials for periodontal and orthopedic applications.Graphical Abstract: Keywords: periodontal bone regeneration, pH-responsive, inflammatory modulation, antibacterial activity, biomimetic nanoplatform

Xuelian Tang,1 Keyi Yu,2 Wenjun Yu2 1College of Science and Technology Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 2Department of Psychology, Ningbo University, Ningbo, Zhejiang, People’s Republic of ChinaCorrespondence: Wenjun Yu, 818 Fenghua Road, Ningbo, Zhejiang, People’s Republic of China, Tel +86 18868646620, Email yuwenjun@nbu.edu.cnPurpose: There is ample evidence that investors respond negatively to firm’s unethical behavior. However, researchers cannot explain investors’ reactions and the mechanisms of change when faced with firm’s unethical behavior. By collecting and analyzing data from questionnaires, this study investigated the effects of firm’s unethical behavior on investors’ willingness to invest and further focused on different targets involved in unethical events. Moreover, this study explored the roles of firm development stages and the moderation effect of investors’ moral support level. It aims to reveal investors’ decisions on firm’s unethical behaviors in different situations.Methods: This study employed a 2 (behavioral ethics: unethical behavior versus normal behavior) X 2 (stages of firm development: startups versus mature firms) X 4 (targets involved in the events: employees, peers, customers, and society) mixed design. Two hundred and fifty-seven participants were finally recruited for final analysis, and then repeated-measures ANOVAs were adopted to assess the valid data collected from 257 participants.Results: The results showed that disclosure of unethical behavior in due diligence reports significantly decreased investors’ willingness to invest. However, investor willingness was higher for startups with unethical behavior than for unethical mature firms. Investors’ willingness to invest decreased most significantly when evaluating firms with unethical behavior toward employees, followed by society and peers. Their willingness to invest decreased the least when evaluating firms exhibiting unethical behavior toward customers. The level of investors’ moral support moderated the above effects, that is, the higher the moral support, the more considerable the decrease in investment willingness in unethical firms.Conclusion: Current results demonstrated that when facing firms with unethical behaviors, investors would make investment decisions after considering the firm’s stage of development and the stakeholder of the unethical event. This study provides a valuable theoretical basis for decision-making by government, institutional investors, and firm managers.Keywords: unethical behavior, startups, mature firms, willingness to invest, level of moral support

Huimin Li,1,2,&ast; Shue Wang,3,&ast; Shuai Wang,4 Hai Yu,1 Wenhao Yu,5,6 Xiaomin Ma,3 Xiaodong He1,6 1Department of Physical and Chemical Inspection, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2National Human Genetic Resources Center; National Research Institute for Health and Family Planning; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3Preventive Medicine Experimental Teaching Center, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 4Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 5Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 6Institute for Medical Dataology, Shandong University, National Institute of Health Data Science of China, Jinan, Shandong, 250012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong He, Tel/Fax +86 531 88382554, Email xiaodong.he@sdu.edu.cnPurpose: The prevalence of hyperlipidemia and related illnesses is on its rise, and atorvastatin is the frequently used hypolipidemic agent. However, there is still uncertainty about the mechanisms, especially the relationship between the lipid-lowering effect, intestinal microbiome, and metabolic profiles. We aim to intensively explain the mechanism of the hypolipidemic effect of atorvastatin through multi-omics perspective of intestinal microbiome and metabolomics.Methods: Multi-omics methods play an increasingly important role in the analysis of intestinal triggers and evaluation of metabolic disorders such as obesity, hyperlipidemia, and diabetes. Therefore, we were prompted to explore intestinal triggers, underlying biomarkers, and potential intervention targets of atorvastatin in the treatment of dyslipidemia through multi-omics. To achieve this, SPF Wistar rats were fed a high-fat diet or normal diet for 8 weeks. Atorvastatin was then administered to high-fat diet-fed rats.Results: By altering intestinal microbiome, a high-fat diet can affect feces and plasma metabolic profiles. Treatment with atorvastatin possibly increases the abundance of Bacteroides, thereby improving “propanoate metabolism” and “glycine, serine and threonine metabolism” in feces and plasma, and contributing to blood lipid reduction.Conclusion: Our study elucidated the intestinal triggers and metabolites of high-fat diet-induced dyslipidemia from the perspective of intestinal microbiome and metabolomics. It equally identified potential intervention targets of atorvastatin. This further explains the mechanism of the hypolipidemic effect of atorvastatin from a multi-omics perspective.Keywords: hyperlipidemia, 16S rRNA sequencing, intestinal microbiome, metabolomics, atorvastatin calcium trihydrate

Liren Zhang,1 Weibin Yu,2 Yuwu Zhao,1 Xiaohua Chen,3 Peng Wang,3 Xiaohong Fan,4 Zhouwei Xu1 1Department of Neurology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Radiology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Infectious Disease, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Respiratory Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Zhouwei Xu, Department of Neurology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Tel +8615921704083, Email xzwsp@sina.comBackground: The coronavirus disease 2019 (COVID-19) pandemic has caused enormous mortality worldwide. Low albumin level is a risk factor for increasing mortality among patients in the intensive care unit (ICU). This study investigated the effect of albumin infusion on critical COVID-19 patients with hypoalbuminemia.Methods: A total of 114 COVID-19 ICU patients with hypoalbuminemia were recruited from Wuhan Leishenshan Hospital and Zhongnan Hospital of Wuhan University. Clinical features and laboratory variables were collected through electronic medical records. The cohorts were divided into two groups: albumin infusion and non-albumin infusion. Propensity-matched analysis was used to compare patients who received albumin to controls. Statistical analyses were used to investigate the survival time and inflammation-related blood biomarkers between groups.Results: Lactate dehydrogenase, interleukin (IL)-6, IL-2 receptor, and IL-8 levels were significantly downregulated in the albumin infusion group. Significant upregulations of lymphocyte counts and IL-10 were found in the albumin infusion group. There was a negative association between albumin level and D-dimer or procalcitonin levels after treatment. The albumin infusion group had a significantly longer survival time and shorter hospitalization time than control patients. Notably, a 1g increase in albumin level reduced the risk of death by approximately 7.3% after adjusting for age and sex. Patients with increased albumin levels after treatment had better prognoses than those without.Conclusion: Albumin administration can regulate COVID-19-related biomarkers and reduce the risk of death in critical patients with hypoalbuminemia. Clinicians should pay more attention to these risk factors. Targeted clinical interventions should be implemented to minimize the negative impacts of hypoalbuminemia and improve disease outcomes.Keywords: albumin, COVID-19, critical, prognosis, hypoalbuminemia

Tian Wang,1,&ast; Feng Lin,2,&ast; Yujing Huang,2 Guowei Qian,2 Wenxi Yu,2 Haiyan Hu,2 Tong Ji,3 Lina Tang,2 Yang Yao2 1The Eighth People’s Hospital of Shanghai, Shanghai, People’s Republic of China; 2Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 3Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Yao; Lina Tang, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University, No. 600 Yishan Road, Xuhui Distinct, Shanghai, 200233, People’s Republic of China, Tel +86 2164369181 ; +86 2164701361, Email yangyao_6@hotmail.com; Tina_8042@hotmail.comPurpose: The options for the second-line treatment of metastatic osteosarcoma are still limited. Anlotinib is a multi-kinase inhibitor which has shown promising efficacy and good tolerability in various cancer types. This retrospective study was conducted to evaluate the efficacy and safety of anlotinib combined with gemcitabine/docetaxel (GD) in patients with metastatic osteosarcoma who have failed first-line chemotherapy.Patients and Methods: The data of patients who received anlotinib combined with GD or GD were collected. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate and safety.Results: From July 2013 to November 2020, a total of 32 patients were enrolled, 13 received anlotinib combined with GD and 19 received GD. Median PFS was 9.0 months (95% CI 6.7– 39.1) in the combination group and 5.0 months (95% CI 1.2– 6.7) in the chemotherapy group. ORR were 38.4% and 15.8%, DCR were 69.2% and 38.1% in the combination and chemotherapy group, respectively. The most common adverse events included fatigue (78.9% in the combination group vs 69.2% in the chemotherapy group), hypertension (46.2% vs 10.5%), diarrhea (38.5% vs 21.1%), hypothyroidism (38.5% vs 15.8%), neutropenia (23.1% vs 36.8%) and AST elevation (30.8% vs 21.1%). The most common grade 3 or worse adverse events included hand-foot reaction (7.7% vs 5.3%), hypothyroidism (15.4% vs 0), neutropenia (0 vs 10.5%).Conclusion: The combination of anlotinib and GD showed favorable efficacy with manageable toxicities compared with GD in the second-line treatment for metastatic osteosarcoma. This combination therapy deserves further investigations in patients with osteosarcoma.Keywords: anlotinib, refractory metastatic osteosarcoma, combination therapy

Hai Yin,1 Qiliang Ma,2 Junwei Zhuang,1 Wei Yu,1 Zhongyou Wang3 1School of Biomedical Engineering and Medical Imaging, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, People’s Republic of China; 2School of Mathematics and Computer, Wuhan Textile University, Wuhan, 430200, People’s Republic of China; 3School of Computer Science and Technology, Hubei University of Science and Technology, Xianning, 437100, People’s Republic of ChinaCorrespondence: Zhongyou Wang, Email wzy1963@163.comIntroduction: Heart sound signal is an important physiological signal of human body, and the identification and research of heart sound signal is of great significance.Methods: For abnormal heart sound signal recognition, an abnormal heart sound recognition system, combining hidden semi-Markov models (HSMM) with deep neural networks, is proposed. Firstly, HSMM is used to build a heart sound segmentation model to accurately segment the heart sound signal, and then the segmented heart sound signal is subjected to feature extraction. Finally, the trained deep neural network model is used for recognition.Results: Compared with other methods, this method has a relatively small amount of input feature data and high accuracy, fast recognition speed.Discussion: HSMM combined with deep neural network is expected to be deployed on smart mobile devices for telemedicine detection.Keywords: heart sound signal, recognition, hidden semi-Markov, neural network

Xianglei Wu,1,&ast; Ying Liu,1,&ast; Jiafang Zhu,1,&ast; Wenxin Yu,1 Xiaoxi Lin1,2 1Department of Laser and Aesthetic Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenxin Yu; Xiaoxi Lin, Department of Laser and Aesthetic Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email 860382817@qq.com; kernelldz@sina.comBackground: Infraorbital dark circles (IDC) are commonly consulted in aesthetic practice. There is not yet a multifactorial approach to facilitating their treatment.Objective: To investigate the safety and efficacy of the microneedle fractional radiofrequency (MRF) system for the treatment of IDC.Methods: A prospective, split-face, evaluator-blind clinical trial was conducted to study the change in the overall appearance, color, and wrinkles in 21 female patients with mixed type IDC before and after MFR treatment.Results: Both patients and independent evaluators found significant improvement on the global aesthetic scales after the MFR treatment, especially on periorbital wrinkles (p=0.031). Trends in decreased melanin density in the IDC area were found, but no statistical differences were established. No side effects were observed.Conclusion: MFR is a safe and effective modality for improving mixed type IDC by correcting the structural factors.Keywords: infraorbital dark circles, microneedle fractional radiofrequency, radiofrequency, periorbital hyperpigmentation

Xi Chen,1 Lu Gao,1 Zhen Zhen,1 Ying Wang,1 Jia Na,1 Wen Yu,1 Xinyuan Chu,1 Yue Yuan,1 Suyun Qian2 1Department of Cardiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 2Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of ChinaCorrespondence: Yue Yuan, Department of Cardiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56, Nanlishilu, District Xicheng, Beijing, 100045, People’s Republic of China, Email yuanyuebjdr@163.com; yuanyuebj22@sina.com Suyun Qian, Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56, Nanlishilu, District Xicheng, Beijing, 100045, People’s Republic of China, Email qiansuyunbj12@163.com; suyunqian1211@163.comPurpose: To explore the risk factors and develop predictive models for intravenous immunoglobulin (IVIG) resistance in children with recurrent Kawasaki disease (KD).Patients and Methods: Patients with recurrent KD were retrospectively reviewed. Clinical and laboratory data at recurrence were collected and compared between patients with and without IVIG resistance. The patients were randomly divided into training and validation cohorts for model development and validation. All variables were subjected to standard Lasso and its variant group Lasso analyses, respectively, to construct predictive models. Model performance was evaluated by receiver operating characteristics (ROC) curves, calibration curves, and Hosmer-Lemeshow tests.Results: A total of 90 children with recurrent KD were included. A total of 16 cases were IVIG resistant. The patients with IVIG resistance had higher age and IVIG resistance probability at the first episode, increased CRP levels, neutrophil count, neutrophil percentage, direct bilirubin level, prothrombin time, and international normalized ratio, and decreased lymphocyte count, lymphocyte percentage, and serum sodium levels. Five variables including age and IVIG resistance at the first episode, lymphocytes count, serum sodium levels, and CRP levels were finally selected by standard Lasso (lLasso model) and four variables including age and IVIG resistance at the first episode, neutrophil percentage, and CRP levels were selected by group Lasso (gLasso). ROC curves suggested lLasso and gLasso models had similar excellent discrimination in both the training cohort (0.895 vs 0.906) and the validation cohort (0.855 vs 0.909). Hosmer-Lemeshow tests suggested the two models exerted a good calibration. Two nomograms were also constructed to facilitate the potential application of the two models.Conclusion: Age and IVIG resistance at the first episode and some laboratory variables may be risk factors for IVIG resistance in recurrent KD. Two predictive models for IVIG resistance with excellent performance were established in recurrent KD. External validation should be performed before clinical use.Keywords: recurrent Kawasaki disease, intravenous immunoglobulin, resistance, risk factor, predictive model

Yong Lu,1 Yiping Wang,1 Can Shen,1 Jianping Luo,1 Wanjun Yu2 1Laboratory Medicine Center, The Affiliated People’s Hospital of Ningbo University, Ningbo, 315040, People’s Republic of China; 2Department of Respiration, The Affiliated People’s Hospital of Ningbo University, Ningbo, 315040, People’s Republic of ChinaCorrespondence: Wanjun Yu, Email nbyyywj@163.comBackground: The aim of this study was to analyse changes in influenza detection rates of the influenza seasons 2017/2018, 2018/2019, 2019/2020, and 2020/2021 and the changes in personal awareness of protection during the COVID-19 pandemic.Methods: This retrospective study included patients tested for influenza virus A and B from November 2017 to March 2021 at the Affiliated People’s Hospital of Ningbo University (Ningbo, China). Influenza virus A and B tested by direct RT-PCR. A small group of 100 regular participants in influenza virus detection were surveyed on the use of protective measures in four different influenza seasons.Results: There were 14,902, 14,762, 25,070, and 1107 tests of influenza virus A and B in the four influenza periods, for total positive rates of 32.45%, 35.77%, 29.40%, and 0.54%, respectively. In the two periods of four influenza seasons, from November to January, the total number of influenza samples was 8530, 4980, 22,925, 868; from February to March, the number of tests was 6372, 9782, 2145, 239. Total number of tests and positive rate decreased significantly from February/March onwards of the 2019/2020 season, coinciding with the beginning of COVID-19. The proportion of people taking protective measures also increased during the 2019/20 and 2020/21 flu seasons.Conclusion: The influenza virus has a high incidence in this area. The diagnosis rate of influenza decreased after the start of the COVID-19 pandemic. The COVID-19 pandemic had an important impact on the detection rates for influenza virus.Keywords: influenza, COVID-19, pandemic

Yang Cheng,1,2,&ast; Rui Tang,1,&ast; Xiangzhao Li,3 Biao Wang,4 Yanling Cheng,1 Shuzhe Xiao,1 Penghui Sun,5 Wenxuan Yu,2 Cheng Li,2 Xinsheng Lin,2 Yun Zhu2,&ast; 1Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 2Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China; 5Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Zhu, Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Email zyfreemail@126.comBackground: New predictors of the efficacy of hepatocellular carcinoma (HCC) immunotherapy are needed. The ability of a single gene mutation to predict the therapeutic effect of immune checkpoint inhibitors (ICI) in HCC remains unknown.Methods: The most frequently mutated genes in HCC were analyzed using the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Mutant genes that correlated with the tumor mutational burden (TMB) and prognosis were obtained. The mutation pattern and immunological function of one of the most frequently mutated genes, LRP1B, were determined. A pan-tumor analysis of LRP1B expression, association with cancer prognosis, and immunological role was also explored. A retrospective clinical study was conducted using 102 HCC patients who received ICI treatment to further verify whether gene mutations can predict the effectiveness of immunotherapy and prognosis of HCC.Results: LRP1B is among the most frequently mutated genes in HCC cohorts in TCGA and ICGC datasets. TCGA data showed that the LRP1B mutation activated immune signaling pathways and promoted mast cell activation. Patients with LRP1B mutations had significantly higher TMB than those with wild-type LRP1B. LRP1B expression correlated with the cancer-immunity cycle and immune cell infiltration. High LRP1B expression was also associated with poor survival among HCC patients. Results from the clinical study showed that HCC patients in the LRP1B mutation group had a poor response to ICI and worse prognosis than the wild-type group. The LRP1B mutation group had significantly higher TMB and mast cell infiltration in tumor tissues.Conclusion: This study is the first to report that a single gene LRP1B mutation is associated with a poor clinical response to ICI treatment and negative outcomes in HCC patients. HighLRP1B expression correlated with tumor immunity and HCC prognosis.Keywords: LRP1B mutation, ICI treatment response, prognosis, HCC, TMB

Yingsha Chen,1,2 Shuaibing Ying,1 Lushun Jiang,1 Shaohua Dong,1 Jinyao Dai,1 Xuehang Jin,1 Wei Yu,1 Yunqing Qiu1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Infectious Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Wei Yu; Yunqing Qiu, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China, Tel +86-571-87236606, Fax +86-571-87236606, Email wyu@zju.edu.cn; qiuyq@zju.edu.cnBackground: Our study aimed to explore the risk factors in bloodstream infections Klebsiella pneumoniae (BSI-KP) patients and establish nomograms to predict the probability of BSI-CRKP and the prognosis of BSI-KP.Methods: A total of 252 BSI-KP patients were enrolled from a tertiary teaching hospital between January 1, 2015, and May 31, 2020. Risk factors associated with BSI-CRKP and factors associated with the 30-day mortality were identified using LASSO analysis, univariate and multivariate analysis.Results: There were 121 (48.0%) patients with carbapenem-resistant K. pneumoniae (CRKP) and 131 (52.0%) patients with carbapenem-susceptible K. pneumoniae (CSKP). The multivariate logistic regression analysis demonstrated that gastric tube indwelling before BSI (OR=2.442, P=0.043) and more types of antibiotics use before BSI (OR=1.305, P=0.009) were independent risk factors for BSI-CRKP. And previous transplantations, prior ICU stay, gastric tube indwelling before BSI, more types of antibiotics use before BSI, lower Hb and cholinesterase were associated with CRKP-BSI. The C-index of models indicated its good accuracy (C-index 0.816, 95% CI 0.763– 0.868). In patients with BSI-CRKP, further logistic regression analysis revealed urinary catheterization (OR=0.298, P=0.017) was found to be an independent risk factor for 30-day mortality, while ceftazidime/avibactam use (OR=8.438, P=0.003) was an independent favorable prognostic factor. The nomogram predicated CRKP, ICU hospitalization, more types of antibiotics use, tigecycline, PLT, urinary catheterization were associated with 30-day mortality in patients with BSI-KP. The discriminative ability of the predictive model, as assessed by C-index, was 0.813 (95% CI: 0.780– 0.867).Conclusion: Previous transplantations, prior ICU stay, gastric tube indwelling before BSI, more types of antibiotics use before BSI, lower Hb and cholinesterase represent significant risk factors for the development of BSI-CRKP. Our nomogram predicated thrombocytopenia was a sign for poor prognosis. Tigecycline resulted in higher mortality for patients with BSI-KP. Rational use of nomograms may help clinicians make better Clinical decisions when treating BSI-KP patients.Keywords: carbapenem-resistant Klebsiella pneumoniae, prognostic model

Wen Hu,1,2,&ast; Panpan Yang,3,&ast; Zhenzhen Fu,1 Yongqing Wang,4 Ying Zhou,1 Zhengqin Ye,1 Yingyun Gong,1 Aijie Huang,1 Luning Sun,4 Yang Zhao,5 Tao Yang,1 Zhong Li,6,7 Xian-Cheng Jiang,8 Weinan Yu,2 Hongwen Zhou1,6 1Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, Jiangsu, People’s Republic of China; 3Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, Jiangsu, People’s Republic of China; 4Research Division of Clinical Pharmacology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5School of Public Health Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 6Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 7Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 8Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA&ast;These authors contributed equally to this workCorrespondence: Hongwen Zhou, Department of endocrinology, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People’s Republic of China, Tel +862583718836-6893, Fax +862583781781, Email drhongwenzhou@njmu.edu.cn Weinan Yu, Department of Endocrinology and Metabolism, Huai’an Hospital Affiliated to Xuzhou Medical University and Huai’an Second People’s Hospital, Huai’an, 223001, People’s Republic of China, Email hayuweinan@163.comObjective: Branched-chain amino acids (BCAAs) are essential AAs which are widely used as antioxidants in patients with liver and kidney dysfunction. However, BCAAs are strongly correlated with insulin resistance (IR) and diabetes. This study aimed to evaluate the relationship among BCAAs, oxidative stress, and type 2 diabetes mellitus (T2DM) in a Chinese population.Methods: Anthropometric and biochemical examinations were performed in 816 individuals who participated in the Huai’an Diabetes Prevention Program. Serum BCAAs concentrations were measured by hydrophilic interaction chromatography-tandem mass spectrometric method. Oxidative stress was evaluated by malondialdehyde (MDA) as an index of lipid peroxidation and the superoxide dismutase (SOD) activity.Results: A total of 816 participants were divided into three groups: normal glucose metabolism (NGM), prediabetes, and newly-diagnosed diabetes mellitus (NDM). Subjects in NDM group show higher MDA and lower SOD levels than subjects in other groups. L-Val levels positively correlated with MDA levels and negatively with SOD in NDM groups. After adjusting for T2DM risk factors, high L-Val levels were significantly associated with higher BMI, WC, FPG, increased LnTG and decreased HDL-C. L-Val was also independently associated with NDM (OR 1.06, 95% CI 1.02– 1.10; P = 0.005). Furthermore, the odds ratios for NDM among participants with high L-Val (≥ 35.25μg/mL) levels showed a 2.25-fold (95% CI 1.11– 4.57; P = 0.024) increase compared to participants with low L-Val (< 27.26 μg/mL) levels after adjusting for MDA and confounding factors.Conclusion: High serum L-Val levels are independently associated with oxidative stress, thus promoting IR and NDM. Further study should be done to clarify the mechanism.Keywords: branched chain amino acids, oxidative stress, new diagnosed type 2 diabetes mellitus, hydrophilic interaction chromatography-tandem mass spectrometric method

Yukun He,1 Wenyi Yu,1 Pu Ning,1,2 Qiongzhen Luo,1,3 Lili Zhao,1 Yu Xie,1 Yan Yu,1 Xinqian Ma,1 Li Chen,1 Yali Zheng,1,4 Zhancheng Gao1,4 1Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing, 100044, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Respiratory & Critical Care Medicine, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 4Department of Respiratory, Critical Care, and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of ChinaCorrespondence: Yali ZhengDepartment of Respiratory, Critical Care, and Sleep Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of ChinaEmail yali_zheng@126.comZhancheng GaoDepartment of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, 100044, People’s Republic of ChinaEmail zcgao@bjmu.edu.cnBackground: Infiltration of the lower respiratory tract (LRT) microenvironment could be significantly associated with respiratory diseases. However, alterations in the LRT microbiome and metabolome in infectious and inflammatory respiratory diseases and their correlation with inflammation still need to be explored.Methods: Bronchoalveolar lavage samples from 44 community-acquired pneumonia (CAP) patients, 29 connective tissue disease-associated interstitial disease (CTD-ILD) patients, and 30 healthy volunteers were used to detect microbiota and metabolites through 16S rRNA gene sequencing and untargeted high-performance liquid chromatography with mass spectrometry.Results: The composition of the LRT microbial communities and metabolites differed in disease states. CAP patients showed a significantly low abundance and both diseases presented a depletion of some genera of the phylum Bacteroidetes, including Prevotella, Porphyromonas, and health-associated metabolites, such as sphingosine (d16:1), which were negatively correlated with infectious indicators. In contrast, Bacillus and Mycoplasma were both enriched in the disease groups. Streptococcus was specifically increased in CTD-ILD. In addition, co-elevated metabolites such as FA (22:4) and pyruvic acid represented hypoxia and inflammation in the diseases. Significantly increased levels of amino acids and succinate, as well as decreased itaconic acid levels, were observed in CAP patients, whereas CTD-ILD patients showed only a handful of specific metabolic alterations. Functions related to microbial lipid and amino acid metabolism were significantly altered, indicating the possible contributions of microbial metabolism. Dual omics analysis showed a moderate positive correlation between the microbiome and metabolome. The levels of L-isoleucine and L-arginine were negatively correlated with Streptococcus, and itaconic acid positively correlated with Streptococcus.Conclusion: In the LRT microenvironment, shared and specific alterations occurred in CAP and CTD-ILD patients, which were associated with inflammatory and immune reactions, which may provide a new direction for future studies aiming to elucidate the mechanism, improve the diagnosis, and develop therapies for different respiratory diseases.Keywords: community-acquired pneumonia, connective tissue disease-associated interstitial disease, microbiome, metabolome, shared and specific alterations

Kangjun Fan,1 Liang Chen,1 Fei Liu,2 Xiaohang Ding,1 Pengyun Yan,1 Mingxin Gao,1 Wenyuan Yu,1 Hongli Liu,1 Yang Yu1 1Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of China; 2Department of Biology, Faculty of Science, Hong Kong Baptist College, Kowloon Tong, Hong Kong, People’s Republic of ChinaCorrespondence: Yang Yu, Tel +86-10-64456868, Fax +86-10-84005030, Email heartyuyang@hotmail.comObjective: To select variables associated with new-onset postoperative atrial fibrillation (POAF) following isolated coronary artery bypass grafting (CABG) and develop a nomogram for risk prediction in a Chinese population.Methods: The study retrospectively enrolled 4854 consecutive patients undergoing isolated CABG from February 2018 to September 2019, they were divided into derivation cohort and validation cohort with a 3:1 ratio according to the order of operation date. In the derivation cohort, significant variables were selected by use of the multivariate logistic backward stepwise regression analysis and a nomogram model was built on the strength of the results. The model performance was assessed in terms of discrimination and calibration. Besides, we compared the discriminative ability for POAF of the nomogram with established prediction models (CHA2DS2-VASc and HATCH scores) in the two cohorts.Results: POAF occurred in 1025 (28.2%) out of 3641 patients in the derivation cohort, and in 337 (27.8%) out of 1213 patients in the validation cohort. A nomogram, composed of eight prognostic variables, namely age, sex, heart rate, hypertension, left ventricular ejection fraction (LVEF) < 50%, left atrial diameter (LAD) > 40mm, estimated glomerular filtration rate (eGFR) level, and on-pump surgery, was constructed from the derivation cohort. The nomogram had substantial discriminative ability in derivation and validation cohorts with the area under the receiver operating characteristic curves (AUCs) of 0.661 (95% confidence interval, 0.642– 0.681) and 0.665 (95% confidence interval, 0.631– 0.699), respectively, and showed well-fitted calibration curves. Compared with CHA2DS2-VASc, HATCH and POAF scores, respectively, the nomogram had superior discrimination performance.Conclusion: We constructed a novel nomogram with improved accuracy for predicting the risk of POAF following isolated CABG, which might help clinicians predict individual probability of POAF and achieve effective prophylaxis.Keywords: coronary artery bypass grafting, atrial fibrillation, high-risk patients, prediction, nomogram

Jianhua Zhen,1,&ast; Pengfei Zhao,1,2,&ast; Yini Li,1,&ast; Yanan Cai,1,&ast; Wanchen Yu,1,&ast; Wei Wang,1 Lu Zhao,1 Hesong Wang,1 Guangrui Huang,1 Anlong Xu1,3 1School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Oncology Department, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3State Key Laboratory of Bio-control, Department of Biochemistry, School of Life Sciences, Sun Yat-Sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Anlong Xu; Guangrui Huang, Email xuanlong@bucm.edu.cn; hgr@bucm.edu.cnObjective: To explore changes in the gut microbiota (GM), urine metabolome and plasma proteome in individuals with allergies using multiomics analyses, and identify the key components and mechanism.Methods: This was a cross-sectional study. All subjects were recruited to collect fecal, urine and blood samples. 16S rDNA sequencing was used to analyze the structure and function of the GM, liquid chromatography mass spectrometry was used to quantify metabolites in the urine, and data-independent acquisition quantitative proteome analysis was used to detect proteins in the plasma. Differences in GM, urine metabolites and plasma proteins between allergic and healthy individuals were displayed using principal component analysis (PCoA) and heatmap, and the co-occurrence network was visualized in Cytoscape using Spearman correlation among differential predominant genera, metabolites and proteins. The functional analysis was performed according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) dataset. The allergy-related cytokines, IL-4, IL-6 and IL-13, were measured to evaluate the effect of indole derivatives on LPS-induced macrophage activation.Results: GM α indexes, β distances and the relative abundance of the core differential genera in the allergic group were different from those of healthy individuals, which resulted in a separate distribution in the PCoA and enterotypes. Similarly, the concentrations of 393 metabolites and 144 proteins were different between allergic and healthy individuals. Then, 634 significant correlations were identified among 6 predominant differential genera, 24 differential metabolites and 104 differential proteins, 301 of which were negative and 333 of which were positive. Notably, a core network centered on tryptophan metabolites, indole-3-butyric acid (IBA) and indole-3-lactic acid (ILA), displayed high consistency with the results of KEGG pathway analysis. In the LPS-stimulated macrophages, IBA reduced the expression of IL-4 and IL-6, and ILA inhibited the upregulation of IL-6.Conclusion: The GM, urine metabolome and plasma proteome underwent systematic change in allergic individuals compared to healthy individuals, among which indole derivatives from tryptophan metabolism might play key roles in the progression of allergies and could serve as therapeutic targets of allergy.Keywords: allergy, multiomics, gut microbiota, urine metabolome, plasma proteome

Chenglong Sun,1 Wenhao Zheng,2 Qiang Zhu,1 Quan Du,1 Wenhua Yu1,3 1Department of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2The Fourth Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Neurosurgery, Hangzhou Ninth People’s Hospital, Hangzhou, People’s Republic of ChinaCorrespondence: Wenhua YuDepartment of Neurosurgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, No. 261, Huansha Road, Hangzhou, People’s Republic of ChinaEmail ywhsyyy@163.comBackground: The pear shape of an inflated balloon is thought to be a gold standard of successful percutaneous balloon compression (PBC). However, neither how nor why it changes in that way (the anatomic basis) has not yet been fully described.Aim: In this article, we try to describe how the balloon in Meckel’s cave (MC) should appear and why; and identify which shapes are good pear shapes, which shapes are not good pear shapes, and which shapes are intermediate.Methods: Radiographs from over 150 percutaneous balloon compression (PBC) cases were thoroughly evaluated. We proposed a model of changing balloon shape in MC and 70 cases were followed up over two years, in which therapeutic effect was measured.Results: We found that the balloon changed stereotypically in MC. The model that we proposed is consistent with the description of MC’s structures and its’ surroundings in the literature. The distinct pear (pear in MC) brought about a far better surgical result than other shapes (p < 0.01).Conclusion: Our study showed how and why the balloon shape changed during PBC surgery. The model provides clear guidance for PBC surgery.Keywords: percutaneous balloon compression, balloon shape transformation, trigeminal neuralgia, Meckel’s cave

Changshan Huang, Wei Yu, Qian Wang, Tao Huang, Yuechao Ding Department of Hepato-Biliary-Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, People’s Republic of ChinaCorrespondence: Changshan HuangDepartment of Hepato-Biliary-Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450003, People’s Republic of ChinaTel +86 371 65587028Email hnhcs@163.comBackground: Circular RNA (circRNA) is a key regulator for the malignant progression of cancer. However, the role of circRNA anthrax toxin receptor 1 (circANTXR1) in hepatocellular carcinoma (HCC) is still unclear.Methods: Quantitative real-time PCR was performed to detect RNA expression. Cell proliferation, migration and invasion were determined using MTT assay, EdU staining, colony formation assay, wound healing assay and transwell assay. The protein levels of metastasis markers, x-ray repair cross complementing 5 (XRCC5) and exosome markers were examined using Western blot analysis. Xenograft tumor models were built to investigate the role of circANTXR1 in HCC tumorigenesis. The relationship between microRNA (miR)-532-5p and circANTXR1 or XRCC5 was confirmed by dual-luciferase reporter assay and RNA pull-down assay. The identification of exosomes were performed using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA).Results: CircANTXR1 was a stable and highly expressed circRNA in HCC. Silenced circANTXR1 inhibited the proliferation, migration and invasion of HCC cells in vitro, and suppressed HCC tumor growth in vivo. MiR-532-5p could be sponged by circANTXR1, and its inhibitor could reverse the inhibition of circANTXR1 silencing on HCC cells progression. In addition, we discovered that XRCC5 was a target of miR-532-5p. Furthermore, XRCC5 overexpression could reverse the suppressive effect of miR-532-5p overexpression on HCC cell proliferation, migration and invasion. Exosome was involved in the transport of circANTXR1 in HCC cells. Exosome circANTXR1 might be a potential serum biomarker for HCC patients.Conclusion: CircANTXR1 promotes the progression of HCC through the miR-532-5p/XRCC5 axis, which might be a potential serum biomarker and therapeutic target of HCC.Keywords: hepatocellular carcinoma, circANTXR1, miR-532-5p, XRCC5, exosome

Jixin Chen,1,2,&ast; Aifeng Liu,1,2,&ast; Qinxin Zhou,1,2 Weijie Yu,1,2 Tianci Guo,1,2 Yizhen Jia,1,2 Kun Yang,1,2 Puyu Niu,1,2 Huichuan Feng1,2 1Department of Orthopaedic Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300381, People’s Republic of China; 2National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Aifeng LiuDepartment of Orthopaedic Surgery, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 88 Changling Road, Xiqing District, Tianjin, 300381, People’s Republic of ChinaTel +86-13803091533Email draifeng@163.comBackground: Acupuncture has been widely used in the clinical management of osteoarthritis of the knee (KOA). Many systematic reviews (SRs) and meta-analyses (MAs) have reported its effectiveness in relieving pain. This overview aimed to summarize SRs and MAs on the effectiveness and safety of acupuncture for KOA and evaluate their methodological and evidence quality of the included SRs and MAs.Methods: We conducted a comprehensive literature search for SRs and MAs in four Chinese and four international databases from their inception until August 2021. Two researchers independently searched the reviews, extracted the data, and cross-checked the data. The Assessing the Methodological Quality of Systematic Reviews 2 (AMSTAR 2) tool was used to evaluate the methodological quality of the included SRs and MAs. The Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used to assess the quality of evidence for the outcomes of the included SRs and MAs.Results: A total of 14 SRs and MAs were included. The evaluation results of the AMSTAR 2 tool showed that the methodological quality of all the 14 SRs and MAs was critically low. The principal causes are the lack of a pre-registration proposal and a list of excluded studies and justify the exclusions, the report on the sources of funding, and the reasons for the study designs for inclusion. The results of the GRADE evaluation showed 25 of 46 outcomes were very low-level evidence. Seventeen were of low level, four were of moderate level and none were of high level. Most outcomes were downgraded in quality of evidence mainly because of publication bias and imprecision.Conclusion: The existing evidence suggests that acupuncture seems to be an effective and safe therapy for KOA. However, the deficiencies in the methodological quality and quality of evidence of the included SRs/MAs have limited the reliability of the conclusions. Therefore, further rigorous and comprehensive studies are warranted to verify the effectiveness and safety of acupuncture in KOA.Keywords: acupuncture, knee osteoarthritis, overview, AMSTAR 2, GRADE, systematic review

Jiajie Zhang,1 Yicheng Huang,1 Hao Xu,2 Shuaibing Ying,2 Hongying Pan,1 Wei Yu2 1Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Hongying PanDepartment of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of ChinaTel/Fax +86-571-85893027Email hypanhz@139.comWei YuState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaTel/Fax +86-571-87236606Email wyu@zju.edu.cnBackground: Vibrio vulnificus (VV) is a causative agent of foodborne diseases with high mortality. The aim of this study was to investigate the genomic and phenotypic profiles of VV.Methods: Six VV isolates were collected and conducted whole-genome sequencing. Biofilm formation and anti-complement killing test were performed to evaluate the pathogenicity. Subsequently, 157 publicly available genomes of VV isolates were selected to determine the evolutionary relationship.Results: The resistant genes norM and tet34 were identified in six isolates. A total of 156 virulence genes were identified. However, there is no obvious difference between strains isolated from blood and puncture fluid. The tendency of growth for six isolates decreased with the lapse of time, while the biofilm formation increased. The genes tadC and flp related to Flp pili were found in isolate 25506 and 30896, resulting in more obvious biofilm formation. In addition, the survival rate of 19656 was less than 20% due to lack of one genomic island including virulence genes (impD-H, clpV-1) relevant to type VI secretion system (T6SS). Multi-locus sequence typing (MLST) revealed 95 different STs and 19 novel STs, indicating that the tendency of 163 isolates was sporadic. Further comparative genomics analysis clearly classified 163 isolates into three distinct evolutionary lineages.Conclusion: VV infections were sporadic in humans and the environment. Virulence genes impD-H and clpV-1 related to T6SS were associated with pathogenicity phenotype of VV.Keywords: resistance genes, virulent factors, biofilm, type VI secretion system

Wenqing Yu,1,&ast; Ningfei Ji,2,&ast; Chengjing Gu,3,&ast; Juan Yao,4 Mingdong Ding,1 Daming Zhou,1 Mao Huang,2 Mingshun Zhang5,6 1Department of Infectious Diseases, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China; 3Department of Pharmacy, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People’s Republic of China; 4Department of Oncology, Huaian Hospital of Huaian City, Huaian, Jiangsu, 223200, People’s Republic of China; 5Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of China; 6NHC Key Laboratory of Antibody Technique, Nanjing Medical University, Nanjing, Jiangsu, 211166, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chengjing GuDepartment of Pharmacy, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People’s Republic of ChinaTel +86 0523-86606290Email chengjingyu706@163.comWenqing YuDepartment of Infectious Diseases, Taizhou People’s Hospital Affiliated to Nantong University, Taizhou, Jiangsu, 225300, People’s Republic of ChinaEmail wenqinggu706@126.comBackground: RORγt+Foxp3+ (Th17-like) Tregs are a plastic Treg subset implicated in immune-related diseases; however, the mechanism of Treg phenotypic transformation in malignant pleural effusion (MPE) has not been elucidated.Methods: The percentage of CD4+CD25+Foxp3+Helios+ and RORγt+Foxp3+ Tregs from peripheral blood and pleural effusion mononuclear cells were measured. The level of interferon regulatory factor 4 (IRF4) mRNA expression was detected by quantitative real-time reverse transcription polymerase chain reaction. The effects of IRF4 on the induction of Tregs from patients with non-small cell lung cancer (NSCLC) were evaluated in vitro. Correlation assays between IRF4 expression and the frequency of RORγt+Foxp3+ Tregs were performed.Results: The frequency of CD4+CD25+Foxp3+Helios+ Tregs and CD4+RORγt+ Th17 cells was both increased in the MPE of NSCLC patients. The group of double-positive Foxp3+RORγt+ Treg phenotype were identified in the pleural effusion. A significant increase in the frequency of Foxp3+RORγt+ Tregs was found in MPE compared with the non-malignant pleural effusion (NPE). Compared to NPE, the relative level of IRF4 expression was increased in the MPE. IRF4 expression was positively associated with the frequency of Foxp3+RORγt+ Tregs in the PE. In vitro, the level of Helios mRNA and protein expression was reduced in induced Tregs following IRF4 over-expression. Additionally, the level of RORγt protein expression was substantially increased. However, ectopic Helios expression in induced Tregs reversed the effects induced by enhanced IRF4 expression.Conclusion: IRF4 may serve as a potential molecule that promotes the conversion of regulatory T cells from MPE to a Th17-like phenotype by modulating Helios.Keywords: malignant pleural effusion, lung cancer, IRF4, regulatory T cells, phenotypic transformation

Wenqiang Chen,1 Mingxia Jiang,1 Wenjing Yu,1 Zhiwei Xu,1 Xinyue Liu,1 Qingmiao Jia,1 Xiuwen Guan,1– 3 Weifen Zhang1– 3 1College of Pharmacy, Weifang Medical University, Weifang, 261053, People’s Republic of China; 2Collaborative Innovation Center for Target Drug Delivery System, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang Medical University, Weifang, 261053, People’s Republic of ChinaCorrespondence: Xiuwen Guan; Weifen Zhang Tel +86-536-8462490Email gxw2603@wfmc.edu.cn; zhangwf@wfmc.edu.cnAbstract: Cancer has been a serious health hazard to the people all over the world with its high incidence and horrible mortality. In recent years, tumor vaccines in immunotherapy have become a hotspot in cancer therapy due to their many practical advantages and good therapeutic potentials. Among the various vaccines, nanovaccine utilized nanoparticles (NPs) as the carrier and/or adjuvant has presented significant therapeutic effect in cancer treatment. For tumor nanovaccines, unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) is a commonly used adjuvant. It has been reported that CpG ODN was the most effective immune stimulant among the currently known adjuvants. It could be recognized by toll-like receptor 9 (TLR9) to activate humoral and cellular immunity for preventing or treating cancer. In this review, the topic of CpG-based nanovaccines for cancer immunotherapy will be focused. The types and properties of different CpG will be introduced in detail first, and then some representative tumor nanovaccines will be reviewed according to the diverse loading modes of CpG, such as electrostatic adsorption, covalent bonding, hydrophilic and hydrophobic interaction, and DNA self-assembly, for summarizing the current progress of CpG-based tumor nanovaccines. Finally, the challenges and future perspectives will be discussed. It is hoped that this review will provide valuable references for the development of nanovaccines in cancer immunotherapy.Keywords: cancer immunotherapy, nanovaccine, nanoparticle, adjuvant, CpG

JinJian Yao,1,&ast; Hangfei Wang,2,&ast; Weiling Yu,3,&ast; Yimin Li,4 Zhiqian Luo,2 Biao Wu,5 Wei Zhang,6 Xiaoran Liu,2 Chuanzhu Lv6,7 1Emergency Center, Hainan General Hospital Affiliated to Hainan Medical University, Haikou, Hainan, People’s Republic of China; 2Department of Emergency, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, People’s Republic of China; 3Oncology Department, Haikou City People’s Hospital, Haikou, Hainan, People’s Republic of China; 4Department of General Surgery, Yang Jiang Hospital of Qiongzhong, Qiongzhong, Hainan, People’s Republic of China; 5Department of Infectious Disease, Hainan General Hospital Affiliated to Hainan Medical University, Haikou, Hainan, People’s Republic of China; 6Emergency and Trauma College of Hainan Medical University, Haikou, Hainan, People’s Republic of China; 7Key Laboratory of Emergency and Trauma, Ministry of Education of Hainan Medical University, Haikou, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoran LiuDepartment of Emergency, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, People’s Republic of ChinaTel +8613118901829Email liuxiaoran3192@163.comChuanzhu LvKey Laboratory of Emergency and Trauma, Ministry of Education of Hainan Medical University, Haikou, Hainan, People’s Republic of ChinaTel +8617789830771Email lvchuanzhu677@126.comIntroduction: Close contacts of individuals with COVID-19 may directly gain immunity against SARS-CoV-2 despite lacking a detectable infection. This study examined SARS-CoV-2-specific antibodies levels based on gender, age, and exposure source in close contacts of individuals with COVID-19 and compared antibody levels to patients with an asymptomatic or symptomatic COVID-19 infection.Methods: Two patients had confirmed COVID-19 infections at a community hospital in Qiongzhong, Hainan province. Contact tracing identified all individuals in the community who had been exposed to the two patients during the 14 days before their diagnoses. Close contacts quarantined for 14 days, underwent two SARS-CoV-2 tests, and were screened for SARS-CoV-2-specific antibodies at 7 and 12 weeks after the end of quarantine. SARS-CoV-2-specific antibody levels for the close contacts were compared to those for patients with an asymptomatic or symptomatic COVID-19 infection at 7 and 12 weeks after their diagnoses.Results: Contact tracing identified 10,573 individuals in the community, including 360 (3.4%) close contacts. At 7 weeks, 30 (8.33%) close contacts were positive for SARS-CoV-2-specific antibodies (IgG, n = 26 [7.22%]; IgM, n = 4 [1.11%]), which were lower than the proportion of patients with an asymptomatic (IgG, 100% [12/12]) or symptomatic (IgG, 93.6% [44/47]) COVID-19 infection. SARS-CoV-2-specific IgM antibody levels were significantly higher in close contacts who were exposed through a relative compared to a doctor–patient relationship (P = 0.032). SARS-CoV-2-specific IgG antibody levels were significantly higher in close contacts aged < 18 years vs 18– 64 years (P = 0.014). At 12 weeks, SARS-CoV-2-specific IgG antibody levels among close contacts were significantly lower than among patients with an asymptomatic (P = 0.004) or symptomatic COVID-19 infection (P < 0.001).Conclusion: Immune protection conferred by close contact is short term and unlikely to contribute to herd immunity. There remains an unmet public health need for mass vaccination of populations to increase levels of protective antibodies and achieve and maintain herd immunity.Keywords: SARS-CoV-2, COVID-19, antibody, close contact

Yuanyuan Dai,1 Wenjiao Chang,1 Xin Zhou,1 Wei Yu,2 Chen Huang,2 Yunbo Chen,2 Xiaoling Ma,1 Huaiwei Lu,1 Rujin Ji,2 Chaoqun Ying,2 Peipei Wang,2 Zhiying Liu,2 Qingfeng Yuan,1 Yonghong Xiao2 1Department of Laboratory, First Affiliated Hospital of University of Science and Technology of China, Hefei, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Yonghong Xiao Tel/Fax +865 718 723 6421Email xiao-yonghong@163.comPurpose: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa.Methods: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen.Results: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤ 8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51– 89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121– 190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa. When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa.Conclusion: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses.Keywords: Gram-negative bacteria, extended-spectrum β-lactamase, dosage regimens, pharmacokinetics, pharmacodynamics, minimum inhibitory concentration

Jiepeng Tong,1 Yiheng Jiang,2 Hao Xu,1 Xuehang Jin,1 Li Zhang,1 Shuaibing Ying,1 Wei Yu,1 Yunqing Qiu1 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Clinical Medicine, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Wei Yu; Yunqing Qiu Email wyu@zju.edu.cn; qiuyq@zju.edu.cnPurpose: The emergence of vancomycin resistant Enterococci (VRE) is shortening the choices for clinical anti-infective therapy. The aim of this study was to investigate the mechanism of vancomycin resistance and evaluate the effect of fosfomycin (FM), rifampin (RIF), vancomycin (VAN), linezolid (LNZ), daptomycin (DAP) alone or in combination against VRE.Methods: Eight VRE isolates were collected. A total of 18 antibiotics susceptibility tests were further done for VRE. Whole genome sequencing and bioinformatics analysis were performed. The effect of FM, RIF, VNA, LNZ, DAP alone or in combination was determined using anti-biofilm testing and the time-kill assay.Results: All isolates were susceptible to LNZ and DPA. The high-level resistance determinant of VAN in these strains was due to VanA-type cassette. MLST revealed two different STs for vancomycin-resistant Enterococcus faecium (VREm) and four different STs for vancomycin-resistant E. faecalis (VREs). Virulence genes in VREs were more than VREm, especially for 4942 isolated from blood. Gene acm and uppS were only identified in VREm, while virulence genes related to cytolysin were only found in E. faecalis. Further in vitro studies indicated FM (83 mg/L) combined with DAP (20.6 mg/L) and DAP monotherapy (47.1 mg/L) had bactericidal effect against VRE isolates at 24h.Conclusion: High-level resistance determinant of VAN in tested isolates was due to VanA-type cassette. FM combined with DAP is a potential therapeutic option for VRE infections.Keywords: vancomycin, daptomycin, combination therapy, biofilm

Qi Li,&ast; Wanbing Dai,&ast; Xuemei Chen, Diansan Su, Weifeng Yu, Xiyao Gu Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiyao GuDepartment of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People’s Republic of ChinaTel +86-21-68383256Email gxykevin@126.comPurpose: Aging populations and increasing quality of life requirements have attracted growing efforts to study chronic postsurgical pain (CPSP). However, a diverse range of factors are involved in CPSP development, which complicates efforts to predict and treat this disease. To advance research in this field, our study aimed to use bibliometric analysis to quantitatively and qualitatively evaluate CPSP research and predict research hot spots over the last 10 years.Methods: Relevant publications between 2011 and 2020 were extracted from the Web of Science Core Collection database. CiteSpace software (v5.7.R2) and the Online Analysis Platform of Literature Metrology were used to analyze research attributes including countries and authors, keywords and co-occurrence, and burst detection to predict trends and hot spots.Results: A total of 2493 publications were collected with the number of annual publications showing nearly threefold increase over the past decade. Articles were the primary publication type with the United States as the leading country and the center of national collaboration. Johns Hopkins University provided the leading influence within the CPSP field. Postoperative pain, multimodal analgesia, quality of life, opioid, microglia, cesarean delivery, inguinal hernia, chronification, genetic polymorphism, and lidocaine were the top 10 clusters in co-occurrence cluster analysis. Moreover, burst detection was shown that epidural analgesia, nerve injury, total hip arthroplasty were the new hot spots within the CPSP field.Conclusion: Bibliometric mapping not only defined the overall structure of CPSP-related research but its collective information provides crucial assistance to direct ongoing research efforts. The prominent keywords including ”risk factor” and “multimodal analgesia” indicate that CPSP prevention and new treatment methods remain hot spots. Nonetheless, the recognition that CPSP is complex and changeable, proposes comprehensive biopsychosocial approaches are needed, and these will be essential to improve CPSP interventions and outcomes.Keywords: chronic postsurgical pain, bibliometric analysis, CiteSpace, co-citation analysis, burst detection with keywords

Siyu He,1 Kornkanok Tripanpitak,2 Yu Yoshida,2 Shozo Takamatsu,3 Shao Ying Huang,4 Wenwei Yu2,5 1Graduate School of Engineering, Chiba University, Chiba, Japan; 2Graduate School of Science and Engineering, Chiba University, Chiba, Japan; 3Omron Healthcare Co., Ltd, Kyoto, Japan; 4Engineering Product Development, Singapore University of Technology and Design, Singapore; 5Center for Frontier Medical Engineering, Chiba University, Chiba, JapanCorrespondence: Wenwei YuGraduate School of Science and Technology, Building1-501, Yayoi-Cho, Inage-Ku, Chiba, 263-8522, JapanTel/Fax +81 043 290 3231Email yuwill@faculty.chiba-u.jpPurpose: Few investigations have been conducted on the selective stimulation of small-radius unmyelinated C nerves (C), which are critical to both the recovery of damaged nerves and pain suppression. The purpose of this study is to understand how an anodal pulse in an anodal-first stimulation could improve C-selectivity over myelinated nociceptive Aδ nerves (Aδ) and to further clarify the landscape of the solution space.Materials and Methods: An adapted Hodgkin–Huxley (HH) model and the McIntyre–Richardson–Grill (MRG) model were used for modeling C and Aδ, respectively, to analyze the underlying ion dynamics and the influence of relevant stimulation waveforms, including monopolar, polarity-symmetric, and asymmetric pulses.Results: The results showed that polarity asymmetric waveforms with preceding anodal stimulations benefit C-selectivity the most, underlain by the decrease in the potassium ion current of C.Conclusion: The optimal parameters for C-selectivity have been identified in the low-frequency band, remarkably benefiting the design of selective stimulation waveforms for the recovery of damaged nerves and pain management.Keywords: anodal-first stimulation, C-selectivity, ion dynamics, polarity-asymmetric waveforms