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Wei Xiao,1 Yanqiong Liu,2 Hua Tang,3 Qin Xie,2 Yanlan Luo,2 Tao Mei1 1Department of Neurosurgical Care Unit, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, 415003, People’s Republic of China; 2Cardiovascular Medicine Department, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, 415003, People’s Republic of China; 3Neurosurgery Department, Changde Hospital, Xiangya School of Medicine, Central South University, Changde, 415003, People’s Republic of ChinaCorrespondence: Tao Mei, Email yilan1008@sina.comBackground: Intracerebral hemorrhage (ICH) affects up to 1% of chronic oral anticoagulation (OAC) users per year. This study explored the knowledge, attitude and practice (KAP) towards ICH prevention among patients taking OACs.Methods: This multicenter cross-sectional survey was conducted at 4 hospitals from February to May 2023, and a self-administered questionnaire was developed to assess KAP toward ICH prevention among patients taking OACs. Structural equation modeling was used to assess the relationship between KAP.Results: A total of 536 valid questionnaires (67.25%) were analyzed, from 43.8% participants on Warfarin, 40.5% on Rivaroxaban and 15.7% on Dabigatran. The average knowledge, attitudes and practice scores were 9.22, 24.11, and 28.01 out of 16, 35 and 40, respectively. Participants who received Rivaroxaban had lower knowledge scores but higher attitude and practice store compared to those who received Warfarin or Dabigatran (all p < 0.001). According to Structure Equation Modeling, attitude had direct positive effect on practice (β = 0.694 [0.603– 0.804], p = 0.012), while knowledge had direct negative effect on attitude (β = − 2.077 [− 2.507– 1.651], p = 0.013), as well as negative effect on practice, both direct (β = − 0.450[− 0.689– 2.03], p=0.012), and indirect (β = − 1.441 [− 1.928– 1.192], p = 0.004).Conclusion: Patients taking OACs showed insufficient knowledge, negative attitude and proactive practice regarding ICH; practice scores were affected by age, type of anticoagulation medication, and attitude rather than knowledge.Keywords: cerebral hemorrhage, anticoagulants, warfarin, dabigatran, rivaroxaban, knowledge, attitude, practice

Shi-Yuan Fan,1,&ast; Zi-Chi Zhao,1,&ast; Xing-Lv Liu,1 Ying-Gang Peng,1 Hui-Min Zhu,1 Shi-Fan Yan,2 Yan-Juan Liu,2 Qin Xie,2 Yu Jiang,2 Sai-Zhen Zeng1 1The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China; 2Department of Emergency, Institute of Emergency Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sai-Zhen Zeng, The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), 61 Jie-Fang West Road, Fu-Rong District, Changsha, Hunan, 410005, People’s Republic of China, Email 55445321@qq.com Yu Jiang, Department of Emergency, Institute of Emergency Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), 61 Jie-Fang West Road, Fu-Rong District, Changsha, 410005, People’s Republic of China, Email jiangyu@hunnu.edu.cnBackground: Globally, the subsequent complications that accompany sepsis result in remarkable morbidity and mortality rates. The lung is among the vulnerable organs that incur the sepsis-linked inflammatory storm and frequently culminates into ARDS/ALI. The metformin-prescribed anti-diabetic drug has been revealed with anti-inflammatory effects in sepsis, but the underlying mechanisms remain unclear. This study aimed to ascertain metformin’s effects and functions in a young mouse model of sepsis-induced ALI.Methods: Mice were randomly divided into 4 groups: sham, sham+ Met, CLP, and CLP+ Met. CLP was established as the sepsis-induced ALI model accompanied by intraperitoneal metformin treatment. At day 7, the survival state of mice was noted, including survival rate, weight, and M-CASS. Lung histological pathology and injury scores were determined by hematoxylin–eosin staining. The pulmonary coefficient was used to evaluate pulmonary edema. Furthermore, IL-1β, CCL3, CXCL11, S100A8, S100A9 and NLRP3 expression in tissues collected from lungs were determined by qPCR, IL-1β, IL-18, TNF-α by ELISA, caspase-1, ASC, NLRP3, P65, p-P65, GSDMD-F, GSDMD-N, IL-1β and S100A8/A9 by Western blot.Results: The data affirmed that metformin enhanced the survival rate, lessened lung tissue injury, and diminished the expression of inflammatory factors in young mice with sepsis induced by CLP. In contrast to sham mice, the CLP mice were affirmed to manifest ALI-linked pathologies following CLP-induced sepsis. The expressions of pro-inflammatory factors, for instance, IL-1β, IL-18, TNF-α, CXCL11, S100A8, and S100A9 are markedly enhanced by CLP, while metformin abolished this adverse effect. Western blot analyses indicated that metformin inhibited the sepsis-induced activation of GSDMD and the upregulation of S100A8/A9, NLRP3, and ASC.Conclusion: Metformin could improve the survival rate, lessen lung tissue injury, and minimize the expression of inflammatory factors in young mice with sepsis induced by CLP. Metformin reduced sepsis-induced ALI via inhibiting the NF-κB signaling pathway and inhibiting pyroptosis by the S100A8/A9-NLRP3-IL-1β pathway.Keywords: sepsis, pediatric, inflammation, pyroptosis, ALI

Qian Xie,1,&ast; Chang Liu,1,&ast; Fen Liu,2 Xuehe Zhang,1 Zhiyang Zhang,1 Xin An,1 Yining Yang,3– 6 Xiaomei Li1 1Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 3Department of Cardiology, People’s Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, People’s Republic of China; 4Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, People’s Republic of China; 5State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, People’s Republic of China; 6Key Laboratory of Cardiovascular Disease Research, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yining Yang, Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830054, People’s Republic of China, Tel +86-991-4361690, Email yangyn5126@163.com Xiaomei Li, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, 830054, People’s Republic of China, Tel +86-991-4362611, Email lixm505@163.comPurpose: Metabolic Syndrome (MS) greatly increases the risk of heart disease and Heart Failure(HF). Insulin Resistance (IR) is considered to be the key to the pathophysiology of MS. The purpose of this study was to evaluate the predictive effect of different alternative indicators of IR on adverse cardiovascular events in patients with MS complicated with HF.Methods: Patients with HF who were diagnosed with MS in the heart center of the first affiliated Hospital of Xinjiang Medical University were selected continuously. The baseline data of the patients in the group were compared. The diagnostic value of alternative indexes of IR was evaluated by the working characteristic curve of subjects. The relationship between different alternative indicators of IR and survival rate was evaluated by survival curve. COX regression was used to analyze the effects of different alternative indicators of IR on the risk of end-point events.Results: The levels of TyG, TyG-BMI, TyG-WC, TG/HDL-C and METS-IR were significantly increased in patients with Major Adverse Cardiovascular Events (MACEs). Among the five alternative indexes of IR, METS-IR had the highest AUC (0.691, 95% CI:0.657– 0.752, P < 0.001) in predicting MACEs. No matter which alternative index of IR was used, the survival rate of MACEs in High group was significantly decreased. TyG, TyG-BMI, TyG-WC, TG/HDL-C and METS-IR can independently predict the occurrence of MACEs events, even if some confounding factors are adjusted.Conclusion: Our study shows that alternative indicators of IR, especially METS-IR, are independently associated with adverse cardiovascular events in patients with MS and HF.Keywords: insulin resistance indexes, metabolic syndrome, heart failure, predictive

Tao Sun,1,2 Shilin Xiao,1 Miaomiao Wang,1 Qian Xie,1 Liang Zhang,1 Mingfu Gong,1 Dong Zhang,1 Chunyu Zhou1 1Department of Radiology, Xinqiao Hospital, Army Medical University, Chongqing, People’s Republic of China; 2Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, People’s Republic of ChinaCorrespondence: Dong Zhang; Chunyu Zhou, Department of Radiology, Xinqiao Hospital, Army Medical University, No. 183, Xinqiao Street, Shapingba District, Chongqing, People’s Republic of China, Tel +86 23 68763842, Email hszhangd@tmmu.edu.cn; zhouchy@tmmu.edu.cnAbstract: Acute liver injury (AIL), a fatal clinical disease featured with a swift deterioration of hepatocyte functions in the short term, has emerged as a serious public health issues that warrants attention. However, the effectiveness of existing small molecular antioxidants and anti-inflammatory medications in alleviating AIL remains uncertain. The unique inherent structural characteristics of liver confer it a natural propensity for nanoparticle capture, which present an opportunity to exploit in the formulation of nanoscale therapeutic agents, enabling their selective accumulation in the liver and thereby facilitating targeted therapeutic interventions. Significantly increased reactive oxygen species (ROS) accumulation and inflammation response have been evidenced to play crucial roles in occurrence and development of AIL. Nanozymes with ROS-scavenging capacities have demonstrated considerable promise in ROS elimination and inflammation regulation, thereby offering an appealing therapeutic instrument for the management of acute liver injury. In this review, the mechanisms of different type of ALI were summarized. In addition, we provide a comprehensive summary and review of the available ROS-scavenging nanozymes, including transition metal-based nanozymes, noble metal nanozymes, carbon-based nanozymes, and some other nanozymes. Furthermore, the challenges still need to be solved in the field of ROS-scavenging nanozymes for ALI alleviation are also discussed.Keywords: acute liver injury, nanozyme, ROS-scavenging, antioxidant, anti-inflammation

Xuehe Zhang,1,&ast; Jixin Zhang,1,&ast; Fen Liu,2 Wenling Li,1 Tong Zhang,1 Binbin Fang,2 Zhiyang Zhang,1 Qian Xie,1 Yining Yang,3 Xiaomei Li1 1Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 2State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China; 3Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yining Yang, Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, 91 Tianchi Road, Urumqi, 830054, People’s Republic of China, Tel +86-991-4361690, Email yangyn5126@163.com Xiaomei Li, Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, 830054, People’s Republic of China, Tel +86-991-4362611, Email lixm505@163.comPurpose: There is a lack of research on nutritional status and poor prognosis in patients with metabolic syndrome and heart failure. This study evaluated the relationship between nutritional status as defined by the PNI and adverse outcomes in patients with metabolic syndrome and heart failure.Methods: A total of 1048 heart failure patients with metabolic syndrome admitted to the Heart Center of the First Affiliated Hospital of Xinjiang Medical University from January 2015 to December 2019 were consecutively. PNI was used to assess their nutritional status.Results: A total of 51.0% of the patients were in the nonmalnutrition group (PNI≥ 45), 27.9% were in the mild malnutrition group (40≤PNI< 45), and 21.1% of patients were in the malnutrition group (PNI< 40). At 36 months of follow-up, after adjusting for other confounding factors, malnutrition (PNI< 40) was independently associated with all-cause death (HR: 1.787, 95% CI: 1.451– 2.201, P< 0.001) and cardiovascular death (HR: 1.837, 95% CI: 1.467– 2.301, P< 0.001). PNI showed additional prognostic predictive value when included in the established risk factor model, both for all-cause death (AUC: 0.620, 95% CI: 0.579– 0.661, P< 0.001) and cardiovascular death (AUC: 0.596, 95% CI: 0.555– 0.636, P< 0.001).Conclusion: In patients with metabolic syndrome and heart failure, malnutrition assessed by PNI is an independent predictor for all-cause death and cardiovascular death, and PNI is negatively correlated with the occurrence of adverse outcomes.Keywords: prognostic nutritional index, metabolic syndrome, heart failure, malnutrition, prognosis

Li Zhou,1 Lai Wei,1 Yalin Chu,1 Qinhong Xie2 1Department of Health Management, School of Management, Zunyi Medical University, Zunyi, People’s Republic of China; 2Center for Mental Health Research, School of Management, Zunyi Medical University, Zunyi, People’s Republic of ChinaCorrespondence: Qinhong Xie, Center for Mental Health Research, School of Management, Zunyi Medical University, Zunyi, People’s Republic of China, Email xqinhongzmc@163.comObjective: The current study aimed to explore comprehensively college graduates’ negative life experiences, coping strategies, and enlightenment in a qualitative way.Methods: This was a qualitative study. Purposeful sampling was used to select 31 college graduates majoring in various subjects from a Chinese University. The one-on-one semi-structured interviews were conducted online through Tencent QQ/WeChat and were recorded and transcribed verbatim. A phenomenological approach was used to guide this research in the data collection and analysis. Thematic analysis was used to identify themes across interviews around their negative life experiences, coping strategies, and enlightenment.Results: College graduates’ negative life experiences were mainly focused on three aspects: negative work experience (eg, lack of adaptation, busy schedule, low salary), negative personal life experience (eg, multiple pressure, psychological problems, the hardship of life), and negative social life experience (eg, the incomprehension of those around you, complex interpersonal relationship, social complexity). The coping strategies they used can be classified into two categories: emotion-focused strategies (eg, accepting reality, self-persuasion, keeping a positive attitude), and problem-focused strategies (eg, goal-setting, asking for help to solve the problem, persistence). As for life enlightenment, six themes emerged: accept life, strive to life, love life, cherish life, recognize life, and learn to live.Conclusion: College graduates’ negative experiences came from multiple levels, and they use multiple coping strategies to deal with the challenges. Our results provide important guidance for researchers and policymakers to design effective and targeted intervention programs to improve college graduates’ coping abilities in response to negative life experiences and help them better transition from school to work. Specifically, future research and intervention to promote college graduates’ mental health should target various social-ecological levels, focus on promoting coping from an ecological perspective, as well as facilitate post-traumatic growth to help them grow from negative life experiences and cope positively.Keywords: college graduates, negative life experiences, coping, enlightenment, qualitative research, COVID-19 pandemic

Zike Sheng,1 Junjie Li,2 Chihua Chen,3 Jing Xie,4 Yumin Xu,5 Huijuan Zhou,1 Qing Xie1 1Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 5Department of Infection Control/Department of Nursing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Huijuan Zhou, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Building 36, 197 Ruijin Er Road, Shanghai, 200025, People’s Republic of China, Tel +86-21-64370045-680419, Fax +86-21-64454930, Email hjzhou419@163.comIntroduction: Human melioidosis is an emerging infectious disease in tropical areas of China, and chronic melioidosis can be a rare cause of fever of unknown origin (FUO). Timely diagnosis may improve the prognosis of melioidosis.Case Presentation: We report a case of melioidosis with splenic abscesses caused by Burkholderia pseudomallei in a 57-year-old man, who presented with FUO. Positron emission tomography/computed tomography (PET/CT) revealed multiple hypermetabolic lesions in the spleen. The spleen biopsy was conducted and metagenomics next-generation sequencing (mNGS) of the spleen specimen identified the presence of B. pseudomallei, confirming the diagnosis of melioidosis. Antimicrobial treatment was initiated with intravenous meropenem, followed by oral faropenem. During the follow-up, the patient was in good condition except having a low-grade fever occasionally. A splenectomy was performed, and subsequent culture and mNGS of the spleen pus were both positive for B. pseudomallei. Histopathological characteristics of chronic splenic melioidosis were noted.Conclusion: Melioidosis is a serious endemic disease, and it is critical to raise awareness about this disease.Keywords: melioidosis, Burkholderia pseudomallei, metagenomics next-generation sequencing, splenectomy

Qian Xie,1,* Shi Gao,1,* Rui Tian,2 Guohao Wang,3,4 Zainen Qin,5 Minglong Chen,1 Wenhui Zhang,1 Qiang Wen,1 Qingjie Ma,1 Lei Zhu1 1Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, NHC Key Laboratory of Radiobiology, School of Public Health of Jilin University, Changchun, 130033, People’s Republic of China; 2Department of Ophthalmology Second Hospital, Jilin University, Changchun, 130033, People’s Republic of China; 3Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 4Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, SAR, 999078, People’s Republic of China; 5Department of Oral Radiology, Guangxi Medical University College of Stomatology, Nanning, 530021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingjie Ma; Lei Zhu, Email maqj@jlu.edu.cn; zeh.ray8@gmail.comIntroduction: Combination therapy is a promising approach to promote the efficacy and reduce the systemic toxicity of cancer therapy. Herein, we examined the potency of a combined chemo-phototherapy approach by constructing a hyaluronidase- and reactive oxygen species-responsive hyaluronic acid nanoparticle carrying a chemotherapy drug and a photosensitizer in a tumor-bearing mouse model. We hypothesized that following decomposition, the drugs inside the nanocomplex will be released in the tumors to provide effective tumor treatment. We aimed to design a smart drug delivery system that can improve traditional chemotherapy drug delivery and enhance the therapeutic efficacy in combination with photodynamic therapy.Methods: Hydrophilic hyaluronic acid (HA) was covalently modified with a hydrophobic 5β-cholanic acid (CA) via an ROS-cleavable thioketal (tk) linker for a targeted co-deliver of 10-Hydroxy camptothecin (HCPT) and Chlorin e6 (Ce6) into tumors to improve the efficiency of combined chemo-photodynamic therapy.Results: The obtained HA-tk-CA nanoparticle carrying HCPT and Ce6, named HTCC, accumulated in the tumor through the enhanced permeable response (EPR) effect and HA-mediated CD44 targeting after intravenous administration. Upon laser irradiation and hyaluronidase degradation, HTCC was disrupted to release HCPT and Ce6 into the tumors. Compared to the monotherapy approach, HTCC demonstrated enhanced tumor growth inhibition and minimized systemic toxicity in a tumor-bearing mouse model.Conclusion: Our results suggested that controlled dual-drug release not only improved tumor drug delivery efficacy, but also reduced systemic side effects. In addition to HCPT and Ce6 delivery, the HA-tk-CA nanocomplex can be used to deliver other drugs in synergistic cancer therapy. Since most current combined therapy uses free drugs with distinct spatiotemporal distributions, the simultaneous co-delivery of dual drugs with a remote on-demand drug delivery nanosystem provides an alternative strategy for drug delivery design.Keywords: chemotherapy, photodynamic therapy, hyaluronic acid, responsive nanoparticle, drug delivery

Qiaoyi Xie,1 Xiaote Zhang,2 Wei Cui,1 Yajiao Pang1 1Department of Pediatrics, The Affiliated People’s Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Otolaryngology Head and Neck Surgery, Ningbo Yinzhou No.2 Hospital, Ningbo, People’s Republic of ChinaCorrespondence: Qiaoyi Xie, Department of Pediatrics, The Affiliated People’s Hospital of Ningbo University, No. 251, Baizhang East Road, Ningbo, 315040, People’s Republic of China, Tel + 86 0574-87016888, Email qiaoyi_xie@126.comObjective: The individualized prediction of treatment regimens of macrolide-unresponsive Mycoplasma pneumoniae pneumonia (MUMPP) is scarce. The aim of this study was, therefore, to evaluate the relevant data of patients and construct a nomogram for identifying refractory Mycoplasma pneumoniae pneumonia (RMPP) among children continued to be treated with macrolide after the confirmation of MUMPP, providing a reference for the choice of treatment regimen.Methods: We performed a retrospective study involving 162 children who continued to be treated with macrolide (azithromycin) after the confirmation of MUMPP without antibiotic changes between January 2020 and January 2022. We collected data on clinical feature, hospitalization period, treatments, laboratory data, extrapulmonary symptoms, parapneumonic effusion, and connections with other respiratory pathogens. In addition, the independent risk factors for RMPP were determined through univariate and multivariate analyses, and then a nomogram was constructed and validated.Results: In this study, the multivariate logistic regression analysis showed that age, leukocyte count, neutrophil proportion, serum procalcitonin, and lactate dehydrogenase were independent risk factors for RMPP. Using the five independent associated factors, the nomogram for identification of RMPP was constructed. Moreover, the area under the ROC curve (AUC) was 0.925 (95% CI: 0.882– 0.968) for the nomogram showing excellent discrimination. The calibration curve, close to the 45-degree line, exhibited good calibration of nomogram.Conclusion: We constructed and validated a visual and user-friendly nomogram for individualized prediction of RMPP risk in children who continued to be treated with macrolide after the confirmation of MUMPP based on five variables. According to the nomogram model, continuation of macrolide should be considered rather than second-line antibiotics including tetracyclines (doxycycline or minocycline) and fluoroquinolones for MUMPP children with low predictive values.Keywords: nomogram, refractory, Mycoplasma pneumoniae, pneumonia, children

Jianbing Wu,1,&ast; Jie Zhang,1,&ast; Qiangli Xie,2 Xiaohuan He,3 Zhangchao Guo,1 Bo Zheng,4 Sisong Wang,5 Qiumei Yang,6 Chunfu Du1 1Department of Neurosurgery, Ya’an People’s Hospital, Ya’an, 625000, People’s Republic of China; 2Department of Cardiovascular Medicine, Chengdu Qingbaijiang District People’s Hospital, Chengdu, 610300, People’s Republic of China; 3Department of the Fifth Dispatched Outpatient, The General Hospital of Western Theater Command, Chengdu, 610083, People’s Republic of China; 4Department of Neurology, Ya’an People’s Hospital, Ya’an, 625000, People’s Republic of China; 5Department of Neurosurgery, the Chengdu 363 Affiliated Hospital of Southwest Medical University, Chengdu, 610041, People’s Republic of China; 6Department of Geriatrics, Luzhou People’s Hospital, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunfu Du, Department of Neurosurgery, Ya’an People’s Hospital, 358 Chenghou Road, Ya’an, Sichuan, 625000, People’s Republic of China, Tel +86-835-2862065, Email 1012036559@qq.comPurpose: Neuroinflammation is considered a critical pathological process in various central nervous system (CNS) diseases and is closely related to neuronal death and dysfunction. Bergaptol is a natural 5-hydroxyfurocoumarin found in lemon, bergamot and other plants. Some studies have confirmed its anti-cancer, anti-inflammatory and anti-atherogenic functions, indicating that it may have significant medicinal value. In this study, we investigated the potential effect of Bergaptol in vitro and in vivo neuroinflammatory models.Methods: Mice were injected with LPS (40 μg/kg) into the hippocampal CA1 region and then injected intraperitoneally with Bergaptol (10, 20 and 40 mg/kg) once a day for two weeks. In addition, to verify the effect of Bergaptol on BV2 cells, Bergaptol with different concentrations (5, 10 and 20 μg/mL) was firstly incubated for 1 hour, then LPS with a concentration of 1 μg/mL was added and incubated for 23 hours.Results: Bergaptol treatment significantly improved the cognitive impairment induced by LPS. In addition, Bergaptol significantly inhibited the reduction of dendritic spines and the mRNA level of inflammatory factors (TNF-α, IL-6 and IL-1β) in hippocampal induced by LPS. In vitro, Bergaptol inhibited the production of TNF-α, IL-6 and IL-1β from LPS-treated BV-2 cells. In addition, Bergaptol treatment significantly reduced the phosphorylation levels of JAK2, STAT3 and p65 in LPS-stimulated BV-2 cells.Conclusion: In conclusion, our results suggest that Bergaptol alleviates LPS-induced neuroinflammation, neurological damage and cognitive impairment by regulating the JAK2/STAT3/P65 pathway, suggesting that Bergaptol is a promising neuroprotective agent.Keywords: Bergaptol, neuroinflammation, LPS, JAK2/STAT3/p65

Zike Sheng,1,&ast; Junjie Li,2,&ast; Tingting Chen,3 Yan Zhu,4 Xueping Yu,5 Xiuhua He,5 Yijuan Zheng,5 Cuiping Ma,6 Minghui Zheng,5 Peiyun Wang,1 Ziqiang Li,1 Yumin Xu,7 Qing Xie,1 Zhijun Su,5 Sumei Chen5 1Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Pharmacy, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 4Clinical Laboratory, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 5Department of Infectious Diseases, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 6Department of Infection Control, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, People’s Republic of China; 7Department of Infection Control, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhijun Su; Sumei Chen, Department of Infectious Diseases, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Licheng District, Quanzhou, People’s Republic of China, Tel +86-595-22277011 ; +86-595-22277173, Fax +86-595-222781, Email su2366@sina.com; chensm561119190@sina.comPurpose: Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various infections. This study aimed to investigate the clinical and microbiological characteristics of bloodstream infection (BSI) caused by hvKP.Patients and Methods: The clinical data of hospitalized patients with K. pneumoniae BSI were retrospectively analyzed. The K. pneumoniae strains were collected and re-identified, and antimicrobial susceptibility testing was performed using the broth microdilution method. Capsular serotypes and virulence genes were detected using polymerase chain reaction, and hvKP was defined as aerobactin positive. Molecular typing was done by multilocus sequence typing. The hvKP and classic K. pneumoniae (cKP) subgroups were compared.Results: Of the 66 nonrepetitive BSI K. pneumoniae strains included, 29 (43.9%) were hvKP. In these BSI hvKP strains, salmochelin and yersiniabactin accounted for 86.2% and 72.4%, respectively. The prevalence of rmpA, iroBCD cluster, ybtS, clbA, and allS was 89.7%, 86.2%, 72.4%, 51.7%, and 41.4%, respectively, which were all significantly different between the hvKP and cKP subgroups. Serotypes K1 and K2 were strongly associated with hypervirulence (P < 0.05). Nineteen sequence types were scattered in the 29 hvKP strains, and the most common was ST23 (24.1%). None of the hvKP strains were carbapenem resistant. Compared with cKP, hvKP was more capable of developing a liver abscess. However, the 30-day mortality rate was lower (13.8% vs 21.6%) in the hvKP subgroup than in the cKP subgroup.Conclusion: This study demonstrated a high proportion of hvKP in BSI K. pneumoniae, most of which were RmpA and siderophore producing, and of multiclonal origin.Keywords: capsular serotypes, hypervirulence, infection, mortality, sequence type

Suipeng Chen,1,&ast; Mengjiao Kuang,1,&ast; Ying Qu,1,2 Shirui Huang,1 Binbin Gong,1 Suzhen Lin,1 Huiyan Wang,1 Guiye Wang,1 Hongqun Tao,1 Jian Yu,1 Zuqin Yang,3 Minghua Jiang,1 Qipeng Xie1 1Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 2Department of Clinical Laboratory, Wenzhou People’s Hospital, The Third Affiliated Hospital of Shanghai University, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 3Newborn Department of Pediatrics, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qipeng Xie, Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +86 15157787159, Email pandon2002@163.comObjective: Sepsis remains a major cause of neonatal death. To better characterize the inflammatory response during neonatal sepsis, we compared the differences in serum cytokines and chemokines between full-term neonates with sepsis and without infection.Methods: We enrolled 40 full-term neonates with sepsis and 26 full-term neonates without infection as controls between October 2016 and June 2018. Forty cytokines /chemokines in serum were analyzed using the Luminex Bead Immunoassay System.Results: Our results showed that serum IL-6, IL-8, TNF-α, IL-1β, MIF, CXCL13, CXCL1, CXCL2, CXCL5, CXCL6, CXCL16, CCL27, CCL2, CCL8, CCL3, CCL20, CCL23, and CX3CL1 levels were significantly increased in neonates with sepsis compared to those in the control group (all p< 0.05). The levels of serum CCL20, and IL-17 were higher in late-onset sepsis (LOS) than those in early-onset sepsis (EOS) (all p< 0.05). Conversely, serum CXCL16 was lower in LOS than that in EOS (p< 0.05).Conclusion: Our findings revealed that excessive pro-inflammatory cytokines might be involved in neonatal sepsis. In addition, chemokines significantly increased the recruitment of immune cells after infection to participate in the anti-infection defense of neonates, but this could lead to damage.Keywords: neonatal sepsis, cytokines, chemokines

For the field of high energy physics to continue to have a bright future,priority within the field must be given to investments in the development ofboth evolutionary and transformational detector development that is coordinatedacross the national laboratories and with the university community,international partners and other disciplines. While the fundamental sciencequestions addressed by high energy physics have never been more compelling,there is acute awareness of the challenging budgetary and technical constraintswhen scaling current technologies. Furthermore, many technologies are reachingtheir sensitivity limit and new approaches need to be developed to overcome thecurrently irreducible technological challenges. This situation is unfoldingagainst a backdrop of declining funding for instrumentation, both at thenational laboratories and in particular at the universities. This trend has tobe reversed for the country to continue to play a leadership role in particlephysics, especially in this most promising era of imminent new discoveries thatcould finally break the hugely successful, but limited, Standard Model offundamental particle interactions. In this challenging environment it isessential that the community invest anew in instrumentation and optimize theuse of the available resources to develop new innovative, cost-effectiveinstrumentation, as this is our best hope to successfully accomplish themission of high energy physics. This report summarizes the current status ofinstrumentation for high energy physics, the challenges and needs of futureexperiments and indicates high priority research areas.

Xiaoxiao Qu,1,&ast; Shishi Wang,1,&ast; Ying Qu,2 Huiyan Wang,1 Xuanmei Ye,1 Luming Tang,3 Qipeng Xie1 1Department of Clinical Laboratory, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China; 2Department of Clinical Laboratory, Wenzhou People’s Hospital, The Third Affiliated Hospital of Shanghai University, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 3Emergency Department, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qipeng Xie, Department of Clinical Laboratory, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +86 151 577 87159, Email pandon2002@163.comPurpose: To clarify the distribution of pathogenic bacteria by analyzing the bacterial susceptibility characteristics and risk factors for adult sepsis in The Wenzhou city, Zhejiang province, China, and to aid early diagnosis, monitoring, and prognosis prediction in cases of bacterial sepsis.Patients and Methods: We retrospectively analyzed 329 patients with sepsis admitted to the Second Affiliated Hospital of Wenzhou Medical University between January 2018 and March 2021. Laboratory data were collected before and after treatment; moreover, the bacterial susceptibility characteristics and risk factors for sepsis were comprehensively analyzed using the Sequential Organ Failure Assessment (SOFA) score.Results: The SOFA score was negatively correlated with the prognosis (P < 0.05). We isolated 47 pathogenic strains from blood culture samples, including 29 gram-positive strains, 18 gram-negative strains. The most common gram-negative pathogens in blood cultures are Klebsiella pneumoniae and Escherichia coli, while the most common gram-positive pathogens are Staphylococcus aureus and Staphylococcus hominis. Gram-negative pathogens had resistance rates of 77% and 62.5% to ciprofloxacin and ceftriaxone, respectively. Gram-positive bacteria had a high resistance to penicillin at 100%. Prognostic factors for sepsis included patients’ consciousness, SOFA score, prothrombin time, international normalized ratio, fibrinogen, D-dimer, and aspartate aminotransferase (P < 0.05). Of these, the D-dimer level could predict the outcome of patients with sepsis (AUC = 0.661, P < 0.05).Conclusion: The pathogens detected in adult sepsis in Wenzhou are mainly Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Staphylococcus hominis. The pathogens exhibited differences in drug susceptibility. The optimal antibiotics should be chosen based on the principles of rational use and drug susceptibility. Combined with D-dimer levels, these parameters can be used to determine the optimal strategy for preventing and treating pathogenic bacteria.Keywords: adult sepsis, drug susceptibility characteristics, risk factors, D-dimer

Qingqing Xie,1 Caixia Sun,2 Zhenghua Fei,1 Xujing Yang1 1Department of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China; 2Department of Nursing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of ChinaCorrespondence: Xujing YangDepartment of Radiation and Medical Oncology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, 325000, People’s Republic of ChinaEmail wzyyysj7979@126.comBackground: Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers, and some tumors have profound and durable tumor regression. However, immunotherapy is still in the clinical trial stage with elusive long-term effects and complications as a new strategy. It is unclear whether patients possess an accurate understanding of the clinical benefits associated with these agents.Objective: To investigate the anxiety and depression of patients with advanced cancer who received immunotherapy using programmed death-1 or programmed death-ligand 1 after multiline treatment failure, explore the influencing factors, and provide a reference for clinical medical staff and psychological support for patients.Methods: The Hospital Anxiety and Depression Scale was used to calculate the anxiety and depression scores before and after 1, 2, and 3 courses of treatment, respectively. The patients with anxiety and depression were counted. Purposive sampling was used to conduct face-to-face semi-structured interviews with 21 patients to find out the reasons. The obtained data were analyzed and collated using Colaizzi’s phenomenological method.Results: One hundred and twenty-six patients with advanced cancers were included in the study. Before and after 1, 2 and 3 courses of treatment, 18.26%, 23.0%, 50% and 54% of patients suffered from anxiety and depression, respectively. The proportion of patients with anxiety and depression during immunotherapy kept increasing, mainly due to therapeutic efficacy below expectation, lack of timely information after treatment, lack of awareness of treatment and drugs, and lack of family and social support.Conclusion: Patients with advanced tumors after multiline treatment failure are susceptible to anxiety and depression during immunotherapy. It is necessary to test the emotional state of patients in time and carry out early intervention. Nursing staffs and medical staffs should adopt personalized measures to meet the psychological needs of patients.Keywords: anxiety, depression, cancer, immunotherapy, quality of life

Lei Xia,1 Wei Liang,2 Dan Que,2 Qichao Xie2 1Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing City, 400000, People’s Republic of China; 2Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing City, 400000, People’s Republic of ChinaCorrespondence: Qichao Xie Tel +86 23-60353465Email qichaoxieyubei@163.comBackground: The role of circRNA circ_0071662 has been studied in bladder cancer. The present study aimed to analyze its involvement in esophageal squamous cell carcinoma (ESCC).Methods: Patients with ESCC (n = 66), esophageal ulcer (EU, n = 66), or gastroesophageal reflux disease (GERD, n = 66) and healthy controls (n = 66) were enrolled in this study. Plasma samples were collected from all patients and controls. ESCC and paired non-tumor tissue samples were collected from ESCC patients. Circ_0071662 levels in these samples were determined by RT-qPCRs. Diagnostic and prognostic values of circ_0071662 for ESCC were analyzed with ROC curve and survival curve analyses.Results: Circ_0071662 level was decreased in ESCC, but not in GERN and EU compared to the controls and in ESCC tissues compared to the non-tumor tissues. Plasma circ_0071662 was closely correlated with patients’ tumor size but not with other clinical features. Decreased plasma circ_0071662 levels separated ESCC patients from GERN patients, EU patients, and healthy controls. Low plasma circ_0071662 levels were closely correlated with worse survival outcomes of ESCC patients.Conclusion: Circ_0071662 is lowly expressed in ESCC and may serve as a potential diagnostic and prognostic biomarker for ESCC.Keywords: esophageal squamous cell carcinoma, circ_0071662, diagnosis, prognosis

Yanxin Li,1 Ke Ma,2 Qi Xie,3 Xianwei Zhang,3 Xiulei Zhang,4 Kui Chen,1 Lingfei Kong,3 Rongjun Qian1 1Department of Neurosurgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China; 2Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 3Department of Pathology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China; 4Department of Microbiome Laboratory, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of ChinaCorrespondence: Rongjun QianDepartment of Neurosurgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, No. 7, Wei Wu Road, Zhengzhou, Henan, 450003, People’s Republic of ChinaTel +86 15037138200Email qrjqqx@163.comLingfei KongDepartment of Pathology, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, No. 7, Wei Wu Road, Zhengzhou, Henan, 450003, People’s Republic of ChinaTel +86 18538298216Email lfkong@zzu.edu.cnPurpose: HOXD10 is a tumor modulator that can either be a tumor-suppressor or a tumor-promoting gene. However, the role of HOXD10 in glioblastoma multiforme (GBM) remains unclear.Methods: Immunohistochemistry (IHC) was applied to detect protein expression of HOXD10 in GBM and normal brain tissue patients. Clinicopathological characteristics with GBM were recorded, and a Kaplan–Meier curve was plotted. Additionally, the mRNA expression of HOXD10 and its effect on prognosis were analyzed using the online tool GEPIA and the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO) databases. Based on the mRNA expression of HOXD10, GBM patients from TCGA database were divided into low- and high-HOXD10 expression groups to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and construct a lncRNA-miRNA-mRNA network and a protein–protein interaction (PPI) network.Results: The mRNA expression of HOXD10 was up-regulated in GBM according to GEPIA, while the protein expression of HOXD10 in GBM was down-regulated according to IHC analysis of samples from patients collected from our hospital. Correlation analysis showed that HOXD10 expression was significantly related to IDH1 status. Univariate analysis revealed that low HOXD10 expression, complete surgical resection, postoperative radiotherapy, postoperative temozolomide chemotherapy and IDH1 mutation were all beneficial prognostic factors. Further multivariate analysis revealed that only complete surgical resection and postoperative radiotherapy were independent prognostic factors. GO and KEGG enrichment analyses indicated that HOXD10 expression is mainly involved in cytokine-cytokine receptor interactions. In the ceRNA network, 89 nodes, containing 45 mRNAs, 39 miRNAs and five lncRNAs associated with prognosis were involved. The PPI network revealed a tight interaction between HOXD10 and HOXD8, HOXD9, HOXD11, HOXD13 and HOXB3.Conclusion: Based on our experimental data, although HOXD10 expression is low in GBM compared with normal brain tissue, GBM patients with high HOXD10 expression have a worse prognosis. HOXD10 may play different or even opposite roles in different stages of GBM occurrence and development. For patients with GBM, HOXD10 may be a valid predictor of prognosis.Keywords: HOXD10, GBM, prognosis, ceRNA, protein-protein interaction

Taiyong Bi,1 Qinhong Xie,1,2 Jianhui Gao,1 Tao Zhang,1 Hui Kou1 1Center for Mental Health Research in School of Management, Zunyi Medical University, Zunyi, People’s Republic of China; 2School of Criminal Justice, China University of Political Science and Law, Beijing, People’s Republic of ChinaCorrespondence: Taiyong Bi; Hui Kou Email bitaiyong@126.com; kouhuizmu@163.comBackground: Empathy is shown to affect the attentional processing of painful stimuli and emotional stimuli. However, whether the attentional effects on emotional stimuli depend on emotional valence and the nature of the relationship between the attentional effects on different stimuli are still unknown.Methods: In the present study, 25 high-empathy (HE) participants and 25 low-empathy (LE) participants were recruited to perform dot-probe tasks on painful stimuli and emotional stimuli.Results: The results showed that HE individuals had weak attentional disengagement to painful pictures. More importantly, regarding emotional pictures, HE individuals showed attentional avoidance to negative emotion pictures, while LE individuals showed attentional bias to positive emotion pictures. Correlation analysis showed that the attentional bias score and attentional disengagement score were only associated with each other within the same category of stimuli (painful, positive or negative stimuli).Conclusion: These results revealed that HE individuals mainly showed attentional avoidance to negative stimuli, while LE individuals mainly showed attentional bias to positive stimuli.Keywords: empathy, attentional bias, attentional disengagement, painful stimuli, emotional stimuli

Teng Zhou,1,2,* Mengjiao Kuang,1,* Shirui Huang,1 Jizhen Li,1 Qipeng Xie1 1Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China; 2The Second Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qipeng XieDepartment of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of ChinaTel +86 15157787159Email pandon2002@163.comObjective: Central nervous system infections (CNSI) are serious diseases that endanger human health. Identifying pathogens and their susceptibility to antibiotics, and promptly using antibiotics under this guidance is essential for treatment. The purpose of this study is to investigate the pathogen characteristics of CNSI patients, which can help clinicians choose appropriate empiric antibiotic .Methods: We retrospectively collected data on CNSI patients with cerebrospinal fluid (CSF) culture positive from 2012 to 2020, including demographic characteristics, laboratory data, pathogenic bacteria, and antimicrobial susceptibility test results.Results: A total of 166 patients with 168 isolates out of 8188 patients were available for data analysis. Among the isolates, Gram-positive bacteria, Gram-negative bacteria and fungi accounted for 59.5%, 36.3%, and 4.2%, respectively. Among newborns, children under 12, and patients over 12, the most isolated strains were Streptococcus agalactiae (24/46, 52.2%), Streptococcus pneumoniae (21/68, 30.9%) and Staphylococcus epidermidis (10/54, 18.5%), respectively. Streptococcus agalactiae is more sensitive to linezolid and vancomycin. Streptococcus pneumoniae is more sensitive to vancomycin. Staphylococcus epidermidis is more sensitive to clindamycin and rifampicin. The sugar content in the CSF of Gram-negative bacteria of children ≤ 12 years old was significantly lower than that of Gram-positive bacteria (P< 0.05).Conclusion: We comprehensively studied the etiological characteristics and antimicrobial resistance patterns of positive cerebrospinal fluid cultures in Wenzhou City, Zhejiang Province from 2012 to 2020, which can provide valuable strategies for preventing pathogens and improving evidence-based treatment.Keywords: cerebrospinal fluid, bacterial culture, drug resistance, epidemiological characteristics

Yandi Tan,1,* Shiqi Yang,1,* Yao Ma,2 Jinlin Li,1 Qian Xie,1 Chaoqi Liu,1 Yun Zhao1 1Medical College of China Three Gorges University, Yichang, Hubei, People’s Republic of China; 2Department of Ultrasonography, Yichang Central People’s Hospital, Yichang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Zhao; Chaoqi LiuMedical College of China Three Gorges University, Yichang, Hubei, 443000, People’s Republic of ChinaEmail zhaoyun@ctgu.edu.cn; ctgulcq@163.comPurpose: Immune checkpoint inhibitors (ICIs) and sonodynamic therapy (SDT) are types of immunotherapy. In order to combine soluble programmed cell death protein 1 (sPD-1)-mediated immune checkpoint therapy and chlorin e6 (Ce6)-assisted SDT, nanobubbles (NBs) were generated to simultaneously load sPD-1 and Ce6.Materials and Methods: The sPD-1/Ce6-NBs, which were prepared by thin-film hydration and mechanical oscillation, had a stable physical condition, and delivered sPD-1 and Ce6 in a targeted manner. NBs could strengthen tumor suppression by increasing tumor-targeting accumulation of Ce6 and sPD-1, and by inducing ultrasound-targeted NB destruction. A mouse H22 cell hepatoma xenograft model was used to evaluate the synergetic immunotherapeutic effect and mechanism of sPD-1/Ce6-NBs.Results: By observing the tumor inhibition rate, tissue and cell apoptosis, apoptosis-related genes and protein expression, the best immunotherapeutic effect was exhibited by the sPD-1/Ce6-NBs group. The immunotherapeutic mechanism initially demonstrated that when tumor cells were transfected by sPD-1 delivered by NBs, which downregulated the expression of programmed death-ligand 1 (PD-L1) in tumor cells, and blocked the PD-1/PD-L1 signaling pathway, which improved T-cell-mediated tumor inhibition. Furthermore, ICIs combined with SDT induced immunogenic cell death by translocating calreticulin to the cell surface and then synergistically enhancing antitumor immune responses.Conclusion: In conclusion, sPD-1/Ce6-NBs were successfully designed. Ultrasound-mediated sPD-1/Ce6-NBs are potentially effective delivery systems for combination immunotherapy of hepatocellular carcinoma.Keywords: immune checkpoint inhibitors, ultrasonics, drug delivery, tumor therapy, nanomaterials

Xianyun Xu,1,* Qiongjun Xie,2,* Mingfeng Xie,3 Yong Zeng,3 Qian Liu1 1Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases of Ministry of Education, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of China; 2Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of China; 3Department of Pediatric Surgery, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, The First Affiliate Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qian LiuKey Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases of Ministry of Education, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of ChinaEmail liuqiangmu2017@126.comBackground: Small nucleolus RNA Host Gene 8 (SNHG8) belongs to a subgroup with long non-coding RNAs. LncRNA SNHG8 presents up-regulated in miscellaneous cancers, like gastric cancer, liver cancer, and esophageal squamous cell cancer. Nevertheless, the expression pattern and the pathological function of lncRNA SNHG8 in breast cancer remain obscure.Methods: We examined the expression levels of lncRNA SNHG8 in the tissue samples and cell lines from breast cancer via RT-qPCR in the present study. The functions of lncRNA SNHG8 on the progression of breast cancer cell were examined by CCK-8, EdU, Transwell chamber assays, and flow cytometry analyses. The expression of proteins was assessed using Western blot assay.Results: We found that proliferation, migration, and invasion of breast cancer cells were significantly inhibited due to knockdown of lncRNA SNHG8, while inducing apoptosis of these cells. Mechanistically, SNHG8 functioned as an inhibitor of miR-634 in tumor tissues.Conclusion: LncRNA SNHG8 sponged the miR-634 to increase the expression level of ZBTB20, thus further aggravating the malignancy of breast cancer. Hence, the lncRNA SNHG8-miR-634-ZBTB20 axis may be a promising therapeutic target to treat breast cancers.Keywords: small nucleolus RNA host gene 8, microRNA-634, breast cancer, ZBTB20

Wei Fu, Shanshan Xu, Xiang Dong, Qing Xie, Yadong Gao Department of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Yadong Gao; Wei FuDepartment of Allergology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of ChinaTel +86 15071384536Email gaoyadong@whu.edu.cn; fuwei0511@163.comAbstract: Aspirin is clinically widely used to inhibit platelet aggregation after coronary intervention. Herein we describe a case of aspirin-induced thrombocytopenia that may be related to allergy to aspirin. A 47‐year‐old man developed a delayed hypersensitivity reaction to aspirin, with pruritus, purpura and thrombocytopenia, increased peripheral blood eosinophils and enlarged inguinal lymph node. All the symptoms disappeared in 2 years after stopping aspirin. Aspirin-induced thrombocytopenia related to allergy is rarely reported. Aspirin hypersensitivity should be taken into consideration in case of unexplained thrombocytopenia in patients taking aspirin. Aspirin “allergy”-induced thrombocytopenia may involve both aspirin related IgG and IgE antibodies.Keywords: aspirin, allergy, thrombocytopenia, platelets

Qian Xie,1,* Tao Wen,2,* Aiyun Yang,2 Xue Zhang,2 Bo Chen,3 Jie Meng,2 Jian Liu,2 Ning Gu,4 Haiyan Xu2 1Division of Nephrology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China; 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, People’s Republic of China; 3Materials Science and Devices Institute, Suzhou University of Science and Technology, Suzhou, 215009, People’s Republic of China; 4State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haiyan XuInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, People’s Republic of ChinaEmail xuhy@pumc.edu.cnNing GuState Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People’s Republic of ChinaEmail guning@seu.edu.cnBackground: Contrast-enhanced magnetic resonance imaging (MRI) is a powerful diagnostic tool for many diseases. In many situations, the contrasts are repeatedly administrated in order to monitor and assess the disease progression.Objective: To investigate and compare the biological effects of γ-Fe2O3 nanoparticle (NP) and gadolinium dimeglumine (Gd-DTPA) with high and multiple doses on the kidney of healthy mice.Methods: Polydextrose sorbitol carboxymethyl ether coated γ-Fe2O3 NP with hydrodynamic size of 68.2 nm and clinically applied Gd-DTPA were employed on healthy mice with the repeatedly intravenous administration of high doses. The cell viability of human umbilical vein endothelial cells (HUVEC) in high doses of these two contrast agents were measured using the xCELLigence Real-Time Cell Analysis (RTCA) S16 Instrument. The biological effects of γ-Fe2O3 NP and Gd-DTPA on the kidney were obtained using a biochemical automatic analyzer and multiple proinflammatory factor kit on the serum. Histopathological and immunohistochemistry analysis were taken on kidney tissues.Results: It showed that the proinflammatory responses elicited by the γ-Fe2O3 NPs were weaker than that by Gd-DTPA, evidenced by the relatively much lower level of IL-1β, IL-6, IL-18, TNF-α, C-reactive protein (CRP) and Ferritin. At the same time, the γ-Fe2O3 NPs did not have the biochemical index elevated, while the Gd-DTPA did.Conclusion: The γ-Fe2O3 NPs induced weaker proinflammatory effects in reference to the Gd-DTPA, indicating better renal safety. Therefore, it is suggested that γ-Fe2O3 NPs should be safer and optional choice when repeated contrast-enhanced MRI is necessary.Keywords: iron oxide nanoparticles, proinflammatory, cytokines, renal function

Tao Li,1,2 Xin Li,1 Hui Chen,3 Kai-Zhao Huang,1 Qi Xie,1,2 Han-Yu Ge,1 Shen-Meng Gao,4 Jian-Hua Feng,4 Jun-Jun Yang,1 Zhan-Guo Chen,1 Xiao-Qun Zheng1,2 1Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, The Key Laboratory of Laboratory Medicine, Ministry of Education of China, Wenzhou, Zhejiang, People’s Republic of China; 3Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Zhan-Guo Chen; Xiao-Qun ZhengDepartment of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaTel +86-13968806755; +86-13906653839Email steve0577@126.com; jszhengxq@163.comPurpose: Red blood cell distribution width (RDW) has been considered as a potential indicator of the effects of treatment or as a prognostic indicator for various malignancies. Most chronic myeloid leukemia (CML) patients are in the chronic phase, but some have transformed to accelerated phase or blast phase (blast crisis). However, the clinical significance of RDW in CML remains limited.Patients and Methods: In the present study, detailed clinical information and the RDW of 168 healthy people and 153 CML patients (106 patients for the training cohort and 47 patients for the validation cohort) were retrospectively assessed.Results: Multivariate analysis demonstrated that patient age (OR, 1.081; 95CI% 1.039∼ 1.125; p < 0.001), platelet counts (OR, 0.997; 95CI% 0.994∼ 0.999; p = 0.001) and RDW at admission (OR,1.469; 95CI% 1.121∼ 1.925; p = 0.005) were significantly associated with the patients with advanced phase. Among CML patients in the chronic phase, higher RDW was significantly associated with overall survival (OS; p = 0.0008) and the event-free survival (EFS; p = 0.0221) among CML patients with chronic phase, but not with Transformation-free survival (TFS; p = 0.0821). Furthermore, higher RDW was associated with higher mortality compared to patients with low RDW (CML-associated deaths; p < 0.0001). In addition, a decline in RDW is associated with the treatment of CML patients with tyrosine kinase inhibitors, especially at 6 and 12 months after the start of treatment.Conclusion: Higher RDW is a potential prognostic biomarker for chronic CML patients.Keywords: red blood cell distribution width, chronic myeloid leukemia, chronic phase, adverse prognosis

Yu Liu,1 Shirui Huang,2 Mengjiao Kuang,2 Huiyan Wang,2 Qipeng Xie2 1Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, People’s Republic of China; 2Department of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People’s Republic of ChinaCorrespondence: Qipeng XieDepartment of Laboratory Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People’s Republic of ChinaTel +86-15157787159Email pandon2002@163.comBackground: LARGE1 plays a pivotal role in glycosylation of alpha-Dystroglycan (α-DG) and is aberrantly downregulated in cell lines originating from epithelium-derived cancers including lung cancer. However, the expression of LARGE1 and its clinical significance in NSCLC are not clear.Materials and Methods: The data were collected from the TCGA database to investigate LARGE1 expression in stage I–III NSCLC and explore its associations with clinicopathological parameters and overall survival of patients. The prognostic role of LARGE1 was examined in subgroups according to clinical features and treatments. The results were validated in external cohorts from the NCBI GEO database. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential molecular mechanisms during LARGE1 alteration in NSCLC.Results: LARGE1 was aberrantly downregulated in NSCLC compared with adjacent tissues and normal lung tissues and in tumors with advanced stage compared with early stage. There was only a trend of association between high LARGE1 with OS in multivariate analysis. Surprisingly, high LARGE1 was significantly associated with improved OS in a subgroup of the patients with adjuvant chemotherapy (ACT) and a significant interaction between LARGE1 expression and ACT was found. Improved OS after ACT was also found in patients with high LARGE1 compared to those with low LARGE1. When combining LARGE1 expression and ACT, compared with patients with non-ACT, HR of low LARGE1/ACT was 0.592 (95% CI=0.432– 0.813, P=0.0012), and HR of high LARGE1/ACT was 0.124 (95% CI=0.031– 0.505, P=0.0036). The results were verified in two external cohorts from the GEO database. GSEA indicated that LARGE1 might downregulate cell cycle pathway to improve ACT sensitivity and subsequently the prognosis in NSCLC.Conclusion: High LARGE1 can be used to identify the patients with resected stage I–III NSCLC most likely to benefit from adjuvant chemotherapy.Keywords: NSCLC, LARGE1, mRNA, overall survival, adjuvant chemotherapy, benefit

Hanrui Zheng,1,* Qian Xie,2,* Mei Zhan,1 Chaohui Jin,1 Qiu Li3,4 1Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2International Medical Center/Ward of General Practice, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4West China Biomedical Big Data Center, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaohui JinDepartment of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaTel +86-28-85421763Email 695025422@qq.comQiu LiDepartment of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaTel +86-28-85423262Email fbqiu9@163.comBackground: Helicobacter pylori (H. pylori) eradication therapy has been shown to reduce the risk of gastric cancer in patients who have a family history of gastric cancer in first-degree relatives. The aim of this study was to assess the cost-effectiveness of H. pylori eradication therapy in a select population in the People’s Republic of China.Methods: A Markov model was applied to evaluate the cost-effectiveness of H. pylori eradication therapy. The long-term costs of H. pylori eradication therapy were calculated from the Chinese perspective. Health outcomes were measured by quality-adjusted life years (QALYs). Epidemiological information and health utilities used in the model were collected from published literatures or statistical bureaus. A sensitivity analysis was conducted to explore the influence of parameters on the uncertainty of the model.Results: Compared with the no eradication therapy group, H. pylori eradication therapy prolonged an average of 4.52 QALYs (32.64 QALYs vs 28.12 QALYs) and saved $3227.07 ($2472.83 vs $5699.90). The cost-effectiveness analysis demonstrated that no H. pylori eradication therapy cost more and produced less QALYs. It was dominated by H. pylori eradication therapy. The one-way sensitive analyses proved that the results were robust to the fluctuations of the input parameters.Conclusion: H. pylori eradication therapy not only reduced the risk of gastric cancer in first-degree relatives of patients with gastric cancer but also was an economical strategy with lower costs and greater efficacy.Keywords: Helicobacter pylori, eradication therapy, gastric cancer, cost-effectiveness analysis

Junjie Li,1,* Qingqing Xu,2,3,* Sean Ogurek,4 Ziqiang Li,5 Peiyun Wang,5 Qing Xie,5 Zike Sheng,5 Minggui Wang2,3 1Department of Respiratory and Critical Care Medicine, Shanghai Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 3Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, People’s Republic of China; 4Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; 5Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing Xie; Zike ShengDepartment of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Building 36, 197 Ruijin Er Road, Shanghai 200025, People’s Republic of ChinaTel +86-21-64370045 ext 680419; Tel +86-21-64370045 ext 680403Fax +86-21-64454930Email xieqingrjh@163.com; shengz12@fudan.edu.cnIntroduction: Drug efflux pumps are critical for resistance in Gram-negative organisms, but there are limited data on the role they play in decreased susceptibility to β-lactam/β-lactamase inhibitor combinations. In this study, we aimed to investigate the impact of efflux pump AcrAB on piperacillin–tazobactam (TZP) and ceftolozane–tazobactam (C/T) susceptibility in tigecycline-non-susceptible Klebsiella pneumoniae (TNSKP) strains.Methods: A tigecycline gradient was used to obtain various TNSKP strains, and in conjunction with the gradient derived strains, a TNSKP clinical strain (TNSKP24) was also included. Minimum inhibitory concentrations (MICs) of antibiotics were determined by the broth microdilution method, and whole-genome sequencing (WGS) was carried out to analyze genomic changes. PCR and sequencing were performed to confirm mutations in ramR, acrR, and the intergenic region of ramR-romA, and qRT-PCR was applied to evaluate levels of gene expression. In-frame acrB knockout and complementation were performed in 3 TNSKP strains.Results: Two derivatives of K. pneumoniae K2606 (K2606-4 and K2606-16) and TNSKP24 overexpressed efflux pump AcrAB were obtained for further study. The MICs of TZP and C/T exhibited a 4- to 8-fold increase in K2606-4 and K2606-16, respectively, when compared with K2606 (TZP, 2/4 μg/mL; C/T, 0.25/4 μg/mL). Deletion of acrB decreased the MICs of TZP and C/T by 4- to 16-fold in TNSKP24, K2606-4, and K2606-16, respectively, and complementation of acrB increased the MICs of these agents. MICs of clavulanate, sulbactam, and avibactam in the presence of β-lactam compounds did not change after acrB deletion and subsequent introduction of complementation mutants.Conclusion: This study highlights that decreased susceptibility to TZP and C/T could be caused by the multidrug efflux pump AcrAB in TNSKP strains.Keywords: drug efflux pump, Enterobacteriaceae, multidrug resistance, β-lactam/β-lactamase inhibitor combinations