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Shutong Ren,1,&ast; Siyu Chen,2,&ast; Jingru Huang,3 Rong Yu,1 Yunli Wu,4 Xian-E Peng1,4 1Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, 350122, People’s Republic of China; 2State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, 361104, People’s Republic of China; 3Department of Clinical Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China; 4Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xian-E Peng; Yunli Wu, Email fmuxe@163.com; wuyunli422@163.comObjective: This study aimed to explore the association between serum uric acid (sUA) levels and metabolic-associated fatty liver disease (MAFLD) in Southeast China.Methods: We performed a cross-sectional study of 2605 subjects who underwent physical examination between 2015 and 2017 in Southeast China. To explore the association between sUA levels and the risk of MAFLD, we employed logistic regression, restricted cubic spline (RCS), subgroups and multiplicative interaction analysis.Results: Logistic regression analysis showed a positive association between sUA and MAFLD [aOR total population (95% CI)= 1.90 (1.49 ~ 2.42)], [aOR male (95% CI)= 2.01 (1.54 ~ 2.62)], [aOR female (95% CI)= 1.15 (0.62 ~ 2.11)], respectively. The RCS plot presented a significant nonlinear dose–response relationship between sUA levels and MAFLD risk, and the risk of MAFLD increased significantly when sUA> 5.56 mg/dL (Pnonlinear< 0.001). Subgroups analysis revealed that the positive association between sUA and MAFLD was consistent across strata of gender, age, BMI, drinking status, smoking status and tea drinking status. Significant associations between sUA and MAFLD were not only found in males but also existed in subjects whose age ≤ 60, BMI ≥ 24 kg/m2, drinkers, smokers and tea-drinkers. Adjusted ORs were estimated to be 2.01, 1.95, 2.11, 2.29, 2.64 and 2.20, respectively. Multiplicative interactions were not observed between gender, age, drinking status, smoking status, tea drinking status and sUA (all P interaction> 0.05).Conclusion: According to our study, sUA was positively associated with the risk of MAFLD. Additionally, the risk of MAFLD increased significantly when sUA levels exceeded 5.56 mg/dL. Our study may help clarify whether sUA plays a diagnostic role in MAFLD.Keywords: metabolic-associated fatty liver disease, serum uric acid, risk, cross-sectional study

Shanshan Chen,1,2 Youjia Duan,2 Yongchao Zhang,2 Long Cheng,2 Liang Cai,2 Xiaopu Hou,2 Xiaojun Wang,3 Wei Li1,2 1Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Wei Li, Cancer Center, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China, Email weili8989@ccmu.edu.cn Xiaojun Wang, Department of Integrated Traditional Chinese and Western Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China, Email w_xiaojun@ccmu.edu.cnPurpose: To determine the effect of aspirin on hepatocellular carcinoma (HCC) recurrence and survival after thermal ablation.Methods: A retrospective analysis was performed to evaluate the efficacy and safety of aspirin in combination with thermal ablation. The clinical data were collected for the enrolled patients. Progression-free survival (PFS), overall survival (OS), and adverse events were analyzed.Results: A total of 174 patients with HCC were enrolled. The median PFS was 11.1 (95% confidence interval [CI]: 8.1− 14.0) months for patients who took aspirin and 8.6 (95% CI: 5.5− 11.8) months for patients who did not take aspirin. The median OS of patients in the aspirin group was 76.7 (95% CI: 58.1− 95.3) months and that in the non-aspirin group was 53.5 (95% CI: 42.7− 64.3) months. In patients with non-viral HCC, OS was significantly better for the aspirin group (P = 0.03) after ablation. The PFS of patients who underwent ablation alone in the aspirin group was obviously superior to that of patients in the non-aspirin group (P = 0.002). Stratified Cox regression analysis demonstrated that aspirin use after ablation might be a protective factor in specific HCC patient subgroups. The incidence of major adverse events did not significantly differ between the two groups.Conclusion: Low-dose aspirin use was associated with better OS in patients with non-viral HCC after thermal ablation. In patients who received thermal ablation alone, the administration of low-dose aspirin could improve PFS. Aspirin use might be a protective factor in some patients after ablation.Keywords: thermal ablation, aspirin, hepatocellular carcinoma, survival analysis, retrospective study

Huanhuan Wang,1,&ast; Dan Xiao,2,&ast; Hua Zhou,3,&ast; Shu Chen,4 Guangjun Xiao,4 Juan Hu,4 Hui Quan,2 Miao Luo,5 Shaocheng Zhang2,6 1School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China; 2Department of Laboratory Medicine, the Second Affiliated Hospital of Chengdu Medical College (Nuclear Industry 416 Hospital), Chengdu, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Laboratory Medicine, Suining Central Hospital, Suining, Sichuan, People’s Republic of China; 5Department of Laboratory Medicine, the People’s Hospital of Yubei District of Chongqing, Chongqing, People’s Republic of China; 6School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaocheng Zhang; Miao Luo, Email 102024001@cmc.edu.cn; 536513878@qq.comPurpose: Visceral adiposity is a significant risk factor for severe COVID-19. However, the impact of the Chinese visceral adiposity index (CVAI) on the efficacy of SARS-CoV-2 vaccines remains poorly understood. This study aims to explore the impact of CVAI on the production of neutralizing antibodies (NAb) in inactivated SARS-CoV-2 vaccines and the potential mechanism, thereby optimizing vaccination guidance.Methods: In this cross-sectional study, 206 health workers (completed two SARS-CoV-2 vaccination on February 8th and March 10th, 2021, respectively) were recruited. All baseline anthropometric parameters of the participants were collected, and venous blood samples were obtained 6 weeks later to measure peripheral innate immune cells, inflammatory cytokines, and NAb titers against SARS-CoV-2. CVAI were calculated according to the formula and divided participants into two groups depending on CVAI median.Results: The median NAb titer among healthcare workers was 12.94 AU/mL, with an efficacy of 87.86% for the SARS-CoV-2 vaccine. NAb titers were lower in the CVAI dysfunction group than in the CVAI reference group (median: 11.40 AU/mL vs 15.57 AU/mL), the hsCRP levels (median: 0.50 mg/L vs 0.30 mg/L) and peripheral monocyte count (mean: 0.47 × 109/L vs 0.42 × 109/L) in the CVAI dysfunction group were higher than in the CVAI reference group. Additionally, CVAI showed positive correlations with hsCRP, monocytes, lymphocytes, and B-lymphocytes, and a negative correlation with NAb titers.Conclusion: CVAI may inhibit SARS-CoV-2 neutralizing antibody expression through inducing immune dysfunction and chronic inflammation. Thus, more attention should be paid to the vaccination for high CVAI population to improve the effectiveness of vaccination, which could provide more robust support for COVID-19 epidemic prevention and control.Keywords: Chinese visceral adiposity index, immune function, chronic inflammation, SARS-CoV-2 vaccine, neutralizing antibody

Siyuan Chen,1,2 Jia Liu,1,2 Zhili Feng,1,2 Liubo Zhou,1,2 Yuexiang Cai,1,2 Qiancheng Jing1,2 1Department of Otolaryngology Head and Neck Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, People’s Republic of China; 2Institute of Otolaryngology Head and Neck Surgery, Hengyang Medical School, University of South China, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Qiancheng Jing, Department of Otolaryngology Head and Neck Surgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, People’s Republic of China, Email 2022050001@usc.edu.cnBackground: Exosomes carry various types of transcripts and serve as promising biomarkers for inflammatory diseases. However, the role of serum exosomal microRNAs (miRNAs) in chronic rhinosinusitis with nasal polyps (CRSwNP) is poorly clarified.Methods: A prospective exploratory cohort of 10 CRSwNP patients was conducted, and the serum exosome samples were subjected to miRNA sequencing. Two independent prospective cohorts, consisting of 40 and 54 patients respectively, were recruited from different medical centers for validation. These cohorts were monitored for over two years, with postoperative recurrence serving as the primary outcome measure. The top 3 differentially exosomal miRNAs were validated in the serum samples, and their predictive values for recurrence were assessed.Results: Eight CRSwNP patients completed the follow-up, comprising 4 non-recurrent cases and 4 recurrent cases. Distinctive profiles of serum exosomal miRNAs were identified between the two groups. In the first validation cohort, reverse transcription-polymerase chain reaction results indicated elevated serum exosomal miR-3174 and miR-6750-5p expressions, along with reduced miR-192-3p levels in the recurrence group compared to the non-recurrence group. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival analysis demonstrated significant correlations between expressions of exosomal miR-3174 and miR-192-3p and the risk of postoperative recurrence. These findings were further validated in the second cohort, confirming the elevation of both miRNAs in the recurrence group and their associations with recurrence risk. Additionally, serum exosomal miR-3174 levels increased in recurrent cases compared to their baseline levels.Conclusion: Circulating exosomal microRNA signatures may influence the risk of postoperative recurrence in CRSwNP patients. Serum exosomal elevated exosomal miR-3174 and decreased miR-192-3p were correlated with CRSwNP recurrence risk.Keywords: exosome, chronic rhinosinusitis with nasal polyps, biomarker, recurrence

Xiaoming Fu,1 Fuhai Zeng,2 Linling Li,1 Guoquan Liu,1 Qing Zhong,3 Shouwan Chen1 1Department of Burn and Plastic Surgery, The People’s Hospital of Jianyang City, Jianyang, Sichuan, People’s Republic of China; 2Department of Plastic and Maxillofacial Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Science and Technology, The People’s Hospital of Jianyang City, Jianyang, Sichuan, People’s Republic of ChinaCorrespondence: Shouwan Chen, Department of Burn and Plastic Surgery, The People’s Hospital of Jianyang City, No. 180 Hospital Road, Jianyang, Sichuan, 641400, People’s Republic of China, Email drshouwang@163.comBackground: The existing observational research on the relationship between physical activity (PA) and skin cancer (SC) is contentious, which points to the intricate nature of their association and underscores the imperative for more nuanced research to untangle the causal dynamics at play. The aim of this article is to delve deeper into this complex relationship, seeking to clarify whether PA serves as a protective factor against SC, or contributes to its risk.Methods: We utilized data from the genome-wide association study (GWAS) of PA from GWAS Catalog (include self-reported moderate to vigorous PA (MVPA), self-reported vigorous PA (VPA), and accelerometer-based average-accelerated PA). The data of SC is from FinnGen. All of the participants are of European ancestry. We used two-sample Mendelian Randomization (TSMR) to analyze the causal relationship between PA and SC.The research was conducted using inverse variance weighted (IVW) method as the primary approach, and MR Egger regression as supplementary analytical method. To ensure the robustness of the results, Cochran’s Q-test and MR pleiotropy residual sum and outlier (MR-PRESSO) global tests were used to measure sensitivity.Results: Our analysis indicated that average-accelerated PA was associated with an increased risk of SC (ORIVW = 0.94, 95% CI 0.93– 0.96, P

Chengran Wang,1,&ast; Yihong Zhang,1,&ast; Weihui Kong,2 Xin’ao Rong,1 Ziming Zhong,1 Lei Jiang,3 Shuhan Chen,1 Chuang Li,1 Fuqiang Zhang,1 Jinlan Jiang1 1Department of Scientific Research Center, China–Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 2Department of Stomatology, the First Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China; 3Department of Geriatric Medicine, Changchun Central Hospital, Changchun, Jilin Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fuqiang Zhang; Jinlan Jiang, Department of Scientific Research Center, China–Japan Union Hospital of Jilin University, Changchun, Jilin Province, People’s Republic of China, Email zfqzhang@jlu.edu.cn; jiangjinlan@jlu.edu.cnAbstract: Osteosarcoma is the predominant primary malignant bone tumor that poses a significant global health challenge. MicroRNAs (miRNAs) that regulate gene expression are associated with osteosarcoma pathogenesis. Thus, miRNAs are potential therapeutic targets for osteosarcoma. Nanoparticles, widely used for targeted drug delivery, facilitate miRNA-based osteosarcoma treatment. Numerous studies have focused on miRNA delivery using nanoparticles to inhibit the progress of osteosarcoma. Polymer-based, lipid-based, inorganic-based nanoparticles and extracellular vesicles were used to deliver miRNAs for the treatment of osteosarcoma. They can be modified to enhance drug loading and delivery capabilities. Also, miRNA delivery was combined with traditional therapies, for example chemotherapy, to treat osteosarcoma. Consequently, miRNA delivery offers promising therapeutic avenues for osteosarcoma, providing renewed hope for patients. This review emphasizes the studies utilizing nanoparticles for miRNA delivery in osteosarcoma treatment, then introduced and summarized the nanoparticles in detail. And it also discusses the prospects for clinical applications. Keywords: osteosarcoma, MicroRNAs, nanoparticle delivery, molecular targeted therapy

Wenguang Lai,1,&ast; Xiaoli Zhao,2,&ast; Zhiyong Gao,1 Haozhang Huang,3,4 Donghui Huang,1 Yang Zhou,3,4 Guoxiao Liang,3,4 Shiqun Chen,3,4 Jin Liu,3 Yong Liu3 1Department of Pharmacy, Heyuan People’s Hospital; Guangdong Provincial People’s Hospital, Heyuan Hospital, Heyuan, 517001, People’s Republic of China; 2Department of Cardiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, People’s Republic of China; 3Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Liu; Jin Liu, Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People’s Republic of China, Tel +86 02083827812-10528, Fax +86 02083851483, Email liuyong@gdph.org.cn; ljaw397017568@163.comPurpose: Heart failure with preserved ejection fraction (HFpEF) is inherently a complex inflammatory syndrome, and heightened inflammation is strongly associated with an increased risk of death. However, the association of systemic inflammation levels with total and cardiovascular death among patients with HFpEF remains unknown. We aimed to investigate the prognostic impact of systemic inflammation on all-cause and cardiovascular death among patients with HFpEF.Patients and Methods: Patients with HFpEF were included in this study. Systemic inflammation response index (SIRI) is defined as the multiplication of neutrophil and monocyte divided by lymphocyte count, and patients were divided into four groups based on SIRI quartiles. Cox regression models and competing risk models were used to examine the relationships between SIRI and total and cardiovascular‑specific mortality, respectively.Results: 9,986 patients with HFpEF were included in five tertiary hospitals. During a median follow-up period of 4.4 years, a total of 2004 patients died, of which 965 were cardiovascular deaths. After fully adjusting for confounders, elevated SIRI level was significantly related to the increased risk of all-cause death (Q2, Q3, Q4: adjusted hazard ratio (aHR) [95 confidence interval (CI)%] =1.17[1.01– 1.35], 1.31[1.13– 1.52], 1.51[1.30– 1.76], respectively; P for trend < 0.001). The elevated quartile of SIRI showed higher risks of cardiovascular death, but there was no statistically significant increased risk of cardiovascular death across the lower SIRI quartile (model 3: Q2, Q3, Q4: aHR [95CI%] =1.22[0.99– 1.51], 1.50[1.20– 1.86], 1.73[1.37– 2.18], respectively; P for trend < 0.001).Conclusion: Elevated systemic inflammation level on admission was correlated with an increased risk of all-cause and cardiovascular death among patients with HFpEF. The SIRI may serve as a promising marker of risk stratification for patients with HFpEF.Keywords: heart failure with preserved ejection fraction, systemic inflammatory response index, all-cause death, cardiovascular death

Dongzhu Lu,1,&ast; Huapeng Yu,2,&ast; Lichang Chen,3 Jinlan Lin,1 Shijie Chen,1 Yunjian Huang1 1Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 2Department of Respiratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunjian Huang, Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, People’s Republic of China, Tel +86 13805099580, Email yunjian13@126.comPurpose: We compared pulmonary function indices and quantitative CT parameters of airway remodeling, air trapping, and emphysema in asthmatic patients and patients with COPD and asthma–COPD overlap (ACO) and explored their relationships with airflow limitation.Patients and Methods: Patients with asthma (n=48), COPD (n=52), and ACO (n=30) and controls (n=54) who completed pulmonary function tests and HRCT scans were retrospectively enrolled in our study. Quantitative CT analysis software was used to assess emphysema (LAA%), airway wall dimensions (wall area (WA), luminal area (LA), and wall area percentage (WA%)), and air trapping ((relative volume change of − 860 HU to − 950 HU (RVC− 860 to-950) and the expiration-to-inspiration ratio of the mean lung density (MLDE/I))). Differences in pulmonary function and HRCT parameters were compared among the groups. Spearman correlation analysis and regression analysis were utilized to explore structure‒function relationships.Results: The LAA% in COPD and ACO patients was significantly greater than that in asthmatic patients and controls. The WA% and WA in COPD and ACO patients were greater than those in controls, whereas the WA% and LA between asthmatic patients and controls reached statistical significance. The RVC− 860 to − 950 levels decreased in the following order: ACO, COPD, and asthma. RVC− 860 to − 950 independently predicted FEV1% in asthmatic patients; LAA% and MLDE/I in COPD patients; and LAA%, WA% and RVC− 860 to − 950 in ACO patients.Conclusion: Comparable emphysema was observed in patients with COPD and ACO but not in asthmatic patients. All patients exhibited proximal airway remodeling. The bronchi were thickened outward in COPD and ACO patients but are thickened inward in asthmatic patients. Furthermore, air trapping in ACO patients was the most severe among all the groups. Indirect lung densitometry measurements might be more predictive of the degree of airflow limitation than direct airway measurements in obstructive airway diseases.Keywords: asthma, COPD, asthma-COPD overlap, quantitative HRCT, structure-function relationship

Qi-Feng Chen,1,&ast; Xiong-Ying Jiang,1,2,&ast; Yue Hu,1,&ast; Song Chen,1 Jun-Zhe Yi,1 Sui-Xing Zhong,1 Jiong-Liang Wang,1 Ning Lyu,1 Ming Zhao1 1Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510210, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Zhao, Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +862087343272, Email zhaoming@mail.sysu.edu.cnPurpose: The combination of sorafenib and hepatic arterial infusion chemotherapy (SoHAIC) has shown to enhance overall survival rates in patients with advanced hepatocellular carcinoma and major portal vein tumor thrombosis (HCC-Vp3-4) compared to sorafenib alone. Our objective was to evaluate the cost-effectiveness of SoHAIC versus sorafenib for the treatment of HCC-Vp3-4, taking into account the viewpoint of Chinese healthcare payers.Methods: This pharmacoeconomic study employed a Markov model to assess the cost-effectiveness of treating HCC-Vp3-4 with SoHAIC in comparison to sorafenib. The patient characteristics were drawn from individuals from the trial conducted between June 2017 and November 2019, with cost and health value data sourced from published literature. The primary outcome measure in this research was the incremental cost-effectiveness ratio (ICER), which indicates the additional cost per quality-adjusted life year (QALY). The willingness-to-pay (WTP) threshold per QALY was set at &dollar;30,492.00. Furthermore, 1-way sensitivity and probabilistic sensitivity analyses were carried out to validate the consistency of the results.Results: In the baseline scenario, sorafenib resulted in 0.42 QALY at a cost of &dollar;10,507.89, while SoHAIC generated 1.66 QALY at a cost of &dollar;32,971.56. When comparing SoHAIC to sorafenib, the ICER was &dollar;18,237.20 per QALY, which was below the WTP threshold per QALY. Furthermore, the 1-way sensitivity analysis demonstrated that the ICER remained within the WTP threshold despite fluctuations in variables. In the probabilistic sensitivity analysis, SoHAIC had a 98.8% probability of being cost-effective at the WTP threshold, considering a wide range of parameters.Conclusion: In this cost-effectiveness evaluation, SoHAIC demonstrated cost-effectiveness over sorafenib for HCC with major portal vein tumor thrombosis, as observed from the perspective of a Chinese payer.Keywords: HCC, portal vein tumor thrombosis, sorafenib, HAIC, Cost-effectiveness

Huiqian Guo,1,2,&ast; Jing Luo,1,3,&ast; Suming Chen,1 Ting Yu,4 Xiaofei Mu,4 Fangzhou Chen,4 Xiuhui Lu,4 Jiaqi He,4 Yali Zheng,4 Chunmei Bao,2 Peng Wang,4 Zhe Yin,4 Boan Li1– 3 1Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China; 2School of Medical Laboratory, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3Medical School of Chinese PLA, Beijing, 100853, People’s Republic of China; 4State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boan Li, Department of Clinical Laboratory, the Fifth Medical Center of PLA General Hospital, Beijing, 100039, People’s Republic of China, Email lba@263.net Zhe Yin, State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, People’s Republic of China, Email jerry9yin@163.comPurpose: To investigate the genetic diversity of IncG plasmids, we have proposed a typing scheme based on replicon repA and performed comparative genomic analysis of five IncG plasmids from China.Methods: p30860-KPC, p116965-KPC, pA1705-KPC, pA1706-KPC and pNY5520-KPC total in five IncG plasmids from clinical isolates of Pseudomonas and Enterobacteriaceae, respectively, were fully sequenced and were compared with the previously collected reference plasmid p10265-KPC.Results: Based on phylogeny, IncG-type plasmids are divided into IncG-I to IncG-VIII, the five plasmids belong to IncG-VIII. A detailed sequence comparison was then presented that the IncG plasmid involved accessory region I (Tn 5563a/b/c/d/e), accessory region II (ISpa19), and accessory region III (blaKPC-2-region). Expect for the pNY5520-KPC, the rest of the plasmids had the same backbone structure as the reference one. Within the plasmids, insertion sequences Tn 5563d and Tn 5563e were identified, a novel unknown insertion region was found in Tn 5563b/c/d/e. In addition, Tn 6376b and Tn 6376c were newly designated in the study.Conclusion: The data presented here including a typing scheme and detailed genetic comparison which provide an insight into the diversification and evolution history of IncG plasmids.Keywords: IncG plasmids, blaKPC-2, phylogenetic tree, multidrug resistance, mobile elements

Xuanwen Luo, Suqin Chen,&ast; Weiliang Luo,&ast; Qingyun Li, Yening Zhu, Jiming Li Department of Neurology, Huizhou Central People’s Hospital, Huizhou, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiliang Luo; Suqin Chen, Department of Neurology, Huizhou Central People’s Hospital, No. 41, Eling North Road, Huizhou, Guangdong Province, 516001, People’s Republic of China, Tel +8613631986803, Fax +867522288160, Email lwl306@126.com; csq621@139.comPurpose: To investigate the benefit (90-day mRS score) and rate of major complications (early symptomatic intracranial hemorrhage-SICH) after reperfusion therapy (RT) (including intravenous thrombolysis -IVT and mechanical thrombectomy -MT) in patients over 80 years with acute ischemic stroke (AIS).Patients and Methods: AIS patients aged over 80 admitted to Huizhou Central People’s Hospital from September 2018 to 2023 were included in this study. Data on SICH, NIHSS, and mRS were analyzed. A good prognosis was defined as a mRS ≤ 2 or recovery to pre-stroke status at 90 days.Results: Of 209 patients, 80 received non-RT, 100 received IVT and 29 underwent MT. The non-RT group had the lowest baseline NIHSS while the MT group had the highest (non-RT 6.0 vs IVT 12.0 vs MT 18.0, P < 0.001). Higher NIHSS was associated with increased SICH risk (OR 1.083, P=0.032), while RT was not (OR 5.194, P=0.129). The overall SICH rate in the RT group was higher but not significantly different after stratification by stroke severity. Poor prognosis was associated with higher admission NIHSS, stroke due to large artery atherosclerosis (LAA) combined with cardioembolism (CE), and stroke-associated pneumonia (SAP) (OR 0.902, P< 0.001; OR 0.297, P=0.029; OR 0.103, P< 0.001, respectively). The RT group showed a greater reduction in NIHSS (delta NIHSS) than the non-RT group (non-RT 2.0 vs IVT 4.0 vs MT 6.0, P< 0.005). For severe AIS, the IVT group had a better prognosis at 90 days (non-RT 0% vs IVT 38.2%, P=0.039). No 90-day mortality difference was found between groups after stratification.Conclusion: Stroke severity, rather than RT, is an independent risk factor for SICH in AIS patients over 80. RT in severe stroke patients improves NIHSS at 90 days, suggesting RT is safe and effective in this demographic. Further studies with larger samples are required to confirm these findings.Keywords: acute ischemic stroke, elderly, intravenous thrombolysis, mechanical thrombectomy, symptomatic intracranial hemorrhage, therapeutic efficacy

Shuqi Wang,1,2 Boying Jia,1,2 Sifan Niu,2,3 Shuchun Chen1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Internal Medicine, North China University of Science and Technology, Tangshan, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China, Tel/Fax +86 31185988406, Email chenshuc2014@163.comPurpose: To explore the correlation between hemoglobin, albumin, lymphocyte count, platelet count (HALP) score and type 2 diabetic retinopathy (DR).Methods: The study was conducted on 674 patients with type 2 diabetes (T2DM). According to the results of the fundus examination, they were divided into non-diabetic retinopathy group (NDR, n=388) and diabetic retinopathy group (DR, n=286). Collected patients baseline data, calculated HALP score, analyzed the correlation between HALP score and DR.Results: In all patients, male patients and female patients, the HALP score of the DR group was lower than that of the NDR group (P< 0.001), and the HALP score was negatively correlated with the incidence of DR (P< 0.05). HALP score was independent risk factors for DR, regardless of gender. In male patients, HALP score and DR had a linear relationship, but in female patients, HALP score and DR showed a nonlinear relationship, and HALP score was more sensitive to the onset of DR in male patients. The combined diagnostic model of HALP score, course of disease, SBP and BUN was used to diagnose DR, and it was found that the diagnostic value was the highest among male patients, with AUC of 0.761, sensitivity of 58.3% and specificity of 80.3%.Conclusion: HALP score was an independent risk factor for DR, attention should be paid to monitoring HALP score, especially in male T2DM patients. The accuracy of HALP score, disease course, SBP and BUN combined model diagnosis of DR was high, which can become a biological indicator for early screening of DR.Keywords: HALP score, type 2 diabetes, diabetic retinopathy

Zhuoya Jia,1,2 Zelin Li,2 Shuchun Chen2,3 1Graduate School of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Key Laboratory of Metabolic Diseases of Hebei Province, Shijiazhuang, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, 050051, People’s Republic of China, Tel/Fax +86 31185988406, Email chenshuc2014@163.comObjective: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid metabolism and inflammation. This study aimed to investigate the relationship between neutrophil-HDL cholesterol ratio (NHR) and NAFLD in a healthy population.Methods: 1881 healthy people who underwent a physical examination from August to December 2023 at the Hebei General Hospital were chosen for this cross-sectional study. 936 individuals were ultimately included thanks to propensity matching and exclusion criteria. Ultrasound was used to diagnose fatty liver and a t-test or Mann–Whitney test was used to compare the clinical characteristics of participants between groups with and without fatty liver. Logistic regression was used to construct a new model that included NHR. The predictive value of NHR as well as the new model for NAFLD in a healthy population was assessed using logistic regression and subject work characteristic curves.Results: NHR levels were higher among participants in the NAFLD group than those without NAFLD(P< 0.05). NHR is a risk factor for NAFLD in a healthy population(P< 0.05). The odds ratios (ORs) of NHR for predicting NAFLD in Model I (adjusted for sex, age, and BMI) and Model II (adjusted for sex, age, BMI, HbA1c, TC, TG, and ALT) were 1.166 (1.022, 1.331) and 1.248 (1.110, 1.402)(P< 0.05). The new model created by logistic regression predicted NAFLD with an area under the curve of 0.676 (0.645, 0.706). Compared to participants in the low NHR group, the high NHR group exhibited a higher prevalence of NAFLD(p< 0.05).Conclusion: NHR is associated with NAFLD, which is a good predictor of NAFLD in a healthy population.Keywords: neutrophil/high-density lipoprotein cholesterol ratio, nonalcoholic fatty liver disease

Qing Zhu,1,2,&ast; Yijia He,1,2,&ast; Sijia Chen,1,2 Guoqiang Zhang1,2 1Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Hebei Provincial Innovation Center of Dermatology and Medical Cosmetology Technology, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoqiang Zhang, Department of Dermatology, The First Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China, Email 57702800@hebmu.edu.cnAbstract: Vitiligo has been reported to occur in association with lupus erythematosus (LE) and other autoimmune diseases. However, it remains unclear whether this association occurs because of shared immunopathogenesis. We hereby describe a case of discoid lupus erythematosus (DLE) in a 51-year-old man with a 3 years history of skin lesions on his face, arms, and the V zone of the neck, and with the coexistence of vitiligo for 12 years, who developed from DLE to hypertrophic discoid lupus erythematosus (HDLE) after 10 months. We reviewed the previously reported cases to summarize the clinical characteristics of these patients and hope it may provide a reference for dermatologists.Keywords: hypertrophic discoid lupus erythematosus, lupus erythematosus, vitiligo, association

Na Li,1 Liufu Cui,1 Gary Tse,2,3 Panagiotis Korantzopoulos,4 Konstantinos P Letsas,5 George Bazoukis,6,7 Shuohua Chen,8 Nan Zhang,2 Xuemei Yang,9 Peipei Liu,10 Lili Wu,11 Gan-Xin Yan,12,13 Gregory Yoke Hong Lip,14,15 Shouling Wu,8 Tong Liu2 1Department of Rheumatology and Immunology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 2Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China; 3School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, People’s Republic of China; 4First Department of Cardiology, University of Ioannina Medical School, Ioannina, Greece; 5Arrhythmia Unit, Laboratory of Cardiac Pacing and Electrophysiology, Onassis Cardiac Surgery Center, Athens, Greece; 6Department of Cardiology, Larnaca General Hospital, Larnaca, Cyprus; 7European University Cyprus, Medical School, Nicosia, Cyprus; 8Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China; 9School of Clinical Medicine, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 10School of Public Health, North China University of Science and Technology, Tangshan, Hebei Province, People’s Republic of China; 11Department of Cardiology, Shanghai Songjiang District Central Hospital, Shanghai, People’s Republic of China; 12Lankenau Medical Center and Lankenau Institute for Medical Research, Wynnewood, PA, USA; 13Department of Cardiology, Fuwai Huazhong Hospital, Zhengzhou, Henan Province, People’s Republic of China; 14Liverpool Centre for Cardiovascular Sciences, University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK; 15Danish Center for Clinical Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, DenmarkCorrespondence: Tong Liu, Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China, Email liutong@tmu.edu.cn; liutongdoc@126.com Shouling Wu, Department of Cardiology, Kailuan General Hospital, Tangshan, Hebei Province, People’s Republic of China, Email drwusl@163.comObjective: This study aimed to explore the impact of a combination of hyperuricemia (HUA) and excessive high-sensitivity C-reactive protein (hs-CRP) levels on the likelihood of developing cardiac conduction block (CCB). Additionally, it sought to assess whether the influence of uric acid (UA) on CCB is mediated by hs-CRP.Methods: A prospective study was executed utilizing data from the Kailuan cohort, including 81,896 individuals initially free from CCB. The participants were categorized into four groups depending on the existence of HUA and low-grade inflammation (hs-CRP> 3 mg/L). Cox regression analysis was employed to ascertain hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident CCB. A mediation analysis was performed to determine if hs-CRP functioned as a mediator in the connection between UA levels and the incidence of CCB.Results: During a median observation period of 11.8 years, we identified 3160 cases of newly occurring CCB. Compared with the low UA/low CRP group, the combination of HUA and low-grade inflammation elevated the CCB risks (HR:1.56, 95% CI:1.22– 1.99), atrioventricular block (AVB) (HR:1.88, 95% CI:1.27– 2.77), and right bundle branch block (HR:1.47, 95% CI:1.02– 2.12), respectively. Mediation analysis revealed that in the HUA group, compared with the non-HUA group, the risk of CCB elevated by 14.0%, with 10.3% of the increase mediated through hs-CRP.Conclusion: HUA combined with elevated hs-CRP increased the risk of CCB, especially AVB. The connection between UA and the CCB risk was partly mediated by hs-CRP. Keywords: hyperuricemia, inflammation, cardiac conduction block, combined exposure, risk factors, mediation

Hongmei Sun,1,2 Chao Lv,2,3 Xiaoxue Zhang,1,2 Xuan Sun,1,3,4 Siyu Chen,1,3,4 Ke Li,3,4 Yazhuo Hu,2,3 Yuxin Feng,1,2 Tong Yin,2,3 Jianjun Jia2,3 1Medical School, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Institute of Geriatrics, Chinese PLA General Hospital, Beijing, People’s Republic of China; 3National Clinical Research Center of Geriatric Diseases, Chinese PLA General Hospital, Beijing, People’s Republic of China; 4Department of Geriatric Neurology, the Second Medical Centre, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jianjun Jia; Tong Yin, Institute of Geriatrics, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, Haidian District, 100853, People’s Republic of China, Email jiajianjun301@126.com; yintong301@163.comBackground: Genetic variation plays an important role in drug response, there are few relevant studies on patients with Alzheimer’s disease continuum (ADC).Objective: This study focused on the associations between two single nucleotide polymorphisms (SNPs) (rs3793790 and rs2177370) located in the CHAT gene and donepezil response in ADC patients, and further evaluated the associations between the two SNPs and ADC.Material and Methods: According to 2018 National Institute on Aging and Alzheimer’s Association (NIA-AA) standard, amyloid β-protein positive (Aβ+) and negative (Aβ-) patients were recruited according to the Aβ-PET/CT standard. rs3793790 and rs2177370 were genotyped in buccal swab samples by using the MassARRAY system. We used the Mini Mental State Examination (MMSE) in Chinese version, caregiver evaluation, and prescribing behavior to assess therapeutic response during the 9-month period. Using logistic regression models, we analyzed the relationship between the two SNPs and donepezil response in 58 Aβ+ patients treated with donepezil alone at the initial diagnosis of ADC. We also explored a probable link between the two SNPs and ADC in 147 Aβ+ and 73 Aβ– patients using a logistic regression analysis.Results: The chance of donepezil response was higher in patients with the G allele of rs3793790 and/or the A allele of rs2177370 than in those without (odds ratio (OR) 6.83, 95% confidence interval (CI): 1.64– 28.49). Additionally, the rs3793790 variant was not associated with ADC, whereas the A allele in rs2177370 increased 1.51-fold the ADC risk (OR 2.51, 95% CI: 1.28– 4.95).Conclusion: The genetic variants of rs3793790 and rs2177370 were associated with the donepezil response, and rs2177370 may have a moderate relationship with the risk of ADC.Keywords: Alzheimer’s disease, pharmacogenomics, variant, gene, donepezil

Shuqi Wang,1,2 Haina Gao,3 Mengmeng Zhang,1,2 Shuchun Chen1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Internal Medicine, The Second Hospital of Shijiazhuang, Shijiazhuang, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China, Tel/Fax +86 31185988406, Email chenshuc2014@163.comPurpose: To explore the relationship between vitamin D (VitD) deficiency and the apolipoprotein B/apolipoprotein A1 (apo B/A1) in type 2 diabetes mellitus (T2DM) patients.Methods: This was a retrospective study that lasted 2 years and 6 months, collecting information and laboratory data from 784 patients with T2DM. Patients were divided into VitD deficiency group (n = 433) and non-VitD deficiency group (n = 351) based on VitD levels. Calculated apo B/A1 ratio, and patients were further divided into high-apo B/A1 group (n = 392) and low-apo B/A1 group (n = 392) based on the median of the apo B/A1. All data were analyzed using Prism 8.0.1 and R version 4.3.1 software.Results: Apo B/A1 levels of T2DM patients combined with VitD deficiency was significantly higher than that of non-VitD deficiency patients, and the VitD levels of patients with high apo B/A1 was significantly lower than that patients with low apo B/A1 (all P< 0.001). Spearman correlation analysis showed that VitD levels were negatively correlated with apo B/A1 (r=-0.238, P< 0.001). Multiple linear regression analysis revealed after adjusting other factors, VitD levels were significantly negatively associated with apo B/A1 (β=-0.123, P=0.001). Binary logistic regression analysis showed apoB/A1 was an independent risk factor for VitD deficiency in T2DM patients. Restrictive cubic spline indicated a significant linear relationship between apoB/A1 and VitD deficiency (P general trend < 0.0001, P nonlinear = 0.0896), after stratification of gender, the results showed that apo B/A1 was more susceptible to VitD deficiency in female patients. The receiver operating characteristic (ROC) curve analysis showed that the area under the curve, sensitivity and specificity of the apo B/A1 for VitD deficiency were 0.654, 66.3% and 59.8%, respectively.Conclusion: The apo B/A1 was significantly negatively associated with VitD levels and an independent risk factor for VitD deficiency in patients with T2DM.Keywords: type 2 diabetes mellitus, vitamin D deficiency, apolipoprotein B/apolipoprotein A1

Chengzhang Yang,1,2,&ast; Weifang Liu,2,3,&ast; Zijia Tong,1,&ast; Fang Lei,3,4 Lijin Lin,2,3 Xuewei Huang,3,5 Xingyuan Zhang,3,6 Tao Sun,2,3 Gang Wu,1 Huajing Shan,1 Shaoze Chen,1 Hongliang Li2,3 1Department of Cardiology, Huanggang Central Hospital, Huanggang, People’s Republic of China; 2Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Institute of Model Animal, Wuhan University, Wuhan, People’s Republic of China; 4Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 5Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 6School of Basic Medical Science, Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongliang Li, Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China, Tel/Fax +86-27-68759302, Email lihl@whu.edu.cn Shaoze Chen, Department of Cardiology, Huanggang Central Hospital, Huanggang, People’s Republic of China, Tel/Fax +86-713-8381191, Email chenshaoze@hgyy.org.cnAim: The evidence on the association between insulin resistance (IR) and the prevalence or incidence of cardiac dysfunction has been controversial, and the relationship between pre-diabetic IR and cardiac function is lacking. Large sample studies in the Chinese general population are urgently needed to explore the association between IR and the risk of left ventricular hypertrophy (LVH) and decreased left ventricular diastolic function with preserved ejection fraction (LVDFpEF).Methods: Based on a National Health Check-up database in China, we conducted a multicenter cross-sectional retrospective study in 344,420 individuals. Furthermore, at a single center, we performed two retrospective longitudinal studies encompassing 8270 and 5827 individuals to investigate the association between IR and the development of new-onset LVH and LVDFpEF, respectively. The median follow-up duration exceeded 2.5 years. The triglyceride and glucose (TyG) index, known for its high sensitivity in detecting IR, serves as a reliable alternative marker of IR. The logistic and cox proportional hazard regression models were used to determine the relationships.Results: In the cross-sectional study, IR showed a positive association with the prevalence of LVH and decreased LVDFpEF after adjusting for confounders. In the longitudinal cohort, IR was also correlated with the new onset of LVH and decreased LVDFpEF, with hazard ratios (HR) of 1.986 (95% CI: 1.307, 3.017) and 1.386 (95% CI: 1.167, 1.647) in the fourth quartile of TyG levels compared to the lowest quartile, respectively, after adjusting for confounders. The subgroup analysis in non-hypertensive or non-diabetic people and the sensitivity analysis in the population with homeostasis model assessment of insulin resistance (HOMA-IR) further verified the above-mentioned results.Conclusion: IR was associated with LVH and decreased LVDFpEF. Effective management of IR may prevent or delay the development of adverse LVH and decreased LVDFpEF.Keywords: insulin resistance, triglyceride and glucose index, left ventricular hypertrophy, left ventricular diastolic function

Yongchao Li,1,&ast; Jinfeng Gao,2,&ast; Shuhua Liu,1 Shijian Chen,3 Xiaoyue Wei,3 Yalun Guan,1 Xuejiao Li,1 Yunfeng Li,1 Zhongqiang Huang,1 Ge Li,1 Yuhong Zhao,3 Pinghua Liu,4 Yu Zhang1 1Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, 510663, People’s Republic of China; 2Guangdong Quality Supervision and Testing Station for Medical and Health Care Appliances, Institute of Biological and Medical Engineering, Guangdong Academy of Sciences, Guangzhou, 510632, People’s Republic of China; 3School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China; 4Department of Chemistry, Boston University, Boston, MA, 02215, USA&ast;These authors contributed equally to this workCorrespondence: Yu Zhang; Pinghua Liu, Email zhangyugzh@hotmail.com; pinghua@bu.eduBackground: Ergothioneine (EGT) is an antioxidant, which could be detected in human tissues, and human skin cells could utilize EGT and play an anti-oxidative role in keratinocytes. And in this study we are going to elucidate whether EGT could protect the skin from photoaging by Ultraviolet (UV) exposure in mice and its molecule pathway.Methods: Histological analysis was performed for evaluating the skin structure change. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured with biological assay for evaluating oxidative and antioxidative ability of skin exposed to UV light. And the level of marker molecules in mouse skin were detected by hydroxyproline (Hyp) assay, immunohistochemical analysis, Western blot, and quantitative real-time PCR (qRT-PCR). The markers of skin aging and cell death were tested by cell culture and treatment, Western blot and qRT-PCR.Results: EGT decreased the levels of inflammatory factors induced by UV exposure in mouse skin. MDA and SOD activity detection showed that EGT decreased MDA levels, increased SOD activity, and upregulated PI3K/Akt/Nrf2 signals in mouse skin exposed to UV, which further activated Nrf2 in the nucleus and enhanced the expression of Nrf2 target genes. In the cell model, we revealed that EGT could inhibit the increase in senescence-associated β-galactosidase-positive cells and p16 and γ-H2A.X positive cells induced by etoposide and activate PI3K/Akt/Nrf2 signaling. Moreover, a PI3K inhibitor blocked EGT protection against etoposide-induced cell death.Conclusion: The study showed EGT may play an important protective role against cell damage or death through the PI3K/Akt/Nrf2 signaling pathway in skin.Keywords: ergothioneine, skin aging, PI3K/Akt, Nrf2

Si Chen, Cecilia Cheng Social and Health Psychology Laboratory, Department of Psychology, The University of Hong Kong, Hong Kong, People’s Republic of ChinaCorrespondence: Cecilia Cheng, Social and Health Psychology Laboratory, Department of Psychology, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China, Email ceci-cheng@hku.hkAbstract: The COVID-19 pandemic posed an unprecedented challenge to public well-being, necessitating an examination of its health impact. This review discusses the relationship between pandemic-induced stressors and individual sleep patterns and quality. The pandemic stressors include lockdown or physical distancing measures, direct virus exposure, and the dissemination of misinformation and disinformation. The pandemic led to delayed sleep-wake cycles, except for healthcare professionals, and worsened sleep quality. The prevalence of insomnia was higher for women due to pre-existing conditions and susceptibility stressors such as lockdown stress and family responsibilities. Healthcare professionals, who experienced worsened work conditions during the pandemic, reported higher rates of insomnia and sleep difficulties due to infection anxiety and post-traumatic stress from direct virus exposure. For the general population, stress stemmed from social isolation under lockdown and overwhelming false information available online, resulting in sleep problems. Taken together, the findings highlight the importance of promoting social interactions, providing psychological support services, and caution in navigating health information. In summary, this review underscores the need for individual- and group-centered approaches in ongoing research and interventions to address pandemic-related stress and sleep issues during COVID-19.Keywords: sleep health, sleep disturbance, insomnia, infodemic

Sida Chen, Ling Wen, Jintao Ou, Yuting Lai, Yan Shen Department of Respiratory, Shenzhen Longgang Central Hospital, Shenzhen, Guangdong, 518000, People’s Republic of ChinaCorrespondence: Yan Shen, Shenzhen Longgang Central Hospital 6082 Longgang Boulevard (Longgang Section), Longgang District, Shenzhen, Guangdong, 518000, People’s Republic of China, Tel +86-0755-84806933-5901, Email shenyan5902@163.comBackground: Pulmonary infections are significant global health burdens, and conventional diagnostic methods (culture and polymerase chain reaction), are often limited by slow results and low sensitivity. Metagenomic next-generation sequencing (mNGS) offers a rapid, comprehensive alternative for identifying diverse pathogens, including rare and mixed infections. Thus, we assessed the diagnostic performance of mNGS in pulmonary infections, compared the findings with those of traditional pathogen detection methods, and explored its potential to enhance clinical diagnostics and patient care.Methods: We collected samples from 125 immunocompromised patients diagnosed with pulmonary infection at the Department of Respiratory Medicine of Shenzhen Longgang Central Hospital from March 2020 to July 2022. We compared the rate of pathogen positivity and pathogen distribution between conventional pathogen detection methods and mNGS using samples including sputum, blood, and bronchoalveolar lavage fluid.Results: Among the 125 cases of unexplained pulmonary infection, 82 (65.6%) and 40 (32.0%) tested positive for pathogens using mNGS and routine culture, respectively (P < 0.05). Both methods of pathogen detection were positive in 28 (22.4%) cases (complete match, 9; complete mismatch, 13; partial match, 6). However, 43.2% of cases only tested positive using mNGS, 9.4% only tested positive using routine tests, and 24.8% tested negative using both methods. A viral infection was present in 55.2% of cases. The detection rate of mycobacteria using mNGS (12.8%) was higher than that using conventional pathogen detection methods (5.6%).Conclusion: mNGS technology enhances pathogen detection in unexplained pulmonary infections, enabling targeted antimicrobial therapy and consequently helping to reduce broad-spectrum antibiotic use, aligning treatments more closely with the causative pathogens. Thus, mNGS offers significant clinical value by improving treatment efficacy and potentially reducing antibiotic resistance in pulmonary infection cases.Keywords: mNGS, Unexplained pulmonary infection, Pathogens, BALF

Yanchen Chen,1,2 Yuqin Tu,2,3 Guiling Yan,2,3 Xinyao Ji,2,3 Shu Chen,2,3 Changchun Niu,2 Pu Liao1,2 1Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, People’s Republic of China; 2Department of Clinical Laboratory, Chongqing General Hospital, Chongqing, People’s Republic of China; 3Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Pu Liao, Chongqing General Hospital, 118 Xingguang Avenue, Yubei District, Chongqing, People’s Republic of China, Tel +86 13628358003, Fax +23-63519127, Email liaopu@sina.comPurpose: There is growing evidence that the immune system plays an important role in the progression of Parkinson’s disease, the second most common neurodegenerative disorder. This study aims to address the comprehensive understanding of the immunopathogenesis of Parkinson’s disease and explore new inflammatory biomarkers.Patients and Methods: In this study, Immune-related differential expressed genes (DEIRGs) were obtained from GEO database and Immport database. The hub gene was screened in DEIRGs using LASSO regression and random forest algorithm, and the mRNA expression of the identified hub gene was validated using clinical blood samples.Results: We obtained a total of 157 DEIRGs that played an important role in the immune response. The results of immune cell infiltration analysis showed that the degree of memory B cells infiltration was higher in PD patients, while the degree of Monocytes, resting mast cells and M0 macrophages infiltration was lower (p< 0.05). A total of 8 hub genes were screened by machine learning methods, and RT-PCR results showed that the expression level of CBL gene in PD was significantly increased (p< 0.05).Conclusion: Our findings suggest that CBL is a new potential diagnostic biomarker for PD and that abnormal immune cell infiltration may influence PD development.Keywords: Parkinson’s disease, immune cell infiltration, bioinformatics, immport database, gene expression omnibus database

Jingjing He,1– 3 Jing Gao,1– 3 Yan Zhao,4 Shuai Chen1,3 1Department of Otolaryngology-Head and Neck Surgery, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, People’s Republic of China; 2Teaching Hospital of Fujian Medical University, Xiamen, 361003, People’s Republic of China; 3Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, 361003, People’s Republic of China; 4Army 73rd Group Military Hospital, Chenggong Hospital Affiliated to Xiamen University, Xiamen, 361000, People’s Republic of ChinaCorrespondence: Shuai Chen, Department of Otolaryngology-Head and Neck Surgery, the First Affiliated Hospital of Xiamen University, School of Medicine, No. 55, Zhenhai Road, Siming District, Xiamen, 361005, People’s Republic of China, Email chenshuai@xmu.edu.cn Yan Zhao, Army 73rd group military hospital, Chenggong Hospital Affiliated to Xiamen University, No. 92-96, Wenyuan Road, Siming District, Xiamen, 361000, People’s Republic of China, Email 46330926@qq.comBackground: Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa. However, few studies focus on the distributional characteristics of allergens in AR patients in Southern Fujian Province, China.Methods: A skin prick test (SPT) was performed and eight common allergens including Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dpt), weeds, animal dander, molds, cockroaches, and mangoes were chosen.Results: The positive reactions rate to the allergens was 65.79% in 6689 patients in Southern Fujian Province. Positive reactions to Df and Dpt had a negative association with age, whereas positive reactions to cockroach and weed had a positive association with age. A linear trend analysis demonstrated a significant positive relationship between positive reactions to various allergens from 2016 to 2019. Positive reactions to Df and Dpt were both correlated with the season. Positive reactions to Df, Dpt, cockroach and weed were related to disease duration and positive reactions to cockroach were correlated with city residence. Multivariate analysis revealed that male positive reactions gradually decreased with age (≤ 60), in contrast to female (≤ 60) positive reactions. Statistical difference was observed between the genders with regard to AR incidence from 2016 to 2019. The positive rate of skin tests was highest in summer in men, whereas in women it was lowest in summer. The gender composition ratios of positive cases in Xiamen, Zhangzhou, and Quanzhou cities differed significantly. The proportion of patients with positive reactions to the allergens in the three cities decreased with age. The highest proportions of patients with positive reactions all occurred during summer in the three cities. Furthermore, there were statistically significant differences in the age composition ratios across the seasons.Conclusion: This study analyzed the distributional characteristics of AR allergens in Southern Fujian Province, China. These findings will inform specific immunotherapy for AR patients.Keywords: allergic rhinitis, allergen, skin prick test, Southern Fujian Province in China

Shuhan Chen,1,2 Yanle Xie,1,2 Zenghui Liang,1,2 Yu Lu,3 Jingping Wang,4 Fei Xing,1,2 Yuanyuan Mao,1,2 Xin Wei,1,2 Zhongyu Wang,1,2 Jianjun Yang,1,2 Jingjing Yuan1,2 1Department of Anesthesiology, Pain and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Henan Province International Joint Laboratory of Pain, Cognition and Emotion, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 3Department of Orthopedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 4Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USACorrespondence: Jingjing Yuan; Jianjun Yang, Department of Anesthesiology, Pain and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University, No. 1, Eastern Jianshe Road, Zhengzhou, Henan Province, 450000, People’s Republic of China, Tel +86 13513719631 ; +86 13783537619, Email yjingjing_99@163.com; yjyangjj@126.comAbstract: Sleep is crucial for human health, insufficient sleep or poor sleep quality may negatively affect sleep function and lead to a state of sleep deprivation. Sleep deprivation can result in various health problems, including chronic pain. The intricate relationship between sleep and pain is complex and intertwined, with daytime pain affecting sleep quality and poor sleep increasing pain intensity. The article first describes the influence of sleep on the onset and development of pain, and then explores the impact of daytime pain intensity on nighttime sleep quality and subsequent pain thresholds. However, the primary emphasis is placed on the pivotal role of oxidative stress in this bidirectional relationship. Although the exact mechanisms underlying sleep and chronic pain are unclear, this review focuses on the role of oxidative stress. Numerous studies on sleep deprivation have demonstrated that it can lead to varying degrees of increased pain sensitivity, while chronic pain leads to sleep deprivation and further exacerbates pain. Further research on the role of oxidative stress in the mechanism of sleep deprivation-induced pain sensitization seems reasonable. This article comprehensively reviews the current research on the interrelationship between sleep deprivation, pain and the crucial role of oxidative stress.Keywords: sleep deprivation, pain, oxidative stress, antioxidants

Cheng Wang,1,&ast; Jiaoyang Pan,1,&ast; Shaoqing Chen,2 Lin Qiu,1 Huaanzi Hu,1 Li Ji,3 Jianhao Wang,1 Wenjia Liu,4 Xinye Ni2 1School of Pharmacy, Changzhou University, Changzhou, Jiangsu Province, People’s Republic of China; 2Department of Radiology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 3Department of Otorhinolaryngology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 4Department of Gastroenterology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjia Liu; Xinye Ni, Email 13813016290@126.com; nxy@njmu.edu.cnBackground: The in vivo barriers and multidrug resistance (MDR) are well recognized as great challenges for the fulfillment of antitumor effects of current drugs, which calls for the development of novel therapeutic agents and innovative drug delivery strategies. Nanodrug (ND) combining multiple drugs with distinct modes of action holes the potential to circumvent these challenges, while the introduction of photothermal therapy (PTT) can give further significantly enhanced efficacy in cancer therapy. However, facile preparation of ND which contains dual drugs and photothermal capability with effective cancer treatment ability has rarely been reported.Methods: In this study, we selected curcumin (Cur) and doxorubicin (Dox) as two model drugs for the creation of a cocktail ND (Cur-Dox ND). We utilized polyvinylpyrrolidone (PVP) as a stabilizer and regulator to prepare Cur-Dox ND in a straightforward one-pot method.Results: The size of the resulting Cur-Dox ND can be easily adjusted by tuning the charged ratios. It was noted that both loaded drugs in Cur-Dox ND can realize their functions in the same target cell. Especially, the P-glycoprotein inhibition effect of Cur can synergistically cooperate with Dox, leading to enhanced inhibition of 4T1 cancer cells. Furthermore, Cur-Dox ND exhibited pH-responsive dissociation of loaded drugs and a robust photothermal translation capacity to realize multifunctional combat of cancer for photothermal enhanced anticancer performance. We further demonstrated that this effect can also be realized in 3D multicellular model, which possibly attributed to its superior drug penetration as well as photothermal-enhanced cellular uptake and drug release.Conclusion: In summary, Cur-Dox ND might be a promising ND for better cancer therapy. Keywords: one-pot synthesis, size-tunable, multifunctional, cancer

Xiaoyu Pan,1,2 Shuqi Wang,1,2 Boying Jia,1,2 Lin Yue,1,3 Shuchun Chen1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China; 3Department of Endocrinology, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China, Tel/Fax +86 31185988406, Email chenshuc2014@163.comBackground: The objective of this investigation was to explore the health status and epidemiological features of civil servants working in Hebei Province, China.Methods: Data was collected through a cross-sectional survey that involved 50,039 adult civil servants in Hebei Province. The research was conducted at the Hebei Provincial Medical Examination Centre and included inquiries about demographics, health behaviours, chronic illnesses, and abnormal check-up indicators. Statistical data were used to determine the prevalence of chronic diseases and abnormal health examination indicators. Subgroup analyses by sex were then conducted to calculate the similarities and differences in health status between men and women.Results: The findings of the survey indicate that 14.2% of individuals who work in civil service suffer from obesity. Additionally, a considerable proportion of this group display poor health behaviours, including smoking and alcohol consumption. Hypertension (21.03%), dyslipidaemia (10.88%), and diabetes mellitus (8.56%) were identified as the top three chronic diseases, while cardiovascular diseases were prevalent at 6.27% among civil servants. Ultrasound showed a high prevalence of fatty liver, non-smooth gallbladder and liver cysts (44.61%, 33.24% and 23.26% respectively). The occurrence of pulmonary nodules was alarmingly high at 88.48%, while thyroid nodules were found in as much as 62.65% of patients. Abnormal E/A values≤ 1, prostate hyperplasia, breast nodules, and carotid plaques were also prevalent, with percentages ranging from 46.76% to 63.04%. In subgroup analyses by gender, the prevalence of chronic diseases and abnormal screening indicators was consistently higher in men than in women, with the exception of thyroid nodules and thyroid surgery.Conclusion: The survey revealed a large proportion of civil servants in Hebei Province, China, suffering from chronic diseases, underscoring the necessity for enhanced attention to chronic disease prevention and management in this group and emphasising the requirement for focused interventions aimed at improving health outcomes.Keywords: civil servants, health status, ultrasound, real-world study, Hebei Province, China

Suling Chen,1,&ast; Yuanhui Jiang,1,&ast; Xiaoli Lin,1,&ast; Hongjie Chen,1 Xiaoxuan Wu,2 Zhe Qian,3 Xuwen Xu,1 Huiqun Zhong,1 Jie Peng,1 Shaohang Cai1 1Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Department of Communicable and Endemic Disease Control and Prevention, Haizhu District Center for Disease Control and Prevention, Guangzhou, People’s Republic of China; 3Second Department of Elderly Respiratory, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Geriatrics Institute, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huiqun Zhong; Jie Peng, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China, Email lovely870821@163.com; pjie138@163.comPurpose: This study aims to investigate the relationship between estimated pulse wave velocity (ePWV) and metabolic syndrome (MetS) in people living with HIV (PLWH), proposing a novel and convenient predictor for early detection of MetS in PLWH.Patients and Methods: A total of 485 PLWH were enrolled. These participants were categorized into two groups based on the estimated pulse wave velocity (ePWV) level. Demographic and clinical data were collected to investigate the correlation between ePWV and MetS.Results: The cohort of 485 PLWH was categorized into high-ePWV and low-ePWV groups based on ePWV cutoff value of 10 m/s. We observed significant differences in components of MetS including triglycerides (TG, P < 0.05), HDL cholesterol (HDL-C, P < 0.01), systolic blood pressure (SBP, P < 0.001), diastolic blood pressure (DBP, P < 0.05), and fasting plasma glucose (FPG, P < 0.001) between the two groups. Furthermore, we employed receiver operating characteristic (ROC) curves to demonstrate the effectiveness of ePWV as a predictive indicator for MetS in PLWH (AUC = 0.739, P

Shaohua Tan,1,&ast; Xiangchen Li,2,&ast; Bing Lu,1,3 Yibin Lin,3 Yunxiang Cai,1 Jie He,4 Sisi Chen,2 Junli Gao,2 Junshun Gao,2 Xinhua Qiang1 1Department of Clinical Laboratory, The First People’s Hospital of Huzhou, Huzhou, Zhejiang, 313000, People’s Republic of China; 2Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang, 310020, People’s Republic of China; 3School of Medicine, Huzhou University, Huzhou, Zhejiang, 313000, People’s Republic of China; 4Department of Infectious Diseases, The First People’s Hospital of Huzhou, Huzhou, Zhejiang, 313000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xinhua Qiang, Department of Clinical Laboratory, The First People’s Hospital of Huzhou, No. 158 Back Square Road, Wuxing District, Huzhou, Zhejiang, 313000, People’s Republic of China, Email qiangxinhua@zjhu.edu.cnAbstract: Carbapenem-resistant Salmonella enterica (S. enterica) pose a significant threat to public health, causing gastroenteritis and invasive infections. We report the first emergence of a carbapenem-resistant S. enterica serovar London strain, A132, carrying the blaNDM-5 gene in China. Whole-genome sequencing and bioinformatics analysis assigned A132 to be ST155, a multidrug-resistant clone frequently reported in China. The strain A132 exhibited resistance to multiple antibiotics, with 20 acquired antibiotic resistance genes (ARGs) identified, predominantly located on the IncFIB plasmid (pA132-1-NDM). Notably, the blaNDM-5 gene was located within an IS 26 flanked-class 1 integron-ISCR1 complex, comprising two genetic cassettes. One cassette is the class 1 integron, which may facilitate the transmission of the entire complex, while the other is the blaNDM-5-containing ISCR1-IS 26-flanked cassette, carrying multiple other ARGs. Genbank database search based on the blaNDM-5-carrying cassette identified a similar genetic context found in transmissible IncFIA plasmids from Escherichia coli (p91) and Enterobacter hormaechei (p388) with a shared host range, suggesting the potential for cross-species transmission of blaNDM-5. To our knowledge, this is the first reported case of Salmonella serovar London ST155 harboring blaNDM-5 gene. Phylogenetic analysis indicated a close relationship between A132 and eight S. London ST155 strains isolated from the same province. However, A132 differed by carrying the blaNDM-5 gene and four unique ARGs. Given the high transmissibility of the F-type plasmid harboring blaNDM-5 and 18 other ARGs, it is imperative to implement vigilant surveillance and adopt appropriate infection control measures to mitigate the threat to public health.Keywords: blaNDM-5, Salmonella London, ST155, carbapenem resistance, IncFIB, integron

Lihua Zhu,1,&ast; Lingling Zhou,2,3,&ast; Liang Wang,4,&ast; Cunte Chen,2 Jie Qiao,1 Xinran Huang,1 Xiaoyan Su,1 Shaohua Chen,2 Bo Li,2 Xiuli Wu,2 Yangqiu Li2 1Department of Rheumatology and Immunology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, People’s Republic of China; 3Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510632, People’s Republic of China; 4Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yangqiu Li, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, People’s Republic of China, Tel +86 20 85226877, Fax +86 20 85226877, Email yangqiuli@hotmail.com Lihua Zhu, Department of Rheumatology and Immunology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China, Email zhulihua20121113@163.comBackground: There have been several studies regarding the susceptibility of A20 gene SNPs (rs2230926 and rs5029937) in rheumatoid arthritis (RA). However, little is known about the association between polymorphisms in the A20 promoter and RA. The aim of this study was to investigate the characteristics of A20 promoter polymorphisms and the association between these polymorphisms and clinical significance in Chinese RA patients.Methods: PCR and sequencing were used to identify A20 gene polymorphisms in peripheral blood mononuclear cells (PBMCs) from 123 RA cases and 31 healthy individuals.Results: Only one SNP (rs5029924) in the A20 gene promoter was identified in RA patients and healthy individuals. 6 patients who carried heterozygous rs5029924 (3918C>T) together with heterozygous rs5029937 (11,571 G>T) and rs2230926 (12,486 T>G, Phe127Cys) suffered from joints deformity or refractory RA.Conclusion: We reported the A20 promoter polymorphism rs5029924 in RA patients for the first time. rs5029924 concomitant with rs2230926 and rs5029937 may be a prognostic predictor for joint deformity or refractory RA.Keywords: A20, promoter, polymorphism, RA, deformity, refractory, predictor

Shipeng Chen,1– 3 Mengna Li,1– 3 Changning Xue,1– 3 Xiangting Zhou,1– 3 Jianxia Wei,1– 3 Lemei Zheng,1– 3 Yumei Duan,1– 3 Hongyu Deng,1 Faqing Tang,1 Wei Xiong,1– 3 Bo Xiang,1– 3 Ming Zhou1– 3 1NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People’s Republic of China; 2Cancer Research Institute, Central South University, Changsha, 410078, People’s Republic of China; 3The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Central South University, Changsha, 410078, People’s Republic of ChinaCorrespondence: Ming Zhou; Bo Xiang, Email zhouming2001@163.com; xiangbolin@csu.edu.cnPurpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition.Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings.Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay.Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs. Keywords: cinobufotalin injection, liver cancer, cinobufagin, network pharmacology, cell cycle, core ingredients

Suwen Huang,1,&ast; Yanchu Wang,1,2,&ast; Jinrong Zhu,1,3,&ast; Shengqi Li,1,2 Shenyi Lin,1,2 Wei Xie,1,2 Siyao Chen,1,2 Yukai Wang,1,3 Lingsheng Wang,1,2 Qiaoqiao Jin,1,2 Yiyun Weng,1 Dehao Yang4 1Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, People’s Republic of China; 3The Second School of Medicine, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yiyun Weng, Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, Zhejiang, 325000, People’s Republic of China, Tel +86-0577-55579371, Fax +86-0577-55579318, Email wengyiyun2012@126.com Dehao Yang, Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China, Email dehao_yang@zju.edu.cnPurpose: Myasthenia gravis (MG) is a chronic autoimmune disease caused by neuromuscular junction (NMJ) dysfunction. Our current understanding of MG’s inflammatory component remains poor. The systemic inflammatory response index (SIRI) presents a promising yet unexplored biomarker for assessing MG severity. This study aimed to investigate the potential relationship between SIRI and MG disease severity.Patients and Methods: We conducted a retrospective analysis of clinical data from 171 MG patients admitted between January 2016 and June 2021. Patients with incomplete data, other autoimmune diseases, or comorbidities were excluded. Disease severity was evaluated using the Myasthenia Gravis Foundation of America (MGFA) classification and Myasthenia Gravis Activities of Daily Living (MG-ADL) on admission. The association between SIRI and disease severity was assessed through logistic regression analysis, along with receiver operating characteristic (ROC) curve and decision curve analysis (DCA) comparisons with established inflammation indicators.Results: After exclusion, 143 patients were analyzed in our study. SIRI levels significantly differed between patients with higher and lower disease severity (p < 0.001). Univariate logistic regression showed that SIRI had a significant effect on high disease severity (OR = 1.376, 95% CI 1.138– 1.664, p = 0.001). This association remained significant even after adjusting for age, sex, disease duration, history of MG medication and thymoma (OR = 1.308, 95% CI 1.072– 1.597, p = 0.008). Additionally, a positive correlation between SIRI and MG-ADL was observed (r = 0.232, p = 0.008). Significant interactions were observed between SIRI and immunosuppressor (p interaction = 0.001) and intravenous immunoglobulin (p interaction = 0.005). DCA demonstrated the superior net clinical benefit of SIRI compared to other markers when the threshold probability was around 0.2.Conclusion: Our findings indicate a strong independent association between SIRI and disease severity in MG, suggesting SIRI’s potential as a valuable biomarker for MG with superior clinical benefit to currently utilized markers.Keywords: inflammation, myasthenia gravis foundation of America, MGFA, blood cell count, correlation, systemic inflammatory response index

Haohua Yuan,1 Huan Gui,1 Shuanghui Chen,1 Lan Zhu,1 Chenglv Wang,1 Qianyu Jing,2 Hang Lv,1 Quan Wan,2 Shuyi Wang,1 Shengwen Zhou,1 Xiaodong Ren,1 Yingjie Nie,1,3 Linzhao Li1 1Medical College, Guizhou University, Guizhou Province, 550025, People’s Republic of China; 2School of Preclinical Medicine of Zunyi Medical University, Zunyi, Guizhou Province, 563000, People’s Republic of China; 3NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People’s Hospital, Guiyang, Guizhou Province, 550002, People’s Republic of ChinaCorrespondence: Yingjie Nie; Linzhao Li, Medical College of Guizhou University, Guiyang, Guizhou Province, 550025, People’s Republic of China, Tel +86-085188274013; +86-085188274016, Email nienyj@hotmail.com; lzli@gzu.edu.cnPurpose: This study aimed to develop a novel and feasible modification strategy to improve the solubility and antitumor activity of resiquimod (R848) by utilizing the supramolecular effect of 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD).Methods: R848-loaded PLGA nanoparticles modified with 2-HP-β-CD (CD@R848@NPs) were synthesized using an enhanced emulsification solvent-evaporation technique. The nanoparticles were then characterized in vitro by several methods, such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, particle size analysis, and zeta potential analysis. Then, the nanoparticles were loaded with IR-780 dye and imaged using an in vivo imaging device to evaluate their biodistribution. Additionally, the antitumor efficacy and underlying mechanism of CD@R848@NPs in combination with an anti-TNFR2 antibody were investigated using an MC-38 colon adenocarcinoma model in vivo.Results: The average size of the CD@R848@NPs was 376 ± 30 nm, and the surface charge was 21 ± 1 mV. Through this design, the targeting ability of 2-HP-β-CD can be leveraged and R848 is delivered to tumor-supporting M2-like macrophages in an efficient and specific manner. Moreover, we used an anti-TNFR2 antibody to reduce the proportion of Tregs. Compared with plain PLGA nanoparticles or R848, CD@R848@NPs increased penetration in tumor tissues, dramatically reprogrammed M1-like macrophages, removed tumors and prolonged patient survival.Conclusion: The new nanocapsule system is a promising strategy for targeting tumor, reprogramming tumor -associated macrophages, and enhancement immunotherapy.Keywords: R848, 2-HP-β-CD, anti-TNFR2, TIME, immunotherapy

Fubei Nan, Qingxin Tian, Shuangdong Chen Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Shuangdong Chen, Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +8613732058295, Email wfycshuangd@163.comBackground: Treating inflammatory pain (IP) continues to pose clinical challenge, because of the lack of effective pharmacological interventions. Microglial polarization serves as pivotal determinant in IP progress. Obacunone (OB), a low-molecular-weight compound with a diverse array of biological functions, having reported as an activator of nuclear factor E2-related factor 2 (Nrf2), exhibits anti-inflammatory property. However, it remains uncertain whether OB can alleviate IP by facilitating the transition of microglial polarization from the M1 to M2 state through modulating Nrf2/ heme oxygenase-1 (HO-1) pathway.Methods: We induced an mice IP model by subcutaneously administering Complete Freund’s Adjuvant (CFA) into the hind paw. Paw withdrawal latency (PWL) in seconds (s) and paw withdrawal frequency (PWF) were employed to evaluate the establishment of the IP model, while a caliper was used to measure the maximal dorsoventral thickness of the mice paw. Nerve injury was assessed by Hematoxylin-Eosin (HE) Staining. Western blot and got conducted for detection of M1/M2 microglial polarization markers, Nrf2 and HO-1 in spinal cord tissues respectively.Results: In comparison to the control cohort, PWF, M1 phenotype marker iNOS, CD86, paw thickness increased significantly within CFA cohort, while PWL, M2 phenotype marker Arg-1, interleukin-10 (IL-10) decreased in the CFA group. In comparison to model cohort, OB treatment decreased PWF, paw thickness, M1 phenotype marker iNOS, CD86 significantly, while PWL, M2 phenotype marker Arg-1, IL-10, Nrf2, HO-1 increased significantly. The morphological injuries of sciatic nerve in CFA mice were obviously improved by OB treatment. OB inhibited the release of M1-related IL-1β, CXCL1 but promoted M2-related TGF-β, IL-10 in serum in CFA mice. The intervention of the Nrf2 inhibitor ML385 mitigated analgesic effect of OB.Conclusion: We demonstrate that OB is able to attenuate inflammatory pain via promoting microglia polarization from M1 to M2 and enhancing Nrf2/HO-1 signal. OB treatment may be a potential alternative agent in the treatment of IP.Keywords: inflammatory pain, obacunone, Nrf2, HO-1

Qiaofei Tang,1,2 Honggan Yi,1,2 Siping Chen,1,2 Yantian Zheng,1,2 Yitao Wen,1,2 Man Yang1,2 1Reproductive Medicine Center, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Meizhou Municipal Engineering and Technology Research Center for Molecular Diagnostics of Major Genetic Disorders, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Man Yang, Reproductive Medicine Center, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, No. 63 Huangtang Road, Meizhou, Meijiang District, People’s Republic of China, Email 13751992388@163.comBackground: The causes of pregnancy failure after intrauterine insemination (IUI) are controversial. The purpose of this study was to investigate the influencing factors on clinical pregnancy after IUI.Methods: This study retrospectively analyzed 1464 cycles of IUI performed at the Meizhou People’s Hospital between March 2014 and June 2023. The χ2 test and logistic regression analysis was applied to assess the associations between the some factors (maternal age, paternal age, cycle type (natural cycle or ovulation induction cycle), hormone level on the day of endometrial transformation (estradiol (E2), luteinizing hormone (LH), and progesterone (P)), endometrial thickness on the day of endometrial transformation, and forward motile sperm concentration after treatment) and pregnancy failure.Results: Among the 1464 IUI cycles in this study, 268 cycles of assisted reproduction resulted in clinical pregnancy, with a clinical pregnancy rate of 18.3%. During the cycles with clinical pregnancy, there were 25 (12.9%) preterm births and 169 (87.1%) full-term births. The E2 level on the day of endometrial transformation in clinical pregnancy group was higher than that in the pregnancy failure group (658.79± 656.02 vs 561.21± 558.83 pg/mL)(P=0.025). The clinical pregnancy group had a higher percentage of endometrial thickness between 8 and 13mm on the day of endometrial transformation than the pregnancy failure group (83.2% vs 75.0%)(P=0.002). The results of regressions analysis showed that low E2 level on the day of endometrial transformation (< 238.3 pg/mL vs ≥ 238.3 pg/mL: OR 1.493, 95% CI: 1.086– 2.052, P=0.014), and endometrial thickness < 8mm on the day of endometrial transformation (< 8mm vs 8– 13mm: OR 1.886, 95% CI: 1.284– 2.771, P=0.001) may increase risk of pregnancy failure performed IUI.Conclusion: Low estradiol level, and endometrial thickness on the day of endometrial transformation may increase risk of pregnancy failure performed intrauterine insemination.Keywords: intrauterine insemination, pregnancy failure, estradiol, endometrial thickness

Junya Zhou,1 Qingzhu Qin,1 Songge Chen,1 Hongmei Zhang2 1Department of Cardiology, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of China; 2Department of Nursing, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou, Henan, 450003, People’s Republic of ChinaCorrespondence: Hongmei Zhang, Department of Nursing, Henan Provincial Key Medicine Laboratory of Nursing, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, No. 7 Weiwu Road, Zhengzhou, Henan, 450003, People’s Republic of China, Tel +86 15699930876, Email zhang_hongmei2023@yeah.netAbstract: In intensive care units, patients are often restrained to ensure their safety, with physical restraints being the most commonly used method. However, physical restraints compromises the patient’s freedom, health and comfort, and nurses often face moral dilemmas when deciding whether to use physical restraints. This article examines physical restraints through the four universal principles of autonomy, beneficence, non-maleficence and justice. Through these principles, the authors will critically explore whether the physical restraints of patients by nurses is ethical in practice and what moral issues exist. This paper also explores conflicts and moral dilemmas for nurses in this context. Finally, suggestions are made on changes to education and clinical practice.Keywords: physical restraints, ethical dilemmas, ethics

Wei Liao,1,2,&ast; Jiaxuan Lu,3,&ast; Yuyuan Xu,4,&ast; Chulin Yang,1,5 Hongjie Chen,4 Shaohang Cai,4 Lili Liu,1,6 Shuwei Chen1,5 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 5Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 6Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shaohang Cai, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China, Email shaohangcai@foxmail.com Shuwei Chen, Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Dongfeng East Road, Guangzhou, 510060, People’s Republic of China, Email chenshuw@sysucc.org.cnBackground: To compare and analyze the presence of CD4+ and CD8 + lymphocyte infiltrates in Oral squamous cell carcinoma (OSCC) tissue versus adjacent tissue and their clinical significance.Methods: We enrolled a total of 152 patients diagnosed with OSCC, all of whom had confirmed diagnoses through pathological reports. Clinical and demographics data were extracted from medical records. Tissue microarrays were constructed and immunohistochemical staining for CD4 and CD8 was performed.Findings: The average number of infiltrating CD4+ T cells in OSCC tumor tissue was 1026.22± 1163.36 cells/mm2, which did not significantly differ from the count in adjacent tissue, which was 1163.36± 1013.23 cells/mm2. However, the number of CD8+ T cell infiltration in tumor tissue was significantly higher than in adjacent tissue (655.25± 705.70 vs 504.56± 659.26 cells/mm2, p = 0.026). We observed that, among patients who consumed alcohol, the CD4+ T cell infiltration in tumor tissue being significantly lower than that in adjacent tissue (P=0.036). Moreover, the CD8+ T cell infiltration in cancer tissue was significantly higher than in adjacent tissue for T1-2 patients (p=0.005). Patients with higher CD8+ T cell in tumor tissue exhibited significantly improved overall survival (p = 0.043). Multivariate analyses revealed that alcohol consumption had a significant impact on the number of CD4+T lymphocytes in tumor tissue (OR = 0.403, P = 0.033) while T stage was the independent factor affecting CD8+ T lymphocyte infiltration in tumor tissue (OR = 0.459, P = 0.031).Interpretation: OSCC patients with a higher number of CD8+ T lymphocyte infiltration in tumor tissue exhibited an improved prognosis.Keywords: microenvironment, OSCC, CD8 T cells, CD4 T cells, prognosis

Gao-Qiang Meng,1,&ast; Shu Chen,2,&ast; Han-Bin Ye,1 Bao-Jun Ma,1 Shuo Tao,3 Zi Ye1 1Department of Neurosurgery, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, 226000, People’s Republic of China; 2Department of Endocrinology, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, 226000, People’s Republic of China; 3Department of Out-Patient, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, Nantong, 226000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zi Ye, Department of Neurosurgery, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, No. 666 of Shengli Road, Chongchuan District, Jiangsu, Nantong, 226000, People’s Republic of China, Email yezileafff@126.com Shuo Tao, Department of Out-patient, Affiliated Hospital 2 of Nantong University, Nantong First People’s Hospital, No. 666 of Shengli Road, Chongchuan District, Jiangsu, Nantong, 226000, People’s Republic of China, Tel +86 0513 81111429, Email xueleitaonshxzh@126.comObjective: We explored the correlation between the presence of isocitrate dehydrogenase-1 (IDH1) mutations and the incidence of postoperative epilepsy in patients with glioblastoma, as well as assessed the efficacy of preemptive administration of antiepileptic medications in mitigating the occurrence of postoperative epilepsy.Methods: Fifty-three patients who received a postoperative pathological diagnosis of glioblastoma, were enrolled in this study. Tumor specimens were subjected to IDH1 gene analysis. The patient cohort was stratified based on their IDH1 mutation status and the administration of prophylactic antiepileptic drugs during the postoperative phase. We subsequently conducted a comparative analysis of postoperative epileptic complications within each patient subgroup.Results: In the cohort of 53 patients under study, the occurrence of epilepsy was observed in 10 out of 21 patients carrying IDH1 mutations, while 5 out of 32 patients with wild-type IDH1 also experienced epilepsy, revealing a statistically significant difference (P < 0.05). Among the 27 patients who received prophylactic antiepileptic drugs, 6 of them developed epilepsy, whereas 9 out of 26 patients who did not receive prophylactic antiepileptic drugs exhibited concurrent epilepsy, with no statistically significant difference (P > 0.05). However, when performing a subgroup analysis, it was found that 3 out of 12 patients with IDH1 mutations who received prophylactic antiepileptic drugs experienced epilepsy, whereas 7 out of 9 patients who did not receive prophylactic antiepileptic drugs developed epilepsy, demonstrating a statistically significant difference (P < 0.05). Furthermore, within the group of 15 patients with wild-type IDH1, 3 patients who received prophylactic antiepileptic drugs developed epilepsy, while 2 cases of epilepsy occurred among the 17 patients who did not receive prophylactic antiepileptic drugs, with no statistically significant difference (P > 0.05).Conclusion: In individuals with IDH1 mutant glioblastoma who have undergone surgical resection, the implementation of preventive antiepileptic therapy demonstrates a potential to diminish the occurrence of postoperative epilepsy.Keywords: epilepsy, glioblastoma, isocitrate dehydrogenase-1, prophylactic antiepileptic therapy

Jingjing Yuan,1,2,&ast; Zenghui Liang,1,&ast; Muhoza Bertrand Geoffrey,1 Yanle Xie,1,2 Shuhan Chen,1,2 Jing Liu,1,2 Yuzhong Xia,1 Huixin Li,1 Yanling Zhao,1 Yuanyuan Mao,1,2 Na Xing,1,2 Jianjun Yang,1,2 Zhongyu Wang,1 Fei Xing1,2 1Department of Anesthesiology, Pain and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Henan Province International Joint Laboratory of Pain, Cognition and Emotion, Zhengzhou, Henan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fei Xing; Zhongyu Wang, Department of Anesthesiology, Pain and Perioperative Medicine, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road Erqi District, Zhengzhou City, Henan Province, People’s Republic of China, Tel +86-15936275656, Email fccxingf@zzu.edu.cn; wzy781217@163.comPurpose: Explore the median effective dose of ciprofol for inducing loss of consciousness in elderly patients and investigate how frailty influences the ED50 of ciprofol in elderly patients.Patients and Methods: A total of 26 non-frail patients and 28 frail patients aged 65– 78 years, with BMI ranging from 15 to 28 kg/m2, and classified as ASA grade II or III were selected. Patients were divided into two groups according to frailty: non-frail patients (CFS< 4), frail patients (CFS≥ 4). With an initial dose of 0.3 mg/kg for elderly non-frail patients and 0.25 mg/kg for elderly frail patients, using the up-and-down Dixon method, and the next patient’s dose was dependent on the previous patient’s response. Demographic information, heart rate (HR), oxygen saturation (SpO2), mean blood pressure (MBP), and bispectral index (BIS) were recorded every 30 seconds, starting from the initiation of drug administration and continuing up to 3 minutes post-administration. Additionally, the total ciprofol dosage during induction, occurrences of hypotension, bradycardia, respiratory depression, and injection pain were recorded.Results: The calculated ED50 (95% confidence interval [CI]) and ED95 (95% CI) values for ciprofol-induced loss of consciousness were as follows: 0.267 mg/kg (95% CI 0.250– 0.284) and 0.301 mg/kg (95% CI 0.284– 0.397) for elderly non-frail patients; and 0.263 mg/kg (95% CI 0.244– 0.281) and 0.302 mg/kg (95% CI 0.283– 0.412) for elderly frail patients. Importantly, no patients reported intravenous injection pain, required treatment for hypotension, or experienced significant bradycardia.Conclusion: Frailty among elderly patients does not exert a notable impact on the median effective dose of ciprofol for anesthesia induction. Our findings suggest that anesthesiologists may forego the necessity of dosage adjustments when administering ciprofol for anesthesia induction in elderly frail patients.Keywords: ciprofol, median effective dose, elderly patients, frailty, loss of consciousness

Yan Liu, Yang Li, Song Yuan, Wei Ma, Si Chen, Li-Yi Wang Department of Infection Control, the Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Li-Yi Wang, Department of Infection Control, the Second Hospital of Hebei Medical University, No. 215 of Heping West Road; Xinhua District, Shijiazhuang, Hebei, 050000, People’s Republic of China, Tel +86 13673160996, Fax +86 0311 83179721, Email wangliyi66@163.comObjective: To examine the risk factors linked with occupational blood exposure (OBE) among nursing staff (NS), we pinpoint deficiencies in the compliance with policies of infection prevention and control, and assess the expenditures associated with infection prevention and control.Methods: Healthcare workers that completed an “Occupational Blood Exposure Report Form” were divided into NS (observation) group and non-NS (control) group. Univariate and multivariable analyses were conducted to compare both groups in various aspects. We also explored design patents intended to minimize occupational exposure.Results: The highest incidence of OBE was observed in the department of neurosurgery. Among NS, OBE incidence was found to be influenced by independent risk factors, such as gender, age, occupational title, work location, and incidence of sharps injuries. Protective factors against OBEs included the use of arterial blood gas needles and suture needles. Personal protective equipment (PPE) usage rates were low in both groups prior to OBEs (0.74% vs 0.00%, P > 0.05). Correct emergency management could be improved promptly by both groups following an OBE (P > 0.05). However, the observation group exhibited a higher proportion of blood expression after a sharps injury and a higher re-evaluation rate at 6 months post-exposure compared to the control group (P < 0.05). In 2018, the per capita costs of infection prevention and control for NS were the Chinese Yuan (RMB) 339.43 per individual. In response to these findings, two utility model patents have been authorized.Conclusion: The risk and protective factors related to the occurrence of OBEs were investigated in this study, suggesting that there is a need for improvement in the rate of PPE usage and the re-evaluation rate of OBEs among NS. Additionally, focused training on emergency blood expression and compliance with policies among non-NS personnel is deemed necessary.Keywords: compliance, infection prevention and control, nursing staff

Zhang Wang,1 Xue Yang,1 Longxin Li,1 Xiaobo Zhang,2 Wenlin Zhou,1 Sixue Chen1 1Department of Geriatrics, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 2The Third People’s Hospital of Beichuan Qiang Autonomous County, Mianyang, People’s Republic of ChinaCorrespondence: Zhang Wang, Department of Geriatrics, The General Hospital of Western Theater Command, No. 270 Rongdu Road, Chengdu, 610083, People’s Republic of China, Tel +86-18981780413, Email 969281094@qq.comPurpose: To evaluate the performance of the Framingham cardiovascular risk score (FRS)/pooled cohort equations (PCE)/China prediction for atherosclerotic cardiovascular disease (ASCVD) risk (China-PAR model) in a prospective cohort of Chinese older adults.Patients and Methods: We assessed 717 older adults aged 75– 85 years without ASCVD at the baseline from the Sichuan province of China. The participants were followed annually from 2011 to 2021. We obtained the participants’ information through the medical records of physical examination and evaluated their 10-year ASCVD risk using FRS, PCE, and China-PAR. We further evaluated the predictive abilities of three assessment models.Results: During the 10-year follow-up, 206 participants developed ASCVD, with an incidence rate of 28.73%. The FRS and China-PAR moderately underestimated the risk of ASCVD (22.1% and 12.4%, respectively), but while PCE overestimated the risk (36.1%). FRS and China-PAR were found to underestimate the risk of ASCVD (26% and 63%, respectively) for men, while PCE overestimated the risk by 8%; For women, FRS and China-PAR were found to underestimate the risk of ASCVD (14% and 35%, respectively), while PCE overestimated the risk by 88%.Conclusion: The 10-year ASCVD risk was found to be overestimated by PCE. China-PAR had the most accurate predictions in women, while FRS was particularly well-calibrated in males. All three risk models have good discrimination, with FRS and PCE being well-calibrated in men and all three being well-calibrated in women. Therefore, accurate risk models are warranted to facilitate the prevention of ASCVD at the baseline among Chinese older adults.Keywords: ASCVD, risk prediction model, FRS, PCE, China-PAR

Jinji Chen,1,&ast; Herong Zhu,2,&ast; Shaohua Chen,3 Hua Mi1 1Department of Urology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Urology, Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Foshan, People’s Republic of China; 3Department of Urology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hua MiDepartment of Urology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China, Email mihua2019@163.comShaohua ChenDepartment of Urology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China, Email silverchan1994@163.comBackground: Apolipoprotein E (APOE) is a polymorphic protein that plays a role in lipoprotein transformation and metabolism. It is involved in numerous physiological processes within the body and is closely associated with tumor growth and metastasis. However, the role of APOE in pan-cancer has yet to be evaluated. Therefore, studying the association between APOE and various cancer types is crucial for providing a basis for individualized treatment strategies and clinical prognosis assessment.Methods: We investigated the diagnostic and prognostic significance of APOE across 33 tumor types, as well as its correlation with tumor mutation burden (TMB) and microsatellite instability (MSI). Additionally, we employed the ESTIMATE and CIBERSORT algorithms to analyze the potential impact of APOE on the immune system. Furthermore, gene set enrichment analysis (GSEA) was conducted to explore its underlying physiological function.Results: Based on observations from a pan-cancer dataset, APOE expression was significantly different between cancer and normal tissues, and was simultaneously associated with survival outcomes in terms of cancer type, clinical annotation, TMB, MSI, and TICs abundance. In addition, the results also showed that expression of APOE may respond to a variety of cancer chemotherapy.Conclusion: The findings from this study strongly indicate a close association between APOE and tumor development. Moreover, APOE shows promise as a potential biomarker for predicting prognosis and response to immunotherapy in patients with pan-cancer.Keywords: apolipoprotein E, APOE, pan-cancer, prognosis, immune infiltration

Shuqin Chen,1,&ast; Xuepeng Wang,2,&ast; Yong Jin,3 Xueqin Chen,4 Qifa Song,5 Gang Wei,6 Li Li1 1Department of Endocrinology and Metabolism, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Infectious Disease, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 3Department of Internal Medicine, Ningbo Yinzhou No.2 Hospital, Ningbo, People’s Republic of China; 4Department of Traditional Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 5Medical Data Center, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 6Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Li, Department of Endocrinology and Metabolism, The First Affiliated Hospital of Ningbo University, Ningbo, 31500, People’s Republic of China, Email lilyningbo@163.com Gang Wei, Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100000, People’s Republic of China, Email gangwei_2013@163.comBackground: Changes in body composition accompanied by glucagon-like peptide 1 receptor agonist (GLP-1RA) induced weight loss have drawn much attention. However, fewer studies have reported body composition changes in patients receiving dulaglutide therapy in Chinese population.Methods: A total of 70 overweight/obese type 2 diabetes mellitus (T2DM) patients who received dulaglutide therapy were included. Clinical data were collected. Visceral fat area (VFA) and body composition were also measured. Changes in clinical indicators and body composition of patients before and after intervention were also analyzed. Correlation analysis and multiple linear regression model were used to evaluate the association between hemoglobin A1C (HbA1c) and body composition.Results: The results showed that body weight (BW), VFA, body fat (BF), lean body mass (LBM), skeletal muscle mass (SMM) and water content were reduced after 3 months dulaglutide intervention. The lean body mass percentage (LBMP) and skeletal muscle mass percentage (SMMP) significantly increased. Moreover, there was no significant difference in bone mineral quality (BMQ) after the intervention. The multiple linear regression model revealed that the % change in BF was independently associated with % change in HbA1c (β = 0.449, t = 3.148, p=0.002).Conclusion: These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss, and % change in BF was independently associated with improved glucose control during dulaglutide therapy. This study offers some positive results to support the clinical application of dulaglutide.Keywords: dulaglutide, obesity, diabetes, body fat mass, visceral fat

Xiaoyan He,1 Guozhen Zai,1 Lidan Zhou,2 Shengyang Chen,3 Guizhi Wang1 1Department of Pathology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Radiology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Guizhi Wang, Email wgz2019@126.comBackground: Research has indicated that VRK1 is essential for the tumor cell cycle. However, its prognostic and immunotherapeutic predictive significance has not been documented in hepatocellular carcinoma (HCC).Methods: The TCGA, ICGC, and GSE14520 datasets were used to investigate VRK1 expression and its predictive significance of survival outcomes. The qRT-PCR and immunohistochemistry (IHC) were used to confirm the findings. The immunotherapeutic response of VRK1 was anticipated by the IMvigor210 cohort. Lastly, the association between immune infiltration, m6A modification, and functional enrichment of differentially expressed genes (DEGs) was investigated in connection to VRK1 expression.Results: VRK1 expression was markedly elevated on both the mRNA and protein levels in HCC. In HCC patients, a high expression of VRK1 was linked to a poor prognosis. Furthermore, there was a substantial positive correlation seen between increased VRK1 expression and the response rate to anti-PD-L1 immunotherapy. Relationships between VRK1 and m6A-related genes as well as different immune cells were shown by correlation studies. Lastly, enrichment analysis revealed a tight relationship between VRK1 and important biological functions, including DNA replication, cell cycle control, and fatty acid metabolism.Conclusion: Our research reveals the potential of VRK1 as a novel biomarker for prognosis and immunotherapy response in HCC patients.Keywords: VRK1, immune infiltration, immunotherapy, m6A, HCC

Yu Yang,1,2 Xiaoyu Pan,1,3 Shuchun Chen1,3 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 3Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel/Fax +86 311 85988406, Email chenshuchunwork88@163.comObjective: This study utilized proteomics to investigate changes in protein expression associated with lung health in obese mice exposed to semaglutide and empagliflozin through a high-fat diet.Methods: Twenty-eight male C57BL/6JC mice were randomly assigned to two groups: a control diet group (n = 7) and a high-fat diet group (n = 21). The HFD group was further divided into three groups: HFD group (n = 7), Sema group (n = 7), and Empa group (n = 7). Post-treatment, mice underwent assessments including glucose tolerance, lipids, oxidative stress markers, body weight, lung weight, and structure. Proteomics identified differentially expressed proteins (DEPs) in lung tissue, and bioinformatics analyzed the biological processes and functions of these proteins.Results: Semaglutide and empagliflozin significantly attenuated obesity-induced hyperglycemia, abnormal lipid metabolism, oxidative stress response, and can decrease alveolar wall thickness, enlarge alveolar lumen, and reduce collagen content in lung tissue. Both medications also attenuated lung elastic fibre cracking and disintegration. In the HFD/NCD group, there were 66 DEPs, comprising 30 proteins that were increased and 36 that were decreased. Twenty-three DEPs overlapped between Sema/HFD and Empa/HFD, with 11 up-regulated and 12 down-regulated simultaneously. After analysing DEPs in different groups, four proteins - LYVE1, BRAF, RGCC, and CHMP5 - were all downregulated in the HFD group and upregulated by semaglutide and empagliflozin treatment.Conclusion: This study demonstrates that obesity induced by a high-fat diet causes a reduction in the expression of LYVE1, BRAF, RGCC, and CHMP5 proteins, potentially affecting lung function and structure in mice. Significantly, the administration of semaglutide and empagliflozin elevates the levels of these proteins, potentially offering therapeutic benefits against lung injury caused by obesity. Merging semaglutide with empagliflozin may exert a more pronounced impact.Keywords: semaglutide, empagliflozin, proteomics, obesity, pulmonary structure

Ye Liu,1,&ast; Lifan Zhang,1– 4,&ast; Yan Chen,1,&ast; Guiren Ruan,1– 3 Yuchen Liu,1 Shi Chen,1 Lantian Xie,1 Fengying Wu,1 Xiaochun Shi,1– 3 Xiaoqing Liu1– 4 1Division of Infectious Diseases, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 4Clinical Epidemiology Unit, Peking Union Medical College, International Clinical Epidemiology Network, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaochun Shi; Xiaoqing Liu, Division of Infectious Diseases, Department of Internal Medicine, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Beijing, 100005, People’s Republic of China, Email shixch7722@163.com; liuxq@pumch.cnBackground: The population with latent tuberculosis infection (LTBI) represents a potential pool of patients with active tuberculosis (ATB). T-SPOT.TB is an important test tool for screening LTBI. Owing to the large population of LTBI patients in China, it is necessary to identify a high-risk group for LTBI and enlarge tuberculosis preventive treatment (TPT) to reduce the incidence of ATB.Methods: Hospitalized patients with positive T-SPOT.TB results were recruited from January 2013 to December 2016. Patients with ATB were excluded. Basic information was collected and the development of ATBs was examined during follow-up. The life-table method was used to calculate cumulative incidence rates. Potential risk factors were analyzed through Cox regression analysis.Results: A total of 1680 patients with LTBI were recruited in the follow-up cohort, and 377 (22.44%) patients dropped out. With a median follow-up time of 81 months [interquartile range (IQR):61– 93], 19 of 1303 patients with LTBI developed ATB. The 1-year incidence of ATB was 614 per 100,000 individuals [95%confidence interval (95% CI):584– 644]. Over 5-year period, the cumulative incidence of ATB was 1496 per 100,000 [95% CI:1430– 1570], and the incidence density was 240 per 100,000 person-years[95% CI:144– 375]. In the Cox regression model, exposure of pulmonary tuberculosis (PTB) [adjusted hazard ratio (aHR)=10.557, 95% CI:2.273– 49.031], maximum daily dosage of glucocorticoids (GCs)≥ 50 mg/d (aHR=2.948, 95% CI:1.122– 7.748), leflunomide (LEF) treatment (aHR=8.572, 95% CI:2.222 − 33.070), anemia (aHR=2.565, 95% CI:1.015– 6.479) and T-SPOT.TB level≥ 300SFCs/106 PBMCs (aHR=4.195, 95% CI:1.365– 12.892) were independent risk factors for ATB development in LTBI patients.Conclusion: The incidence of ATB is significantly higher in hospitalized patients with LTBI than in the general population. The exposure history of PTB, maximum daily dosage of GCs≥ 50 mg/day, LEF treatment, anemia, and T-SPOT.TB level≥ 300SFCs/106PBMCs, were the risk factors of tuberculosis reactivation. Hospitalized LTBI patients with the above factors may need TPT.Keywords: latent tuberculosis infection, active tuberculosis, incidence, risk factors

Qun Ding,1– 4,&ast; Congcong Yu,2,3,&ast; Xiang Xu,1,3 Yinjiao Hou,1,3 Yingwen Miao,2,3 Sijue Yang,2,3 Shihua Chen,2,3 Xuelin Ma,2,3 Zhou Zhang,2,3 Yan Bi1– 3 1Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, People’s Republic of China; 3Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, People’s Republic of China; 4Department of Endocrinology, the Second People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhou Zhang, Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Branch of National Clinical Research Centre for Metabolic Diseases, No. 321, Zhongshan Road, Nanjing, 210008, People’s Republic of China, Tel + 86 25-83106666, Email zhangzhou@smail.nju.edu.cn Yan Bi, Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Branch of National Clinical Research Centre for Metabolic Diseases, No. 321, Zhongshan Road, Nanjing, 210008, People’s Republic of China, Tel + 86 25-83105313, Email biyan@nju.edu.cnAim: Numerous evidence suggests that diabetes increases the risk of cognitive impairment. This study aimed to develop and validate a multivariable risk score model to identify mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).Methods: This cross-sectional study included 1256 inpatients (age: 57.5 ± 11.2 years) with T2DM in a tertiary care hospital in China. MCI was diagnosed according to the criteria recommended by the National Institute on Aging-Alzheimer’s Association Workgroup, and a MoCA score of 19– 25 indicated MCI. Participants were randomly allocated into the derivation and validation sets at 7:3 ratio. Logistic regression models were used to identify predictors for MCI in the derivation set. A scoring system based on the predictors’ beta coefficient was developed. Predictive ability of the risk score was tested by discrimination and calibration methods.Results: Totally 880 (285 with MCI, 32.4%) and 376 (167 with MCI, 33.8%) patients were allocated in the derivation and validation set, respectively. Age, education, HbA1c, self-reported history of severe hypoglycemia, and microvascular disease were identified as predictors for MCI and constituted the risk score. The AUCs (95% CI) of the risk score were 0.751 (0.717, 0.784) in derivation set and 0.776 (0.727, 0.824) in validation set. The risk score showed good apparent calibration of observed and predicted MCI probabilities and was capable of stratifying individuals into 3 risk categories by two cut-off points (low risk: ≤ 3, medium risk: 4– 13, and high risk ≥ 14).Conclusion: The risk score based on age, education, HbA1c, self-reported history of severe hypoglycemia, and microvascular disease can effectively assess MCI risk in adults with T2DM at different age. It can serve as a practical prescreening tool for early detection of MCI in daily diabetes care.Keywords: mild cognitive impairment, type 2 diabetes mellitus, risk score, prescreening tool

Ruoxi Zhen,1,2 Shuqi Wang,1,2 Shuchun Chen1– 3 1Graduate School of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, People’s Republic of China; 3Hebei Key Laboratory of Metabolic Diseases, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Shuchun Chen, Department of Endocrinology, Hebei General Hospital, 348 Heping West Road, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel/Fax +86 31185988406, Email chenshuc2014@163.comPurpose: This study was designed to analyze correlations between the uric acid to high-density lipoprotein cholesterol ratio (UHR) and peripheral nerve conduction velocity (NCV) among type 2 diabetes mellitus (T2DM) patients.Patients and Methods: This was a single-center cross-sectional analysis of 324 T2DM patients. All patients were separated into a group with normal NCV (NCVN) and a group with abnormal NCV (NCVA). Patients were also classified into groups with low and high UHR values based on the median UHR in this study cohort. Neurophysiological data including motor and sensory conduction velocity (MCV and SCV, respectively) were measured for all patients.Results: Relative to patients with low UHR values, those in the high UHR group presented with greater NCVA prevalence (P = 0.002). UHR remained negatively correlated with bilateral superficial peroneal nerve SCV, bilateral common peroneal nerve MCV, bilateral ulnar nerve SCV, and bilateral right median nerve MCV even after adjustment for confounding factors. UHR was identified as an NCVA-related risk factor, with a 1.370-fold increase in NCVA prevalence for every unit rise in UHR (P < 0.001).Conclusion: These results identify UHR as a risk factor associated with NCVA that was independently negatively associated with NCV among T2DM patients.Keywords: type 2 diabetes mellitus, diabetic peripheral neuropathy, peripheral nerve conduction velocity, uric acid to high-density lipoprotein cholesterol ratio

Hongjie Cai,1 Song Chen,2 Zhiqiang Wu,1 Fan Wang,1 Shuangyan Tang,1 Ludan Chen,1 Wenbo Guo1 1Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510062, People’s Republic of China; 2Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center and Sun Yat-Sen University State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of ChinaCorrespondence: Wenbo Guo, Email guowenbo@mail.sysu.edu.cnPurpose: Local in combination with systemic therapy might be an option for patients with advanced unresectable hepatocellular carcinoma (uHCC). This study examined the clinical benefits and adverse events (AEs) of first-line transarterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC) combined with atezolizumab (Atezo) and bevacizumab (Bev) in patients with uHCC of a diameter larger than 8 cm.Patients and methods: This retrospective study included patients with uHCC of a diameter larger than 8 cm who were treated with first-line Atezo-Bev and TAE+HAIC at the First Affiliated Hospital of Sun Yat-Sen University between September 30, 2019, and September 30, 2022. Progression-free survival (PFS), overall survival (OS), tumor response according to mRECIST, and AEs were analyzed. Multivariable Cox analyses were performed to examine the factors associated with PFS.Results: Thirty patients were included. The objective response rate (ORR) was 74.4% (95% confidence interval [CI], 59.3%-89.5%), and the disease control rate (DCR) was 93.3% (95% CI, 85.4%-98.6%). The median follow-up was 11.4 (inter-quartile range [IQR], 5.5– 17.9) months. The median PFS was 6.8 (95% CI, 2.6– 11.1) months. The 3-, 6-, 9-, and 12-month survival rates were 86.2%, 82.5%, 68.6%, and 60%, respectively. The median OS was not estimated. Extrahepatic metastasis was independently associated with PFS (hazard ratio [HR]=3.468, 95% CI, 1.001– 12.023). The most common AEs were fever (46.7%). Grade 4 AEs occurred one time as hematemesis but no 5 AEs were observed.Conclusion: Atezo-Bev combined with TAE and HAIC might benefit patients with uHCC of a diameter larger than 8 cm, with manageable AEs.Keywords: immune checkpoint inhibitors, tyrosine kine inhibitors, local therapy, systemic therapy, large unresectable hepatocellular carcinoma

Shaoqing Chen,1,2 Cheng Wang,3 Yanyan Meng,1– 3 Pengyin Li,1– 3 Yiwen Pan,1– 3 Mu He,1,2 Xinye Ni1,2 1Department of Radiotherapy, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, Jiangsu, 213003, People’s Republic of China; 2Jiangsu Province Engineering Research Center of Medical Physics, Changzhou, Jiangsu, 213003, People’s Republic of China; 3School of Pharmacy, Changzhou University, Changzhou, Jiangsu, 213164, People’s Republic of ChinaCorrespondence: Xinye Ni, Email nxy@njmu.edu.cnBackground: Radiation stimulates the secretion of tumor stroma and induces resistance, recurrence, and metastasis of stromal-vascular tumors during radiotherapy. The proliferation and activation of tumor-associated fibroblasts (TAFs) are important reasons for the production of tumor stroma. Telmisartan (Tel) can inhibit the proliferation and activation of TAFs (resting TAFs), which may promote radiosensitization. However, Tel has a poor water solubility.Methods: In this study, self-assembled telmisartan nanoparticles (Tel NPs) were prepared by aqueous solvent diffusion method to solve the insoluble problem of Tel and achieve high drug loading of Tel. Then, erythrocyte membrane (ECM) obtained by hypotonic lysis was coated on the surface of Tel NPs (ECM/Tel) for the achievement of in vivo long circulation and tumor targeting. Immunofluorescence staining, western blot and other biological techniques were used to investigate the effect of ECM/Tel on TAFs activation inhibition (resting effect) and mechanisms involved. The multicellular spheroids (MCSs) model and mouse breast cancer cells (4T1) were constructed to investigate the effect of ECM/Tel on reducing stroma secretion, alleviating hypoxia, and the corresponding promoting radiosensitization effect in vitro. A mouse orthotopic 4T1 breast cancer model was constructed to investigate the radiosensitizing effect of ECM/Tel on inhibiting breast cancer growth and lung metastasis of breast cancer.Results: ECM/Tel showed good physiological stability and tumor-targeting ability. ECM/Tel could rest TAFs and reduce stroma secretion, alleviate hypoxia, and enhance penetration in tumor microenvironment. In addition, ECM/Tel arrested the cell cycle of 4T1 cells to the radiosensitive G2/M phase. In mouse orthotopic 4T1 breast cancer model, ECM/Tel played a superior role in radiosensitization and significantly inhibited lung metastasis of breast cancer.Conclusion: ECM/Tel showed synergistical radiosensitization effect on both the tumor microenvironment and tumor cells, which is a promising radiosensitizer in the radiotherapy of stroma-vascular tumors.Keywords: telmisartan, tumor-associated fibroblasts, tumor hypoxia, G2/M arrest, radiosensitization

Yang Liu,&ast; Xiaoli Wu,&ast; Siting Chen, Wenxia Meng Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenxia Meng, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, People’s Republic of China, Email mengwx2008@foxmail.comAbstract: Acanthosis nigricans (AN) is a dermatological condition characterised by the symmetrical development of velvety, hyperpigmented plaques predominantly in intertriginous areas such as the axillae, neck, inframammary regions, and groin. The malignant variant of AN is frequently associated with internal malignancies, particularly gastric adenocarcinoma, accounting for 55– 61% of cases. Patients exhibiting characteristic skin lesions are commonly initially evaluated in dermatology departments. This case report details a rare instance of a patient diagnosed with malignant acanthosis nigricans, presenting with only a mild form of florid oral papillomatosis concomitant with ovarian carcinoma. The early identification and management of these subtle clinical manifestations enabled timely intervention for the tumor, resulting in patient survival. There are few reported cases of malignant acanthosis nigricans associated with ovarian cancer. Oral medicine specialists should be cognisant of conditions manifesting as extensive oral papillary hyperplasia, and the possibility of an underlying malignant disease should be considered, particularly in cases of elderly-onset AN presenting exclusively with oral lesions.Keywords: malignant acanthosis nigricans, ovarian cancer, papillary hyperplasia