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Na Ren,&ast; Fengyan Ma,&ast; Mengbai Tian, Guochao Zhang, Qi Xing, Xu Zheng, Wei Wu, Yimin Qi, Mingyu Wang, Liang Zhao Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang Zhao, Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China, Email drzhaoliang@126.comAim: Patients with lung cancer often experience a high level of self-perceived burden, which significantly affects their quality of life and psychological health. Social support is closely related to the self-perceived burden, yet there is scant research on the relationship between social support, facilitation of patient involvement, and self-perceived burden. This study aims to understand the current situation of self-perceived burden in postoperative lung cancer patients and to explore the mediating role of social support between facilitation of patient involvement and self-perceived burden.Methods: A cross-sectional design was used in this study. Using a convenience sampling method, a total of 331 lung cancer patients who were hospitalized for surgical treatment at a tertiary cancer hospital in Beijing, China, from August 2022 to May 2023, were selected to participate in this survey. The survey included a self-designed sociodemographic questionnaire, the Facilitation of Patient Involvement Scale (FPIS), the Perceived Social Support Scale (PSSS), and the Self-Perceived Burden Scale (SPBS). Data were analyzed using SPSS 24.0 for statistical description and Pearson correlation analysis, while AMOS 24.0 was utilized to construct a structural equation model to examine the mediation effect.Results: The score of self-perceived burden in lung cancer patients was 26.42 ± 8.23 points. Bot facilitation of patient involvement and social support was negatively correlated with self-perceived burden (r = − 0.313, r = − 0.332, P < 0.001). Social support plays a partially mediated role in the relationship between facilitation of patient involvement and self-perceived burden, accounting for 44.3% of the total effect.Conclusion: The self-perceived burden of patients after lung cancer surgery was at a moderate level, and social support partially mediates the relationship between facilitation of patient involvement and self-perceived burden. Medical staff should encourage patient participation in their own treatment decisions and alleviate the burden associated with lung cancer and surgical treatment by enhancing their social support.Keywords: facilitation of patient involvement, self-perceived burden, social support, mediation analysis, lung cancer

Maoliang Tian,1,&ast; Wenqiang Li,1,&ast; Xiaoyu He,2 Qian He,3 Qian Huang,4 Zhiping Deng1 1Zigong First People’s Hospital, Zigong City, Sichuan Province, 643000, People’s Republic of China; 2North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People’s Republic of China; 3West China Second Hospital of Sichuan University, Chengdu, Sichuan Province, 610044, People’s Republic of China; 4Dazhou Dachuan District People’s Hospital (Dazhou Third People’s Hospital), Dazhou, Sichuan Province, 635000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qian Huang, Dazhou Dachuan District People’s Hospital (Dazhou Third People’s Hospital), Dazhou, Sichuan Province, 635000, People’s Republic of China, Email hq15196767955@163.com Zhiping Deng, Zigong First People’s Hospital, Zigong City, Sichuan Province, 643000, People’s Republic of China, Email dengzp1016@163.comBackground: In human health, vitamins play a vital role in various metabolic and regulatory processes and in the proper functioning of cells. Currently, the effect of Vitamin E (VE) intake on multiple causes of death in Chronic obstructive pulmonary disease (COPD) patients is unclear. Therefore, this paper aims to investigate the relationship between VE and multiple causes of death in COPD patients, to guide the rationalization of dietary structure and reduce the risk of COPD death.Methods: This study screened patients with COPD aged ≥ 40 years from the National Health and Nutrition Examination Survey (NHANES) database 2008– 2018. Weighted COX regression was used to analyze the association between VE intake and multiple causes of death in COPD. The restricted cubic spline(RCS) is drawn to show their relationship. Finally, we conducted a subgroup analysis for further verification.Results: A total of 1261 participants were included in this study. After adjustment for multiple covariates, VE intake was associated with all-cause death in COPD patients, and chronic lower respiratory disease (CLRD) deaths were linearly associated with cardiovascular disease (CVD) deaths there was no such correlation. Subgroup analyses showed no interaction between subgroups, further validating the robustness of the relationship.Conclusion: In COPD patients, VE intake was negatively associated with all-cause mortality and CLRD death. Higher VE intake reduces the risk of all-cause mortality and CLRD death in COPD patients.Keywords: vitamin E, COPD, CVD, CLRD, COX regression analyses

Yong Chen,1 Mang He,1 Si-Jin Zhao,2 Yan-Juan Chen,1 Yong-Qiao Zhang,2 Xiao-Long Chen,2 Chuan-Jie Yang,2 Yu-Zhuo Luo,2 Kutty Selva Nandakumar,3 Zhou-Xiong Xing,4 Mei Tian1 1Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China; 2Undergraduate Students of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of China; 3Docent, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; 4Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, People’s Republic of ChinaCorrespondence: Mei Tian; Zhou-Xiong Xing, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi City, Guizhou Province, People’s Republic of China, Email 348820517@qq.com; xingzhouxiong111@126.comPurpose: To investigate the clinical value of adding Jin-gu-lian (JGL) capsules into rheumatoid arthritis (RA) treatment by examining its impact on disease activity and quality of life (QoL) through a real-world study (RWS).Patients and methods: RWS was conducted to compare the inflammatory markers, including IgM-RF, ESR, and CRP, between RA patients treated with only Western medicine (reference group) and Western medicine plus JGL (study group) during one-year follow-up. The clinical data was acquired from the hospital information system (HIS). Telephone call-based follow-up on QoL (SF-36) and accompanying symptoms, including gastrointestinal complaints, attacks of pneumonia, herpes zoster, URTIs, UTIs, and LTBIs. Finally, the anti-rheumatic drugs given to both groups were also compared. RWS was further validated for its feasibility by performing studies with hydroxychloroquine (HCQ) treatment, which is a commonly used anti-rheumatic drug for RA with mild effect.Results: The study group failed to show a significant effect on inflammatory markers, especially on the CRP levels, indicating no additional clinical value of supplementing with JGL. Similarly, at the endpoint, no significant differences between the two groups on QoL and related symptoms were observed. Our study suggests that the patients in the study group might need more anti-rheumatic drugs to fill the treatment insufficiency, and the application ratio of NSAIDs would be significantly higher than the reference group. By conducting this study on HCQ treatment, the positive aspects of controlling disease activity and reducing NSAIDs application were found, which demonstrates the utility of performing the RWS to evaluate the effect of JGL.Conclusion: Adding JGL did not significantly improve the clinical efficacy of RA treatment by this RWS. Folk herbal prescriptions such as JGL are suggested to underwent strict clinical trials before application.Keywords: real-world study, rheumatoid arthritis, traditional Chinese medicine, disease activity, hydroxychloroquine

Xiangdong Gongye,1,2,&ast; Peng Xia,1,2,&ast; Tianyin Ma,1,2,&ast; Yibo Chai,1,2 Zhang Chen,1,2 Yimin Zhu,1,2 Chengming Qu,1,2 Jie Liu,1,2 Wing Wa Guo,1,2 Minghe Zhang,1,2 Yingyi Liu,1,2 Ming Tian,1,2 Yufeng Yuan1– 3 1Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Hubei, People’s Republic of China; 3Taikang Center for Life and Medical Sciences of Wuhan University, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Tian; Yufeng Yuan, Email dr.med.mingtian@whu.edu.cn; yuanyf1971@whu.edu.cnBackground: The liver’s regenerative capacity allows it to repair itself after injury. Extracellular vesicles and particles (EVPs) in the liver’s interstitial space are crucial for signal transduction, metabolism, and immune regulation. Understanding the role and mechanism of liver-derived EVPs in regeneration is significant, particularly after partial hepatectomy, where the mechanisms remain unclear.Methods: A 70% hepatectomy model was established in mice, and EVPs were isolated and characterized using electron microscopy, nanocharacterization, and Western blot analysis. Combined metabolomic and transcriptomic analyses revealed β-sitosterol enrichment in EVPs and activation of the Hedgehog signaling pathway during regeneration. The role of β-sitosterol in EVPs on the Hedgehog pathway and its targets were identified using qRT-PCR, Western blot analysis. The regulation of carnitine synthesis by this pathway was determined using a dual luciferase assay. The effect of a β-sitosterol diet on liver regeneration was verified in mice.Results: After 70% hepatectomy, the liver successfully regenerated without liver failure or death. At 24 hours post-surgery, tissue staining showed transient regeneration-associated steatosis (TRAS), with increased Ki67 positivity at 48 hours. EVPs displayed a spherical lipid bilayer structure with particle sizes of 70– 130 nm. CD9, CD63, and CD81 in liver-derived EVPs were confirmed. Transcriptomic and metabolomic analyses showed EVPs supplementation significantly promoted carnitine synthesis and fatty acid oxidation. Tissue staining confirmed accelerated TRAS resolution and enhanced liver regeneration with EVP supplementation. Mass spectrometry identified β-sitosterol in EVPs, which binds to Smo protein, activating the Hedgehog pathway. This led to the nuclear transport of Gli3, stimulating Setd5 transcription and inducing carnitine synthesis, thereby accelerating fatty acid oxidation. Mice with increased β-sitosterol intake showed faster TRAS resolution and liver regeneration compared to controls.Conclusion: Liver-derived EVPs promote regeneration after partial hepatectomy. β-sitosterol from EVPs accelerates fatty acid oxidation and promotes liver regeneration by activating Hedgehog signaling pathway. Keywords: liver regeneration, extracellular vesicles and particles, β-sitosterol, carnitine synthesis, hedgehog signaling pathway

Yamei Bai,&ast; Yuqing Chen,&ast; Meng Tian, Jiaojiao Gao, Yulei Song, Xueqing Zhang, Haiyan Yin, Guihua Xu School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guihua Xu, School of Nursing, Nanjing University of Chinese Medicine, No. 138, Xianlin Avenue, Qixia District, Nanjing, Jiangsu Province, 210023, People’s Republic of China, Tel +86-153-6513-2927, Email 7115@njucm.edu.cnPurpose: Social isolation and depression have an impact on cognitive frailty. However, the underlying mechanisms between these variables have not been well defined. This study aims to investigate the mediating role of depressive symptoms in the association between social isolation and cognitive frailty among older adults in China.Methods: From Mar 2023 to Aug 2023, a cross-sectional study was conducted with 496 community-dwelling older adults aged ≥ 60 years in Nanjing, Jiangsu Province, China. Demographic information was collected using the General Information Questionnaire. The Lubben Social Network Scale-6 (LSNS-6), Geriatric Depression Scale 15-item (GDS-15), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and FRAIL scale were used for the questionnaire survey. Multiple linear regression and binary logistic regression were utilized to explore the associations among social isolation, depressive symptoms, and cognitive frailty, and Bootstrap analysis was used to explore the mediating role of depressive symptoms in social isolation and cognitive frailty.Results: Linear regression results revealed that social isolation was positively associated with depressive symptoms (β = 0.873, p < 0.001). Logistic regression analysis showed that social isolation (OR = 1.769, 95% CI = 1.018~3.075) and depressive symptoms (OR = 1.227, 95% CI = 1.108~1.357) were significantly associated with cognitive frailty. Mediation analysis demonstrated that depressive symptoms significantly mediated the relationship between social isolation and cognitive frailty, with an indirect effect of 0.027 (95% CI = 0.003~0.051), and the mediating effect accounted for 23.6% of the total effect.Conclusion: Social isolation is associated with cognitive frailty in community-dwelling older adults, and depressive symptoms partially mediate the effect between social isolation and cognitive frailty. Active promotion of social integration among older individuals is recommended to enhance their mental health, reduce the incidence of cognitive frailty, and foster active aging.Keywords: cognitive frailty, social isolation, depressive symptoms, older adults

Guang Zeng,1,&ast; Yong-Zhi Jin,1,&ast; Yi Huang,1 Jun-Sheng Hu,1 Meng-Fan Li,2 Ming Tian,3 Jun Lu,4 Rong Huang1 1Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, People’s Republic of China; 2Department of General Surgery, LiQun Hospital, Shanghai, 200333, People’s Republic of China; 3Department of Burn, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, People’s Republic of China; 4Department of Endocrinology, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Lu; Rong Huang, Email lujundoctor@163.com; huangrongsci@163.comBackground: The pathological damage mechanism of type 2 diabetes (T2D) and macroangiopathy is extremely complex, and T2D and arteriosclerosis obliterans have different biological behaviors and clinical features. To explore the mechanism of lower extremity arteriosclerosis occlusion (LEAOD) in T2D patients, we utilized RNA-seq to identify unique gene expression signatures of T2D and LEAOD through transcriptomic analysis.Methods: We obtained blood samples and performed RNA sequencing from four patients with T2D, five of whom had LEAOD. Another six age- and gender-matched blood samples from healthy volunteers were used for control. By exploring the general and specific differential expression analysis after transcriptome sequencing, specific gene expression patterns of T2D and LEAOD were verified.Results: Transcriptome analysis found differentially expressed genes in T2D, and T2D + LEAOD (vs normal) separately, of which 35/486 (T2D/T2D + LEAOD) were up-regulated and 1290/2970 (T2D/T2D + LEAOD) were down-regulated. A strong overlap of 571 genes across T2D, LEAOD, and coexisting conditions was mainly involved in extracellular exosomes and the transcription process. By exploring the sex difference gene expression features between T2D, T2D + LEAOD, and healthy controls, we noticed that sex chromosome-associated genes do not participate in the sexual dimorphism gene expression profiles of T2D and LEAOD. Protein–Protein Interaction Network analysis and drug target prediction provided the drug candidates to treat T2D and LEAOD.Conclusion: This study provides some evidence at the transcript level to uncover the association of T2D with LEAOD. The screened hub genes and predicted target drugs may be therapeutic targets.Keywords: type 2 diabetes mellitus, lower extremity arterial disease, gene expression profile, hub gene

Zhengjia Zhang,1,&ast; Xinyi Luo,1,&ast; Xiaoxia Xue,1 Mingshi Pang,1 Xiangpeng Wang,1 Liuchunyang Yu,1 Jinxiu Qian,1 Xiaoyu Li,1 Meng Tian,1 Aiping Lu,2 Cheng Lu,3 Yuanyan Liu1 1School of Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hongkong, People’s Republic of China; 3Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanyan Liu; Cheng Lu, Email yyliu_1980@163.com; lv_cheng0816@163.comBackground: The morbidity and mortality of triple-negative breast cancer (TNBC) are still high, causing a heavy medical burden. CCL5, as a chemokine, can be involved in altering the composition of the tumor microenvironment (TME) as well as the immunosuppressive degree, and has become a very promising target for the treatment of TNBC. Dysregulation of microRNAs (miRNAs) in tumor tissues is closely related to tumor progression, and its utilization can be used to achieve therapeutic purposes. Engineered exosomes can avoid the shortcomings of miRNAs and also enhance their targeting and anti-tumor effects through engineering. Therefore, we aimed to create a cRGD-modified exosome for targeted delivery of miR-588 and to investigate its effect in remodeling immunosuppressive TME by anchoring CCL5 in TNBC.Methods: In this study, we loaded miR-588 into exosomes using electroporation and modified it with cRGD using post insertion to obtain cRGD-Exos/miR-588. Transmission electron microscopy (TEM), nanoparticle tracking assay technique (NTA), Western Blots, qPCR, and flow cytometry were applied for its characterization. CCK-8, qPCR and enzyme-linked immunosorbent assay (ELISA), in vivo fluorescence imaging system, immunohistochemistry and H&E staining were used to explore the efficacy as well as the mechanism at the cellular level as well as in subcutaneous graft-tumor nude mouse model.Results: The cRGD-Exos/miR-588 was successfully constructed and had strong TNBC tumor targeting in vitro and in vivo. Meanwhile, it has significant efficacy on TME components affected by CCL5 and the degree of immunosuppression, which can effectively control TNBC with good safety.Conclusion: In this experiment, cRGD-Exos/miR-588 was prepared to remodel immunosuppressive TME by anchoring CCL5, which is affected by the vicious cycle of immune escape. Overall, cRGD-Exos/miR-588 explored the feasibility of targeting TME for the TNBC treatment, and provided a competitive delivery system for the engineered exosomes to deliver miRNAs for antitumor therapy drug.Keywords: engineered exosome, triple negative breast cancer, miR-588, CCL5, tumor environment

Yan He,1,&ast; Ying Tang,2,&ast; Caiyun Wang,3 Zilie Zhou,3 Wei Li,4 Man Tian3 1Department of Infection Management, Nanjing Drum Tower Hospital, Nanjing, Jiangsu, People’s Republic of China; 2Department of Ultrasound Diagnostic, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Respiratory, Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Clinical Research, Children’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Li; Man Tian, Email weili126@126.com; tmsweet@163.comAbstract: Monkeypox virus (MPXV), a member of the Orthopoxvirus genus, shares its genus with Variola virus (VARV), the causative agent of smallpox, and Vaccinia virus (VACV), used for smallpox vaccination. While smallpox has been eradicated, MPXV and related poxviruses continue to pose a global health threat. Monkeypox (Mpox), similar in clinical presentation to smallpox but milder, is endemic in Central and West Africa. Sporadic outbreaks emphasize the potential for wider dissemination. Understanding their biology, transmission, immune evasion, and clinical features informs disease control strategies. The intersection of medical innovation and biotechnology with poxviruses underscores their importance in both disease and scientific advancement. Further research is essential to enhance prevention, management, and therapeutic interventions for these viruses.Keywords: monkeypox, poxviruses, biology, epidemiology, vaccines and antivirals, biotechnology

Maolu Tian,1– 3 Zuping Qian,4 Yanjun Long,1,2 Fangfang Yu,1 Jing Yuan,1 Yan Zha1,2 1Department of Nephrology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 2NHC Key Laboratory of Pulmonary Immunological Disease, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, People’s Republic of China; 3Medical College, Guizhou University, Guiyang, Guizhou, People’s Republic of China; 4Clinical Medical College, Zunyi Medical University, Zunyi, Guizhou, People’s Republic of ChinaCorrespondence: Yan Zha, Department of Nephrology, Guizhou Provincial People’s Hospital, 83 Zhongshan Road, Nanming District, Guiyang, Guizhou, 550002, People’s Republic of China, Email zhayansy@163.comObjective: Depression is a common psychiatric disorder and related to poor outcomes in patients undergoing maintenance hemodialysis (MHD). Previous studies have reported some associations between sarcopenia and depressive symptoms. Recently, intracellular water (ICW) and total body water (TBW) have been found to reflect muscle function and muscle mass. ICW/TBW ratio is a marker of sarcopenia that is simple to assess. However, the relationship between ICW/TBW ratio and depression has not been explored in MHD patients.Methods: In our cross-sectional and multi-center study, 3300 adult MHD patients were included from June 1, 2021, to August 30, 2021. Depressive symptoms were evaluated using the Beck Depression Inventory-II (BDI-II). TBW and ICW were measured by Body Composition Monitor (BCM). Multivariable logistic regression, stratified analyses, and interactive analyses were conducted to assess the relationship between ICW/TBW ratio and depression.Results: About 16.5% of the 3300 MHD patients were found to have depressive symptoms. The prevalence of depression increased with decreasing quartiles of ICW/TBW ratios, and decreased ICW/TBW ratio was independently associated with depression after adjusting for potential confounders. Patients in Quartile 1 of ICW/TBW ratios were more likely to have depressive symptoms (odds ratio 1.55, 95% confidence interval 1.07– 2.22; p=0.002) than those in Quartile 4. History of diabetes and education status had interactive roles in the relationship between depression and ICW/TBW ratios (p < 0.05). The association of ICW/TBW ratios and depression existed in patients of both genders and different education levels, but only in non-diabetic patients.Conclusion: In MHD patients, the decreased ratio of ICW/TBW was independently related to high depression rates.Keywords: depression, hemodialysis, intracellular water, total body water

Peng Wang,1 Xiao Wang,1 Tao Gao,1 Xiqing Yuan,1 Qiulian Xing,1 Xinyu Cheng,1 Yu Ming,1 Mei Tian2 1School of Psychology, Shandong Normal University, Jinan, People’s Republic of China; 2Library, Shandong Normal University, Jinan, People’s Republic of ChinaCorrespondence: Mei Tian, Library, Shandong Normal University, No. 1 University Road, Changqing District, Jinan, People’s Republic of China, Tel +86 15650023569, Email tiammei_sdnu@163.comPurpose: Based on the Cognitive-Behavioral model and the Interaction of Person-Affect-Cognition-Execution model, this study examined the developmental trajectory of problematic Internet use (PIU) in early adolescents and explored whether there were gender differences in the onset level and rate of development of this developmental trajectory, and tested whether developmental changes in loneliness could have an impact on the developmental trajectory of problematic Internet use.Participants and Methods: This longitudinal study collected data on PIU and loneliness from 296 early adolescents (Mage=11.65, SD=0.58) in four waves. The development of PIU in adolescents and the effects of gender and loneliness development on PIU development were examined using a latent growth model.Results: The results revealed that individuals’ PIU development showed a nonlinear latent growth model, with PIU significantly higher than 0 in grade 6 and its growth rate slowing down as PIU increased. Individuals’ PIU at low starting levels developed more rapidly later. Boys had higher initial levels of PIU but their PIU developed and increased at the same rate as girls’. Both the initial value and slope of loneliness had a significant effect on the initial value and slope of boys’ and girls’ PIU.Conclusion: Interventions for PIU in early adolescents also need to consider loneliness at the same time, and intervention groups can focus on individuals with low initial levels of PIU, boys, and individuals with high levels of loneliness.Keywords: problematic internet use, loneliness, latent growth model, gender, early adolescents

Jia-Bin Xu, Meng Tian, Jing Wang, Guo-Bin Lin, Qian-Le Lei, Xian-Hao Lin, Qin Jiang The School of Health, Fujian Medical University, Fuzhou, People’s Republic of ChinaCorrespondence: Qin Jiang; Xian-hao Lin, School of Health, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China, Email jiangqin@fjmu.edu.cn; linxh@fjmu.edu.cnPurpose: To explore the structure of postgraduate research innovation ability and verify the Postgraduate Research Innovation Ability Scale.Patients and Methods: This study was based on the componential theory of creativity. First, we drafted an item pool from the literature review, semi-structured interviews, and group discussions. A total of 125 postgraduates were selected for the pre-test. After item selection and exploratory factor analysis, an 11-item, 3-factor postgraduate research innovation ability scale was formed. The scale was applied to a sample of 330 postgraduates from various domestic universities. Exploratory factor analysis and confirmatory factor analysis were used to examine the factor structure of the scales.Results: The results support a three-factor model including creativity-relevant processes, domain-relevant skills, and intrinsic motivation for the Postgraduate Research Innovation Ability Scale. The scale showed good internal consistency (α =0.89) and test-retest reliability (r=0.86). Exploratory factor analysis showed that the KMO value was 0.87, and the Bartlett’s sphericity test results were significant. Confirmatory factor analysis confirmed that the three-factor construct demonstrated a good model fit (χ 2/df=1.945, GFI=0.916, CFI=0.950, RMSEA=0.076).Conclusion: The Postgraduate Research Innovation Ability Scale has good reliability and validity, and it can be used for future research in related fields.Keywords: postgraduate, research innovation ability, validity, reliability

Jun Li,1,&ast; Yangyang Yang,2,&ast; Xiumin Han,3,&ast; Jing Li,2 Mengxiao Tian,1 Wenjing Qi,1 Huniu An,3 Chuanchuan Wu,1 Yao Zhang,1 Shuai Han,4 Liping Duan,4 Weisi Wang,4 Wenbao Zhang1 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, the First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 2Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, People’s Republic of China; 3Qinghai Provincial People’s Hospital, Xining, Qinghai, People’s Republic of China; 4NHC Key Laboratory of Parasite and Vector Biology, WHO Collaborating Centre for Tropical Diseases, National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenbao Zhang; Weisi Wang, Tel +86 991 4366319 ; +86 21 64377008, Email wenbaozhang2013@163.com; wangws@nipd.chinacdc.cnBackground: Alveolar echinococcosis (AE) is a lethal parasitic disease caused by infection with the metacestode of the dog/fox tapeworm Echinococcus multilocularis, which primarily affects the liver. Although continued efforts have been made to find new drugs against this orphan and neglected disease, the current treatment options remain limited, with drug delivery considered a likely barrier for successful treatment.Methods: Nanoparticles (NPs) have gained much attention in the field of drug delivery due to their potential to improve delivery efficiency and targetability. In this study, biocompatible PLGA nanoparticles encapsulating a novel carbazole aminoalcohol anti-AE agent (H1402) were prepared to promote the delivery of the parent drug to liver tissue for treating hepatic AE.Results: H1402-loaded nanoparticles (H1402-NPs) had a uniform spherical shape and a mean particle size of 55 nm. Compound H1402 was efficiently encapsulated into PLGA NPs with a maximal encapsulation efficiency of 82.1% and drug loading content of 8.2%. An in vitro uptake assay demonstrated that H1402-NPs rapidly penetrated the in vitro cultured pre-cyst wall and extensively accumulated in the pre-cysts of E. multilocularis within only 1 h. The biodistribution profile of H1402-NPs determined through ex vivo fluorescence imaging revealed significantly enhanced liver distribution compared to unencapsulated H1402, which translated to improved therapeutic efficacy and reduced systemic toxicity (especially hepatotoxicity and cytotoxicity) in a hepatic AE murine model. Following a 30-day oral regimen (100 mg/kg/day), H1402-NPs significantly reduced the parasitic burden in both the parasite mass (liver and metacestode total weight, 8.8%) and average metacestode size (89.9%) compared to unmedicated infected mice (both p-values < 0.05); the treatment outcome was more effective than those of albendazole- and free H1402-treated individuals.Conclusion: Our findings demonstrate the advantages of encapsulating H1402 into PLGA nanoparticles and highlight the potential of H1402-NPs as a promising liver-targeting therapeutic strategy for hepatic AE.Graphical Abstract: Keywords: alveolar echinococcosis, Echinococcus multilocularis, PLGA, nanoparticles, liver targeting, oral administration

Miao Tian,1,&ast; Zhijia Wang,2,&ast; Yanbin Zhu,1,3 Yunxu Tian,1 Kexin Zhang,1 Xiuting Li1 1Department of Orthopedic Surgery, the Third Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Joint Surgery, Huai ‘an Hospital of Huai‘an City, Huai‘an, People’s Republic of China; 3Hebei Orthopedic Research Institute, Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiuting Li; Yanbin Zhu, Email lixiuting2021@126.com; zhuyanbin111@126.comAim: The purpose of this study was to examine the incidence and cause of unplanned readmission after Surgically Treated Hip Fractures in Elderly Patients and identify the associated risk factors.Methods: This study retrospectively collected the data on elderly patients who underwent hip fracture surgery at two institutions from January 2020 to December 2021, and identified those who were readmitted within 12 months postoperatively. Based on the presence or not of postoperative readmission, they were divided into readmission and non-readmission groups. Demographics, surgery-related variables, and laboratory parameters were compared between groups. The specific causes for documented readmission were collected and summarized. Multivariate logistic regression analysis was performed to identify the associated risk factors.Results: There were 930 patients including 76 (8.2%) patients who were readmitted within 12 months postoperatively. Overall, cardiac and respiratory complications and new-onset fractures were the first three common causes of readmission, taking an overwhelming proportion of 53.9% (41/76). Over 60% (61.8%, 47/76) of readmissions occurred within 30 days after surgery, with medical complications taking a predominance (89.4%, 42/47). New-onset fractures accounted for a proportion of 18.4% (14/76), occurring at different time points; especially, at 90– 365 days, it accounted for 44.4% (8/18). Multivariate analysis revealed that age ≥ 80 years (OR, 1.0, 95% CI, 1.0 to 1.1; P=0.032), preoperative albumin level ≤ 21.5 g/L (OR, 1.1, 95% CI, 1.0 to 1.2; P=0.009), the postoperative occurrence of DVT (OR, 4.2, 95% CI, 2.5 to 7.2; P=0.001), and local anesthesia (OR, 2.1, 95% CI, 1.1 to 4.0; P=0.029) were independent risk factors for unplanned readmissions.Conclusion: This study identified several risk factors for unplanned readmissions after elderly hip fractures, and provided detailed information about unplanned readmissions.Keywords: hip fracture, the elderly, unplanned readmissions, cause, risk factors

Tingting Liu,&ast; Wu Yang,&ast; Kun Li, Siruo Guo, Manman Tian, Xueling Fang Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xueling Fang, Department of Critical Care Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79, Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, People’s Republic of China, Tel +86-13588785095, Fax +86 571-87236838, Email 1191012@zju.edu.cnAbstract: Hemorrhagic fever with renal syndrome (HFRS), caused by hanta viruses (HTNV), can be complicated by severe complications. Seventeen percent of the HFRS patients with abdominal pain had acute pancreatitis (AP). The reported prevalence of AP among HFRS patients has a conspicuous high mortality rate. Of note, acute capillary cholangitis (ACC) among HFRS patients presenting with abdominal pain appears extremely rare, particularly independent of HFRS patients complicated with AP. The main pathophysiological mechanism of HFRS complicated with AP and ACC may be that it preferentially damages the microvascular and induces plasma leakage. To date, the management of severe HFRS cases is mainly based on supportive treatment, including extracorporeal blood purification and mechanical ventilation. Here, we describe an exceptionally rare case of a 34-year man who developed HFRS with AP and ACC while improving from HTNV infection via antiviral and supportive treatment.Keywords: hemorrhagic fever with renal syndrome, hantaviruses, abdominal pain, acute pancreatitis, acute acalculous cholangitis

Zhihuan Zhang, Wenhan Huang, Feifeng Ren, Lei Luo, Jun Zhou, Mengxue Tian, Zhongjie Wang, Dandan Chen, Lin Tang Department of Rheumatology and Immunology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Lin Tang, Department of Rheumatology and Immunology of the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China, Email hopetang@163.comPurpose: To explore the risk factors for thrombi occurring in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and establish a risk prediction model to better predict the risk of thrombosis in patients with AAV.Patients and Methods: We retrospectively analyzed 117 AAV patients who had been hospitalized in The Second Affiliated Hospital of Chongqing Medical University between October 2010 and December 2021. For all patients, we recorded demographic characteristics and clinical data, analyzed the risk factors for thrombosis in AAV patients and then developed a risk prediction model.Results: Stepwise logistic regression analysis indicated that a high complement C3 level, a high BVAS score and a high Padua score were independent risk factors for thrombosis in AAV patients. According to multivariate analysis, a predictive model for thrombus risk was successfully established; the area under the ROC curve(AUC) was 0.803 (95% CI: 0.716– 0.890) and the maximum Youden index, sensitivity and specificity were 0.487, 59.0% and 89.7%, respectively.Conclusion: A high complement C3 level, high BVAS score, and a high Padua score were shown to be independent risk factors for thrombosis in AAV patients. We developed a risk prediction model based on these three risk factors that could predict the risk of thrombosis in AAV patients to some extent.Keywords: antineutrophil cytoplasmic antibody, thromboembolism, risk factors, risk prediction model

Qingyu Wang,1,2 Xing Qu,3 Shannon H Houser,4 Yan Zhang,5 Meirong Tian,3 Qiong Zhang,6,7 Wei Zhang3 1West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, People’s Republic of China; 2HEOA Group, Institute for Healthy Cities and West China Research Center for Rural Health Development, Sichuan University, Chengdu, People’s Republic of China; 3Institute of Hospital Management, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Department of Health Services Administration, the University of Alabama at Birmingham, Birmingham, AL, USA; 5Department of Maternity and Child Health Management, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, People’s Republic of China; 6Department of Pediatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu, People’s Republic of China; 7State Key Laboratory of Oral Diseases & National Clinical Research, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Xing Qu, Institute of Hospital Management, West China Hospital, Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, People’s Republic of China, +86 13880713452, Email qvxing@163.comBackground: Limited information is known about dental implementation by pediatric primary care physicians (PCPs) at the primary care level in China. This study aimed to explore the current status of primary oral care implementation and related influencing factors.Methods: A cross-sectional survey was conducted among PCPs in Sichuan Province, China. Multivariable logistic regression was used to analyse factors associated with CRA and dental referral for high caries-risk children.Results: A total of 504 out of 524 questionnaires remained for analysis. In all, 93.8% of PCPs reported that they usually or sometimes performed dental screening for children, 31.3% performed CRA, and 49.0% referred high caries-risk children to dentists. More CRA activities were associated with PCPs who encountered a greater number of children with caries during systematic care (adjusted OR: 2.37, 95% CI:[1.08,5.18], had dental knowledge training by pediatric dentists (aOR: 2.26, 95% CI:[1.36, 3.75], and learned pediatric dental knowledge on their own (aOR: 2.87, 95% CI: [1.51, 5.45]). In addition to the above associators, a higher rate of dental referrals for high caries-risk children was associated with having a dental department in the same work institute (aOR: 1.72, 95% CI: [1.09, 2.70] and having more confidence in their dental knowledge (aOR: 1.29, 95% CI: [1.04, 1.61]).Conclusion: Paediatric PCPs commonly implement dental screening but perform fewer CRAs and dental referrals for high caries-risk children during systematic health management in western China. To increase CRA activities and dental referral by paediatric PCPs, health policymakers could encourage interdisciplinary cooperation between dental professionals and paediatric PCPs.Keywords: caries risk assessment, dental referral, paediatric physicians, primary care, China

Meimei Tian,1,2,&ast; Zihua Li,1,&ast; Xujuan Chen,1 Qiting Wu,1 Huimin Shi,1 Yuchang Zhu,1 Yan Shi2 1Department of Orthopedics, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China; 2Department of Nursing, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Shi, Tel +86 21 66307304, Fax +86 21 66307542, Email shi_yan2018@outlook.comBackground: Pain relief is the most important issue in the long-term outcome of arthroplasty surgery, with nearly one-third of patients still suffered persistent pain and caused dissatisfaction after the surgery.Methods: A total of 713 patients underwent primary elective primary TKA and UKA were included consecutively between July 2018 and December 2019, using binary logistic method to analyze the data.Results: The prevalence of CPSP at rest and on movement at 2-year was 12.1% and 37.7% respectively after primary knee arthroplasty and CPSP at rest factors included: age above 80 (odds ratio [OR]= 6.72, 95% confidence interval [CI] 1.58 to 28.56), BMI above 30 (2.339, 1.02 to 5.383), and moderate to severe pain variables: preoperative pain, (1.95, 1.11 to 3.41); APSP on movement, 4.9 (2.31– 10.6); and follow-up contralateral knee pain-at-rest scores (12.6, 5.5 to 28.5). Factors associated with presence of CPSP on movement included: no smoking (2.59, 1.07 to 6.26); and moderate to severe pain variables: preoperative pain, (1.57, 1.073 to 2.30); APSP at rest, (1.85, 1.13 to 3.02); APSP on movement, 6.11 (3.82 to 9.78); and follow-up contralateral knee pain-on-movement scores, 3.22 (2.08 to 5.00). Factors to occurrence of moderate to severe CPSP on movement include: presence of COPD (12.20, 2.19 to 67.98); and moderate to severe pain variables: preoperative pain (2.36, 1.32 to 4.23); APSP on movement (4.68, 1.95 to 11.25); and follow-up contralateral knee pain-on-movement scores (2.71, 1.66 to 4.42).Conclusion: Prevention strategies should be targeted to different types of pain, and the comorbidity of COPD undergoing knee arthroplasty should receive early identification and attention.Keywords: chronic postsurgical pain, acute-postoperative pain, total knee arthroplasty, rest pain, movement pain

Zemin Hou,1,2,&ast; Wencheng Zhou,1,2,&ast; Xi Guo,2 Rui Zhong,3 Ao Wang,4 Jiehua Li,4 Ying Cen,1 Chao You,2 Hong Tan,4 Meng Tian2 1Department of Burn and Plastic Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College, Chengdu, Sichuan, People’s Republic of China; 4College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Meng Tian, Department of Neurosurgery and Neurosurgery Research Laboratory, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of China, Tel +86 28 85164168, Email tianmeng@scu.edu.cnBackground: The main challenge of polymeric micelles as drug delivery systems is that the actual delivery efficiency is not as high as expected, which is closely related with the interactions with the complex biological environments such as blood components, phagocytosis, and biodistribution. Herein, we expect to understand these concerns for the clinically relevant micelles that composed of methoxypolyethylene glycol (MPEG) with identical chain length And poly(&epsiv;-caprolactone) (PCL) with tunable chain length (PCLn-MPEG) (n=20, 30, and 40) wherein doxorubicin was encapsulated as a model drug.Methods: The doxorubicin-loaded PCLn-MPEG micelles were prepared by a dialysis method and characterized by dynamic light scattering and transmission electron microscopy. The surface PEG density and chain conformation were investigated by dissipative particle dynamics simulation. The stability of the micelles was detected by nanoparticle tracking analysis. The effects of PCL chain length on the blood components, phagocytosis, and biodistribution were assayed in vitro and in vivo.Results: The micelles exhibited spherical morphology with a diameter about 30nm. The PEG chain conformation from “mushroom-like” to “brush-like” was evident. The micelles have no remarkable effect on the red blood cells, blood coagulation, and platelet activation. Interestingly, the protein adsorption was affected and dependent on the chain conformation, with lowest adsorption for PCL30-MPEG, which also has the loWest phagocytosis. The stability of the micelles was in the order of PCL40-MPEG>PCL30-MPEG>PCL20-MPEG which was dependent on the PCL chain length. The micelles mainly accumulated in liver, with the order consistent with their stability, indicating that, besides the phagocytosis, the stability of the micelle plays an important role in biodistribution as well. The related mechanisms were proposed and discussed.Conclusion: Manipulating the PEG/PCL ratio of the micelle is an effective approach to modulate the protein adsorption, phagocytosis, and biodistribution, which may be a prerequisite for clinical applications.Keywords: micelles, blood components, phagocytosis, biodistribution

Yunxu Tian,1 Yanbin Zhu,1,2 Kexin Zhang,1 Miao Tian,1 Shuhui Qin,2 Xiuting Li1 1Department of Orthopaedic Surgery, The 3rd Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, People’s Republic of China; 2Hebei Bone Research Institute, Key Laboratory of Biomechanics of Hebei Province, Shijiazhuang, 050051, Hebei, People’s Republic of ChinaCorrespondence: Yanbin Zhu; Xiuting Li, Department of Orthopaedic Surgery, The 3rd Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, People’s Republic of China, Email zhuyanbin111@126.com; lixiuting2021@126.comBackground: Pneumonia is a devastating complication following geriatric hip fracture surgery, and preoperative hypoalbuminemia may be a potentially modifiable factor leading to improved outcome. This study aimed to quantify the relationship between preoperative hypoalbuminemia and postoperative pneumonia.Methods: We retrospectively reviewed the medical records of elderly patients (≥ 60 years) who underwent surgeries for hip fracture in a tertiary referral center between 2016 and 2020. According to the preoperative serum albumin level, they were divided into two groups: < 35 g/ L and ≥ 35 g/ L. To reduce potential confounding, propensity score matching (PSM) in a 1:1 ratio was performed, with the caliper value set as 0.002; and further conditional logistic regression analysis was used to control the other potential confounders to determine the association strength.Results: Among 3,147 eligible patients included, PSM yielded 1,318 matched patients, with 659 in each respective group, suggesting significantly improved balance in most variables (standardized mean deviation improvement range, 20.7% to 99.1%), except for basophil count. The conditional logistic regression analysis, adjusted for PS and other intra- or post-operative variables, showed 6.18-fold (relative ratio, 6.18; 95% CI, 3.15– 11.98; P< 0.001) increased risk of postoperative pneumonia associated with preoperative hypoalbuminemia.Conclusion: Preoperative hypoalbuminemia was identified to be independently and highly associated with development of postoperative pneumonia in elderly patients undergoing hip fracture surgeries. However, whether the patients who had such condition may benefit from preoperative targeted nutritional support needs to be clarified by more prospective studies.Keywords: hip fracture, geriatric population, hypoalbuminemia, pneumonia

Yanwu Nie,1,&ast; Chenchen Wang,2,&ast; Lei Yang,3 Zhen Yang,4 Yahong Sun,4 Maozai Tian,5,6 Yuhua Ma,7,8 Yuxia Zhang,9 Yimu Yuan,10 Liping Zhang6 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Public Health, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 2Center for Disease Control and prevention of Xinjiang Uygur Autonomous Region, Urumqi, 830017, People’s Republic of China; 3School of Nursing, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 4School of Public Health, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 5Center for Applied Statistics, School of Statistics, Renmin University of China, Beijing, 100872, People’s Republic of China; 6College of Medical Engineering and Technology, Xinjiang Medical University, Urumqi, 830017, People’s Republic of China; 7Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People’s Republic of China; 8Department of Pathology, Karamay Central Hospital of XinJiang Karamay, Karamay, Xinjiang Uygur Autonomous Region, 834000, People’s Republic of China; 9Department of Clinical Nutrition, Urumqi Maternal and Child Health Institute, Urumqi, 830001, People’s Republic of China; 10Department of General Practice Medicine, Xinjiang Corps Hospital, Urumqi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liping Zhang, Email zhanglp1219@163.comPurpose: The role of inorganic arsenic (iAs) in the risk of metabolic syndrome (MetS) remains unclear. This investigation focused on the effect of iAs exposure on MetS and whether the results are consistent in different subgroups.Patients and Methods: The present study was conducted on 629 men and 616 women aged 35– 70 years and living in Xinjiang Uygur Autonomous Region, China. The 1:1 propensity score matching (PSM) was adopted to regulate the confounding factors, and the multivariate logistic regression was performed to assess the relationship between urinary iAs and MetS.Results: The median content of urinary iAs was examined as 2.20 μg/dL (interquartile range: 1.30– 3.20 μg/dL), and the MetS prevalence reached 23.69% (295 cases/950 participants). After the confounding factors were adjusted, the ORs (95% CIs) for MetS from the minimal to the maximum urinary iAs quartiles reached 1.171 (0.736,1.863), 1.568 (1.008, 2.440) and 2.011 (1.296, 3.120), respectively (referencing 1.00) (P for trend=0.001). After the PSM, the urinary iAs content still plays a potential prediction role in MetS (P for trend=0.011). In addition, as revealed from the subgroup analysis, the urinary iAs content was a predictor of MetS in the female patients, whereas it did not serve as a significant predictor of MetS in the male patients (P for interaction< 0.05).Conclusion: The increased urinary iAs content was associated with the increased prevalence of MetS in Chinese population. More attention should be paid to female urinary iAs content to avoid the high prevalence of MetS.Keywords: metabolic syndrome, urinary inorganic arsenic, propensity score matching, subgroup analysis

Wenxian Sun,1 Luyang Zhang,1 Weishi Liu,1 Mengke Tian,1 Xin Wang,1 Jing Liang,1 Yuying Wang,1 Lan Ding,1 Lulu Pei,1 Jie Lu,2 Yuming Xu,1 Bo Song1 1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Epidemiology and Health Statistics College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Bo SongDepartment of Neurology, The First Affiliated Hospital of Zhengzhou University, 1st Jianshe Eastern Road, Zhengzhou, 450052, Henan Province, People’s Republic of ChinaTel +86-13603983297Fax +86-371-66975140Email fccsongb@zzu.edu.cnBackground: Stroke and myocardial infarction (MI) are associated with each other, as demonstrated in observational studies. However, it is unclear whether this relationship is causal, and the purpose of this study was to explore the bidirectional causality between stroke and MI.Methods: Causality between stroke and MI was assessed using two-sample Mendelian randomization (MR). All genetic instruments related to stroke (40,585 cases; 406,111 controls) and MI (43,676 cases; 128,199 controls) were derived from large published genome-wide association study. The MR analysis was calculated with inverse-variance weighting, MR-Egger, weighted mode, weighted median, and simple mode methods, and sensitivity analyses are used to detect the heterogeneity or pleiotropy.Results: Genetically predicted large-artery stroke (LAS) was causally related to higher odds of MI (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.06– 1.20, p = 1.0× 10− 4), and the causal effect of LAS on MI was significantly weakened (OR = 1.09, 95% CI: 1.02– 1.17, p = 0.017) after excluding the multipotent single-nucleotide polymorphisms (SNPs). MI phenotypes were genetically correlated with all ischemic strokes (OR = 1.15, 95% CI: 1.03– 1.28, p = 0.013) and LAS (OR = 1.39, 95% CI: 1.14– 1.71, p = 0.001); but a causal effect of MI on all ischemic strokes (OR = 1.00, 95% CI: 0.95– 1.28, p = 0.219) and LAS (OR = 1.26, 95% CI: 0.93– 1.69, p = 0.130) was not observed after excluding the multipotent SNPs.Conclusion: This MR analysis provides evidence to support the causal effect of LAS subtype on MI, and some factors act as confiding factors whereas others may act as mediators.Keywords: causal inference, single-nucleotide polymorphism, genome-wide association study, epidemiologic methods, large-artery stroke

Yongliang Li,1,&ast; Mi Tian,2,&ast; Dongqing Zhang,1 Yifei Zhuang,1 Zhimin Li,1 Shenqi Xie,1 Keyu Sun1 1Department of Emergency, Minhang Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 2Department of Intensive Care Unit, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Keyu SunDepartment of Emergency, Minhang Hospital, Fudan University, Shanghai, 200040, People’s Republic of ChinaTel +86 18930536861Email hoceima@126.comBackground: Long non-coding RNAs (lncRNAs) have been reported to play critical roles in human tumours, including gallbladder carcinoma (GBC). However, their biological functions and molecular mechanisms in tumorigenesis and progression remain largely unknown.Methods: Quantitative polymerase chain reaction (qPCR) was used to verify the expression of lncRNA myosin light chain kinase antisense RNA 1 (MYLK-AS1) in 120 pairs of GBC tissues and paired adjacent non-tumour tissues, as well as in six different GBC cell lines (NOZ, EH-GB1, OCUG-1, GBC-SD, SGC-996 and QBC-939). Cell counting kit 8 was applied to explore cell proliferation and drug sensitivity assays. The target miRNAs (miR) of MYLK-AS1 and downstream target genes were predicted using Starbase 3.0 software and confirmed by double luciferase reporting test. The expression of proteins was assessed using Western blot assay.Results: Here, we demonstrated that MYLK-AS1 was significantly upregulated and correlated with a poor prognosis and poor clinical characteristics in GBC. Furthermore, the forced expression of MYLK-AS1 significantly promoted GBC cell proliferation and resistance to gemcitabine in vitro. Mechanistically, MYLK-AS1 functioned as an efficient miR-217 sponge, thereby releasing the inhibition of enhancer of zeste 2 polycomb repressive complex 2 (EZH2) subunit expression. MYLK-AS1 promoted GBC cell proliferation and resistance to gemcitabine by upregulating EZH2 expression, and EZH2 was confirmed as a direct target of miR-217.Discussion: Our results confirmed that the chemoresistant driver MYLK-AS1 might be a promising candidate as a therapeutic target for the treatment of advanced GBC.Keywords: chemoresistance, GBC, lncRNA, proliferation

Peiying Wei,1,2,&ast; Chang Shao,3,&ast; Min Tian,4 Mengwei Wu,5 Haibin Wang,2 Zhijiang Han,2 Hongjie Hu1 1Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Department of Radiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Pathology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 4The Fourth Clinical Medical College, Zhejiang Traditional Chinese Medicine University, Hangzhou, People’s Republic of China; 5Department of Radiology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhijiang HanDepartment of Radiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, No. 261, Huansha Road, Hangzhou, 310006, People’s Republic of ChinaEmail hzjsyy@126.comHongjie HuDepartment of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, People’s Republic of ChinaEmail hongjiehu@zju.edu.cnObjective: To investigate the value of the signal intensity on T2-weighted magnetic resonance (MR) imaging using quantitative analysis in the differentiation of parotid tumors.Materials and Methods: MR data of 80 pleomorphic adenomas (PAs), 68 Warthin tumors (WTs), and 34 malignant tumors (MTs) confirmed by surgery and histology were retrospectively analyzed. The signal intensities of tumor, normal parotid gland, spinal cord, and buccal subcutaneous fat were measured, and the signal intensity ratios (SIRs) between the tumor and the three references were calculated. Receiver operating characteristic curve was used to determine the optimal threshold and diagnostic efficiency of SIR for differentiating PAs, WTs, and MTs.Results: The area under the curve (AUC) of tumor to parotid gland SIR (SIRP), tumor to spinal cord SIR (SIRC), and tumor to buccal subcutaneous fat SIR (SIRF) for differentiating PAs and WTs was 0.922, 0.918, and 0.934, respectively. The sensitivity and specificity at an optimal SIR threshold were 86.3% and 91.2%, 80.0% and 97.1%, and 85.0% and 94.1%, respectively. The AUC of SIRP, SIRC, and SIRF for distinguishing PAs from MTs was 0.793, 0.802, and 0.774, respectively. The sensitivity and specificity at an optimal SIR threshold was 86.3% and 61.8%, 80.0% and 73.5%, and 82.5% and 73.5%, respectively. The AUC of SIRP, SIRC, and SIRF for distinguishing WTs from MTs was 0.716, 0.709, and 0.759, respectively. The sensitivity and specificity at an optimal SIR threshold were 61.8% and 82.4%, 55.9% and 82.4%, and 64.7% and 86.8%, respectively.Conclusion: SIRP, SIRC, and SIRF on T2-weighted MR images had high diagnostic efficiency for differentiating between PAs and WTs, while SIRP and SIRC for differentiating between PAs and MTs, and SIRF for differentiating between WTs and MTs had relatively high diagnostic efficiency.Keywords: parotid tumor, signal intensity ratio, pathology, magnetic resonance imaging, T2-weighted imaging

Jiaying Tan,1,* Mi Tian,1,* Feng Zhao,1 Shuixiang Deng,1 Peng Jin,1 Yao Wang,1 Huimei Wen,1 Xiaohua Qin,2,3 Ye Gong1,4 1Department of Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 2Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China; 3Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, 200040, People’s Republic of China; 4Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohua QinInstitute of Antibiotics, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of ChinaEmail 0456240@fudan.edu.cnYe GongDepartment of Critical Care Medicine, Huashan Hospital, Fudan University, No. 12 Middle Urumqi Road, Shanghai, 200040, People’s Republic of ChinaEmail gong_ye@fudan.edu.cnBackground: Male genitourinary abscess is one of the serious complications of urinary tract infections (UTIs). There were few researches on the clinical and pathogenic characteristics of male genitourinary abscess.Patients and Methods: A retrospective observational study was conducted between January 2004 and April 2019. Male patients with genitourinary abscess originated from urinary tract, including sites of scrotum, testis, epididymis, spermatic cord, and prostate, were enrolled. Clinical and microbial records were collected and analyzed, and antimicrobial susceptibility testings were performed according to CLSI standard. Whole-genome sequencing was applied to detect the β-lactamase genes and virulence genes, as well as to determine the multilocus-sequence typing (MLST) of the collected Klebsiella pneumoniae (K. pneumoniae) isolates.Results: A total of 22 male patients were included. The main clinical symptoms were fever (86.4%), scrotal swelling (68.2%), local skin warmth (59.1%) and ulceration (45.5%). Urinary irritation was often presented in prostate involved abscess. Ultrasound features had a 94.7% positive rate. Surgical treatment, including abscess drainage, was helpful to the prognosis. No matter where the specimens obtained from, including blood, urine or pus, multidrug-resistant K. pneumoniae was the dominant (11 cases, 50.0%) microorganism in positive cultures. Nine of eleven K. pneumoniae isolates had been preserved and recovered. As for MLST typing, all the nine available isolates of K. pneumoniae belonged to the ST11 type and characterized with blaKPC-2 carbapenemase gene. Virulence genes rmpA2, ybtS, kfuC, wzi, aerobactin genes (iucABCD and iutA) and type 3 fimbriae genes (mrkAD) were identified in all the K. pneumoniae isolates.Conclusion: It seemed that more patients under 35 years old were vulnerable to genitourinary abscess. There was an increasing trend that multidrug-resistant K. pneumoniae isolates with multiple virulence genes were involved in male genitourinary abscess. Prompt and proper antibiotic use, combined with adequate drainage of the abscess, was important to prognosis.Keywords: male genitourinary abscess, carbapenem-resistant Klebsiella pneumoniae, virulence genes, MLST type

Cuiyun Dai, Yichi Zhang, Xiaoni Zhan, Meihui Tian, Hao Pang Department of Forensic Genetics and Biology, School of Forensic Medicine, China Medical University, Shenyang, 110122, People’s Republic of ChinaCorrespondence: Hao Pang Tel +86-24-31939435Email hpang@cmu.edu.cnPurpose: Sequencing potentially causal and susceptible genes and genome-wide association studies in samples from Parkinson’s disease (PD) patients has revealed several related loci. The genes for synaptosome-associated protein of 25 kDa (SNAP25), histamine-N-methyltransferase (HNMT), FCH and double SH3 domains 1 (FCHSD1) and dopamine β-hydroxylase (DBH) are candidate loci and have not been studied in a northern Chinese population. We explored the genetic distribution of four single-nucleotide polymorphisms (rs3746544, rs11558538, rs456998, rs129882) located on SNAP25, HNMT, FCHSD1 and DBH, respectively.Patients and Methods: A total of 330 patients with sporadic PD and 332 healthy controls (HCs) were recruited from a northern Chinese population. Polymerase chain reaction restriction fragment length polymorphism was used to genotype these four SNPs.Results: After statistical analyses and correction of the genotyping results, the mutant-allele T in rs456998 of FCHSD1 was found to be significantly related to reducing the PD risk (P = 0.029, OR = 0.754, 95% CI = 0.586– 0.971, power = 0.591). However, rs3746544, rs11558538, and rs129882 did not show an association with PD.Conclusion: FCHSD1 rs456998 may have a protective role in PD in a northern Chinese population, but more studies are needed to support this suggestion.Keywords: Parkinson’s disease, single nucleotide polymorphism, SNAP25, HNMT, FCHSD1, DBH, association study

Hang Pan, Wenhan Huang, Zhongjie Wang, Feifeng Ren, Lei Luo, Jun Zhou, Mengxue Tian, Lin Tang Department of Rheumatology and Immunology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Lin TangDepartment of Rheumatology and Immunology, Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, People’s Republic of ChinaTel +86 13795683033Fax +86 23 62888265Email hopetang@163.comPurpose: Angiotensin 1– 7 [Ang-(1-7)] has been identified as an important anti-inflammatory and anti-fibrotic factor. This study determined how the ACE2-Ang-(1-7)-Mas axis affected M1/M2 macrophage polarization and thus contributed to anti-inflammatory processes in the cecal ligation and puncture (CLP)-induced inflammation model.Materials and Methods: ELISA, western blotting, and qRT-PCR were used to verify that Ang-(1-7) decreased the expression of pro-inflammatory cytokines and increased anti-inflammatory cytokines. The differentiation of M1/M2 macrophages was assessed by flow cytometry for assessing the cell-surface markers, CD86 and CD206. The related key receptors and pathways were analyzed by Western blotting, qRT-PCR, and immunofluorescence. CLP-induced inflammatory mice models were used for in vivo studies. Hematoxylin and eosin and immunohistochemical and immunofluorescence staining protocols were used to analyze histological changes in the spleen, and the related key pathway proteins were analyzed by western blotting.Results: Ang-(1-7) decreased the expressions of the TNF-α and IL-6 pro-inflammatory cytokines and increased the expressions of the IL-4 and IL-10 anti-inflammatory cytokines. INOS and TNF-α, which represented M1 macrophage polarization, were decreased by Ang-(1-7). ARG1 and CD163, which represented M2 macrophage polarization, were increased by Ang-(1-7). Both Mas receptor and ACE2 are expressed on macrophages. Furthermore, the ACE2-Ang-(1-7)-MAS axis modulated macrophage polarization by ameliorating TLR4 expression and regulating the NF-кB and MAPK pathways. In addition, splenomegaly and macrophage infiltration were observed in the spleen of the CLP-induced mouse models and macrophages in the spleen suspension of CLP models were shifted to M1 phenotype and were effectively inhibited by Ang-(1-7) via the TLR4-mediated NF-кB and MAPK pathways, which could be partially rescued by A-779.Conclusion: Ang-(1-7) inhibited inflammatory responses in vivo and in vitro, and repressed macrophage polarization toward the M1 phenotype and promoted it toward the M2 phenotype, which provided new evidence for the anti-inflammation activity of the ACE2-Ang-(1-7)-MAS axis.Keywords: ACE2-Ang-(1‑7)-MAS axis, macrophage polarization, sepsis, NF-kB pathway, MAPK pathway

Liu Zi,1,2,* Wencheng Zhou,1,3,* Jiake Xu,1,4 Junshu Li,5 Ning Li,2 Jianguo Xu,1,4,6 Chao You,1,4,6 Chengwei Wang,1,2 Meng Tian1,4,6 1Neurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Integrated Traditional and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Department of Burn and Plastic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 5State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People’s Republic of China; 6West China Brain Research Centre, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chengwei Wang; Meng TianNeurosurgery Research Laboratory, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaTel/Fax +86 28 85164168Email 21270526@qq.com; tianmong007@gmail.comBackground: Intracerebral hemorrhage (ICH), a devastating subtype of stroke, has a poor prognosis. However, there is no effective therapy currently available due to its complex pathological progression, in which neuroinflammation plays a pivotal role in secondary brain injury. In this work, the use of statin-loaded nanomicelles to target the neuroinflammation and improve the efficacy was studied in a mouse model of ICH.Methods: Rosuvastatin-loaded nanomicelles were prepared by a co-solvent evaporation method using polyethylene glycol-poly(ϵ-caprolactone) (PEG-PCL) copolymer as a carrier. The prepared nanomicelles were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS), and then in vitro and in vivo studies were performed.Results: TEM shows that the nanomicelles are spherical with a diameter of about 19.41 nm, and DLS shows that the size, zeta potential, and polymer dispersity index of the nanomicelles were 23.37 nm, − 19.2 mV, and 0.221, respectively. The drug loading content is 8.28%. The in vivo study showed that the nanomicelles significantly reduced neuron degeneration, inhibited the inflammatory cell infiltration, reduced the brain edema, and improved neurological deficit. Furthermore, it was observed that the nanomicelles promoted the polarization of microglia/macrophages to M2 phenotype, and also the expression of the proinflammatory cytokines, such as IL-1β and TNF-α, was significantly down-regulated, while the expression of the anti-inflammatory cytokine IL-10 was significantly up-regulated. The related mechanism was proposed and discussed.Conclusion: The nanomicelles treatment suppressed the neuroinflammation that might contribute to the promoted nerve functional recovery of the ICH mouse, making it potential to be applied in clinic.Keywords: rosuvastatin, nanomicelles, neuroinflammation, intracerebral hemorrhage

Leorah Freeman,1 Arianna Kee,2 Marc Tian,2 Rina Mehta2 1Dell Medical School, The University of Texas at Austin, TX, USA; 2Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Leorah FreemanHealth Discovery Building, Dell Medical School, The University of Texas at Austin, 1601 Trinity Street, Austin, TX 78701, USATel + 1-512-495-5355Email leorah.freeman@austin.utexas.eduPurpose: Early diagnosis and treatment of multiple sclerosis (MS) with disease-modifying therapy (DMT) can reduce relapse number and severity, which has cost implications. We describe treatment patterns, healthcare utilization, and cost among MS patients newly initiating DMTs (index).Patients and Methods: DMT-naïve adults with 12 months’ continuous enrollment pre- and post-index and ≥ 2 MS claims (2009‒2018) were identified from the Optum Clinformatics Data Mart database. Treatment adherence and persistence were measured as time on index DMT. Relapses were identified using a validated claims-based algorithm. All-cause and MS-related healthcare expenditures and utilization were captured pre- and post-index. Outcomes were stratified by route of administration. Multivariate analyses assessed differences in outcomes and costs.Results: The analysis included 5906 MS patients (mean age, 46.6 years). The majority initiated injectable (63.5%) followed by oral (28.8%) and infusion (7.7%) DMTs. Post-index, 45.3% of patients were nonadherent and 39.4% were nonpersistent. Relapse rates decreased from pre- to post-index (oral: 24.3%‒16.1%; injectable: 25.0%‒17.1%; infusion: 29.3%‒15.5%). Post-index mean (SD) all-cause total costs were lowest with oral ($70,970 [$36,681]) vs injectable ($82,521 [$58,569]) and infusion ($80,871 [$49,627]) DMTs. MS-related total costs were lowest with oral ($65,149 [$65,133]) vs injectable ($76,197 [$60,204]) and infusion ($72,703 [$47,287]) DMTs. Multivariate analysis showed no differences between oral and injectable DMTs in adherence, persistence, or relapse rate; however, oral DMTs had significantly lower all-cause and MS-related costs.Conclusion: With similar outcomes across DMT administration routes, initiating the least costly DMT may be warranted for many patients. In newly treated MS patients, the need exists to improve adherence and persistence.Keywords: administrative claims, healthcare costs, treatment adherence and compliance, drug administration routes

Jiangping Yang,1,* Jiaqi Han,1,* Maolang Tian,1 Kun Tian,2 Wenjun Liao,1 Xi Yan3,4 1Department of Head and Neck Oncology and Department of Radiation Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 2Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 3Department of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 4Laboratory of Molecular Diagnosis of Cancer, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi YanDepartment of Head, Neck and Mammary Gland Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People’s Republic of ChinaTel +86 189 8060 1777Email yanxi@scu.edu.cnPurpose: Ribociclib has provided significant improvements in progression-free survival (PFS) and overall survival (OS) of postmenopausal patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). However, given the high cost of ribociclib, its value must be evaluated based on cost-effectiveness. Thus, we aimed to explore the cost-effectiveness of ribociclib for postmenopausal patients with HR-positive and HER2-negative ABC.Methods: A comprehensive Markov model was developed to estimate the cost-effectiveness of ribociclib plus fulvestrant versus placebo plus fulvestrant as first-line treatment for HR-positive, HER2-negative ABC. Variables were estimated based on data from the randomized Phase III MONALEESA-3 trial. Ten-year values were estimated for quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Direct treatment costs were estimated from the perspective of a United States payer. One-way and probabilistic sensitivity analyses were conducted to confirm the model’s robustness.Results: Ribociclib plus fulvestrant increased the treatment cost by $382,172 and provided 0.47 QALYs, relative to fulvestrant alone, which corresponded to an ICER of $813,132 per QALY. Sensitivity analyses revealed that ribociclib was unlikely to be cost-effective even under the most favorable assumptions. When the cost of ribociclib was 50% chance of cost-effectiveness at a willingness-to-pay threshold of $150,000/QALY. Subgroup analyses also confirmed that ribociclib was not cost-effective.Conclusion: At current drug prices in the United States, ribociclib is unlikely to be cost-effective for treating postmenopausal patients with HR-positive HER2-negative ABC. Despite the clinical benefits of ribociclib, its cost would need to decrease to provide more favorable economic outcomes.Keywords: cost-effectiveness, ribociclib, fulvestrant, breast cancer, hormone receptor positive

David L Kaplan,1 Brian L Ung,2 Corey Pelletier,2 Chuka Udeze,2 Ibrahim Khilfeh,3 Marc Tian2 1Adult & Pediatric Dermatology, Overland Park, Kansas, USA; 2US HEOR, Celgene Corporation, Summit, New Jersey, USA; 3US HEOR, Amgen Inc, Thousand Oaks, California, USACorrespondence: Corey Pelletier Email Corey.Pelletier@bms.comPurpose: Compare treatment switching rates and costs among biologic-naive psoriasis patients initiating apremilast or biologics.Methods: This retrospective claims analysis used IBM MarketScan Commercial and Medicare Supplemental databases to identify patients who initiated apremilast or a biologic (ie, tumor necrosis factor [TNF] or interleukin [IL] inhibitor) for psoriasis treatment between January 1, 2015, and December 31, 2016. A 1:1 propensity score matching was used to adjust for possible selection bias and maximize the number of patients available for analysis. Treatment switching, days to switch, and healthcare costs were assessed at 12 months. T-test and chi-square test were used to evaluate differences between cohorts for continuous and categorical variables as appropriate; Wilcoxon rank-sum tests were used to assess cost differences.Results: In total, 88,025 patients newly initiated apremilast, a TNF inhibitor, or an IL inhibitor. After inclusion/exclusion criteria were applied and patients were propensity score matched, 1645 (apremilast), 1207 (TNF inhibitor), and 438 (IL inhibitor) patients were included in this analysis. Twelve-month switch rates were significantly lower for apremilast initiators compared with TNF inhibitor initiators (14% vs 25%; p< 0.01) and comparable to IL inhibitors (14% vs 11%; p> 0.05). No statistical difference was observed in days to switch at 12 months for any treatment group. Total healthcare costs were lower for apremilast initiators compared with TNF and IL inhibitor initiators ($34,028 vs $55,973 and $64,430; p< 0.0001). Per-patient per-month (PPPM) costs were significantly lower for apremilast initiators compared with TNF inhibitor and IL inhibitor initiators ($2834 vs $4662 and $5366; p< 0.0001).Conclusion: Over a 12-month follow-up, biologic-naive psoriasis patients initiating apremilast had significantly lower switching rates compared with patients on TNF inhibitors and similar rates as patients on IL inhibitors. PPPM and total healthcare costs were significantly lower for patients initiating apremilast vs TNF or IL inhibitors, primarily due to lower pharmacy costs.Keywords: adherence, apremilast, healthcare costs, IL inhibitors, TNF inhibitors, treatment pattern

Ganhua You, 1, 2 Xiangshu Long, 3, 4 Fang Song, 3, 4 Jing Huang, 3, 4 Maobo Tian, 3, 4 Yan Xiao, 3, 4 Shiyan Deng, 3, 4 Qiang Wu 3, 4 1Guizhou University School of Medicine, Guiyang 550025, People’s Republic of China; 2Guizhou Institute for Food and Drug Control, Guiyang 550004, People’s Republic of China; 3Department of Cardiology, Guizhou Provincial People’s Hospital, Guiyang 550002, People’s Republic of China; 4Department of Cardiology, People’s Hospital of Guizhou University, Guiyang 550002, People’s Republic of ChinaCorrespondence: Qiang WuDepartment of Cardiology, Guizhou Provincial People’s Hospital, 83 Zhongshan East Road, Guiyang, Guizhou, People’s Republic of ChinaTel +86-0851-85937194Fax +86-0851-85924943Email wqgz0851@126.comBackground: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS.Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS.Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS.Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.Keywords: metformin, taurine up-regulated gene 1, AMPK/mTOR, autophagy, atherosclerosis

Wenjun Liao, Maolang Tian, Nianyong Chen Department of Radiation Oncology, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Nianyong ChenDepartment of Radiation Oncology, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of ChinaTel +86 28 8542 3278Fax +86 28 8542 2952Email n_ychen@hotmail.comAbstract: Nasopharyngeal carcinoma (NPC) is rare in Western countries, but its incidence in China and Southeast Asia is notably high. NPC shows a high rate of distant metastasis including metachronous metastasis (mmNPC, metastasis after definitive chemo-radiotherapy) and synchronous metastasis (smNPC, metastasis at initial diagnosis). 4–10% of patients would be diagnosed as smNPC annually, and the survival outcomes of these patients are quite poor. As with few clinical trials exclusively focusing on this population, treatment on smNPC is not unified and many problems remain unsolved. To date, systematic chemotherapy (CT) still remains a fundamental treatment in smNPC. Although no randomized trial has been conducted to compare different CT regimens in smNPC, gemcitabine and taxanes in combination with platinum seem optimal in first-line setting. In second-line CT, there is no consensus: mono-chemotherapy with drugs such as gemcitabine, taxanes or capecitabine could be taken into consideration. Immunotherapy based on checkpoint inhibitors shows promising efficacy both in first-line and in the following lines of therapy. In addition to CT, local therapy in smNPC is also very important. Locoregional radiotherapy (RT) for primary tumor in combination with CT could strikingly increase OS with acceptable toxicities. And local treatment, such as surgery and RT, for metastatic lesions could bring extra survival benefit in patients with solitary or limited metastases. Overall, the present study provides an overview of the literature on the various studies of smNPC.Keywords: nasopharyngeal carcinoma, radiotherapy, chemotherapy, immunotherapy, metachronous

Rui Ren,1,2 Yu Ma,2 Fang Deng,1 Tao Li,1 Hongyan Wang,2 Jing Wei,3 Xiaoyan Jiang,2 Min He,1 Mingyuan Tian,4 Dongfang Liu,4 Bing Chen,1 Wuquan Deng1,21Department of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, People’s Republic of China; 2Department of Endocrinology, Southwest Hospital, Army Medical University, Chongqing, People’s Republic of China; 3Department of Endocrinology, General Hospital of Xinjiang Military Region, PLA, Urumqi, People’s Republic of China; 4Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Wuquan DengDepartment of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, No. 1 Jiankang Road, Yuzhong District, Chongqing, People’s Republic of ChinaTel +86 236 369 2185Email wuquandeng@gmail.comBackground: Whether a relationship exists between various metabolic factors and thyroid-stimulating hormone (TSH) levels in euthyroid persons remains unknown. This study aims to explore the relationship between TSH levels and metabolic factors in euthyroid individuals.Methods: A total of 2,663 subjects were enrolled from a nationwide population-based cross-sectional survey of iodine nutrition, thyroid disease and diabetes in China (2014–2017). Euthyroid individuals were divided into four groups according to quartiles of TSH levels: group A (n=305, 0.3–1.3 mIU/L), group B (n=829, 1.3–2.2 mIU/L), group C (n=673, 2.2–3.2 mIU/L) and group D (n=349, 3.2–4.2 mIU/L). Anthropometric parameters, biochemical indicators and TSH levels were determined.Results: A total of 2,156 euthyroid subjects with serum TSH levels within the normal range accounted for 86.8% of the sample. The systolic blood pressure (SBP) in group D was significantly higher than that in the other three groups. Group C displayed significantly lower thyroid peroxidase antibody (TPOAb) levels than the other three groups. Group C also had lower anti-thyroglobulin antibody (TgAb) levels than groups A and D, whereas the TgAb levels in group B were only lower than those in group A. Spearman’s or Pearson’s linear regression analysis showed that SBP (r=0.054; P=0.013) was positively correlated with TSH, but cholesterol (TC) (r=−0.043, P=0.047) was negatively correlated with TSH. Multiple stepwise regression analysis revealed that SBP, the urinary iodine concentration (UIC), waist circumference (WC), body mass index (BMI), TC, triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-C) were independent predictors of serum TSH levels.Conclusion: This large population-based study demonstrates a significant interaction between metabolic factors and TSH levels. An adverse weight status, high blood pressure levels, blood lipid metabolism disorder and excessive iodine intake may be early manifestations of thyroid disease in euthyroid subjects.Keywords: thyroid-stimulating hormone, metabolic syndrome, iodine nutrition, euthyroid state

Lei Wan,1 Liu-Jia-Zi Shao,1 Yang Liu,2 Hai-Xia Wang,1 Fu-Shan Xue,1 Ming Tian11Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of ChinaPurpose: This study aimed to assess the effect of intravenous dexmedetomidine (DEX) on sevoflurane EC50 for supraglottic airway device (SAD) insertion in spontaneously breathing morbidly obese patients.Patients and methods: Thirty-eight morbidly obese patients with a body mass index 40–57 kg/m2, who were scheduled for bariatric surgery under general anesthesia requiring tracheal intubation were randomly allocated to two groups receiving the different treatments: group S, saline was given intravenously, and group D, a bolus dose of DEX 1 μg/kg was administered intravenously over 10 mins, followed by intravenous DEX infusion at a rate of 0.5 μg/kg/h. Five percent sevoflurane was initially inhaled for anesthesia induction and then end-tidal expiratory sevoflurane concentration (ETsev) was adjusted to a target value as to the modified Dixon’s up-and-down method. Patients’ response to SAD insertion was classified as “movement” or “no movement”. The average of the midpoints of all crossover points was defined as calculated sevoflurane EC50 for successful SAD insertion. Furthermore, the probit regression analysis was used to determine sevoflurane end-tidal concentrations where 50% (EC50) and 95% (EC95) insertions of SAD were successful. After the observation was completed, flexible bronchoscope-guided intubation was performed through the SAD.Results: The calculated sevoflurane EC50 for successful SAD insertion was significantly lower in group D than in group S (1.75±0.32% vs 2.92±0.26%, p

Li Zhang,1 Xinli Ding,2 Zhe Wu,3 Min Wang,1 Ming Tian1 1Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, 2Department of Rehabilitation Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, 3Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University, Beijing 100012, China Background: Cognitive impairment is a common complication in patients with chronic neuropathic pain, without effective therapy. Recent works have indicated that curcumin (Cur) possesses antinociceptive and neuroprotective potentials, suggesting its possible effectiveness for the treatment of this complication.Objective: The aim of this study was to explore the effects of Cur on pain behaviors and cognitive impairment in rats with cobra venom-induced trigeminal neuralgia (TN).Design: This is a randomized, controlled experiment.Setting: This study was conducted at the Experimental Animal Center, Beijing Friendship Hospital, Capital Medical University.Subjects: A total of 40 adult male Sprague Dawley rats were used in this study.Methods: A cobra venom solution was injected into the sheath of infraorbital nerve. Cur was administered intragastrically at 45 mg/kg twice daily for 28 successive days from postoperative day 15. Mechanical allodynia was evaluated using von Frey filaments. Free behaviors were observed using video recording. Cognitive capacity was tested using the Morris water maze. Both morphology and ultrastructure of the CA1 hippocampal region were visualized using hematoxylin and eosin (HE) staining and transmission electron microscopy, respectively.Results: Cur treatment reduced mechanical allodynia and face-grooming activities but increased exploratory activities and improved spatial learning and memory deficits. Microscopic examination revealed nucleus pyknosis, swollen organelles, and decreased synapse density in the CA1 hippocampal region after cobra venom injection. However, chronic Cur treatment reversed damage to hippocampal neurons and synapses.Conclusion: Cur can alleviate pain, improve spatial learning and memory deficits, and restore the damage to hippocampal neurons and synapses in cobra venom-induced TN rats. Cur may be useful as an adjuvant to treat chronic neuropathic pain-induced cognitive deficits. Keywords: curcumin, cognitive impairment, trigeminal neuralgia, cobra venom, hippocampus, ultrastructural changes

Jilong Wang,1,2,* Hubo Sun,1,2,* Peijun Meng,1,2 Mengmeng Wang,1,2 Mi Tian,3 Yamin Xiong,1,2 Xueying Zhang,1,2 Peili Huang1,2 1School of Public Health, Capital Medical University, 2Beijing Key Laboratory of Environmental Toxicology, 3Medical Experiment and Test Center, Capital Medical University, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Although quantum dot (QD)-induced toxicity occurs due to free radicals, generation of oxidative stress mediated by reactive oxygen species (ROS) formation is considered an important mechanism. However, free radical mechanisms are essentially difficult to elucidate at the molecular level because most biologically relevant free radicals are highly reactive and short-lived, making them difficult to directly detect, especially in vivo. Antioxidants play an important role in preventing or, in most cases, limiting the damage caused by ROS. Healthy people and animals possess many endogenous antioxidative substances that scavenge free radicals in vivo to maintain the redox balance and genome integrity. The antioxidant capacity of an organism is highly important but seldom studied. In this study, the dose and time effects of CdTe QDs on the antioxidant capacities of the liver and kidneys were investigated in mice using the electron paramagnetic resonance (EPR) spin-trapping technique. We found that the liver and kidneys of healthy mice contain specific antioxidant capacities that scavenge ·OH and ·O2-. Furthermore, oxidative stress markers (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], glutathione [GSH] and malondialdehyde [MDA]) were examined. In dose course studies, the free radical scavenging efficiencies of the liver and kidneys were found to gradually decrease with increasing concentration of CdTe QD exposure. The activities and levels of SOD, CAT, GPx and MDA were observed to increase in treated groups, whereas those of GSH were reduced. The time course studies revealed that the QD-induced antioxidant efficiency reduction was time dependent with GSH decrease and could recover after a period of time. These experimental results offer new information on QD toxicity in vivo. Specifically, CdTe QDs can deplete GSH to reduce the elimination ability of the liver and kidneys for ·OH and ·O2-, thus inducing oxidative damage to tissues. Keywords: quantum dot, antioxidative capacity, free radical elimination, hydroxyl radical, superoxide anion radical, spin-trapping

Purpose: With the rise of big data, deep learning neural networks have garnered attention from psychology researchers due to their ability to process vast amounts of data and achieve superior model fitting. We aim to explore the predictive accuracy of neural network models and linear mixed models in tracking data when subjective variables are predominant in the field of psychology. We separately analyzed the predictive accuracy of both models and conduct a comparative study to further investigate. Simultaneously, we utilized the neural network model to examine the influencing factors of problematic internet usage and its temporal changes, attempting to provide insights for early interventions in problematic internet use., Patients and Methods: This study compared longitudinal data of junior high school students using both a linear mixed model and a neural network model to ascertain the efficacy of these two methods in processing psychological longitudinal data., Results: The neural network model exhibited significantly smaller errors compared to the linear mixed model. Furthermore, the outcomes from the neural network model revealed that, when analyzing data from a single time point, the influences of seventh grade better predicted Problematic Internet Use in ninth grade. And when analyzing data from multiple time points, the influences of sixth, seventh, and eighth grades more accurately predicted Problematic Internet Use in ninth grade., Conclusion: Neural network models surpass linear mixed models in precision when predicting and analyzing longitudinal data. Furthermore, the influencing factors in lower grades provide more accurate predictions of Problematic Internet Use in higher grades. The highest prediction accuracy is attained through the utilization of data from multiple time points., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Tian et al.)

Purpose: This study aimed to assess the effect of intravenous dexmedetomidine (DEX) on sevoflurane EC 50 for supraglottic airway device (SAD) insertion in spontaneously breathing morbidly obese patients. Patients and methods: Thirty-eight morbidly obese patients with a body mass index 40-57 kg/m 2 who were scheduled for bariatric surgery under general anesthesia requiring tracheal intubation were randomly allocated to two groups receiving the different treatments: group S, saline was given intravenously, and group D, a bolus dose of DEX 1 μg/kg was administered intravenously over 10 mins, followed by intravenous DEX infusion at a rate of 0.5 μg/kg/h. Five percent sevoflurane was initially inhaled for anesthesia induction and then end-tidal expiratory sevoflurane concentration (ET sev ) was adjusted to a target value as to the modified Dixon's up-and-down method. Patients' response to SAD insertion was classified as "movement" or "no movement". The average of the midpoints of all crossover points was defined as calculated sevoflurane EC 50 for successful SAD insertion. Furthermore, the probit regression analysis was used to determine sevoflurane end-tidal concentrations where 50% (EC 50 ) and 95% (EC 95 ) insertions of SAD were successful. After the observation was completed, flexible bronchoscope-guided intubation was performed through the SAD. Results: The calculated sevoflurane EC 50 for successful SAD insertion was significantly lower in group D than in group S (1.75±0.32% vs 2.92±0.26%, p <0.001). By the probit regression analysis, EC 50 and EC 95 of sevoflurane for successful SAD insertion were 1.59% (95% CI, 1.22-1.90%) and 2.15% (95% CI, 1.86-3.84%) in group D, respectively, and 2.81% (95% CI, 2.35-3.29%) and 3.32% (3.02-6.74%) in group S. Conclusion: When sevoflurane inhalational induction is performed in spontaneous breathing morbidly obese patients, intravenous DEX can reduce sevoflurane EC 50 for successful SAD insertion by about 40%. Chinese Clinical Trial Registry: No. ChiCTR1800016868., Competing Interests: The authors report no conflicts of interest in this work.

Background: CD19-modified CAR-T cells greatly influence responses in patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, recurrence remains a challenge, and reinfusion of CAR-T cells is not always effective. Sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells may overcome this issue and induce remission., Methods: We examined treatment with sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells in a patient with relapsed ALL previously exposed to murine-derived anti-CD19 CAR-T cells., Results: At ~6 weeks after treatment, repeated bone marrow smear and flow cytometry analysis revealed no lymphoblasts., Conclusion: Our results suggest that sequential infusion of humanized CD19-modified and CD22-modified CAR-T cells is a valuable option for relapsed patients with prior infusion of murine-derived, CD19-directed CAR-T cells., Competing Interests: Disclosure The authors report no conflicts of interest in this work.