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Shaojie Li,1,* Qiangqiang Feng,1,* Jiayin Wang,1 Baofang Wu,1 Weizhi Qiu,1 Yiming Zhuang,2 Yong Wang,3 Hongzhi Gao1 1Department of Neurosurgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, People’s Republic of China; 2Internal Medicine, Quanzhou Quangang District Hillside Street Community Health Service Center, Quanzhou, Fujian, 362000, People’s Republic of China; 3Child and Adolescent Psychiatry, The Third Hospital of Quanzhou, Quanzhou, Fujian, 362000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong Wang; Hongzhi Gao, Email 120432246@qq.com; gaohongzhi@fjmu.edu.cnObjective: To develop a validated machine learning (ML) algorithm for predicting the risk of hospital-acquired pneumonia (HAP) in patients with traumatic brain injury (TBI).Materials and Methods: We employed the Least Absolute Shrinkage and Selection Operator (LASSO) to identify critical features related to pneumonia. Five ML models—Logistic Regression (LR), Extreme Gradient Boosting (XGB), Random Forest (RF), Naive Bayes Classifier (NB), and Support Vector Machine (SVC)—were developed and assessed using the training and validation datasets. The optimal model was selected based on its performance metrics and used to create a dynamic web-based nomogram.Results: In a cohort of 858 TBI patients, the HAP incidence was 41.02%. LR was determined to be the optimal model with superior performance metrics including AUC, accuracy, and F1-score. Key predictive factors included Age, Glasgow Coma Score, Rotterdam Score, D-dimer, and the Systemic Immune Response to Inflammation Index (SIRI). The nomogram developed based on these predictors demonstrated high predictive accuracy, with AUCs of 0.818 and 0.819 for the training and validation datasets, respectively. Decision curve analysis (DCA) and calibration curves validated the model’s clinical utility and accuracy.Conclusion: We successfully developed and validated a high-performance ML algorithm to assess the risk of HAP in TBI patients. The dynamic nomogram provides a practical tool for real-time risk assessment, potentially improving clinical outcomes by aiding in early intervention and personalized patient management.Keywords: traumatic brain injury, machine learning, hospital-acquired pneumonia, dynamic nomogram, imaging metrics

Yuya Wen,1 Chenling Zhao,1 Jie Chen,1 Liwei Tian,1 Bojin Wu,1 Wenting Xie,1 Ting Dong1,2 1Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, People’s Republic of China; 2Key Laboratory of Xin’An Medicine, Ministry of Education, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, People’s Republic of ChinaCorrespondence: Ting Dong, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, People’s Republic of China, Tel +13965107566, Email dongting2002@sina.comPurpose: Neuroinflammation is a main cause of neurological damage in Wilson’s disease (WD). Ferroptosis is present in the WD pathological process, which is also closely related to the neuroinflammation. LCN2, a ferroptosis-related gene in WD, is linked with the activation of NLRP3 inflammasome. Our group has previously demonstrated that Gandouling (GDL) can effectively improve neuroinflammation in WD. This study aims to investigate the protective effect of GDL on neuroinflammation in animal and cell models of WD, and whether the pharmacological mechanism is related to the LCN2/NLRP3 signaling pathway.Methods: Toxic milk (TX) mice and HT22 cells stimulated by copper ions were selected as models. The pathology of hippocampal tissues in TX mice were observed by HE staining and transmission electron microscopy. High-throughput sequencing analysis was conducted to screen ferroptosis-related genes in WD. The expression of LCN2 and GPX4 in hippocampus of TX mice were detected by immunohistochemical. The expression of LCN2, NLRP3, GPX4, and SLC7A11 was determined in TX mice and HT22 cells by Western blotting and RT-qPCR. The levels of Fe2+, inflammatory factor indicators TNF-α, IL-1β and IL-6 and oxidative stress indicators 4-HNE, MAD, SOD, GSH and ROS were detected in each group by ELISA.Results: The results showed that GDL ameliorated pathological and mitochondrial damages in hippocampus of TX mice. The analysis of bioinformatics showed that LCN2 was a differential gene associated with ferroptosis in WD. The results of Western blotting and RT-qPCR indicated that GDL reduced the expression of LCN2 and NLRP3, and enhanced the expression of GPX4 and SLC711 in TX mice and HT22 cells. The ELISA results showed that GDL decreased the expression of Fe2+ and inflammatory factors TNF-α, IL-1β and IL-6 in TX mice with ferroptosis inducer intervention and copper ion-loaded HT22 cells. GDL decreased the expression of oxidative stress indicators ROS, 4-HNE and MDA, and increased the expression of oxidative stress indicators GSH and SOD in TX mice and copper ion-loaded HT22 cells.Conclusion: GDL has anti-inflammatory and antioxidant effects. LCN2 is a differential gene associated with ferroptosis in WD. GDL may alleviate ferroptosis by inhibiting the LCN2/NLPR3 signaling pathway, thereby improving neuroinflammatory responses and exerting neuroprotective effects in WD. Keywords: neuroinflammation, ferroptosis, Wilson’s disease, LCN2, NLRP3

Peiru Li,1,* Wenjie Zhang,1,* Beibei Wu2 1Health Management Center, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjie Zhang; Beibei Wu, Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Jingkou District, Zhenjiang, Jiangsu Province, 212001, People’s Republic of China, Email zhangwj7878@163.com; 13775538037@163.comPurpose: Cardiac rehabilitation (CR) is a multidisciplinary intervention program aimed at enhancing the physical, psychological, and social functioning of patients with cardiovascular disease. Although CR is cost-effective and reduces mortality and readmission rates, and many patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) do not adhere to CR. This review aimed to synthesize the evidence on adherence to CR in patients with AMI after PCI (AMI-PCI).Patients and Methods: The review was conducted using the methodology proposed by the Joanna Briggs Institute (JBI) to guide reviews and reporting using the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extended for Scoping Reviews (PRISMA-ScR). We searched PubMed, Web of Science, CINAHL, Embase, Ovid, and Scopus databases, and two reviewers independently screened the abstracts and full texts of eligible studies against the inclusion and exclusion criteria. Disagreements were resolved in consultation with a third reviewer.Results: A total of 10 studies were included in the analysis. The results demonstrated that CR reduces the incidence of complications and improves the quality of life of patients with AMI-PCI. However, the CR adherence rate was low, and the factors affecting it are complex and varied, including age, sex, and employment status. Furthermore, interventions to improve adherence in patients with AMI-PCI mainly combined the internet-based interventions, including videoconferencing tele-training, with wearable device monitoring and intelligent management platform follow-up. All these interventions have shown promising results compared with routine care.Conclusion: Adherence to CR in patients with AMI-PCI is generally low, and CR adherence is affected by many factors; however, relevant research designs are rare and simple. Healthcare professionals should pay more attention to adherence to CR in this population and use a variety of interventions to improve it.Keywords: cardiac rehabilitation, adherence, acute myocardial infarction, PCI, scoping review

Ying Chen,1 Mengxia Yan,1 Haoyan Chen,1 Yanan Sheng,2 Zhenhua Wang,3 Bin Wu1 1Clinical Research Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, People’s Republic of China; 2Medical Affairs, Takeda (China) International Trading Company, Beijing, 100006, People’s Republic of China; 3Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201112, People’s Republic of ChinaCorrespondence: Bin Wu, Tel/Fax +86-21-68383427, Email scilwsjtu-wb@yahoo.comPurpose: Understanding the quality of life and the factors that influence it for patients with short bowel syndrome (SBS) and their caregivers is of utmost importance in order to enhance their well-being. Therefore, This study aimed to provide a comprehensive understanding of the impact of SBS on patients and their caregivers, as well as its associated factors, by synthesizing the available evidence.Methods: A systematic review of the literature was done using PubMed, Embase databases, CNKI, and ISPOR conference papers. Included articles were manually searched to identify any other relevant studies. Quality was assessed using appropriate Joanna Briggs Institute critical appraisal tools.Results: This review included 16 studies, comprising 15 observational studies and 1 randomized controlled trial. The findings revealed that the QoL of patients with SBS was lower than that of the general population regarding physical functioning and psychological domain. Meanwhile, caregivers experienced challenges in maintaining their QoL. The QoL of SBS patients was found to be influenced by various factors such as treatment, age, sex, stoma, and small intestine length. Among them, the treatment is the most noteworthy factor that can be effectively improved through external interventions.Conclusion: While numerous studies have provided insights into the compromised QoL experienced by individuals with SBS and their caregivers, there remains a scarcity of large-sample quantitative investigations examining the determinants of QoL. The existing body of literature on caregivers is also notably deficient.Keywords: caregiver, malabsorption, quality of life, short bowel syndrome, stoma, age

Mengnan Li,1,2,&ast; Xifeng Yang,1,2,&ast; Ru Li,1,2 Baofeng Wu,1,2 Jinxuan Hao,1,2 Yijie Qi,1,2 Tao Bai,1 Luyang Yang,1 Yi Zhang,3 Yunfeng Liu1,4 1Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2First Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China; 4Clinical Research Center of Endocrine and Metabolic Diseases in Shanxi Medical University, Taiyuan, Shanxi, 030001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunfeng Liu, Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China, Email nectarliu@163.com Yi Zhang, Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China, Email yizhang313@163.comPurpose: There is evidence that long-term vascular risk remains increased in patients with hyperthyroidism even after normalization of thyroid function, and the mechanisms that regulate this risk are unclear. The aim of this study was to assess how visceral fat area and subcutaneous fat area change after hyperthyroidism treatment, and to further explore the relationship between thyroid hormones, abdominal fat area (visceral fat area and subcutaneous fat area), and lipids.Patients and Methods: 50 patients with newly diagnosed Graves’ disease were selected. Anthropometric parameters (weight, height, body mass index, waist circumference, neck circumference), laboratory parameters (thyroid hormones, lipid metabolism indices), abdominal fat area (visceral fat area and subcutaneous fat area), and drug dose were collected. Measurements were made at baseline, 6 and 12 months after treatment. We used linear mixed-effects models for analysis.Results: The results showed that the following indexes changed significantly at different time points: visceral fat area, subcutaneous fat area, free triiodothyronine, free thyroxine, thyroid stimulating hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, body weight, neck circumference, body mass index, waist circumference, and drug dose (All P< 0.001). We found that free triiodothyronine and free thyroxine were significantly negatively associated with abdominal fat area (P< 0.01). There was no significant correlation between drug dose and abdominal fat area (P> 0.05). Total cholesterol and low-density lipoprotein were significantly positively associated with abdominal fat area (P< 0.01). However, high-density lipoprotein (P=0.06) was not correlated with abdominal fat area. Moreover, the results showed a significant negative correlation between thyroid hormones and lipids (P< 0.001).Conclusion: After anti-thyroid medicine treatment, patients had elevated visceral fat area and subcutaneous fat area and altered lipid profiles. These changes may be one of the reasons why metabolic and cardiovascular diseases remain increased after thyroid function is restored.Keywords: visceral fat area, subcutaneous fat area, thyroid hormones, lipids, Graves’ disease

Jiamin Cao, Feng Zhang, Haiyan Chen, Bingxuan Wu, Jiayang Yin, Changci Chenzhao, Wei Xiong Department of Ophthalmology, Central South University, Changsha City, People’s Republic of ChinaCorrespondence: Wei Xiong, Email weixiong420@csu.edu.cnBackground: Manifestations of thyroid-associated ophthalmopathy (TAO) vary greatly. Few tools and indicators are available to assess TAO, restricting personalized diagnosis and treatment.Aim: To identify an aptamer targeting thyroid-stimulating hormone receptor (TSHR) and utilize this aptamer to evaluate clinical activity in patients with TAO.Methods: An aptamer targeting TSHR was developed by exponential enrichment and systematic evaluation of TSHR ligands. After truncation and optimization, the affinity, equilibrium dissociation constant, and serum stability of this aptamer were evaluated. The affinity of the TSHR-targeting aptamer to isolated fibrocytes was assessed, as was aptamer internalization by fibrocytes. The mechanism of binding was determined by molecular docking. The correlation between disease manifestations and the percentage of TSHR-positive cells was assessed by correlation analysis.Results: The aptamer TSHR-21-42 was developed to bind to TSHR, with the equilibrium dissociation constant being 71.46 Kd. Isolated fibrocytes were shown to bind TSHR-21-42 through TSHR, with its affinity maintained at various temperatures and ion concentrations. TSHR-21-42 could compete with anti-TSHR antibody, both for binding site to TSHR and uptake by cells after binding. In addition, TSHR-21-42 could bind to leukocytes in peripheral blood, with this binding differing in patients with TAO and healthy control subjects. The percentage of TSHR-positive monocytes, as determined by binding of TSHR-21-42, correlated positively with clinical activity score in patients with TAO, indicating that TSHR-21-42 binding could assess the severity of TAO.Conclusion: This aptamer targeting TSHR may be used to objectively assess disease activity in patients with TAO, by evaluating the percentages of TSHR positive cells in peripheral blood.Keywords: thyroid-associated ophthalmopathy, thyroid-stimulating hormone receptor, aptamer, clinical activity score, precision medicine

Tianwen Lai,1,&ast; Chaole Luo,1,&ast; Yalian Yuan,2,&ast; Jia Fang,1,&ast; Yun Wang,1 Xiantong Tang,1 Lihuan Ouyang,1 Keyan Lin,1 Bin Wu,2 Weimin Yao,1 Ruina Huang1 1Department of Respiratory and Critical Care Medicine, the First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523121, People’s Republic of China; 2Respiratory Diseases Research Institute, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ruina Huang; Weimin Yao, Email wolidedd@163.com; yaoweimin@gdmu.edu.cnIntroduction: Chronic obstructive pulmonary disease (COPD), an incurable chronic respiratory disease, has become a major public health problem. The relationship between the composition of intestinal microbiota and the important clinical factors affecting COPD remains unclear. This study aimed to identify specific intestinal microbiota with high clinical diagnostic value for COPD.Methods: The fecal microbiota of patients with COPD and healthy individuals were analyzed by 16S rDNA sequencing. Random forest classification was performed to analyze the different intestinal microbiota. Spearman correlation was conducted to analyze the correlation between different intestinal microbiota and clinical characteristics. A microbiota-disease network diagram was constructed using the gut MDisorder database to identify the possible pathogenesis of intestinal microorganisms affecting COPD, screen for potential treatment, and guide future research.Results: No significant difference in biodiversity was shown between the two groups but significant differences in microbial community structure. Fifteen genera of bacteria with large abundance differences were identified, including Bacteroides, Prevotella, Lachnospira, and Parabacteroides. Among them, the relative abundance of Lachnospira and Coprococcus was negatively related to the smoking index and positively related to lung function results. By contrast, the relative abundance of Parabacteroides was positively correlated with the smoking index and negatively correlated with lung function findings. Random forest classification showed that Lachnospira was the genus most capable of distinguishing between patients with COPD and healthy individuals suggesting it may be a potential biomarker of COPD. A Lachnospira disease network diagram suggested that Lachnospira decreased in some diseases, such as asthma, diabetes mellitus, and coronavirus disease 2019 (COVID-19), and increased in other diseases, such as irritable bowel syndrome, hypertension, and bovine lichen.Conclusion: The dominant intestinal microbiota with significant differences is related to the clinical characteristics of COPD, and the Lachnospira has the potential value to identify COPD.Keywords: chronic obstructive pulmonary disease, intestinal microbiota, 16S rDNA sequencing, Lachnospira, gut-lung axis

Ru Li,1,2,&ast; Baofeng Wu,1,2,&ast; Minmin Han,1,2 Mengnan Li,1,2 Xifeng Yang,1,2 Jian Zhang,1,2 Yi Zhang,3 Yunfeng Liu1 1Department of Endocrinology, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2The First Clinical Medical College, Shanxi Medical University, Taiyuan, People’s Republic of China; 3Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunfeng Liu, Department of Endocrinology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan, People’s Republic of China, Tel +86 18703416196, Email nectarliu@163.com Yi Zhang, Department of Pharmacology, Shanxi Medical University, Taiyuan, People’s Republic of China, Email yizhang313@163.comAbstract: Uric acid (UA) is the end product of purine metabolism in the human, and the imbalance between production and excretion results in the disturbance of serum uric acid (SUA). There is evidence suggesting that pituitary-target gland hormones can affect UA metabolism through regulating the activity of xanthine oxidase and UA transporters. Related endocrine diseases including thyroid dysfunction, polycystic ovary syndrome, acromegaly and Cushing’s syndrome are often accompanied by elevated UA levels. In addition to the direct influence of abnormal hormones, obesity and insulin resistant play a pivotal role. Diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion also present with abnormal SUA levels due to the action of antidiuretic hormone. However, certain evidence within the population is disputed. This review summarized the effects of pituitary-target gland hormones on UA metabolism, and preliminarily described the related mechanisms, offering a theoretical foundation for assessing SUA in endocrine disorders as well as guiding its management.Keywords: uric acid, hyperuricemia, pituitary-target gland, endocrine disease, insulin resistant

Li Bao,1,2 Bowen Wu,3 Chunjing Yang,1,2 Xiqiao Xu,1,2 Zhengyuan Shi,1,2 Dechun Jiang1,2 1Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing, People’s Republic of China; 3Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRIST, Department of Automation, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Zhengyuan Shi; Dechun Jiang, Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi-Road, Haidian District, Beijing, 10038, People’s Republic of China, Tel +86-10-63926405 ; +86-10-63926723, Email shizhengyuan2980@bjsjth.cn; jdc@bjsjth.cnPurpose: Amino acids are the important metabolites in the body and play a crucial role in biological processes. The purpose of this study is to provide a profile of amino acids change in the serum of T2DM patients and identify potential biomarkers.Patients and Methods: In this study, we quantitatively determined the serum amino acid profiles of 30 T2DM patients and 30 healthy volunteers. T test and multivariate statistical analysis were used to identify candidate biomarkers with GraphPad Prism 9.5 software and MetaboAnalyst 5.0 on-line platform.Results: Thirty-four amino acids were quantified, and 19 amino acid levels differed significantly between T2DM and Healthy groups. Screened by the specific screening criteria (VIP> 1.0; P< 0.05; FC> 1.5, or FC< 0.67) in MetaboAnalyst 5.0 platform, 8 amino acids were identified as potential biomarkers. Pearson rank correlation test showed 14 differential amino acids were significantly correlated with T2DM-related physiological parameters.Conclusion: The results of this study provide theoretical basis for the subsequent development of dietary supplements for the prevention or treatment of T2DM and its complications.Keywords: diabetes mellitus type 2, T2DM, targeted metabolomics, amino acids, biomarker

Jin Lu,1,&ast; Yibo He,2,3,&ast; Yanfang Yang,1,&ast; Xuejing Zhong,1 Shaowen Chen,1 Bo Wu,1 Yuxiong Pan,1 Yizhang Wang,1 Jiaming Xiu,1 Yu Kang,3,4 Jin Liu,2,3 Yong Liu,2,3 Shiqun Chen,5 Kaihong Chen,1 Liling Chen1 1Department of Cardiology, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, People’s Republic of China; 2Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 3Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, People’s Republic of China; 4Department of Cardiology, Shantou University Medical College, Shantou, 515041, People’s Republic of China; 5Global Health Research Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science, Southern Medical University, Guangzhou, 510100, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liling Chen; Shiqun Chen, Tel +86 5973082105 ; +86 02083827812-10528, Fax +86 5972100500 ; +86 2083851483, Email chenliling19790206@163.com; shiqunchen@126.comBackground: The association between uric acid (UA) and contrast-induced acute kidney injury (CI-AKI) following coronary angiography (CAG) has been established. However, whether the association would vary with age remained undetermined.Methods: We performed the retrospective analysis based on the Cardio-renal Improvement II study, (ClinicalTrials.gov NCT05050877), which enrolled consecutive patients undergoing coronary angiography in 5 teaching hospitals in China from 2007 to 2020. The primary outcome was CI-AKI defined as the rise of serum creatinine (SCr) ≥ 0.5 mg/dL or 25% compared with the baseline value within 48 hours following CAG. The effect of age on the association between uric acid and CI-AKI was assessed by the logistic regression model.Results: A total of 36,550 patients (mean age 63.08± 5.6-year-old, 41.7% men) were included in the study. After adjusting for the confounders, the risk of CI-AKI between each quartile of uric acid was insignificant in the young group. In patients of the middle group, lower UA was associated with a lower risk of CI-AKI while higher UA was associated with a higher risk (Q1 OR: 0.853, 95% CI: 0.734– 0.993; Q4 OR: 1.797, 95% CI: 1.547– 2.09). In patients of the elder group, lower and higher UA were both associated with a higher risk of CI-AKI (Q1 OR: 1.247, 95% CI: 1.003– 1.553; Q4 OR: 1.688, 95% CI: 1.344– 2.124). The restricted cubic spline indicated a non-linear association between UA and CI-AKI in middle and elder age groups but a linear association in the young age group.Conclusion: The association between uric acid and CI-AKI vary in patients of different age. Patients with elder age should maintain a middle level of uric acid while patients with middle age should consider a lower level of uric acid to reduce the risk of CI-AKI. The level of UA was an insignificant risk factor for CI-AKI in young patients.Keywords: uric acid, coronary angiography, CI-AKI, age-related

Huimin Tian, Haitao Shang, Yichi Chen, Bolin Wu, Chunyue Wang, Xiaodong Wang, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email hrbchengwen@163.comBackground: Apoptosis resistance of hepatocellular carcinoma (HCC) often leads to treatment failure. Nonetheless, overcoming the resistance of HCC to apoptosis by inducing necroptosis of tumor cells to bypass the apoptotic pathway may be a promising treatment strategy. Sonodynamic therapy (SDT) has broad prospects in disease treatment because of its noninvasive characteristic and spatiotemporal control. The combination of SDT and shikonin in the treatment of HCC is expected to be a new tumor treatment method that can overcome apoptosis resistance.Methods: In this study, the antitumor effect was evaluated using normal liver cell line WRL68, HCC cell line HepG2 and HepG2 xenograft mouse models. Indocyanine green (ICG) was loaded on nanobubbles (NBs) to construct ICG-loaded nanobubbles (ICG-NBs). Combined sonosensitizer nanoplatforms with ultrasound (US) to achieve efficient SDT, the combination of SDT and shikonin in treating HCC can activate shikonin-induced necroptosis. As a result, tumor cells that produced apoptosis resistance were destroyed by necroptosis.Results: The results indicated a successful preparation of ICG-NBs with a uniform particle size of 273.0 ± 118.9 nm spherical structures. ICG-NB-mediated SDT, in combination with shikonin treatment, inhibited the viability, invasion, and migration of tumor cells. SDT + shikonin treatment group caused a substantial increase in necroptotic cells. The increased degree of tumor necrosis and the upregulated expression of receptor-interacting protein 3 kinase were observed in vivo studies, which indicated that the antitumor effect was accompanied by enhanced necroptosis in the SDT + shikonin treatment group.Conclusion: ICG-NB-mediated SDT combined with shikonin inhibits the growth of HCC by increasing the necroptosis of tumor cells. Therefore, this combination therapy is a promising treatment strategy against the specific cancer.Keywords: sonodynamic therapy, hepatocellular carcinoma, necroptosis, shikonin, sonosensitizer

Minghua Li,1,&ast; Jiawei Gui,1,&ast; Hao Wang,2 Jun An,3 Ruoqing Wu,1 Xiaotong Liu,1 Bo Wu,1 Hui Xiao1 1Department of Otolaryngology-Head and Neck Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150081, People’s Republic of China; 2Department of Otolaryngology-Head and Neck Surgery, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210019, People’s Republic of China; 3Department of Otolaryngology-Head and Neck Surgery, Xuzhou Central Hospital, Xuzhou, 221009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hui Xiao, Email 13946129836@163.comBackground: Laryngeal cancer was one of the most common malignancies of the head in those years. It has become one of the most common causes of death due to its high recurrence rate and high metastasis rate. It was well known that platelets, especially activated platelets, promote the proliferation, division, and invasion of tumor cells. Activated platelets promote cancer progression and metastasis. However, the prognostic value of platelet aggregation function in laryngeal cancer remains poorly understood. The purpose of this study was to investigate the predictive significance of platelet aggregation function in laryngeal cancer.Materials and Methods: Between January 2015 and December 2016, we conducted a retrospective analysis of 203 patients who were diagnosed with laryngeal cancer consecutively. The patients were stratified by platelet aggregation function into two groups: low “adenosine diphosphate induced light transmittance aggregometry (ADP-induced LTA) ≤ 15.1” and high (ADP-induced LTA > 15.1). Pathological tissues from different parts of the operation were collected and the pathologist determined the pathological type. We assessed the prognostic significance of platelet aggregation function using Kaplan-Meier curves and Cox regression.Results: The low cohort had a significantly higher lymphocyte count than the high cohort. Compared with the high cohort, the low cohort had significantly lower levels of platelet-to-lymphocyte ratio (PLR), ADP-induced LTA, and Interleukins (IL)-6. The ADP-induced LTA (hazard ratio, 1.212; P < 0.001) was independently related with 5-year overall survival rate.Conclusion: Patients with ADP-induced LTA > 15.1 experience poor outcomes. Platelet aggregation function, when elevated, could be a new prognostic indicator for laryngeal cancer.Keywords: laryngeal carcinoma, platelet aggregation function, platelet-to-lymphocyte ratio, inflammation, overall survival rate

Yanjun Gao,1,2 Yingge Li,1,2 Zheming Liu,1,2 Yi Dong,1,2 Siqi Yang,1,2 Bin Wu,1,3 Mengxia Xiao,1,4 Chen Chen,5 Yingmei Wen,1,2 Lei Chen,1 Haijuan Jiang,6 Yi Yao1,2 1Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 2Hubei Provincial Research Center for Precision Medicine of Cancer, Wuhan, 430200, People’s Republic of China; 3Department of Oncology, Huang-Gang Central Hospital, Huanggang, 438000, People’s Republic of China; 4Department of Oncology, Yichun People’s Hospital, Yichun, 336000, People’s Republic of China; 5Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 6Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of ChinaCorrespondence: Yi Yao, Email yaoyi2018@whu.edu.cnBackground: Activator of heat shock protein 90 (HSP90) ATPase Activity 1 (AHSA1) regulates proliferation, apoptosis, migration, and invasion of osteosarcoma and hepatocellular carcinoma (HCC). However, the novel mechanism of AHSA1 in the tumor biology of hepatocellular carcinoma (HCC) remains unclear.Methods: We analyzed AHSA1 expression in 85 pairs of clinical samples of HCC and the Cancer Genome Atlas database. The role of AHSA1 in HCC was proved by cell proliferation, colony formation, migration, cell cycle analysis in vitro, xenograft models and tumor metastasis assay in vivo, and bioinformatics.Results: High AHSA1 expression was demonstrated in HCC and associated with invasive depth, clinical stage, and poor overall survival of patients. Univariate Cox analysis confirmed that AHSA1 was an independent prognostic factor for patients with HCC. Meanwhile, AHSA1 upregulation promoted cell proliferation, colony formation, and cell migration in vitro and tumor cell proliferation and metastasis of HCC cells in vivo. AHSA1 upregulation increased the cell cycle transition from G1 to S phase by increasing the expression of cyclinD1, cyclinD3, and cyclin-dependent kinase 6(CD). Transforming growth factor beta 1 (TGF-β 1)-induced protein kinase B (Akt) signaling regulated the expression of downstream targets, including cyclinD1. AHSA1 expression was closely correlated with the expression of TGF-β, Akt, cyclinD1, cyclinD3, and CDK6 using the Gene Expression Profiling Interactive Analysis database. AHSA1 upregulation participated in HCC progression by regulating TGF-β/Akt-cyclinD1/CDK6 signaling.Conclusion: AHSA1 might serve as a biomarker for predicting the clinical outcome of patients with HCC. It is vital in tumor metastasis and disease progression of HCC and may facilitate the development of clinical intervention strategies against HCC.Keywords: AHSA1, AKT/cyclinD1/CDK6 signaling, cell cycle, hepatocellular carcinoma, TGF-&#x03B2

Xiaodong Wang, Chunyue Wang, Huimin Tian, Yichi Chen, Bolin Wu, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin Wu, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13313677182 ; +86 15663615088, Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnPurpose: Sonodynamic therapy (SDT) is a promising and significant measure for the treatment of tumors. However, the internal situation of hepatocellular carcinoma (HCC) is complex, separate SDT treatment is difficult to play a good therapeutic effect. Here, we used SDT combined with MG-132 to mediate apoptosis and autophagy of HCC cells to achieve the purpose of treatment of cancer.Methods: To determine the generated reactive oxygen species (ROS) and the change of mitochondrial membrane potential (ΔΨm), HepG2 cells were stained by 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) and 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide (JC-1) staining to determine the IR-820@NBs-mediated SDT to achieve HCC therapy through the mitochondrial pathway. Cell counting kit 8 (CCK-8) assay and flow cytometry were used to detect cell viability and apoptosis rate of HepG2 cells. Autophagy was detected by mCherry-GFP-LC3B fluorescence labeling. Chloroquine (Cq) pretreatment was used to explore the relationship between autophagy and apoptosis. To detect the ability of HepG2 cells migration and invasion, cell scratch assay and transwell assay were used.Results: The successfully prepared IR-820@NBs could effectively overcome the shortcomings of IR-820 and induce lethal levels of ROS by ultrasound irradiation. As a dual agonist of apoptosis and autophagy, MG-132 could effectively enhance the efficacy of SDT in the process of treating HCC. After pre-treatment with Cq, the cell activity increased and the level of apoptosis decreased, which proved that apoptosis and autophagy were induced by combined therapy, autophagy, and apoptosis have the synergistic anti-tumor effect, and part of apoptosis was autophagy-dependent. After combined therapy, the activity and invasive ability of HCC cells decreased significantly.Conclusion: SDT combined with MG-132 in the process of treating liver cancer could effectively induce apoptosis and autophagy anti-tumor therapy, which is helpful to the research of new methods to treat liver cancer.Keywords: sonodynamic therapy, MG-132, apoptosis, autophagy, hepatocellular carcinoma

Yichi Chen,1– 3 Bolin Wu,1– 3 Haitao Shang,1– 3 Yucao Sun,1– 3 Huimin Tian,1– 3 Huajing Yang,1– 3 Chunyue Wang,1– 3 Xiaodong Wang,1– 3 Wen Cheng1– 3 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 3Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin, 150081, People’s Republic of ChinaCorrespondence: Wen Cheng, Department of Ultrasound, Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of China, Tel +86 13313677182, Fax +86 451 85718392, Email chengwen@hrbmu.edu.cnBackground: Despite the clinical efficacy of immunotherapy in treating malignant tumors, its effectiveness is often hampered by the immunosuppressive nature of the tumor microenvironment (TME). In this study, we propose the design of a nanoscale ultrasound contrast agent capable of triggering macrophage polarization and immunogenic cell death (ICD) for the treatment of hepatocellular carcinoma (HCC) through sonodynamic treatment (SDT) and immunotherapy.Methods: The re-educator (designated as ICG@C3F8-R848 NBs) is composed of the Toll-like receptor agonist resiquimod (R848) and the sonosensitizer Indocyanine green (ICG), utilizing nanobubbles (NBs) as carriers. The technique known as ultrasound-targeted nanobubble destruction (UTND) employs nanosized microbubbles and low-frequency ultrasound (LFUS) to ensure accurate drug delivery and enhance safety.Results: Following intravenous delivery, ICG@C3F8-R848 NBs have the potential to selectively target and treat primary tumors using SDT in conjunction with ultrasonography. Importantly, R848 can enhance antitumor immunity by inducing the polarization of macrophages from an M2 to an M1 phenotype.Conclusion: The SDT-initiated immunotherapy utilizing ICG@C3F8-R848 NBs demonstrates significant tumor suppression effects with minimal risk of systemic toxicity. The utilization of this self-delivery re-education technique would contribute to advancing the development of nanomedicine for the treatment of hepatocellular carcinoma.Keywords: hepatocellular carcinoma, synergistic sono-immunotherapy strategy, tumor-associated-macrophage

Lijuan Zhang,1,2 Weiyi Zhu,1 Beiwen Wu1 1Department of Nursing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2School of Nursing, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Beiwen Wu, Department of Nursing, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Ruijin Er Road, Shanghai, 200025, People’s Republic of China, Tel +86 18917762079, Fax +86 54314096, Email Gaoan2005new@163.comBackground: This study aimed to examine how personality traits, social support and clinical features including pain, disease activity, functional status, sleep quality, and fatigue influence on depressive symptoms in Chinese rheumatoid arthritis (RA) patients.Methods: This study was conducted from November, 2022 to June, 2023 among Chinese RA patients. Pain, disease activity, functional status, sleep quality, fatigue, social support, personality traits, and depressive symptoms were assessed. The following relationships among three hypotheses were analyzed by structural equation model (SEM): H1: clinical features have a direct effect on depressive symptoms; H2: personality traits might work as a mediator between clinical features and depression; H3: social support is related to depressive symptoms, being a direct effect or an indirect effect through clinical features or personality traits.Results: The final model including 326 RA patients presented a good fit (χ2=103, χ2/df=1.69; GFI=0.96; AGFI=0.93; CFI=0.97; TLI=0.96; RMSEA=0.046). Clinical features had a total effect of 0.59 on depressive symptoms, of which β=0.33 (P=0.013) was an indirect effect through personality traits, indicating a mediating influence between this relationship; moreover, there was a significant direct association between clinical features and depressive symptoms (β=0.26; P=0.022). Personality traits (β=− 0.65; P< 0.001) had a much stronger relation with depressive symptoms than with clinical features. Social support had a total effect of 0.81 on personality traits, being a direct effect of β=0.52 (P< 0.001) and an indirect effect of β=0.29 (P< 0.001) through clinical features. The final proposed model explained 77% of the variance of depressive symptoms.Conclusion: Personality traits had a considerable influence upon depressive symptoms, while social support seemed to have a major effect on personality traits. It is necessary to apply comprehensive assessment and interventions of patients’ personality traits, clinical features, as well as social support, which could optimize their mental health.Keywords: rheumatoid arthritis, depressive symptoms, structural equation model, personality traits

Yongzhen Zhou,1,2,&ast; Chenjie Qiu,3,&ast; Qingsheng Fu,2 Tao Li,1 Xudong Zhang,1 Chunfu Zhu,1 Xihu Qin,1 Baoqiang Wu1,2 1Department of General Surgery, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, People’s Republic of China; 2Graduate School, Bengbu Medical College, Bengbu, 233003, People’s Republic of China; 3Department of General Surgery, Changzhou Hospital of Traditional Chinese Medicine, Changzhou, 213000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baoqiang Wu, Email yddf999@163.comBackground: RAD54L is a prominent member of the SWI2/SNF2 protein family, primarily involved in the homologous recombination repair (HRR) process, thereby playing a pivotal role in the repair of DNA double-strand breaks (DSBs). RAD54L has been implicated in the development of numerous tumors. Consequently, we aimed to investigate the potential contribution of RAD54L in pan-cancer.Methods: Various databases and analytical tools were employed for bioinformatics analysis. Moreover, in vitro experiments were conducted to corroborate the findings from the bioinformatics analysis and delve deeper into the role of RAD54L in hepatocellular carcinoma (HCC).Results: RAD54L expression demonstrated a significant elevation in the majority of tumors, and its overexpression was strongly associated with unfavorable survival outcomes. RAD54L displayed robust correlations with the infiltration levels of various immune cells, including cancer associated fibroblasts (CAFs), endothelial cells, and myeloid-derived suppressor cells (MDSCs). Additionally, associations were observed between RAD54L and key factors such as tumor mutation burden (TMB), microsatellite instability (MSI), multiple immune checkpoints, and immune cell infiltration. Moreover, a close relationship was observed between RAD54L expression levels in HCC and clinicopathological characteristics, as well as immune cell infiltration. Experimental techniques including qRT-PCR, Western blotting, colony-forming, Cell Counting Kit-8 (CCK-8), wound-healing, and transwell assays were employed, which collectively demonstrated that RAD54L promoted the proliferation and migration of HCC cells.Conclusion: RAD54L exhibits robust expression in both pan-cancer and HCC, exerting a significant influence on the proliferation and migration of HCC cells. These findings highlight its potential as a promising biomarker for pan-cancer and a prospective target for immunotherapy.Keywords: RAD54L, pan-cancer, tumor microenvironment, malignant behavior

Jingyi Li,1,2 Haowen Luo,1 Yongsen Chen,1,2 Bin Wu,1,2 Mengqi Han,1,2 Weijie Jia,1,2 Yifan Wu,1,2 Rui Cheng,1,2 Xiaoman Wang,1,2 Jingyao Ke,1,2 Hongfei Xian,1,2 JianMo Liu,1 Pengfei Yu,1 Jianglong Tu,3 Yingping Yi1 1Department of Medical Big Data Research Centre, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2School of Public Health, Nanchang University, Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of ChinaCorrespondence: Yingping Yi, Department of Medical Big Data Research Centre, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, Nanchang, 330006, People’s Republic of China, Email yyp66@126.com Jianglong Tu, Department of Neurology, The Second Affiliated Hospital of Nanchang University, 1 MinDe Road, Nanchang, 330006, People’s Republic of China, Email Tujianglong85@126.comPurpose: To investigate the predictive value of various inflammatory biomarkers in patients with acute ischemic stroke (AIS) and evaluate the relationship between stroke-associated pneumonia (SAP) and the best predictive index.Patients and Methods: We calculated the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), prognostic nutritional index (PNI), systemic inflammation response index (SIRI), systemic immune inflammation index (SII), Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS), and prognostic index (PI). Variables were selectively included in the logistic regression analysis to explore the associations of NLR, PLR, MLR, PNI, SIRI, SII, GPS, mGPS, and PI with SAP. We assessed the predictive performance of biomarkers by analyzing receiver operating characteristic (ROC) curves. We further used restricted cubic splines (RCS) to investigate the association. Next, we conducted subgroup analyses to investigate whether specific populations were more susceptible to NLR.Results: NLR, PLR, MLR, SIRI, SII, GPS, mGPS, and PI increased significantly in SAP patients, and PNI was significantly decreased. After adjustment for potential confounders, the association of inflammatory biomarkers with SAP persisted. NLR showed the most favorable discriminative performance and was an independent risk factor predicting SAP. The RCS showed an increasing nonlinear trend of SAP risk with increasing NLR. The AUC of the combined indicator of NLR and C-reactive protein (CRP) was significantly higher than those of NLR and CRP alone (DeLong test, P< 0.001). Subgroup analyses suggested good generalizability of the predictive effect.Conclusion: NLR, PLR, MLR, PNI, SIRI, SII, GPS, mGPS, and PI can predict the occurrence of SAP. Among the indices, the NLR was the best predictor of SAP occurrence. It can therefore be used for the early identification of SAP.Keywords: stroke-associated pneumonia, acute ischemic stroke, inflammation, prediction

Xin Yao,1 Qingyu Wang,1 Changge Han,1 Jiaojiao Nie,1 Yaotian Chang,1 Lipeng Xu,1 Bingya Wu,1 Jingtian Yan,1 Zhiyuan Chen,1 Wei Kong,1,2 Yuhua Shi,1 Yaming Shan1,2 1National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, 130012, People’s Republic of China; 2Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin, 130012, People’s Republic of ChinaCorrespondence: Yaming Shan, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, 130012, People’s Republic of China, Tel +86 133 2446 4361, Email shanym@jlu.edu.cnIntroduction: Broadly neutralizing antibodies (bNAbs) have the ability to neutralize a considerable breadth of genetically diverse human immunodeficiency virus (HIV) strains. Passive immunization can potentially provide protection against HIV infection in animal models. However, the direct antibody infusion effect is limited due to the short half-life and deficient immunogenicity of the antibody. As an alternative strategy, we propose the use of nano viral vectors, specifically the adeno-associated virus (AAV), to continuously and systematically produce bNAbs against HIV.Methods: Plasmids expressing bNAbs PG9, PG16, 10E8, and NIH45-46 antibodies were constructed, targeting three different epitopes of HIV. Additionally, the bNAbs gene mediated by rAAV8 was administered to generate long-term expression with a single injection. We established both single and combined immunization groups. The neutralizing activity of antibodies expressed in mice sera was subsequently evaluated.Results: The expression of bNAbs in BALB/c mice can last for > 24 weeks after a single intramuscular injection of rAAV8. Further studies show that neutralization of the HIV pseudovirus by sera from co-immunized mice with rAAV8 expressing 10E8 and PG16 was enhanced compared with mice immunized with 10E8 or PG16 alone.Conclusion: The prolonged expression of neutralizing antibodies can be maintained over long periods in BALB/c mice. This combined immunization is a promising candidate strategy for HIV treatment.Graphical Abstract: Keywords: AAV delivery, HIV therapy, passive immunotherapy, combined immunotherapy

Jia Dong,1 Bin Wu,1 Weidong Tian2,3 1Department of Stomatology, People’s Hospital of Longhua Shenzhen, Shenzhen, Guangdong, People’s Republic of China; 2State Key Laboratory of Oral Disease, Engineering Research Center of Oral Translational Medicine, Ministry of Education, West China School of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3National Engineering Laboratory for Oral Regenerative Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Jia Dong; Weidong Tian, Email scu2013dongjia@sina.com; drtwd@sina.comPurpose: A lot of strategies have been attempted to achieve high-quality skin wound healing, among them, fat transplantation has been used for skin wound repair and scar management and has shown beneficial effects. However, the underlying mechanism is still unclear. Recently, studies found that transplanted cells underwent apoptosis within a short period and apoptotic extracellular vesicles (ApoEVs) might play the therapeutic role.Methods: In this study, we directly isolated apoptotic extracellular vesicles from adipose tissue (ApoEVs-AT) and evaluated their characteristics. In vivo, we investigated the therapeutic role of ApoEVs-AT in full-thickness skin wounds. The rate of wound healing, the quality of granulation tissue, and the area of scars were evaluated here. In vitro, we investigated the cellular behaviors of fibroblasts and endothelial cells induced by ApoEVs-AT, including cellular uptake, proliferation, migration, and differentiation.Results: ApoEVs-AT could be successfully isolated from adipose tissue and possessed the basic characteristics of ApoEVs. In vivo, ApoEVs-AT could accelerate skin wound healing, improve the quality of granulation tissue, and reduce the area of scars. In vitro, ApoEVs-AT could be engulfed by fibroblasts and endothelial cells, significantly enhancing their proliferation and migration. Moreover, ApoEVs-AT could promote adipogenic differentiation and inhibit the fibrogenic differentiation of fibroblasts.Conclusion: These findings indicated that ApoEVs could be successfully prepared from adipose tissue and showed the ability to promote high-quality skin wound healing by modulating fibroblasts and endothelial cells.Keywords: apoptotic extracellular vesicles, adipose tissue, skin wound healing, fibroblasts, endothelial cells

Xiaohui Wang,1,&ast; Bo Wu,2,&ast; Guogen Sun,3 Wenxi He,4 Jia Gao,1 Teng Huang,1 Jing Liu,1 Qing Zhou,1 Xiaoyu He,5 Shu Zhang,1 Zixiong Zhang,2 He Zhu1 1The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, Hubei, People’s Republic of China; 2The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Selenium and Human Health Institute, Enshi, Hubei, People’s Republic of China; 3Hubei Selenium and Human Health Institute, Enshi, Hubei, People’s Republic of China; 4Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 5Branch of National Clinical Research Center for Metabolic Diseases, Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zixiong Zhang, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Hubei Selenium and Human Health Institute, No. 158, Muyang Avenue, Enshi, Hubei, People’s Republic of China, Email 596099670@qq.com He Zhu, The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, No. 1095 Jiefang Avenue, Wuhan, Hubei, People’s Republic of China, Email Zhuh@tjh.tjmu.edu.cnPurpose: Pancreatic adenocarcinoma (PAAD) presents an extremely high morbidity and mortality rate. Broccoli has excellent anti-cancer properties. However, the dosage and serious side effects still limit the application of broccoli and its derivatives for cancer therapy. Recently, extracellular vesicles (EVs) derived from plants are emerging as novel therapeutic agents. Thus, we conducted this study to determine the effectiveness of EVs isolated from Se-riched broccoli (Se-BDEVs) and conventional broccoli (cBDEVs) for the treatment of PAAD.Methods: In this study, we first isolated Se-BDEVs and cBDEVs by a differential centrifugation method, and characterized them by using nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Then, miRNA-seq was combined with target genes prediction, and functional enrichment analysis to reveal the potential function of Se-BDEVs and cBDEVs. Finally, the functional verification was conducted in PANC-1 cells.Results: Se-BDEVs and cBDEVs exhibited similar characteristics in size and morphology. Subsequent miRNA-seq revealed the expression of miRNAs in Se-BDEVs and cBDEVs. Using a combination of miRNA target prediction and KEGG functional analysis, we found miRNAs in Se-BDEVs and cBDEVs may play an important role in treating pancreatic cancer. Indeed, our in vitro study showed that Se-BDEVs had greater anti-PAAD potency than cBDEVs due to increased bna-miR167a_R-2 (miR167a) expression. Transfection with miR167a mimics significantly induced apoptosis of PANC-1 cells. Mechanistically, further bioinformatics analysis showed that IRS1, which is involved in the PI3K-AKT pathway, is the key target gene of miR167a.Conclusion: This study highlights the role of miR167a transported by Se-BDEVs which could be a new tool for counteracting tumorigenesis.Graphical Abstract: Keywords: selenium, broccoli, extracellular vesicles, apoptosis, pancreatic cancer

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

Bangqi Wu,1,&ast; Yi Ding,1,2,&ast; Maohan Peng,1,2,&ast; Xuhui Wang,1 Yibing Li,1,2 Xinyue Cheng1,2 1First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China; 2Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bangqi Wu, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 88, Changling Road, Xiqing District, Tianjin, 300381, People’s Republic of China, Tel +8613622026323, Fax +86-022-27982908, Email wbqwbq1980@outlook.comBackground: Limb motor disorders after stroke are very common, and the clinical related factors of improving limb motor function are still unclear. As a part of comprehensive rehabilitation strategy, acupuncture has been widely used in rehabilitation after stroke in China. But more evidence is needed for the influence of acupuncture and some other clinical factors on post-stroke motor disorders.Patients and Methods: A retrospective study was conducted using the database of patients with post-stroke motor disorders admitted to the Neurological Rehabilitation Unit of the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine. The included patients were grouped according to whether NIHSS improved or muscle strength improved. The positive logistic regression was used to analyze the influencing factors of possible NIHSS improvement. Combined with the influencing factors of NIHSS improvement and muscle strength improvement, the influencing factors of limb motor function recovery after stroke were obtained.Results: When analyzing the baseline of the included patients, it was found that patients with NIHSS improvement had earlier acupuncture intervention time (M, (IQR):13.5 (14), OR=0.716, 95% CI [0.591– 0.869], p=0.001), more cumulative acupuncture treatment times (M,(IQR):29 (12), OR=0.744, 95% CI [0.608– 0.910], p=0.004), and less hypertension history (OR=0.256, 95% CI [0.082– 0.801], p=0.019). Smoking history only has positive significance in univariate and multivariate analysis of NIHSS, not muscle strength (OR=0.274, 95% CI [0.097– 0.779], p=0.015).Conclusion: The earlier acupuncture intervention and the more cumulative acupuncture treatment times are, the more beneficial the limb function of stroke patients with motor disorders will be. The previous history of hypertension is the influencing factor of limb motor function not improving in patients with limb motor disorder after a stroke. The effect of smoking history on limb movement function of patients with limb motor disorder after stroke needs further study.Keywords: acupuncture, stroke, limb motor disorder, retrospective study, influencing factors

Yuxuan Xu,&ast; Zhihui Lin,&ast; Chenxi Zhu,&ast; Dongyan Song, Bosen Wu, Kangting Ji, Jin Li Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kangting Ji; Jin Li, Department of Cardiology, Key Laboratory of Panvascular Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Xueyuanxi Road, No. 109, Wenzhou, 325027, People’s Republic of China, Tel/Fax +86-577-85676627, Email jikt@wmu.edu.cn; lijin1982@wzhealth.comObjective: The present study aimed to evaluate the relationship between all-cause mortality and the neutrophil percentage-to-albumin ratio (NPAR) in patients with atrial fibrillation (AF).Methods: We obtained clinical information from patients with AF from the Medical Information Mart for Intensive Care-IV version 2.0 (MIMIC-IV) database and the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University (WMU). The clinical endpoints were all-cause death measured at 30-day, 90-day, and one-year intervals. For endpoints associated with the NPAR, logistic regression models were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Receiver operating characteristic (ROC) curves and area under the curve (AUC) were developed to compare the ability of different inflammatory biomarkers to predict 90-day mortality in patients with AF.Results: Higher NPAR was associated with a higher risk of 30-day (OR 2.08, 95% CI 1.58– 2.75), 90-day (OR 2.07, 95% CI 1.61– 2.67), and one-year mortality (OR 1.60, 95% CI 1.26– 2.04) in patients with AF in 2813 patients from MIMIC-IV. The predictive performance of NPAR (AUC = 0.609) for 90-day mortality was better than that of neutrophil-to-lymphocyte ratio (NLR) (AUC = 0.565, P < 0.001), and platelet-to-lymphocyte ratio (PLR) (AUC = 0.528, P < 0.001). When NPAR and sequential organ failure assessment (SOFA) were combined, the AUC increased from 0.609 to 0.674 (P < 0.001). Higher NPAR was associated with a higher risk of 30-day mortality (OR 2.54, 95% CI 1.02– 6.30) and 90-day mortality (OR 2.76, 95% CI 1.09– 7.01) in 283 patients from WMU.Conclusion: An increased 30-day, 90-day, and one-year mortality risk among patients with AF were linked to a higher NPAR in MIMIC-IV. NPAR was thought to be a good predictor of 90-day all-cause mortality. Higher NPAR was associated with a higher risk of 30-day and 90-day mortality in WMU.Keywords: atrial fibrillation, neutrophil percentage-to-albumin ratio, mortality, inflammatory biomarker

Yubei Xiao,1 Mingfan Liu,2 Biyun Wu2 1SILC Business School, Shanghai University, Shanghai, 201899, People’s Republic of China; 2Center of Mental Health Education and Research, School of Psychology, Jiangxi Normal University, Nanchang, 330022, People’s Republic of ChinaCorrespondence: Mingfan Liu, Center of Mental Health Education and Research, School of Psychology, Jiangxi Normal University, 99 Ziyang Avenue, Nanchang, 330022, People’s Republic of China, Tel +86 13437080905, Email lmfxub@163.comPurpose: With the rise of social media, an increasing number of young females have focused more attention on their body image, leading to social appearance anxiety. Thus, the current study aimed to investigate a moderated mediation model of social appearance anxiety and online impulse purchases of fashionable outfits through self-control moderated by subjective socioeconomic status during the pandemic.Methods: A total of 1651 female college students (Age = 17– 24, Mage = 19.30, SD = 1.14) with more than one month of closed-off management experience completed self-report questionnaires concerning social appearance anxiety, self-control, online impulse purchases of fashionable outfits, and subjective socioeconomic status.Results: After controlling for the potential influence of coronavirus stress, the results indicated that social appearance anxiety was positively related to online impulse purchases of fashionable outfits among female college students during the pandemic, mediated by self-control. Furthermore, subjective socioeconomic status moderated the indirect link between social appearance anxiety and the online impulse purchase of fashionable outfits. Specifically, subjective socioeconomic status buffers the negative effect of social appearance anxiety on self-control and the risk effect of low self-control on the online impulse purchases of fashionable outfits.Implications: The current study deepens the research on the relationship between social appearance anxiety and online impulse purchases during pandemic periods; meanwhile, it provides evidence for preventing excessive online impulse purchases of fashionable outfits among young females.Keywords: social appearance anxiety, self-control, online impulse purchases, fashionable outfits, subjective socioeconomic status, pandemic periods

Yitian Lang,1 Bin Wu,2 Xiaoyan Liu1 1Department of Pharmacy, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Medical Decision and Economic Group, Department of Pharmacy, Ren Ji Hospital, South Campus, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of ChinaCorrespondence: Xiaoyan Liu, Department of Pharmacy, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 58 Puyu East Roa, Huangpu Districtd, Shanghai, 200011, People’s Republic of China, Email liuxiaoyanrj@sjtu.edu.cnPurpose: Recently, the DESTINY-Breast04 trial revealed that significant benefits in both overall survival (OS) and progression-free survival (PFS) in patients with HER2-low advanced or metastatic breast cancer treated with trastuzumab deruxtecan (T-DXd) compared with chemotherapy. The current study assessed the cost-effectiveness of T-DXd from the perspective of the United States payer.Methods: We developed a partitioned survival model to project the disease course of breast cancer. The OS and PFS data were derived from the DESTINY-Breast04 trial. We extrapolate the survival data beyond the follow-up time to assess the long-term survival prognosis. Direct medical costs and utility data were collected. The incremental cost-utility ratio (ICUR) was the primary outcome that evaluated the cost-effectiveness of a therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty of outputs.Results: In the base-case, the ICUR of T-DXd versus chemotherapy is &dollar;346,571.8/QALY and &dollar;337,789.4/QALY for all patients group and hormone-receptor-positive (HR+) subgroup, respectively. One-way sensitivity analyses revealed that the hazard ratio of OS, the unit cost of T-DXd, and body weight had a relatively large impact on the base-case result. Probabilistic sensitivity analyses showed that the likelihood that T-DXd was cost-effective is 14.5% and 12.6% for all patients group and HR+ subgroup, respectively.Conclusion: The cost-effectiveness analysis suggested that, at current price, trastuzumab deruxtecan is unlikely to be a preferred option for patients with HER2-low breast cancer at a threshold of &dollar;150,000/QALY from a US payer perspective.Keywords: cost-effectiveness, HER2-low breast cancer, trastuzumab deruxtecan, partitioned survival approach

Jie Bai,1– 3,&ast; Bibo Wu,1– 3,&ast; Shasha Zhao,1– 3,&ast; Gang Wang,1– 3,&ast; Shengfa Su,1– 3 Bing Lu,1– 3 Yinxiang Hu,1– 3 Yichao Geng,1,3 Zhengneng Guo,1– 3 Jun Wan,2,3 Weiwei OuYang,1– 3 Cheng Hu,1– 3 Jie Liu1– 3 1Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 2Department of Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 3Department of Oncology, School of Clinical Medicine, Guizhou Medical University, Guiyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shengfa Su, Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China, Tel +8613608550432, Fax +86513076, Email sushengfa2005@163.comPurpose: To explore the effect of PD-1 inhibitors combined with irradiation on myocardial injury and the changes of HMGB1-associated inflammatory markers.Methods: Four groups of five mice were used, each groupformed by randomly dividing 20 mice (group A control; group B PD-1 inhibitors; group C Irradiation; group D PD-1 inhibitors+irradiation; n = 5 for each). The mice were treated with either PD-1 inhibitors or a 15 Gy dose of single heart irradiation, or both. Hematoxylin-eosin staining assessed the morphology and pathology of heart tissue; Masson staining assessed heart fibrosis; Tunel staining evaluated heart apoptosis; flow cytometry detected CD3+, CD4+, and CD8+ T lymphocytes in heart tissues; enzyme linked immunosorbent assay evaluated IL-1β, IL-6, and TNF-ɑ of heart tissue; Western blot and quantitative real-time PCR (qPCR) detected the expression of protein and mRNA of HMGB1, TLR-4, and NF-κB p65 respectively.Results: The degree of heart injury, collagen volume fraction (CVF) and apoptotic index (AI) in groups B, C, and D were higher than group A, but the differences between the CVF and AI of group A and group B were not statistical significance (P> 0.05). Similarly, the absolute counts and relative percentage of CD3+ and CD8+ T lymphocytes and the concentrations of IL-1β, IL-6, and TNF-α in heart tissue with group D were significantly higher than the other groups (P< 0.05). In addition, compared with group A, the expression of protein and mRNA of HMGB1 and NF-κB p65 in other groups were higher, and the differences between each group were statistically significant while TLR4 was not. In addition, interaction by PD-1 inhibitors and irradiation was found in inflammatory indicators, especially in the expression of the HMGB1 and CD8+ T lymphocytes.Conclusion: PD-1 inhibitors can increase the expression of HMGB1-associated inflammatory cytokines and aggravate radiation-induced myocardial injury.Keywords: HMGB1, PD-1 inhibitors, radiotherapy, heart injury

Bing Wu, Jun Yang, Yonghong Dai, Le Xiong Department of Critical Care Medicine, Jiangjin Central Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Le Xiong, Department of Critical Care Medicine, Jiangjin Central Hospital, No. 725, Jiangzhou Road, Dingshan Street, Jiangjin District, Chongqing, 402260, People’s Republic of China, Tel +86-2347521342, Email xiongle2022@126.comPurpose: To evaluate the predictive value of combination of Bedside Index for Severity in AP (BISAP) score and miR-155 for the severity of acute pancreatitis (AP).Patients and Methods: A total of 1046 AP patients were divided into control group and case group according to the severity of AP [mild and moderately severe AP vs severe AP (SAP)]. Demographic data, comorbidities, clinical characteristics and laboratory data were collected. Multivariate analysis was conducted for the variables with two-sided P< 0.10 in univariate analysis to identify independent associated factors for progression to SAP in AP patients. The predictive values were evaluated using receiver operating characteristic (ROC) curve, and the area under curve (AUC) was compared using Z test.Results: A total of 117 (11.2%) patients were evaluated as SAP. Univariate analysis showed that there were significant differences in age, hypertension, ICU admission, hospital stay, Leukocytes, CRP, BUN, BISAP score and miR-155 between case group and control group (P< 0.05), and the P value of Fibrinogen was < 0.10. Multivariate analysis showed that the BISAP score, BUN, Leukocytes, age and CRP were independent risk factors for progression to SAP among AP patients after adjusting for hypertension, ICU admission, hospital stay and Fibrinogen, while miR-155 was a protective factor. The ROC curves demonstrated the AUCs of BISAP score, miR-155 and their combination were 0.842 (SE: 0.017, 95% CI: 0.809– 0.874), 0.751 (SE: 0.022, 95% CI: 0.708– 0.793) and 0.945 (SE: 0.007, 95% CI: 0.931– 0.959), respectively. Z test showed that the AUC of combination prediction was significantly higher than that of individual predictions (0.945 vs 0.842, Z=5.602, P< 0.001; 0.945 vs 0.751, Z=8.403, P< 0.001). The sensitivity, specificity and negative predictive value (NPV) of combination prediction were 95.7%, 93.6% and 99.4%, respectively.Conclusion: The combination of the BISAP score and miR-155 should be utilized to elevate the predictive value for the severity of AP in clinic.Keywords: severe acute pancreatitis, Bedside Index for Severity in AP score, miR-155, prediction

Chunyue Wang, Yuhang Tian, Bolin Wu, Wen Cheng Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin Wu, Department of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Tel +86 13313677182 ; +86 15663615088, Fax +86 451 85718392 ; +86 451 86298651, Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnAbstract: Sonodynamic therapy (SDT) is a rapidly developing non-surgical therapy that initiates sensitizers’ catalytic reaction using ultrasound, showing great potential for cancer treatment due to its high safety and non-invasive nature. In addition, recent research has found that using different diagnostic and therapeutic methods in tandem can lead to better anticancer outcomes. Therefore, as essential components of SDT, sonosensitizers have been extensively explored to optimize their functions and integrate multiple medical fields. The review is based on five years of articles evaluating the combined use of SDT and imaging in treating cancer. By developing multifunctional sonosensitive particles that combine imaging and sonodynamic therapy, we have integrated diagnosis into the treatment of precision medicine applications, improving SDT cell uptake and antitumor efficacy utilizing different tumour models. This paper describes the imaging principle and the results of cellular and animal imaging of the multifunctional sonosensitizers. Efforts are made in this paper to provide data and design references for future SDT combined imaging research and clinical application development and to provide offer suggestions.Keywords: sonodynamic therapy, multifunctional sonosensitizers, imaging, ultrasound

Bifa Fan,1 Shuiqing Li,2 Baishan Wu,3 Jinghua Zhang,4 Jing Zhou5 1Department of Pain, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Pain, Peking University Third Hospital, Beijing, People’s Republic of China; 3Department of Pain, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Department of Pain, Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5KANTAR China, Beijing, People’s Republic of ChinaCorrespondence: Bifa Fan, Department of Pain, China-Japan Friendship Hospital, 2 Yinghua East Road, Chaoyang District, Beijing, People’s Republic of China, Tel +86 15010101616, Email fyinsuo@yeah.netBackground: While there is an extensive body of research regarding pain and its treatment in developed countries, little research on this topic has been performed in developing countries. This study aimed to investigate the diagnosis, treatment, and treatment satisfaction in individuals with pain in urban China using real-world data.Methods: All respondents from the 2013, 2015, and 2017 China National Health and Wellness Survey were included in the analysis and were classified into diagnosed and undiagnosed groups according to their self-reported physician diagnosis or experience in the past month. The following five categories of pain were analysed: headache, cancer-associated pain, musculoskeletal pain, neuropathic pain, and fibromyalgia. Rates for diagnosis, treatment, and satisfaction with medication were calculated overall and for each pain type.Results: A total of 3802 respondents reported experience of at least one type of pain in the past month. Among those, 61.2% were diagnosed with a pain-related condition, the majority of which (84.0%) were receiving treatment. For diagnosed respondents taking over-the-counter and/or prescription medication, 70.3% were satisfied with their treatment. Comparing between pain types, the diagnosis rates for cancer-associated pain (32.7%) and fibromyalgia (22.8%) were relatively low, whereas respondents with musculoskeletal pain has the highest diagnosis rate (61.1%). Respondents with cancer-associated pain had the lowest satisfaction (30.0%) with over-the-counter and prescription medication, while respondents with headache (76.2%) had the highest satisfaction rate with such medications.Conclusion: Our study highlights the importance of raising awareness for pain management as well as education and training for healthcare providers and patients.Keywords: pain management, diagnosis, treatment, treatment satisfaction, China

Bowen Wu,1 Li Tan,2 Weihua Wang,3 Xingzhong Feng,4 Dan Yan1,5,6 1Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Center of Pharmaceutical Technology, Tsinghua University, Beijing, People’s Republic of China; 4Tsinghua University Yuquan Hospital, Beijing, People’s Republic of China; 5Beijing Institute of Clinical Pharmacy, Beijing, People’s Republic of China; 6Beijing Key Laboratory for Evaluation of Rational Drug Use, Beijing, People’s Republic of ChinaCorrespondence: Xingzhong Feng, Tsinghua University Yuquan Hospital, No. 5 Shijingshan Road, Shijingshan District, Beijing, People’s Republic of China, Email fengxz9797@sina.com Dan Yan, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong’an Road, Xicheng District, Beijing, People’s Republic of China, Email pharmsci@126.comBackground: Imidazole Propionate (ImP) is a new marker of Type 2 diabetes mellitus (T2DM), which can induce impaired glucose metabolism and weaken the efficacy of metformin. An extensive exploration into literature suggests that ImP may be associated with stool consistency.Purpose: Through an in-depth study of the relationship between stool consistency, bile acids, fecal microbiota and ImP, we intend to explore the mechanism driving the ImP content difference in T2DM.Patients Under Study and Methods: This is a single-center, prospective, cross-sectional study. Plasma ImP and stool consistency were analyzed among 96 diabetic subjects and 45 healthy subjects. All subjects were divided into the stool consistency normal (N) group and the stool consistency abnormal group, of which the abnormal group was sub-divided into the hard stool (H) group and the soft stool (S) group. After identifying the correlation between ImP and stool consistency, we analyzed the influence of bile acids and fecal microbiota on ImP in diabetic subjects.Results: For T2DM patients, the ImP level of the abnormal stool consistency group was significantly higher than that of the normal stool consistency group (P < 0.001). Results were verified in 45 healthy subjects (P = 0.002). ImP was significantly associated with taurocholic acid (TCA) (P = 0.003) in feces, taurodeoxycholate (TDCA) (P = 0.003), glycochenodeoxycholate (GCDCA) (P = 0.021), and glycocholic acid (GCA) (P = 0.031) in plasma. The Shannon index of Group N was significantly higher than that of Group H (P = 0.041) and Group S (P = 0.003).Conclusion: ImP was higher in diabetic patients with abnormal stool consistency than in those with normal stool consistency, which was related to the proportion of bile acids and fecal microbial structure. These findings may improve our understanding of ImP and contribute to the treatment of T2DM by improving stool consistency.Keywords: ImP, T2DM, stool consistency, bile acids

Bingfeng Wu,1,&ast; Yufei Tang,1,2,&ast; Kai Wang,3 Xuemei Zhou,3 Lin Xiang1,4 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3School of Chemical Engineering, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuemei Zhou, School of Chemical Engineering, Sichuan University, No. 24th, South Section 1, Yihuan Road, Chengdu, 610065, People’s Republic of China, Email xuemeizhou@scu.edu.cn Lin Xiang, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases Sichuan University, No. 14th, 3rd Section, Renmin South Road, Chengdu, 610041, People’s Republic of China, Tel +86 28 85503579, Email dentistxiang@126.comAbstract: Titanium implants have been widely applied in dentistry and orthopedics due to their biocompatibility and resistance to mechanical fatigue. TiO2 nanotube arrays (TiO2 NTAs) on titanium implant surfaces have exhibited excellent biocompatibility, bioactivity, and adjustability, which can significantly promote osseointegration and participate in its entire path. In this review, to give a comprehensive understanding of the osseointegration process, four stages have been divided according to pivotal biological processes, including protein adsorption, inflammatory cell adhesion/inflammatory response, additional relevant cell adhesion and angiogenesis/osteogenesis. The impact of TiO2 NTAs on osseointegration is clarified in detail from the four stages. The nanotubular layer can manipulate the quantity, the species and the conformation of adsorbed protein. For inflammatory cells adhesion and inflammatory response, TiO2 NTAs improve macrophage adhesion on the surface and induce M2-polarization. TiO2 NTAs also facilitate the repairment-related cells adhesion and filopodia formation for additional relevant cells adhesion. In the angiogenesis and osteogenesis stage, TiO2 NTAs show the ability to induce osteogenic differentiation and the potential for blood vessel formation. In the end, we propose the multi-dimensional regulation of TiO2 NTAs on titanium implants to achieve highly efficient manipulation of osseointegration, which may provide views on the rational design and development of titanium implants.Keywords: nanostructure, TiO2 nanotube arrays, titanium implant, osseointegration, anodization

Yitian Lang,1 Bin Wu,2 Zhilin Sun,3 Erjia Ye,4 Guanshen Dou,4 Xin Guan3 1Department of Pharmacy, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China; 2Medical Decision and Economic Group, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201100, People’s Republic of China; 3Department of Dermatology, Peking University Third Hospital, Peking University, Haidian District, Beijing, People’s Republic of China; 4Lilly China Drug Development and Medical Affairs Center, Eli Lilly and Company, Shanghai, People’s Republic of ChinaCorrespondence: Xin Guan, Department of Dermatology, Peking University Third Hospital, Peking University, No. 49, Huayuan North Road, Haidian District, Beijing, People’s Republic of China, Email guanxin1@sina.comObjective: Assessments of patients’ preferences can support in clinical decision-making regarding biologic therapies for psoriasis. Our objective was to investigate patient preference for biologic treatments in patients with psoriasis in China.Methods: From October 2020 to January 2021, psoriasis patients were recruited for a survey that included demographic and disease-related questions, as well as a discrete choice experiment to measure their preferences for biologic therapy. A discrete-choice experiment was used in which respondents selected psoriasis treatments based on benefits (ie, early onset of efficacy, long-term efficacy, sustained efficacy) and treatment costs. We analyzed choice data using conditional logit model.Results: This study included 236 patients with moderate-to-severe psoriasis. The relative importance of the cost of biologic treatments, probability of keeping PASI100 at 5 years, probability of achieving PASI100 at 3 months and time to achieve PASI50 after initiation the biologic treatment were 0.593, 0.137, 0.185 and 0.085. Over 50% of patients regarded the cost of biologic treatments as the most important attribute. High-income and low-income subgroups had higher preference weight in probability of achieving PASI100 at 3-month and monthly cost.Conclusion: The cost of biologic treatments was found as the most important attribute for Chinese patients with psoriasis. Among efficacy attributes, the probability of achieving PASI100 at 3 months showed most sensitive. These results may be helpful to understand patient preference for biologic treatments used for psoriasis in China.Keywords: biologics, discrete choice experiment, Chinese setting, patient preference, psoriasis

Yuan Yang,1,2 Ting Cui,1 Zuoxiao Li,2 Jinglun Li,2 Ting Duan,3 Zhengzhou Yuan,2 Changyi Wang,1 Jincheng Wan,1 Cao Li,4 Shujiang Zhang,2 Ling Li,2 Fayun Hu,1 Bo Wu1 1Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Neurology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4Department of Radiology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of ChinaCorrespondence: Bo Wu; Fayun Hu, Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China, Tel +86-18980602142 ; +86-15902861270, Email dr.bowu@hotmail.com; hufayun2006@163.comObjective: This study examined the functional outcomes and safety of endovascular treatment (EVT) in acute ischemic stroke (AIS) patients owing to large vessel occlusion of the anterior circulation, presented during a late-time window (6– 24 hours after last seen well (LSW)) in a real-world practice.Methods: This was a retrospective analysis from a bi-center prospective cohort. According to the stroke treatment, patients with continuous Alberta Stroke Plan Early Aspect score (ASPECTS) ≥ 6 on non-contrast CT (NCCT) and moderate to good collateral state on CT angiography (CTA) were divided into EVT group and standard medical treatment (SMT) group. The primary outcome was the rate of functional independence (90-day mRS ≤ 2). Safety outcomes were the occurrence of symptomatic intracranial hemorrhage (sICH) and the 90-day mortality.Results: Among the 288 enrolled patients (53.5% male, median age 64 years), there were 167 patients in the EVT group and 121 in the SMT group. After multivariable adjustments for potential confounders, EVT was associated with functional independence (adjusted OR: 3.052; 95% confidence interval (CI): 1.553– 5.997; p = 0.001). In the PSM cohort, 44.2% (42/95) of patients in the EVT group versus 18.9% (18/95) in the SMT group achieved functional independence (OR: 3.39, 95% CI: 1.763– 6.517), and there was a significant difference favoring EVT over the SMT in the overall distribution of mRS (OR: 2.170, 95% CI: 1.302– 3.618) at 90 days. The rate of sICH did not differ between the EVT and SMT groups (10.5% vs 8.4%, p = 0.804) nor did 90-day mortality (18.9% vs 22.1%, p = 0.719). No interaction was found in p-values with statistical significance in subgroup analysis.Conclusion: This real-world experience suggests that EVT for late-presenting stroke patients, based on small core on NCCT and moderate to good collaterals on CTA, is associated with better outcomes than SMT alone, with no increase in sICH and 90-day mortality rates.Keywords: endovascular treatment, late time window, propensity score matching, real-world study

Yichao Geng,1– 3,* Shengfa Su,2,3,* Li Cao,2,* Ting Yang,4 Weiwei Ouyang,2,3 Lingfeng Liu,2,3 Bibo Wu,2,3 Qiuning Zhang,5 Bing Lu,2,3 Xiaohu Wang1,5 1The First School of Clinical Medicine, Lanzhou University, Lanzhou, People’s Republic of China; 2Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 3Department of Oncology, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, People’s Republic of China; 4Department of Pathophysiology, Guizhou Medical University, Guiyang, People’s Republic of China; 5Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaohu WangThe First School of Clinical Medicine, Lanzhou University, Lanzhou, People’s Republic of China, Tel +8613909407551,Fax +86 931 5196196, Email xhwang@impcas.ac.cn; Bing Lu Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China, Tel +8613809432527, Fax +86 851 6513076, Email lbgymaaaa@163.comPurpose: This study was designed to evaluate the effects of PD-1 inhibitor on lung tissue morphology and the immune system in a mouse model of radiation-induced lung injury (RILI) and to assess interactions between radiation therapy and PD-1 inhibition.Methods: Twenty C57BL/6 mice were divided randomly into four groups of five mice each. Mice were treated with an anti-mouse PD-1 monoclonal antibody, whole thorax irradiation, both or neither. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining; lung fibrosis was assessed by Masson staining and analysis of hydroxyproline; CD3+, CD4+, and CD8+ T lymphocytes in lung tissues were detected immunohistochemically; and the concentrations of transforming growth factor-β 1 (TGF-β 1) and interleukin-6 (IL-6) in lung tissue were evaluated by cytokine multiplex analysis.Results: Lung injury scores and indicators of pulmonary fibrosis were higher in mice administration whole thorax irradiation than in control mice. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions and hydroxyproline contents in lung tissues were all significantly higher in mice administered PD-1 inhibitor plus irradiation than in the other three groups. Similarly, the percentages of CD3+ and CD8+T cells and the concentrations of IL-6 and TGF-β 1 in lung tissue were significantly higher in mice treated with radiation and PD-1 inhibitor than in the other groups. However, PD-1 inhibitor and irradiation interacted significantly only in the elevation of TGF-β 1 level.Conclusion: Whole thorax X-ray irradiation in mice can cause pulmonary injury and fibrosis, which could be exacerbated by PD-1 inhibitors. Radiotherapy combined with PD-1 inhibitors may aggravate RILI by synergistically upregulating TGF-β 1 expression, thereby affecting the immune-inflammatory microenvironment in the lungs.Keywords: PD-1 inhibitors, radiotherapy, radiation fibrosis, lung injury, transforming growth factor-β 1

Yichi Chen,1 Haitao Shang,1 Chunyue Wang,1 Jiaqi Zeng,2 Shentao Zhang,1 Bolin Wu,1,3 Wen Cheng1,3 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 2School of Life Science and Technology, Computational Biology Research Center, Harbin Institute of Technology, Harbin, People’s Republic of China; 3Department of Interventional Ultrasound, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of ChinaCorrespondence: Wen Cheng; Bolin WuDepartment of Ultrasound, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, Heilongjiang Province, 150081, People’s Republic of ChinaTel +86 13313677182; +86 15663615088Fax +86 451 85718392; +86 451 86298651Email chengwen@hrbmu.edu.cn; wubolin@hrbmu.edu.cnBackground: The combination of sonodynamic therapy and oxygenation strategy is widely used in cancer treatment. However, due to the complexity, heterogeneity and irreversible hypoxic environment produced by hepatocellular carcinoma (HCC) tissues, oxygen-enhancing sonodynamic therapy (SDT) has failed to achieve the desired results. With the emergence of ferroptosis with reactive oxygen species (ROS) cytotoxicity, this novel cell death method has attracted widespread attention.Methods: In this study, nanobubbles (NBs) were connected with the sonosensitizer Indocyanine green (ICG) to construct a 2-in-1 nanoplatform loaded with RAS-selective lethal (RSL3, ferroptosis promoter) (RSL3@O2-ICG NBs), combined with oxygen-enhanced SDT and potent ferroptosis. In addition, nanobubbles (NBs) combined with low-frequency ultrasound (LFUS) are called ultrasound-targeted nanobubble destruction (UTND) to ensure specific drug release and improve safety.Results: MDA/GSH and other related experimental results show that RSL3@O2-ICG NBs can enhance SDT and ferroptosis. Through RNA sequencing (RNA-seq), the differential expression of LncRNA and mRNA before and after synergistic treatment was identified, and then GO and KEGG pathways were used to enrich and analyze target genes and pathways related ferroptosis sensitivity. We found that they were significantly enriched in the ferroptosis-related pathway MAPK cascade and cell proliferation. Then, we searched for the expression of differentially expressed genes in the TCGA Hepatocellular carcinoma cohort. At the same time, we evaluated the proportion of immune cell infiltration and the identification of co-expression network modules and related prognostic analysis. We found that it was significantly related to the tumor microenvironment of hepatocellular carcinoma. The prognostic risk genes “SLC37A2” and “ITGB7” may represent new hepatocellular carcinoma ferroptosis-inducing markers and have guiding significance for treating hepatocellular carcinoma.Conclusion: The therapeutic effect of the in vitro synergistic treatment has been proven to be significant, revealing the prospect of 2-in-1 nanobubbles combined with SDT and ferroptosis in treating HCC.Keywords: ferroptosis, sonodynamic therapy, HCC, RSL3, synergistic therapy

Honglei Hu,1,2,&ast; Shuting Zheng,1,2,&ast; Meirong Hou,1,2 Kai Zhu,1,2 Chuyao Chen,1 Zede Wu,1,2 Li Qi,3 Yunyan Ren,1 Bin Wu,4 Yikai Xu,1 Chenggong Yan,1,5 Bingxia Zhao2,6 1Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 2Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Medical Image Processing, Guangdong Province Engineering Laboratory for Medical Imaging and Diagnostic Technology, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 4Institute of Respiratory Diseases, Respiratory Department, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, People’s Republic of China; 5Guangdong Provincial Key Laboratory of Shock and Microcirculation, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 6Experimental Education/Administration Center, School of Basic Medical Science, Southern Medical University, Guangzhou, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bingxia Zhao; Yikai Xu, Tel +86 20 61647272; +86 20 62787333, Email bingxiaz@gmail.com; yikaixu917@gmail.comBackground: Radiotherapy (RT) is clinically well-established cancer treatment. However, radioresistance remains a significant issue associated with failure of RT. Phototherapy-induced radiosensitization has recently attracted attention in translational cancer research.Methods: Cu-Sb-S nanoparticles (NPs) coated with ultra-small Au nanocrystals (Au@Cu-Sb-S) were synthesized and characterized. The biosafety profiles, absorption of near-infrared (NIR) laser and radiation-enhancing effect of the NPs were evaluated. In vitro and in vivo spectral computed tomography (CT) imaging and photoacoustic (PA) imaging were performed in 4T1 breast cancer-bearing mice. The synergetic radio-phototherapy was assessed by in vivo tumor inhibition studies.Results: Au@Cu-Sb-S NPs were prepared by in situ growth of Au NCs on the surface of Cu-Sb-S NPs. The cell viability experiments showed that the combination of Au@Cu-Sb-S+NIR+RT was significantly more cytotoxic to tumor cells than the other treatments at concentrations above 25 ppm Sb. In vitro and in vivo spectral CT imaging demonstrated that the X-ray attenuation ability of Au@Cu-Sb-S NPs was superior to that of the clinically used Iodine, particularly at lower KeV levels. Au@Cu-Sb-S NPs showed a concentration-dependent and remarkable PA signal brightening effect. In vivo tumor inhibition studies showed that the prepared Au@Cu-Sb-S NPs significantly suppressed tumor growth in 4T1 breast cancer-bearing mice treated with NIR laser irradiation and an intermediate X-ray dose (4 Gy).Conclusion: These results indicate that Au@Cu-Sb-S integrated with spectral CT, PA imaging, and phototherapy-enhanced radiosensitization is a promising multifunctional theranostic nanoplatform for clinical applications.Keywords: Au@Cu-Sb-S nanoparticle, phototherapy, radiotherapy, spectral CT, photoacoustic imaging

Kai Jin, Shu-Yuan Zhang, Li-Wen Li, Yang-Fan Zou, Bin Wu, Liang Xia, Cai-Xing Sun Department of Neurosurgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Cai-Xing SunDepartment of Neurosurgery, Zhejiang Cancer Hospital, 11th Floor, Building 2, Hangzhou City, Zhejiang Province, People’s Republic of ChinaTel +86 572-88128082Email 18744016937@163.comPurpose: Glioma may affect patients of any age. So far, only a limited number of big data studies have been conducted concerning oligodendroglioma (OG) in diverse age groups. This study evaluated the risk factors for OG in different age groups using the Surveillance, Epidemiology, and End Results (SEER) database built by the National Cancer Institute, which is part of the National Institutes of Health.Patients and Methods: A total of 5437 cases within the SEER database were included. These patients were divided into seven age groups. The Kaplan-Meier method was employed for survival analysis. The independent risk factors for the survival of OG patients were identified using the Cox regression model. A nomogram was drawn with R software based on the independent risk factors. The X-tile software was adopted to find the optimal age group at diagnosis.Results: The all-cause mortality and the tumor-specific mortality increased with age. The univariate analysis showed that the patients’ age, gender, primary lesion location, side affected by the primary lesion (left or right), surgery for the primary lesion, and tumor size were correlated with survival (P< 0.05). Multivariate Cox regression analysis showed that age was an independent risk factor for the survival of OG patients (P< 0.05). The optimal cutoff value of age in terms of overall survival (OS) and cause-specific survival (CSS) were identified as 48 and 61 years and 48 and 59 years, respectively.Conclusion: The older the age, the worse the survival would be. That’s, the mortality increased with age. In the clinic, healthcare professionals should be fully aware of the variability in the prognosis of OG patients in different age groups. Therefore, individualized treatments are recommended to OG patients in different age groups to optimize the prognosis.Keywords: oligodendroglioma, SEER, age, prognosis, all-cause mortality, tumor-specific mortality

Morgan Justice Fuoco,1 Richard A Mularski,1 Benjamin Wu,2 Chad Moretz,2 Mary Ann McBurnie,1 Richard H Stanford,2 Phillip Crawford,1 Daniel Gratie,2 Bianca Salas1 1Kaiser Permanente Center for Health Research, Science Programs Department, Portland, OR, USA; 2GlaxoSmithKline, US Value Evidence and Outcomes, Research Triangle Park, Durham, NC, USACorrespondence: Morgan Justice FuocoKaiser Permanente Washington Health Research Institute, 1730 Minor Ave, Suite 1600, Seattle, WA, 98101, USATel +1 256-508-4613Email morgan.j.fuoco@kp.orgBackground: There is currently little research describing patient experience and continuity of care immediately prior, during, and following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This analysis examined clinical characteristics, chronic obstructive pulmonary disease (COPD)‑related medication patterns and outpatient visits before and after an AECOPD.Methods: This retrospective analysis used electronic health records, medical claims, and pharmacy dispensing data for patients within the Kaiser Permanente Northwest Health System. Patients with ≥ 1 AECOPD between January 1, 2015 and December 31, 2017 were identified. The most recent AECOPD was considered the index date. An AECOPD was defined as an inpatient hospitalization with a primary diagnosis of COPD, or respiratory failure with a secondary diagnosis of COPD, or an outpatient visit with a primary diagnosis of COPD and dispensing of respiratory-related antibiotics and/or oral corticosteroids ± 5 days of the visit. Eligible patients were: ≥ 40 years old; ≥ 2 encounters within 12 months of each other or ≥ 1 hospitalization with primary or secondary COPD diagnosis, chronic bronchitis, or emphysema prior to index; and continuously enrolled ± 90 days relative to index. COPD-related inhaled maintenance medication, rescue inhalers, oral corticosteroid use, and ambulatory visits were assessed 90-days pre- and post-index.Results: There were 2829 patients included (mean [standard deviation] age: 69.0 [10.5] years) who had an AECOPD (7% severe; 93% moderate). The percentage of patients on inhaled maintenance therapy increased from 60.6% pre-AECOPD to 68.8% post-AECOPD and increased from 60.0% to 87.4% among patients who experienced a severe AECOPD. COPD-related ambulatory visits increased more than four-fold for primary care and more than doubled for pulmonologist visits in the post-AECOPD period.Conclusion: The low proportion of patients observed with changes to controller and rescue medication (particularly following a moderate AECOPD), yet higher utilization of COPD-related ambulatory visits before and after an AECOPD suggests that there is opportunity to improve pharmacotherapy management.Keywords: COPD, exacerbation, triple therapy, treatment patterns, quality of care

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

Qin Zhang,1 Juan Tan,1 Li Wan,1 Chao Chen,1 Bin Wu,2 Xijian Ke,1 Rongxue Wu,3 Xiao Ran4 1Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Department of Biological Sciences Division/ Cardiology, University of Chicago, Chicago, IL, 60637, USA; 4Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of ChinaCorrespondence: Xiao Ran Email ranxiao1001@tjh.tjmu.edu.cnAim: Disruption of the blood–brain barrier (BBB) is a critical pathological feature after stroke. Although tissue kallikrein (TK) has used in the treatment of stroke in China, the role of TK in modulating BBB permeability is not clear.Methods: We investigated the effect of different doses of TK on BBB by in vivo assessments of Evans blue (EB) and sodium-fluorescein isothiocyanate (FITC) leakage and in vitro assessments of the integrity of BBB and monolayers of microvascular endothelial cells (BMVECs). The expression of zonula occludens-1 (ZO-1) and bradykinin receptor-mediated signaling in BMVECs was detected.Results: A significant increase in BBB permeability was observed in the mice treated with high dose of TK. However, standard and medium doses of TK could only enable sodium-FITC to enter the brain. The result of in vitro study indicated that high-doses of TK, but not standard and medium-dose of TK, reduced normal BBB integrity accompanied by a decreased expression of zonula occludens-1 (ZO-1), upregulated the mRNA levels of bradykinin 2 receptor (B2R) and endothelial nitric oxide synthase (eNOS) and the abundance of B2R. Moreover, standard-dose of TK exacerbated lipopolysaccharide-induced BBB hyperpermeability, upregulated the mRNA levels of bradykinin 1 receptor (B1R) and inducible nitric oxide synthase (iNOS), increased the abundance of B1R and reduced the abundance of ZO-1; these effects were inhibited by TK inhibitor.Conclusion: TK can disrupt tight junctions and increase normal BBB permeability via B2R-dependent eNOS signaling pathway, aggravate impairment of BBB via B1R-dependent iNOS signaling pathway, and consequently serve as a useful adjunctive treatment for enhancing the efficacy of other neurotherapeutics.Keywords: tissue kallikrein, blood–brain barrier, bradykinin, permeability

Carlyne M Averell,1 David Hinds,2 Jolyon Fairburn-Beech,3 Benjamin Wu,1 Robson Lima4 1US Value Evidence & Outcomes, GSK, Research Triangle Park, NC, USA; 2Real World Evidence & Epidemiology, GSK, Collegeville, PA, USA; 3Real World Evidence & Epidemiology, GSK, Stockley Park, UK; 4US Medical Affairs, GSK, Research Triangle Park, NC, USACorrespondence: Carlyne M AverellUS Value Evidence & Outcomes, GlaxoSmithKline plc., Research Triangle Park, NC, 27709-3398, USATel +1 919 315 9835Email Carlyne.M.Averell@gsk.comRationale: The National Heart, Lung, and Blood Institute (NHLBI) recommend a stepwise approach to asthma management, with the goals of maintaining asthma control and reducing exacerbations. Although asthma treatments reduce the frequency of exacerbations, they still occur. We aimed to characterize the treated United States of America (US) adult asthma population, including those experiencing exacerbations, in terms of socio-demographics, clinical characteristics, and healthcare resource utilization (HRU).Patients and Methods: A retrospective cohort of asthma patients aged ≥ 18 years on 01 January 2014 with ≥ 1 ICD-9 asthma code (493.xx) enrolled in a US healthcare claims database during 2013– 2014. Patients who had ≥ 2 asthma medication dispensings during 2013 (baseline), including ≥ 1 in the 90-day period before index date, were classified according to NHLBI step. Patients with chronic obstructive pulmonary disease, cystic fibrosis, or lung cancer diagnoses were excluded. Demographics, comorbidities, clinical characteristics, and HRU were described during baseline. Exacerbations and HRU were described during 2014 (follow-up period).Results: In total, 72,156 patients were included; 10,590 (14.7%) had ≥ 1 exacerbation during follow-up. Approximately 44% of patients were classified as NHLBI Steps 1– 2, 41% as Steps 3– 4, and 11% as Steps 5– 6. Exacerbation frequency increased with step (Steps 1, 2, and 3: 12– 14%; Steps 4, 5, and 6: 16– 26%). Compared with the overall population during baseline, patients with an exacerbation had similar demographics, but differences were observed for comorbid allergic rhinitis (46.4% vs 40.1%, respectively), blood eosinophil counts ≥ 300 cells/μL (45.5% vs 39.6%, respectively), and asthma-related healthcare encounters (62.9% vs 52.4%, respectively). Overall, asthma-related HRU during follow-up increased with NHLBI step.Conclusion: Exacerbations were observed among patients classified at each NHLBI step and were more frequent with increasing step. Exacerbations and asthma-related HRU highlight the continued unmet need in the treated US asthma population.Keywords: asthma, clinical traits, real-world, administrative claims, healthcare costs, healthcare resource utilization

Ganlu Ouyang,1 Xibiao Yang,2 Xiangbing Deng,3 Wenjian Meng,3 Yongyang Yu,3 Bing Wu,2 Dan Jiang,4 Pei Shu,1 Ziqiang Wang,3 Jin Yao,2 Xin Wang1 1Department of Radiation Oncology/Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Radiology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 3Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 4Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Xin WangDepartment of Radiation Oncology/Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 of Wainan Guoxue Lane, Wuhou District, Chengdu, 610041, People’s Republic of ChinaTel +86 18980602291Email wangxin213@sina.comPurpose: To investigate the potential value of magnetic resonance imaging (MRI) in predicting response relevance to total neoadjuvant treatment (TNT) in locally advanced rectal cancer.Methods: We analyzed MRI of 71 patients underwent TNT from 2015 to 2017 retrospectively. We categorized the response of TNT as CR (complete response) vs non-CR, and high vs moderate vs low sensitivity. Logistic regression analysis was used to identify the best predictors of response. Diagnostic performance was assessed using receiver operating characteristic curve analysis.Results: Post-ICT (induction chemotherapy) ∆TL (tumor length), post-CRT (concurrent chemoradiotherapy) ∆LNN (the numbers of lymph node metastases), post-CCT (consolidation chemotherapy) ∆SDWI (maximum cross-sectional area of tumor on diffusion-weighted imaging), post-CCT ADCT (the mean apparent diffusion coefficient values of tumor) and post-CCT ∆LNV (volume of lymph node) were the best CR predictors. Post-ICT ∆TL, post-CRT EMVI (extramural vascular invasion) and post-CCT ∆ST2 (S on T2-weight) were the best significant factors for high sensitivity.Conclusion: Post-ICT ∆TL may be an early predictor of CR and high sensitivity to TNT. Dynamic analysis based on MRI between baseline and post-CCT could provide the most valuable prediction of CR. The grouping modality of CR vs non-CR may be more suitable for treatment response prediction than high vs moderate vs low sensitivity.Keywords: rectal cancer, total neoadjuvant treatment, MRI, response, TRG

Xiao Ran,1 Qin Zhang,2 Shaoping Li,1 Zhen Yu,1 Li Wan,2 Bin Wu,3 Rongxue Wu,4 Shusheng Li1 1Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 4Department of Biological Sciences Division/Cardiology, University of Chicago, Chicago, IL, 60637, USACorrespondence: Qin Zhang Email qzhang8@tjh.tjmu.cnShusheng Li Email Shushengli16@sina.comAim: Sepsis, an acute, life-threatening dysregulated response to infection, affects practically all aspects of endothelial function. Tissue kallikrein (TK) is a key enzyme in the kallikrein–kinin system (KKS) which has been implicated in endothelial permeability. Thus, we aimed to establish a potentially novel association among TK, endothelial permeability, and sepsis demonstrated by clinical investigation and in vitro studies.Methods: We performed a clinical investigation with the participation of a total of 76 controls, 42 systemic inflammatory response syndrome (SIRS) patients, and 150 patients with sepsis, who were followed-up for 28 days. Circulating TK levels were measured with an enzyme-linked immunosorbent assay. Then, the effect of TK on sepsis-induced endothelial hyperpermeability was evaluated by in vitro study.Results: Data showed a gradual increase in TK level among controls and the patients with SIRS, sepsis, and septic shock (0.288± 0.097 mg/l vs 0.335± 0.149 vs 0.495± 0.170 vs 0.531± 0.188 mg/l, respectively, P < 0.001). Further analysis revealed that plasma TK level was positively associated with the severity and mortality of sepsis and negatively associated with event-free survival during 28 days of follow-up (relative risk, 3.333; 95% CI, 2.255– 4.925; p < 0.001). With a septic model of TK and kallistatin in vitro, we found that TK exacerbated sepsis-induced endothelial hyperpermeability by downregulating zonula occluden-1 (ZO-1) and vascular endothelial (VE)-cadherin, and these could be reversed by kallistatin, an inhibitor of TK.Conclusion: TK can be used in the diagnosis of sepsis and assessment of severity and prognosis of disease. Inhibition of TK may be a novel therapeutic target for sepsis through increasing ZO-1 and VE-cadherin, as well as downregulating endothelial permeability.Keywords: tissue kallikrein, sepsis, mortality, endothelial permeability, junction protein

Bin Wu,* Yuanyuan Guo,* Jie Deng, Qibin Chen, Su Min Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Su MinDepartment of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaEmail minsucqmu@126.comPurpose: Depression is a common mood disorder in humans worldwide. Electroconvulsive therapy (ECT) remains the most effective treatment for patients with drug-resistant or severe depression; however, during ECT, electrical resistance can occur, antagonizing ECT efficacy. We aimed to investigate how depressed patients develop resistance to electric shocks during ECT.Methods: Rats exposed to chronic unpredictable stress exert similar impairments in hippocampal synaptic plasticity as those in depressed humans, including hippocampal neuronal atrophy and reduced synaptic function and synapse-related proteins. Therefore, a rat model was used to model depressive-like behaviors in the current study. Depression-like behavior was stimulated in Sprague Dawley (SD) rats that were then randomized into six groups: control group (C); a rat model of stress-induced depression group (D); and four groups in which a rat model of stress-induced depression received one, three, five, or seven electroconvulsive shocks (ECS; DE1, DE3, DE5, and DE7). The sucrose preference test (SPT) and Morris water maze (MWM) were utilized to evaluate anhedonia and spatial learning and memory in rats, respectively. Synaptic plasticity was recorded electrophysiologically in terms of field excitatory postsynaptic potential (fEPSP) and long-term potentiation (LTP).Results: The rat model of stress-induced depression triggered a decrease in the sucrose preference percentage (SPP) and the baseline fEPSP slope relative to those observed for the C group, and these changes were significantly rescued by ECT in a shock number-dependent manner within five shocks. However, the rat model of stress-induced depression displayed an increase in the escape latency and a decrease in space exploration time, in addition to decreased LTP relative to those in the C group, which was further augmented by ECT in a shock number-dependent manner within five shocks.Conclusion: Changes in synaptic plasticity might be responsible for the development of resistance against constant-stimulus ECT in a rat model of stress-induced depression.Keywords: depression, electroconvulsive shocks, electrical resistance, synaptic plasticity

Yuan Ge,1 Chunhong Shi,2 Bin Wu,1 Yannan Liu,3 Ling Chen,1 Yuegui Deng4 1School of Nursing, Guangxi University of Chinese Medicine, Nanning, 530200, People’s Republic of China; 2School of Nursing, Xiangnan University, Chenzhou, 423000, People’s Republic of China; 3Nursing School, Hunan University of Medicine, Huaihua, 418000, People’s Republic of China; 4Nursing Department, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530022, People’s Republic of ChinaCorrespondence: Chunhong ShiSchool of Nursing, Xiangnan University, 889 Chenzhou Avenue, Suxian District, Chenzhou, 423000, Hunan, People’s Republic of ChinaTel +86 15907354840Fax +86-735-2325007Email shichunhong@xnu.edu.cnPurpose: This study explored the impact of COVID-19 on the mental health and adaptation of behavior of Zhuang women in China to provide more specific guidance for the social and medical practice of pregnant women during public health emergencies.Participants and Methods: This cross-sectional study recruited 446 pregnant Zhuang women from obstetric outpatient clinics in four tertiary hospitals and online maternity schools in Nanning, Guangxi, between February 24 and March 1, 2020. Self-designed questionnaires and the Self-Rating Anxiety Scale were used.Results: During the COVID-19 pandemic, the prevalence rate of anxiety among women was 36.77%, and some adaptation of behavior was observed. Logistic regression analysis showed that pregnant women who had an annual household income of less than $7,000, were primiparous, went out for prenatal examination, wanted to self-monitor during pregnancy but did not know how to do it, believed that they should be strictly isolated at home and cancel prenatal examinations, and expected to receive pregnancy healthcare through teleconsultation services showed a higher risk of anxiety. Nevertheless, pregnant Zhuang women who were 22– 35 years old, undergraduate-educated, and in their second trimester were less likely to suffer from anxiety.Conclusion: The COVID-19 pandemic has a significant psychological impact on pregnant women from ethnic minorities. Factors related to quarantine and social isolation policies appear to drive changes in behaviors and anxiety disorders. Multidisciplinary mental health services and culturally sensitive interventions are necessary for minority pregnant women, especially for low-income primiparous women in the first or third trimester.Keywords: pregnant women, minority, psychological, behavior, coronavirus disease 2019

Ping Li,1– 3,* Chang Liu,4– 6,* Shuang Wu,2,3,7 Lin Deng,2,3,8 Guangyuan Zhang,2,3,8 Xin Cai,1– 3 Silong Hu,4– 6 Jingyi Cheng,2,3,6,9 Xiaoping Xu,4– 6 Bin Wu,2,3,10 Xiaomao Guo,2,3,7 Yingjian Zhang,4– 6 Shen Fu,5,11 Qing Zhang1– 3 1Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Radiation Oncology, Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Proton and Heavy ion Radiation Therapy, Shanghai, People’s Republic of China; 4Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 5Key Laboratory of Nuclear Physics and Ion-Beam Application (MOE), Fudan University, Shanghai, People’s Republic of China; 6Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, People’s Republic of China; 7Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of China; 8Department of Radiology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 9Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of China; 10Department of Radiology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of China; 11Department of Radiation Oncology, Shanghai Concord Cancer Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing ZhangDepartment of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of ChinaTel +86 139 1737 4609Fax +86 2138296518Email qing.zhang@hotmail.comShen FuDepartment of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of ChinaEmail shen_fu@hotmail.comPurpose: The purpose of this study was to assess the potential of 99mTc-labeled PSMA-SPECT/CT and diffusion-weighted image (DWI) for predicting treatment response after carbon ion radiotherapy (CIRT) in prostate cancer.Patients and Methods: We prospectively registered 26 patients with localized prostate cancer treated with CIRT. All patients underwent 99mTc-labeled PSMA-SPECT/CT and multiparametric magnetic resonance imaging (MRI) before and after CIRT. The tumor/background ratio (TBR) and mean apparent diffusion coefficient (ADCmean) were measured on the tumor and the percentage changes before and after therapy (ΔTBR and ΔADCmean) were calculated. Patients were divided into two groups: good response and poor response according to clinical follow-up.Results: The median follow up time was 38.3months. The TBR was significantly decreased (p=0.001), while the ADCmean was significantly increased compared with the pretreatment value (p< 0.001). The ΔTBR and ΔADCmean were negatively correlated with each other (p = 0.002). On ROC curve analysis for predicting treatment response, the area under the ROC curve (AUC) of ΔTBR (0.867) for predicting good response was higher than that of ΔADCmean (0.819). The AUC of combined with ΔTBR and ΔADCmean (0.895) was higher than that of either ΔADCmean or ΔTBR alone. The combined use of ΔTBR and ΔADCmean showed 91.4% sensitivity and 95.2% specificity.Conclusion: Our preliminary data indicate that the changes of TBR and ADCmean maybe an early bio-marker for predicting prognosis after CIRT in localized prostate cancer patients. In addition, the ΔTBR seems to be a more powerful prognostic factor than ΔADCmean in prostate cancer treated with CIRT.Keywords: PSMA, DWI, prostate cancer, carbon ion radiotherapy

Dan Huang, Dong Wu, Jinhong He, Min Chen, Xuanna Zhao, Dongming Li, Bin Wu Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of ChinaCorrespondence: Dongming Li; Bin WuDepartment of Respiratory and Critical Care Medicine, Affiliated Hospital of Guangdong Medical University, 57th South Renmin Road, Zhanjiang, Guangdong, 524001, People’s Republic of ChinaTel/Fax +867592387413Email 1335887835@qq.com; wubin621011@126.comPurpose: Chronic obstructive pulmonary disease (COPD) was the fourth leading cause of death in the world. Many studies have shown that COPD often exists with thyroid dysfunction; however, the relationship between thyroid function and COPD is often ignored in clinical. We retrospectively analyze the serum thyroid hormone levels in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and explore the association between thyroid function and AECOPD.Methods: The study included patients hospitalized for AECOPD in our institution between January 2018 and September 2020. Patients with AECOPD were divided into moderate-to-severe and very severe groups based on lung function, and into normal and abnormal thyroid function groups based on thyroid hormone levels. Collected data and compared data between groups to identify risk factors for thyroid dysfunction in patients with AECOPD.Results: The cohort included 97 in the moderate-to-severe group (72.39%) and 37 in the very severe group (27.61%). Compared with the very severe group, the moderate-to-severe group had higher triglyceride (P=0.017), high-density lipoprotein (P< 0.05), partial pressure of carbon dioxide (PaCO2; P< 0.05), and serum thyroid-stimulating hormone (TSH; P< 0.001). FEV1 as a percentage of the predicted value (FEV1%pred) was positively correlated with TSH and FT3 (r=0.329, r=0.192, respectively, both P< 0.05). Duration of hospitalization was negatively correlated with TSH (r=− 0.256, P=0.003). Among the 134 subjects, 98 (73.13%) had normal thyroid function and 36 (26.87%) had abnormal thyroid function. The two groups significantly differed regarding forced vital capacity (FVC), forced expiratory volume in 1 second, FEV1%pred, and albumin level. Logistic regression analysis showed that high FVC correlated with a low risk of thyroid dysfunction in AECOPD.Conclusion: In patients with AECOPD, TSH is related to lung function and duration of hospitalization, and high FVC reduces the risk of thyroid dysfunction.Keywords: AECOPD, thyroid hormone, retrospective cohort study, risk factor

Guang Wang,1,* Bing Wu,2,* Wenzhou Xu,3 Xuefei Jin,4 Kun Wang,5 Heyuan Wang6 1Department of Intensive Care Unit, The First Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of China; 2Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of China; 3Department of Periodontology, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130033, People’s Republic of China; 4Department of Urology, China-Japan Union Hospital of Jilin University, Jilin Key Laboratory of Urologic Oncology, Changchun, Jilin 130033, People’s Republic of China; 5Department of Obstetrics and Gynecology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of China; 6Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of China*These authors contributed equally to this workCorrespondence: Heyuan WangDepartment of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin 130033, People’s Republic of ChinaTel/Fax +86-431-88782222Email wangheyuan220@163.comIntroduction: Deregulation of adipogenesis plays an important role in obesity and other metabolism disorders. PPAR, C/EBP and SREBP1c are key transcriptional factors involved in adipogenesis and lipogenesis. Juglanin is a natural compound belonging to flavonoids, and it has been reported that juglanin has a potent inhibitory effect on inflammation and certain type of cancers. However, the effects of juglanin in adipogenesis have not been reported before.Materials and Methods: 3T3-L1 preadipocytes were incubated with differentiation induction medium in the presence or absence of 0.5, 2.5, or 5 μM juglanin for an 8-day differentiation period. The lipid droplets accumulated in the cytoplasm were monitored by Oil Red O staining on days 0, 2, 5, and 8. The regulatory effects of juglanin on adipogenesis-related genes and proteins were investigated by real-time polymerase chain reaction and Western blot analysis.Results: Juglanin significantly decreased lipid accumulation in differentiated adipocytes. Our findings show that juglanin reduced the expression of C/EBPα, C/EBPβ, and SREBP-1c without affecting PPARα or PPARγ expression. Additionally, juglanin increased the activation of the SIRT1/AMPK signaling pathway through the phosphorylation of AMPKα. Finally, we performed an AMPK inhibitor experiment, which revealed that the inhibitory effects of juglanin on adipogenesis are mediated through AMPK.Discussion: Juglanin can prevent adipogenesis by suppressing lipid accumulation and the differentiation of preadipocytes. The mechanism of juglanin regulating adipogenesis requires further investigation. Future clinical study in vivo could shed more light on its implication in modulating obesity and metabolic disorders.Keywords: Juglanin, adipogenesis, obesity, lipid metabolism, AMPK