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Weilin Lu,1,* Kaiming Li,2,* Haisi Wu,2,* Jinyu Li,2 Yan Ding,2 Xiaolin Li,1 Zhipeng Liu,3 Huae Xu,2 Yinxing Zhu3,4 1The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing, People’s Republic of China; 3Taizhou Affiliated Hospital of Nanjing University of Chinese Medicine, Taizhou, People’s Republic of China; 4Taizhou People’s Hospital affiliated to Nanjing Medical University, Taizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huae Xu; Yinxing Zhu, Email xuhuae@njmu.edu.cn; zhuyinxing@njmu.edu.cnBackground: The causal relationship of breast cancer (BC) with cardiovascular disease (CVD) and the underlying mediating pathways remains elusive. Our study endeavors to investigate the causal association between BC and CVD, with a focus on identifying potential metabolic mediators and elucidating their mediation effects in this causality.Methods: In this study, we conducted two-sample Mendelian randomization (MR) to estimate the causal effect of BC (overall BC, ER+ BC, ER- BC) from the Breast Cancer Association Consortium (BCAC) on CVD including coronary heart disease (CHD), hypertensive heart disease (HHD), ischaemic heart disease (IHD), and heart failure (HF) from the FinnGen consortium. Then, we used two-step MR to evaluate 18 metabolic mediators of the association and calculate the mediated proportions.Results: Genetically predicted ER+ BC was causally associated with an increased risk of CVD including CHD (OR = 1.034, 95% CI: 1.004– 1.065, p = 0.026), HHD (OR = 1.061, 95% CI: 1.002– 1.124, p = 0.041), IHD (OR = 1.034, 95% CI: 1.007– 1.062, p=0.013), and HF (OR = 1.055, 95% CI: 1.013– 1.099, p = 0.010), while no causality was observed for overall BC and ER- BC. Furthermore, high-density lipoprotein cholesterol (HDL-C) was identified as a mediator of the association between ER+BC and CVD, including CHD (with 15.2% proportion)) and IHD (with 15.5% proportion), respectively.Conclusion: This study elucidates the potential causal impact of ER+ BC on subsequent risk of CVD, including CHD, HHD, IHD, and HF. We also outline the metabolic mediator HDL-C as a priority target for preventive measures to reduce excessive risk of CVD among patients diagnosed with ER+BC.Keywords: breast cancer, cardiovascular disease, ER status, Mendelian randomization, metabolic mediators, HDL-C

Zhiyan Dai,1,* Chao Chen,2,3,* Ziyan Zhou,1,2 Mingzhen Zhou,1,2 Zhengyao Xie,1 Ziyao Liu,1 Siyuan Liu,1 Yiqiang Chen,1 Jingjing Li,1 Baorui Liu,2 Jie Shen1,2 1Department of Precision Medicine, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Oncology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Oncology, Jinling Hospital, Clinical College of Nanjing Medical University, Nanjing, 21002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Shen, Department of precision medicine, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, People’s Republic of China, Email shenjie2008nju@163.com Baorui Liu, Department of Oncology, Nanjing Drum Tower Hospital,Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, People’s Republic of China, Email baoruiliu@nju.edu.cnBackground: Immune checkpoint inhibitor (ICI) therapy is a promising treatment for cancer. However, the response rate to ICI therapy in hepatocellular carcinoma (HCC) patients is low (approximately 30%). Thus, an approach to predict whether a patient will benefit from ICI therapy is required. This study aimed to design a classifier based on circulating indicators to identify patients suitable for ICI therapy.Methods: This retrospective study included HCC patients who received immune checkpoint inhibitor therapy between March 2017 and September 2023 at Nanjing Drum Tower Hospital and Jinling Hospital. The levels of the 17 serum biomarkers and baseline patients’ characters were assessed to discern meaningful circulating indicators related with survival benefits using random forest. A prognostic model was then constructed to predict survival of patients after treatment.Results: A total of 369 patients (mean age 56, median follow-up duration 373 days,) were enrolled in this study. Among the 17 circulating biomarkers, 11 were carefully selected to construct a classifier. Receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) of 0.724. Notably, patients classified into the low-risk group exhibited a more positive prognosis (P = 0.0079; HR, 0.43; 95% CI 0.21– 0.87). To enhance efficacy, we incorporated 11 clinical features. The extended model incorporated 12 circulating indicators and 5 clinical features. The AUC of the refined classifier improved to 0.752. Patients in the low-risk group demonstrated superior overall survival compared with those in the high-risk group (P = 0.026; HR 0.39; 95% CI 0.11– 1.37).Conclusion: Circulating biomarkers are useful in predicting therapeutic outcomes and can help in making clinical decisions regarding the use of ICI therapy.Keywords: hepatocellular carcinoma, predictive model, immunotherapy, machine learning

Xiaolan Guo,1 Dansen Wu,1 Xiaoping Chen,2 Jing Lin,1 Jialong Chen,1 Liming Wang,1 Songjing Shi,1 Huobao Yang,1 Ziyi Liu,3 Donghuang Hong1,4 1Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, People’s Republic of China; 2Computer Science and Mathematics, Fujian University of Technology, Fuzhou, Fujian, People’s Republic of China; 3Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou, Fujian, People’s Republic of ChinaCorrespondence: Ziyi Liu, Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160, Pujian Road, Pudong District, Shanghai, 200127, People’s Republic of China, Email liu-ziyi@sjtu.edu.cn Donghuang Hong, Department of Critical Care Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, No. 134, Dongjie Street, Gulou District, Fuzhou, Fujian, 350001, People’s Republic of China, Email hongdh2003@fjmu.edu.cnPurpose: The objective of this study was to identify the risk factors associated with Carbapenem-resistant Enterobacteriaceae (CRE) colonization in intensive care unit (ICU) patients and to develop a predictive risk model for CRE colonization.Patients and Methods: In this study, 121 ICU patients from Fujian Provincial Hospital were enrolled between January 2021 and July 2022. Based on bacterial culture results from rectal and throat swabs, patients were categorized into two groups: CRE-colonized (n = 18) and non-CRE-colonized (n = 103). To address class imbalance, Synthetic Minority Over-sampling Technique (SMOTE) was applied. Statistical analyses including T-tests, Chi-square tests, and Mann–Whitney U-tests were employed to compare differences between the groups. Feature selection was performed using Lasso regression and Random Forest algorithms. A Logistic regression model was then developed to predict CRE colonization risk, and the results were presented in a nomogram.Results: After applying SMOTE, the dataset included 198 CRE-colonized patients and 180 non-CRE-colonized patients, ensuring balanced groups. The two groups were comparable in most clinical characteristics except for diabetes, previous emergency department admission, and abdominal infection. Eight independent risk factors for CRE colonization were identified through Random Forest, Lasso regression, and Logistic regression, including Acute Physiology and Chronic Health Evaluation (APACHE) II score > 16, length of hospital stay > 31 days, female gender, previous carbapenem antibiotic exposure, skin infection, multi-site infection, immunosuppressant exposure, and tracheal intubation. The risk prediction model for CRE colonization demonstrated high accuracy (87.83%), recall rate (89.9%), precision (85.6%), and an AUC value of 0.877. Patients were categorized into low-risk (0– 90 points), medium-risk (91– 160 points), and high-risk (161– 381 points) groups, with corresponding CRE colonization rates of 1.82%, 7.14%, and 58.33%, respectively.Conclusion: This study identified independent risk factors for CRE colonization and developed a predictive model for assessing the risk of CRE colonization.Keywords: carbapenem-resistant Enterobacteriaceae, intensive care unit, colonization, risk factors, risk prediction model

Guiyun Zhang,1 Zhe Liu,1 Zhen Li,2 Yangchun Xu1 1Department of Dermatology, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of China; 2Department of Medical Administration, The Second Hospital of Jilin University, Changchun, 130041, People’s Republic of ChinaCorrespondence: Yangchun Xu, Department of Dermatology, The Second Hospital of Jilin University, No. 218 Ziqiang Street, Nanguan District, Changchun, 130041, People’s Republic of China, Tel +86-431-81136244, Email Xuyc@jlu.edu.cnAbstract: Keloids are pathologic scars that pose a significant functional and cosmetic burden. While the literature on keloid management continues to expand, the absence of standardized guidelines or treatment protocols endorsed by academic governing bodies remains a significant challenge. The pathogenesis of keloid scars is not fully elucidated. This review delves into the intricate pathogenesis of keloids, exploring the molecular and cellular mechanisms underlying their formation. Conventional therapies are analyzed in-depth considering their efficacy and limitations, including surgical excision, pharmacotherapies, radiotherapy, cryotherapy, silicone-based product, pressure therapy, and light-based therapy. The emergence of novel therapeutic approaches is discussed, including pharmacotherapies, physical therapies, and biological therapies, shedding light on their potential in treating keloid scars. We also contemplate future directions in the field, encompassing the application of targeted therapies, gene-editing tools, tissue engineering, and regenerative medicine, together with psychosocial support and patient education. In synthesizing current knowledge, scrutinizing therapeutic modalities, and envisioning future avenues, this review aims to provide a comprehensive reference for clinicians, researchers, and stakeholders engaged in the intricate field of keloid management.Keywords: keloid scars, pathogenesis, therapies

Xiaojing Wang, Qinli Guo, Zhaoxiang Liu, Yanlei Wang, Chenxiang Cao, Lixia Jin, Caihong Li, Jianzhong Xiao, Wenhui Zhao Department of Endocrinology, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Wenhui Zhao, Department of Endocrinology, Beijing Tsinghua Changgung Hospital, LiTang Lu No. 168, Chang Ping District, Beijing, 102218, People’s Republic of China, Tel +86-13810719795, Email zwha01637@btch.edu.cnPurpose: Obesity has become a major public health concern worldwide, increasing the risk of T2DM. Growing evidence indicates gut microbiota dysbiosis is related to metabolic disorders. We aimed to firstly investigate the compositional and functional features of the gut microbiome between obesity with and without T2DM in the Chinese population.Methods: A total of 32 obese individuals accompanied with T2DM and 18 age and gender-matched obesity with normal glucose tolerance (NGT) were enrolled. Fecal samples were collected, and the gut microbiota profile was determined using the Illumina MiSeq platform based on V3-V4 bacterial 16S rRNA gene.Results: Compared with obesity- NGT, obesity-T2DM showed a significantly higher alpha diversity. Principal coordinates analysis based on both Bray-Curtis distance and weighted Unifrac revealed that the global microbial composition was significantly different between the two groups (P = 0.007 and P = 0.005, respectively). At the phylum level, Obesity-T2DM patients exhibited a significant decrease in Bacteroidetes, and a pronounced increase in Firmicutes. Regarding the genus level, Bacteroides and Escherichia-Shigella were found to increase considerably, while Prevotella_9 and Sutterella had an evident decrease in Obesity-T2DM. Furthermore, Spearman correlation analysis revealed that Prevotella_9 and Sutterella were negatively associated with HbA1c and fasting blood glucose.Conclusion: We found clear differences in the gut microbiota composition in obesity-T2DM compared with obesity-NGT. Obesity accompanied with T2DM may aggravate the obesity-associated gut microbiota, and gut microbiota is expected to be a promising novel intervention target for obese management. However, larger sample size and more in-depth taxonomic identification studies are warranted.Keywords: gut microbiota, obesity, type 2 diabetes

Wenyi Li,1,2 Zhenguo Liu,1 Min Song,1 Zhenpeng Shi,1 Jihang Zhang,3 Junyu Zhou,1 Yidan Liu,1 Yun Qiao,4 Deshan Liu4 1First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 2Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 3Traditional Chinese Medicine College, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 4Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Deshan Liu, Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, People’s Republic of China, Tel +86 18560087381, Email liudeshan@sdu.edu.cnContext: Diabetic nephropathy (DN) and cognitive dysfunction (CD) are common complications of diabetes. Yi-Qi-Bu-Shen Recipe (YQBS) can effectively reduce blood glucose, improve insulin resistance, and delay the progression of diabetic complications. The underlying mechanisms of its effects need to be further studied.Objective: This study elucidates the mechanism of YQBS in DN with CD through network pharmacology and experimental validation.Materials and Methods: Protein-protein interaction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Male Sprague-Dawley (SD) rats were divided into 6 groups: model, YQBS (2, 4, 8 g/kg), positive control (metformin, 200 mg/kg), and control; the DN model was established by high sugar and high fat diet combined with intraperitoneal streptozotocin injection. After the DN model was established, the rats were gavaged for 10 weeks. Serum, kidneys, and hippocampus tissues were collected to measure the expression levels of TLR4, NF-κB, TNF-α, and IL-6.Results: The network pharmacology analysis showed that quercetin and kaempferol were the main active components of YQBS. TNF and IL-6 were the key targets, and TLR4/NF-κB pathway was crucial to YQBS in treating DN complicated with CD. Experimental validation showed that the intervention of YQBS can reduce TNF-α and IL-6 in serum, and also significantly decreases the protein expression of TLR4 and NF-κB.Conclusion: YQBS exerts anti-inflammatory effects on DN with CD through TLR4/NF-κB pathway. This study provides a biological basis for the scientific usage of YQBS in inflammation diseases and supplies experimental evidence for future traditional Chinese medicine development.Keywords: Yiqi Bushen Recipe, diabetes nephropathy, cognitive dysfunction, network pharmacology, inflammation

Xiuxin Tang,1,* Zhiyun Liu,2,* Danni Li,3 Yan Xiong,3 Kang Liao,1 Yili Chen1 1Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Clinical Laboratory, Huizhou Central People ‘s Hospital, Huizhou, Guangdong, 516001, People’s Republic of China; 3Department of Emergency Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yili Chen, Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Er Road Guangzhou, Guangzhou, Guangdong Province, 510080, People’s Republic of China, Tel +8620-87330808-8461, Fax +8620-87330808, Email chenyli3@mail.sysu.edu.cnBackground: Elizabethkingia anophelis, an opportunistic pathogen that can cause infections in multiple parts of the human body, has multiple drug resistance and a high mortality rate. However, there have been few reports of infective endocarditis (IE) caused by Elizabethkingia anophelis, which means that diagnosis and treatment face challenges that cannot be ignored. Rapid and accurate identification and drug sensitivity results are needed to make timely treatment adjustments.Case Presentation: An 81-year-old man presented with recurrent fever and increased infection index for more than a month. Based on his clinical symptoms, infection index, reduplicative blood cultures, and results of transesophageal echocardiography, he was ultimately diagnosed with infective endocarditis caused by Elizabethkingia anophelis. The patient had a favorable outcome with a 6-week course of intravenous antibiotic therapy.Conclusion: This is a rare and successfully cured case of IE caused by the pathogen of Elizabethkingia anophelis, which is difficult not only in diagnosis but also in treatment. This case provides a certain referential significance to the treatment of Elizabethkingia anophelis-caused IE in clinical practice.Keywords: Elizabethkingia anophelis, infective endocarditis, drug resistance, treatment

Zhihong Liu,1,2,* Xiaofang Liang,1,* Yu Zhang,1 Wenbo Deng,1 Yulin Wang,3 Zhangping Lu,2 Qianqian Liu,2 Lianhua Wei2 1School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, People’s Republic of China; 2Department of Clinical Laboratory, Gansu Provincial Hospital, Lanzhou, Gansu, People’s Republic of China; 3Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lianhua Wei, Email 107306723@qq.comAbstract: The development of antibiotic resistance complicates the treatment of infectious diseases and is a global public health threat. However, drug repurposing can address this resistance issue and reduce research and development costs. Niclosamide is a salicylanilide compound approved by the Food and Drug Administration (FDA), and it has been used clinically for treating parasitic infections for many years. Recent studies have shown that niclosamide can inhibit bacterial and fungus activity by affecting the quorum sensing system, biofilm formation, cell membrane potential, and other mechanisms. Here, we discuss recent advances in the antimicrobial applications of niclosamide and its derivatives to provide new perspectives in treating infectious diseases.Keywords: antimicrobial resistance, multi-drug resistance, niclosamide, a derivative, drug repurposing

Xiaotong Tian,1,2 Jing Lin,1,2 Menglan Zhou,3,4 Ying Ge,1 Taisheng Li,1 Li Zhang,1 Zhengyin Liu1 1Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 2Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China; 4Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, People’s Republic of ChinaCorrespondence: Zhengyin Liu; Li Zhang, Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China, Email liuzhy@pumch.cn; zhangli36@pumch.cnPurpose: To evaluate the clinical outcomes and safety of tigecycline (TGC) plus cefoperazone/sulbactam (CPS) or TGC monotherapy in patients with hospital-acquired pneumonia (HAP) caused by Carbapenem-Resistant Acinetobacter baumannii (CRAB).Methods: This was a retrospective analysis of multicenter data from 62 Chinese hospitals with CRAB HAP. Risk factors for receiving TGC with CPS therapy and predictors of mortality were assessed using multivariate logistic and Cox regression analyses, respectively. Propensity score matching (PSM) evaluated the efficacy and safety of antimicrobial regimens.Results: A total of the 180 patients were included, with 95 receiving TGC monotherapy and 85 receiving combination therapy. Multivariate logistic regression analysis revealed that older age (P = 0.011), and intensive care unit (ICU) admission (P = 0.007) were significant risk factors for combination therapy. Multivariate Cox regression demonstrated that combination therapy was associated with a significantly higher risk of 90-day mortality (P = 0.031). Patients in the standard-dose TGC (SDT) plus CPS subgroup had significantly higher rates of SOFA scores ≥ 7 (P = 0.009) and MV used (P = 0.028), as well as higher 30-/90-day mortality compared to high-dose TGC (HDT) plus CPS group. TGC plus CPS significantly reduced CRP levels (P = 0.009), while the variations in ALT, TBIL, Cr, Hb, and PLT levels did not differ between different antimicrobial regimens after PSM.Conclusion: HDT and CPS combination therapy was more effective in patients with advanced age and more severe condition. Safety profiles of different antimicrobial regimens were similar with liver, kidneys, and coagulation functions.Keywords: carbapenem-resistant Acinetobacter baumannii, hospital acquired pneumonia, tigecycline, cefoperazone/sulbactam, risk factors

Qian Meng,1,* Xiaowei Yang,1,* Zhongcheng Liu,2 Guoxing You,3 Wanyi Chen,3 Bing Zhao,1 Huizi Zhu,4 Liang Xu,1 Yan Zhou,1 Xiang Liu,1 Chunjuan Zhai,5 Rong Wang,1 Lian Zhao,3 Jing Sun1 1Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Cardiovascular, The North City Hospital of Jinan, Jinan, Shandong, 250031, People’s Republic of China; 3Academy of Military Medical Sciences, Beijing, 100850, People’s Republic of China; 4Department of Nephrology, Fuyang People’s Hospital, Fuyang, Anhui, 236000, People’s Republic of China; 5Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Sun, Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, Shandong, 250021, People’s Republic of China, Tel +86 151 6888 6367, Email sunj5708@126.com Lian Zhao, Academy of Military Medical Sciences, 27 Taiping Road, Beijing, 100850, People’s Republic of China, Tel +8613671217095, Email zhaolian@bmi.ac.cnPurpose: Chronic kidney disease (CKD) is associated with persistent systemic inflammation. Reduced red blood cell (RBC) survival in patients with CKD has been identified for several decades. The purpose of this study is to explore whether excessive erythrophagocytosis exists and contributes to systemic inflammation in CKD.Patients and methods: A CKD rat model was induced by 5/6 nephrectomy. Erythrocyte osmotic fragility was determined with hypotonic NaCl solutions. Erythrocyte deformability was evaluated by filterability. RBC cell death was quantified using fluorescence-activated cell sorting analyses of fluorescent annexin V–bound surface phosphatidylserine (PS). Erythrophagocytosis was evaluated in vivo and in vitro. RT-qPCR and immunohistochemistry were used to determine the inflammatory effects after erythrophagocytosis.Results: Erythrocyte osmotic fragility and deformability progressively declined, and the percentage of PS-exposing RBCs progressively increased in CKD rats. Levels of erythrophagocytosis in vivo were evaluated by autologous injection of CFSE-labeled erythrocytes. In comparison with the control group, higher fluorescence intensity of CFSE was detected in the spleen homogenates of rats with CKD. In vitro, more of erythrocytes from 5/6Nx rats were phagocytosed by peritoneal macrophages in comparison to those from control rats. Compared with macrophages phagocytosed control erythrocytes, macrophages phagocytosed CKD erythrocytes exhibited higher mRNA levels of IL-6, CXCL-10, CXCL-11, iNOS, IL-1β, ICAM-1 and MCP-1. Compared with the control group, the red pulp of rats with CKD exhibited higher levels of p-NFκB, IL-6, iNOS and CXCL-10. ELISA results showed significantly increased plasma levels of both IL-6 and CXCL-10 in patients with long-term hemodialysis compared with those in healthy controls (2.30 ± 1.38 pg/mL vs 1.33 ± 0.65 pg/mL, P=0.01; 78.11 ± 27.34 pg/mL vs 37.45 ± 7.08 pg/mL, P=0.001).Conclusion: Our results indicated that excessive erythrophagocytosis may contribute to systemic inflammation in CKD. Keywords: chronic kidney disease, chronic inflammation, erythrocyte, phagocytosis

Ting Liu,1,* Chao Lei,1,* Qinhong Huang,2,* Weiqi Song,3 Chen Li,1 Ning Sun,4,5 Zhihua Liu6 1Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510799, People’s Republic of China; 2The First Clinical College, Guangzhou Medical University, Guangzhou, 511400, People’s Republic of China; 3Department of Public Health, Guangzhou Medical University, Guangzhou, People’s Republic of China; 4Guangzhou 11th People’s Hospital, Guangzhou Cadre and Talent Health Management Center, Guangzhou, 510530, People’s Republic of China; 5The State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, the Hong Kong Polytechnic University, 999077, Hong Kong, China; 6Department of Anorectal Surgery, the Tenth Affiliated Hospital of Southern Medical University (Dongguan People’s Hospital), Dongguan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihua Liu; Ning Sun, Email liuzhihua83@hotmail.com; ning.sun@connect.polyu.hkIntroduction: Obesity, which is associated with gut microbiota dysbiosis, low-grade chronic inflammation and intestinal barrier dysfunction, can cause a variety of chronic metabolic diseases. Phytochemical flavonoids have a variety of biological activities, among which there may be safe and effective anti-obesity solutions.Methods: We tested a plant-derived flavonoid hesperidin and fecal microbiota transplantation (FMT) to alleviate diet-induced obesity. High-fat diet (HFD)-fed mice were treated with hesperidin (100 and 200 mg/kg BW) and FMT.Results: Results indicated that hesperidin had the effects of reducing obesity as indicated by reduction of body weight, fat accumulation and blood lipids, reducing inflammation as indicated by reduction of pro-inflammation factors including TNFα, IL-6, IL-1βand iNOS, and improving gut integrity as indicated by increasing colon length, reducing plasma gut permeability indicators iFABP and LBP, increased mRNA expression of mucus protein Muc2, tight junction p Claudin 2, Occludin and ZO-1 in the HFD-fed mice. The anti-obesity effects of hesperidin treatment have a dose-dependent manner. In addition, 16S rRNA-based gut microbiota analysis revealed that hesperidin selectively promoted the growth of Lactobacillus salivarius, Staphylococcus sciuri and Desulfovibrio C21_c20 while inhibiting Bifidobacterium pseudolongum, Mucispirillum schaedleri, Helicobacter ganmani and Helicobacter hepaticus in the HFD-fed mice. Horizontal feces transfer from the normal diet (ND)-fed mice to the HFD-fed mice conferred anti-obesity effects and transmitted some of the HFD-modulated microbes.Conclusion: We concluded that hesperidin and FMT both affect the reduction of body weight and improve HFD-related disorders in the HFD-fed mice possibly through modulating the composition of the gut microbiota.Keywords: hesperidin, high-fat diet, obesity, gut microbiota, fecal microbiota transplantation

Qian Song,1,2,* Kaili Zheng,1,2,* Zixia Ding,1,2 Zhengmiao Miao,1,2 Zhaoxia Liu,1,2 Ming Cheng,3 Jinyao Yi1,2,4 1Medical Psychological Center, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Medical Psychological Institute, Central South University, Changsha, People’s Republic of China; 3Department of Clinical Psychology, Hunan Brain Hospital, Changsha, People’s Republic of China; 4National Clinical Research Center for Mental Disorders, Changsha, 410011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinyao Yi, Medical Psychological Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China, Email jinyaoyi@csu.edu.cnBackground: There exist four short forms of the Social Interaction Anxiety Scale (SIAS): 10-item version (SIAS-10), 6-item version by Peters et al (SIAS-6P), 6-item version by Fergus et al (SIAS-6F), and 5-item version (SIAS-5). This study aims to comprehensively examine the psychometric properties of the SIAS-10, SIAS-6P, SIAS-6F, and SIAS-5 and to determine which one performs relatively better in Chinese population.Methods: This study enrolled 733 Chinese college students. The unidimensionality of the SIAS-10, SIAS-6P, SIAS-6F, SIAS-5 was examined using Confirmatory Factor Analysis (CFA). Multi-Group CFA was further adopted to assess measurement equivalence across gender. Internal consistency reliability and criteria-related validity were also evaluated. Additionally, the measurement performance of the SIAS-10, SIAS-6P, SIAS-6F, and SIAS-5 was assessed with Item Response Theory (IRT), which estimated the discrimination parameter and the Item Characteristic Curve (ICC) for each item.Results: Except for the SIAS-5, the SIAS-10, SIAS-6P, and SIAS-6F displayed a good-fit to the one-factor model. Furthermore, the SIAS-10 achieved strict equivalence across gender while other versions did not. The SIAS-10, SIAS-6P, SIAS-6F and SIAS-5 all had acceptable internal consistency and significant correlations with criteria scales. The IRT results showed that the SIAS-10 included more items with higher discrimination and peaked ICCs (indicating more informative), whereas the SIAS-6P included more items with lower discrimination and flat ICCs (indicating less informative).Conclusion: For assessing social anxiety in Chinese under constrained conditions, the SIAS-10 is recommended to clinicians for it measuring equivalently across gender, reflecting the relevant criteria variables well, and discriminating various levels of social anxiety sensitively.Keywords: social anxiety, psychometric properties, measurement equivalence, item response theory, Chinese

Shi-liang Chen,1,* Dan Hu,2,* Tian-zhu Chen,3,* Si-yu Shen,4,* Chen-fei Zhao,1,* Cong Wang,1 Shi-yuan Tong,5 Zhao Liu,6 Shao-hua Lin,1 Li-xia Jin,7 Yi-bo He,1 Zhe-zhong Zhang1 1Department of Clinical Lab, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China; 2Department of Clinical Lab, The Cixi Integrated Traditional Chinese and Western Medicine Medical and Health Group Cixi Red Cross Hospital, Cixi, People’s Republic of China; 3Department of Pathology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China; 4The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 5The Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, People’s Republic of China; 6Department of General Surgery, Shaoxing Central Hospital, Shaoxing, People’s Republic of China; 7School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhe-zhong Zhang; Yi-bo He, Department of Clinical Lab, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, People’s Republic of China, Email zhangzhezhong2023@163.com; heyb1992@126.comPurpose: Cancer-associated fibroblasts (CAFs) significantly contribute to tumor progression and the development of resistance to therapies across a range of malignancies, notably breast cancer. This study aims to elucidate the specific role and prognostic relevance of CALU across multiple cancer types.Patients and Methods: The association between CALU expression and prognosis, along with clinical characteristics in BRCA, HNSC, KIRP, LGG, and LIHC, was analyzed using data from the TCGA, GTEx, and GEO databases. Transcriptomic analysis of TCGA BRCA project data provided insights into the interaction between CALU and epithelial-mesenchymal transition (EMT) marker genes. Using TIMER and TISCH databases, the correlation between CALU expression and tumor microenvironment infiltration was assessed, alongside an evaluation of CALU expression across various cell types. Furthermore, CALU’s influence on TNBC BRCA cell lines was explored, and its expression in tumor tissues was confirmed through immunohistochemical analysis of clinical samples.Results: This study revealed a consistent upregulation of CALU across several tumor types, including BRCA, KIRP, LIHC, HNSC, and LGG, with elevated CALU expression being associated with unfavorable prognoses. CALU expression was particularly enhanced in clinical contexts linked to poor outcomes. Genomic analysis identified copy number alterations as the principal factor driving CALU overexpression. Additionally, a positive correlation between CALU expression and CAF infiltration was observed, along with its involvement in the EMT process in both CAFs and malignant cells. In vitro experiments demonstrated that CALU is highly expressed in TNBC-BRCA cell lines, and knockdown of CALU effectively reversed EMT progression and inhibited cellular migration. Immunohistochemical analysis of clinical samples corroborated the elevated expression of CALU in tumors, along with alterations in EMT markers.Conclusion: This comprehensive pan-cancer analysis underscores CALU’s critical role in modulating the tumor microenvironment and facilitating cell migration via the EMT pathway, identifying it as a potential therapeutic target.Keywords: CALU, cancer-associated fibroblasts, epithelial-mesenchymal transition, breast cancer, prognosis, pan-cancer analysis

Qingqing Shen,1– 3,&ast; Qing Zhang,2,3,&ast; Yunxiao Liu,1– 3,&ast; Yingao Cui,1– 3 Jingwen Shang,1– 3 Xiaoping Yuan,2,3 Feng Geng,4 Liang Sun,5 Zhiwei Liu,5 Rongchun Yang,5 Kai Zhang,2,3 Huanzhong Liu2,3,6 1Department of Psychiatry, School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Anhui Psychiatric Center, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 4Department of Psychology and Sleep Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 5Department of Psychiatry, Fuyang Third People’s Hospital, Fuyang, Anhui, People’s Republic of China; 6Brain Bank Construction and Resource Utilization, Anhui Provincial Key Laboratory, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kai Zhang; Huanzhong Liu, Department of Psychiatry, Chaohu Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email zhangkai@ahmu.edu.cn; huanzhongliu@ahmu.edu.cnPurpose: The purpose of this study was to further explore the association of pain intensity and sensitivity with suicidal ideation in adolescents with depressive disorder by comparing the differences in pain intensity and sensitivity between adolescent patients with depressive disorders and healthy controls.Patients and Methods: A consecutive enrollment method was used to select 158 adolescent patients with depressive disorders from three hospitals in Anhui Province as the MDD group, and 47 healthy adolescents were recruited as the Control group. The subjects’ suicidal ideation was assessed using the Positive and Negative Suicide Ideation scale (PANSI), and the intensity of somatic pain was assessed using the Numerical Rating Scale-11 (NRS-11). Subjects were assessed for forearm and tibial pain sensitivity using a hand-held pressure pain instrument, and experimental pain sensitivity measures included pressure pain threshold (PPT) and pressure pain tolerance (PTO). Differences in pain intensity and sensitivity between the MDD group and the Control group were compared, and the association of pain intensity and sensitivity with suicidal ideation was analyzed.Results: The incidence of physical pain in adolescent depressive disorder was higher at 88.6%, which was significantly higher than the Control group (P< 0.001), and the pain intensity in the MDD group (3.77± 2.48) was significantly higher than the Control group (0.617± 0.99) (P < 0.001).The Pain tolerance was significantly higher in the MDD group (forearm 105.37 ± 41.46; tibia 121.29 ± 41.60) than in the Control group (forearm 91.92 ± 37.62; tibia 105.47 ± 35.52) (P < 0.05).Linear regression analysis showed that the greater the pain intensity and pain tolerance, the higher the total PANSI score.Binary logistic regression showed that pain intensity was an influencing factor for suicidal ideation.Conclusion: Adolescents with depressive disorders have higher pain intensity and lower pain sensitivity than healthy adolescents. Increased pain intensity and pain tolerance were positively correlated with suicidal ideation.Keywords: adolescents, depressive disorder, pain intensity, pain sensitivity, suicidal ideation

Yuhang Tian,1 Xiang He,1 Yanchi Yuan,1 Shijie Zhang,2 Chunyue Wang,1 Jialin Dong,1 Zhao Liu,1 Hui Jing1 1Department of Ultrasound, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of China; 2Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, People’s Republic of ChinaCorrespondence: Hui Jing, Department of Ultrasound, Harbin Medical University Cancer Hospital, 150 Haping Road, Nangang District, Harbin, 150081, People’s Republic of China, Email jinghuihrb@163.comBackground: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities.Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37.Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+, which in turn converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+-mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability.Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future.Keywords: mild photothermal therapy, gene therapy, ferroptosis, synergistic therapy, multimodal imaging

Kun Li,1,2 Kun Wang,3 Shu-Xian Xu,1 Xin-Hui Xie,1 Yan Tang,3 Lihong Zhang,2 Zhongchun Liu1,4 1Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Clinical Laboratory, Affiliated Hospital of West Anhui Health Vocational College, Lu’an, Anhui, People’s Republic of China; 3Department of Psychiatry, Affied Hospital of West Anhui Health Vocational College, Lu’an, Anhui, People’s Republic of China; 4Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Zhongchun Liu, Department of Psychiatry, Renmin Hospital of Wuhan University, No. 99 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, People’s Republic of China, Email zcliu6@whu.edu.cnPurpose: To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with plasma BDNF levels.Patients and Methods: Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs.Results: After false discovery rate correction, patients with MDD exhibited higher CD81 levels (PFDR = 0.040) and lower BDNF levels (PFDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (PFDR = 0.002) and Alix (PFDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (PFDR = 0.046), while BDNF levels normalized to CD81 increased (PFDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (ρ=0.117, P = 0.334).Conclusion: This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.Keywords: major depressive disorder, ADEV, BDNF, biomarker, treatment

Xi Wu, Qin Li, Mingxing Wu, Haobo Huang, Zhe Liu, He Huang, Lei Wang Department of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, 411100, People’s Republic of ChinaCorrespondence: Lei Wang, Department of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, 411100, People’s Republic of China, Email heartwl@126.comObjective: The research was carried out to determine and compare the efficiency of completely transradial access (cTRA) and transfemoral access (TFA) in retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI).Background: The cases of retrograde chronic total occlusion (CTO) percutaneous coronary intervention usually need the dual access. The transradial method is now used more frequently in CTO PCI, and improves the safety of CTO PCI.Methods: This retrospective, observational study was carried out in a single center. Participants were patients who underwent dual-access retrograde CTO PCI from January 2017 to October 2023, categorized into two groups: cTRA (biradial access) and TFA (bifemoral, or combined radial and femoral access). All patients in the cTRA group received conventional radial access. All punctures of the femoral artery were performed without fluoroscopic or ultrasound guidance. None of the patients in the TFA group accepted any arterial closure devices. Clinical, angiographic and procedural characteristics and the occurrence of in-hospital major adverse cardiovascular events (MACE) of the cTRA and TFA procedures were recorded.Results: This research involved 187 CTO PCI procedures with dual access, of which 88 were done using cTRA and the rest (99) were carried out through TFA. The J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) score was lower in the cTRA group than TFA group (2.1± 0.6 vs 3.0± 0.8; P < 0.001). The technical success (84.1% vs 82.8%; P= 0.817), procedural success (80.7% vs 79.8%; P= 0.906) and in-hospital MACE rates (5.7% vs 4.0%; P= 0.510) were the same for both groups. For a J-CTO score of 3 or higher, technical success rate was significantly lower in the cTRA group than the TFA group (58.1% vs 74.2%; P < 0.001).Conclusion: In the retrograde CTO PCI, the percentages of success and in-hospital MACE were similar for both cTRA and TFA. Meanwhile, cTRA may be used for simpler lesions (J-CTO score < 3) as compared to TFA.Keywords: transradial approach, transfemoral approach, chronic total occlusion, retrograde, percutaneous coronary intervention

Jingjing Wei,1,&ast; Zhaoyang Liu,1,2,&ast; Mingming Li,1 Lingyun Du,1 Xia Zhu,1 Yi Leng,1 Changyu Han,1 Qingqing Xu,1 Chunhong Zhang1 1Department of Dermato-Venereology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Dermato-Venereology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunhong Zhang, Department of Dermato-Venereology, the Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Beiyuan Dajie Street, Jinan, People’s Republic of China, Tel +86-531-85875027, Fax +86-531-88962544, Email aliu133@163.comBackground: Psoriasis is an immune-mediated chronic inflammatory disease. Qingre Lishi Decoction (QRLSD) has achieved great clinical effect in the treatment of psoriasis. However, the potential bioactive components and the mechanisms are yet unclear.Aim: To analyze the serum parameters of rats fed with QRLSD, screen out the active components of QRLSD, and explore the potential targets and pathway of QRLSD in the treatment of psoriasis.Materials and Methods: The active components of serum containing QRLSD were analyzed using ultra-high performance liquid chromatography quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). The targets of QRLSD in the treatment of psoriasis were predicted by network pharmacology and molecular docking. In vitro experiments verified the underlying mechanism.Results: By UPLC-Q-TOF/MS, 15 prototype components and 22 metabolites were identified in serum containing QRLSD. Subsequently, 260 chemical composition targets and 218 psoriasis targets were overlapped to obtain 23 intersection targets, including LGALS3, TNF, F10, DPP4, EGFR, MAPK14, STAT3 and others. TNF, IL-10, GAPDH, STAT3, EGFR, ITGB1, LGALS3 genes were identified as potential drug targets in the PPI network analyzed by CytoHubba. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that QRLSD may improve psoriasis by regulating immune and inflammatory pathways, the cytokine mediated signal transduction pathways and other signaling pathways. Molecular docking results showed that the main active components of the serum containing QRLSD had higher affinities for TNF and LGALS3. In vitro experiments confirmed that QRLSD may decrease levels of inflammatory cytokines by suppressing the NF-κB signaling pathway activated by TNF-α in human keratinocytes.Conclusion: This study explores the potential compounds, targets and signaling pathways of QRLSD in the treatment of psoriasis, which will help clarify the efficacy and mechanism of QRLSD.Keywords: qingre lishi decoction, psoriasis, UPLC-Q-TOF/MS, network pharmacology, molecular docking, NF-κB signaling pathway

Youqian Li,1,2 Wei Zhong,1,2 Zhidong Liu,1,2 Changjing Huang,1,2 Junyin Peng,1,2 Hanlin Li1,2 1Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Guangdong Provincial Engineering and Technology Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Youqian Li, Center for Cardiovascular Diseases, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, No. 63 Huangtang Road, Meijiang District, Meizhou, People’s Republic of China, Email d_yoyo@163.comBackground: Aldehyde dehydrogenase 2 (ALDH2) is a key catalytic enzyme involved in the aldehyde metabolism that plays an important role in the occurrence and development of acute myocardial infarction (AMI). However, the relationship of ALDH2 polymorphism and susceptibility to AMI may differ among different regions and populations, and it has not yet been reported in Hakka population. The purpose of the present study was to investigate it in this population.Methods: Four hundred and nineteen AMI patients and 636 individuals without AMI were included in the present study. The ALDH2 rs671 polymorphism was genotyped using polymerase chain reaction (PCR)-microarray. Differences in ALDH2 rs671 genotypes and alleles between patients and controls were compared, and the relationship between ALDH2 rs671 genotypes and AMI risk was analyzed.Results: Patients with AMI had a lower frequency of ALDH2 rs671 G/G genotype (43.2% vs 52.7%, p=0.003), and a higher G/A genotype (45.6% vs 38.5%, p=0.025) than controls. And AMI patients had a lower frequency of ALDH2 rs671 G allele (66.0% vs 71.9%), and a higher A allele (34.0% vs 28.1%) (p=0.004) than controls. Logistic regression analysis showed that overweight (body mass index (BMI)≥ 24.0 kg/m2 vs BMI 18.5– 23.9 kg/m2: odds ratio (OR) 2.046, 95% confidence interval (CI): 1.520– 2.754, p< 0.001), history of hypertension (yes vs no: OR 3.464, 95% CI: 2.515– 4.770, p< 0.001), ALDH2 rs671 G/A genotype (G/A vs G/G: OR 1.476, 95% CI: 1.102– 1.976, p=0.009), and A/A genotype (A/A vs G/G: OR 1.656, 95% CI: 1.027– 2.668, p=0.038) maybe the independent risk factors for AMI.Conclusion: Overweight (BMI≥ 24.0 kg/m2), a history of hypertension, and ALDH2 rs671 G/A or A/A genotypes increased the risk of developing AMI in Hakka population.Keywords: aldehyde dehydrogenase 2, acute myocardial infarction, polymorphism, Hakka

Junhai Zhen,1 Chuan Liu,2 Jixiang Zhang,2 Fei Liao,2 Huabing Xie,1 Cheng Tan,2 Ping An,2 Zhongchun Liu,3 Changqing Jiang,4 Jie Shi,5 Kaichun Wu,6 Weiguo Dong2 1Department of General Practice, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People’s Republic of China; 2Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, People’s Republic of China; 3Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China; 4Department of Clinical Psychology, Beijing Anding Hospital, Capital Medical University, Beijing, 100088, People’s Republic of China; 5Department of Medical Psychology, Chinese People’s Liberation Army Rocket Army Characteristic Medical Center, Beijing, 100032, People’s Republic of China; 6Department of Gastroenterology, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of ChinaCorrespondence: Kaichun Wu, Department of Gastroenterology, Xijing Hospital, Air Force Medical University, Xi’an, 710032, People’s Republic of China, Tel/Fax +8629-84771600, Email kaicwu@fmmu.edu.cn Weiguo Dong, Department of Gastroenterology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Tel/Fax +8627-88041911, Email dongweiguo@whu.edu.cnPurpose: Impaired quality of life (QOL) is common in patients with inflammatory bowel disease (IBD). A tool to more quickly identify IBD patients at high risk of impaired QOL improves opportunities for earlier intervention and improves long-term prognosis. The purpose of this study was to use a machine learning (ML) approach to develop risk stratification models for evaluating IBD-related QOL impairments.Patients and Methods: An online questionnaire was used to collect clinical data on 2478 IBD patients from 42 hospitals distributed across 22 provinces in China from September 2021 to May 2022. Eight ML models used to predict the risk of IBD-related QOL impairments were developed and validated. Model performance was evaluated using a set of indexes and the best ML model was explained using a Local Interpretable Model-Agnostic Explanations (LIME) algorithm.Results: The support vector machine (SVM) classifier algorithm-based model outperformed other ML models with an area under the receiver operating characteristic curve (AUC) and an accuracy of 0.80 and 0.71, respectively. The feature importance calculated by the SVM classifier algorithm revealed that glucocorticoid use, anxiety, abdominal pain, sleep disorders, and more severe disease contributed to a higher risk of impaired QOL, while longer disease course and the use of biological agents and immunosuppressants were associated with a lower risk.Conclusion: An ML approach for assessing IBD-related QOL impairments is feasible and effective. This mechanism is a promising tool for gastroenterologists to identify IBD patients at high risk of impaired QOL.Keywords: clinical research, artificial intelligence, model development, clinical decision support system

Ting Sun,1,2,&ast; Jingfang Liu,3,&ast; Hui Wang,3,&ast; Bing Xiang Yang,3– 5 Zhongchun Liu,3 Jie Liu,6 Zhiying Wan,3 Yinglin Li,1 Xiangying Xie,1 Xiaofen Li,3 Xuan Gong,3 Zhongxiang Cai1 1Department of Nursing, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Health Science Center, Yangtze University, Jingzhou, People’s Republic of China; 3Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 4School of Nursing, Wuhan University, Wuhan, People’s Republic of China; 5Population and Health Research Center, Wuhan University, Wuhan, People’s Republic of China; 6Anesthesiology, Virginia Commonwealth University Health System, Richmond, VA, USA&ast;These authors contributed equally to this workCorrespondence: Zhongxiang Cai, Department of Nursing, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Email tg20201228@163.com Xuan Gong, Department of Psychiatry, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Email 12048387@qq.comBackground: Non-suicidal self-injury (NSSI) is a significant social issue, especially among adolescents with major depressive disorder (MDD). This study aimed to construct a risk prediction model using machine learning (ML) algorithms, such as XGBoost and random forest, to identify interventions for healthcare professionals working with adolescents with MDD.Methods: This study investigated 488 adolescents with MDD. Adolescents was randomly divided into 75% training set and 25% test set to testify the predictive value of risk prediction model. The prediction model was constructed using XGBoost and random forest algorithms. We evaluated the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, recall, F Score of the two models for comparing the performance of the two models.Results: There were 161 (33.00%) participants having NSSI. Compared without NSSI, there were statistically significant differences in gender (P=0.035), age (P=0.036), depressive symptoms (P=0.042), sleep quality (P=0.030), dysfunctional attitudes (P=0.048), childhood trauma (P=0.046), interpersonal problems (P=0.047), psychoticism (P) (P=0.049), neuroticism (N) (P=0.044), punishing and Severe (F2) (P=0.045) and Overly-intervening and Protecting (M2) (P=0.047) with NSSI. The AUC values for random forest and XGBoost were 0.780 and 0.807, respectively. The top five most important risk predictors identified by both machine learning methods were dysfunctional attitude, childhood trauma, depressive symptoms, F2 and M2.Conclusion: The study demonstrates the suitability of prediction models for predicting NSSI behavior in Chinese adolescents with MDD based on ML. This model improves the assessment of NSSI in adolescents with MDD by health care professionals working. This provides a foundation for focused prevention and interventions by health care professionals working with these adolescents.Keywords: non-suicidal self-injury, adolescents, major depressive disorder, risk prediction model

Wei Tang,1,2,&ast; Ying Liu,3,&ast; Xin Li,2 Guiyun Leng,2 Ju Gao,2 Yawu Wang,2 Jie Yao,2 Zhou Liu,2 Qiang Zhou,2 Yuanhong Xu1 1Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Department of Clinical Laboratory, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China; 3High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuanhong Xu, Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Shushan District, Hefei, Anhui, 230022, People’s Republic of China, Tel +86 135 0569 4447, Fax +86 551 6292 2125, Email xyhong1964@ahmu.edu.cnPurpose: This study aimed to investigate the microbiological characteristics of clinically isolated Staphylococcus aureus with different hemolytic phenotypes in China.Materials and Methods: Using the three-point inoculation method, the hemolytic phenotypes of 1295 clinically isolated S. aureus strains were detected and categorized. Antimicrobial susceptibility testing of all strains was performed using a VITEK 2 Compact System. After sample size matching, plasma coagulase activity, catalase activity, mRNA expression of hemolysin genes (hla, hlb, hlc, and hld), biofilm formation, growth kinetics, inflammatory response of macrophages and cytotoxicity of S. aureus with different hemolytic phenotypes using the rabbit plasma kit, the catalase test on slides, qRT-PCR, crystal violet staining, the microcultivation assay, the ELISA kits, and the CCK-8 assay, respectively.Results: Seven categories of hemolytic phenotypes were identified. Accordingly, strains were categorized into seven different groups, including S. aureus with complete hemolytic phenotype (SCHP), S. aureus with weak hemolytic phenotype (SWHP), S. aureus with incomplete hemolytic phenotype 1 (SIHP-1), SIHP-2, SIHP-3, SIHP-4 and SIHP-5, the last three of which were reported for the first time. Except for the hemolytic phenotype, all seven groups differed in clinical isolation rates, antibiotic resistance profile, plasma coagulase activity, mRNA expression of hemolysin genes, biofilm formation, growth kinetics, inflammatory response of macrophages, and cytotoxicity.Conclusion: S. aureus with different hemolytic phenotypes have distinctive microbiological characteristics. Clinical microbiologists need to be vigilant about the hemolytic phenotypes when culturing S. aureus strains, and actively enhance communication with clinicians to optimize the treatment of infection.Keywords: Staphylococcus aureus, hemolytic phenotype, hemolysin, microbiological characteristics, antibiotic resistance

Mingyu Shao,1 Zhaohong Liu,1 Tongtong Liu2 1Department of Child Health Care, Zibo Central Hospital, Zibo, Shandong, 255020, People’s Republic of China; 2Department of Pediatrics, Zibo Central Hospital, Zibo, Shandong, 255020, People’s Republic of ChinaCorrespondence: Tongtong Liu, Department of Pediatrics, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, Shandong, 255020, People’s Republic of China, Tel +86-18560290203, Email liutongtong321@126.comIntroduction: Healthcare is essential for asthma control, however, whether family-supported healthcare improves therapeutic effects in childhood asthma remains unclear.Methods: The enrolled patients were randomly divided into control and intervention groups. The pulmonary function was evaluated by forced expiratory volume in 1 s as a percentage of forced vital capacity (FEV1/FVC) and fractional exhaled nitric oxide (FeNO). Asthma control and life quality were assessed via a childhood asthma control test and pediatric asthma quality of life questionnaire. Inflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17) were determined by enzyme-linked immunosorbent assay.Results: No significant differences existed in the basic characteristics of asthma children and their parents among two groups. The increase of FEV1/FVC was higher in the intervention group versus the control group (76.47 ± 10.76% vs 69.76 ± 8.88%, p = 0.001 at the time of post-intervention), and the decrease of FeNO was greater in the intervention group (30.43 ± 6.85 bbp vs 35.64 ± 6.62 bbp, p = 0.003 at the time of post-intervention). Family-supported healthcare highly improved asthma control and quality of life in childhood asthma post-treatment. Meanwhile, the inflammatory cytokines IL-17 (118.14 ± 25.79 pg/mL in intervention group vs 142.86 ± 28.68 pg/mL in control group, p = 0.004 at the time of post-intervention) and IL-6 (103.76 ± 23.11 pg/mL in intervention group vs 119.73 ± 22.68 pg/mL in control group, p = 0.009 at the time of post-intervention) significantly decreased by family-supported healthcare intervention. Importantly, acute exacerbation (80.8% in intervention group vs 95.7% in control group, p = 0.030) and rehospitalization cases (88.5% in intervention group vs 100% in control group, p = 0.028) also decreased by family-supported healthcare intervention.Discussion: Family-supported healthcare improves pulmonary function and quality of life while alleviates inflammation, acute exacerbation, and rehospitalization in childhood asthma post-routine treatment.Keywords: asthma, family-supported healthcare, pulmonary function, IL-6, IL-17

Fangfang Fan,1,2,&ast; Zhe Liang,1,2,&ast; Zhihao Liu,1 Pengfei Sun,1 Lihua Hu,1 Jia Jia,1,2 Yan Zhang,1,2 Jianping Li1,2 1Department of Cardiology, Peking University First Hospital, Beijing, People’s Republic of China; 2Institute of Cardiovascular Disease, Peking University First Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianping Li, Department of Cardiology & Institute of Cardiovascular Disease, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, People’s Republic of China, Email lijianping03455@pkufh.comPurpose: Early identification of new residual risk factors for coronary heart disease (CHD) is warranted. In this study, we aim to investigate the association between the serine concentration, an important amino acid in one-carbon metabolism, and CHD in Chinese hospitalized patients.Patients and Methods: This case–control study included 428 case–control pairs comprising patients with CHD with a maximum coronary artery stenosis degree of > 70% and controls with stenosis of < 30%. The individuals were matched by age, sex, and date of coronary angiography at Peking University First Hospital from January 1, 2016, to December 31, 2019. Conditional logistic regression was used to investigate the associations between the serine concentration and CHD.Results: Patients with CHD were aged 63.48 ± 10.38 years, and 43.73% were male. Compared with controls, patients with CHD had a slightly lower serine concentration (13.35 ± 4.20 vs 13.77 ± 4.08 μg/mL), but the difference was not significant. In the multivariable conditional logistic regression analysis, for every 1 μg/mL increase in serine concentration, the odds of CHD decreased by 6% (95% confidence interval [CI] 0.90– 0.99; P = 0.010). Patients with a serine concentration of ≥ 13.41 μg/mL had a lower CHD risk than those with a serine concentration of < 13.41 μg/mL (odds ratio [OR] 0.57, 95% CI 0.39– 0.84; P = 0.004). Subgroup analyses showed that sex interacted with the relationship between serine concentration and CHD (Pinteraction = 0.039), which was more significant in males (OR 0.93, 95% CI 0.87– 0.98; P = 0.013) than in females.Conclusion: This study observed an inverse association between the serine concentration and CHD prevalence in Chinese hospitalized patients, which revealed that serine might play a protective role in CHD.Keywords: serine, coronary heart disease, case–control, one-carbon metabolism

Zijun Liu,1,&ast; Tianhao Bao,2 Zhilan Yang,2,&ast; Ye Ruan,2 Changqing Gao,2 Jie Wu2 1The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Wu, Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, 650224, People’s Republic of China, Email wujie@kmmu.edu.cn Tianhao Bao, Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, 650224, People’s Republic of China, Email Doctor@kmmu.edu.cnObjective: Based on Conservation of resources theory, process model of emotion regulation and attachment theory, the present study examined how psychological capital affects anxiety through the mediation of emotion regulation strategies and explored the moderating role of parent-child relationship.Methods: Using a longitudinal study method, 962 college students were surveyed twice at one-year intervals.Results: (1) College students’ emotion regulation strategies (including cognitive reappraisal and expressive suppression) partially mediated psychological capital and anxiety mood; (2) parent-child relationship moderated the pathways of psychological capital and expressive suppression on anxiety, respectively.Conclusion: College students with higher levels of parent-child relationship had stronger predictive effects of psychological capital and weaker predictive effects of expressive suppression on anxiety mood. The research findings clarify the combined effects of emotion regulation and parent-child relationships on anxiety among college students, providing valuable reference for the design and implementation of interventions to promote individual psychological well-being.Keywords: psychological capital, emotion regulation strategies, anxiety, parent-child relationship

Yue Han,1,&ast; Chao Guo,2,&ast; Qianmei Zhu,1 Zijia Liu,1 Yuelun Zhang,3 Shanqing Li,2 Le Shen1 1Department of Anesthesiology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, People’s Republic of China; 2Department of Thoracic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Department of Medical Research Center, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zijia Liu, Department of Anesthesiology, Chinese Academy of Medical Sciences & Peking Union Medical College Hospital, Beijing, 100730, People’s Republic of China, Tel/Fax +861069155580, Email liu-zj02@126.comBackground: Atrial fibrillation (AF) has become the most common postoperative arrhythmia of thoracic surgery. This study aimed to investigate the risk factors and complications of perioperative atrial fibrillation (PoAF) in elderly patients who underwent video-assisted thoracoscopic surgery (VATS).Methods: Data were collected from patients who underwent VATS between January 2013 and December 2022 at Peking Union Medical College Hospital (PUMCH). Univariable analyses and multivariable logistic regression analyses were used to determine the factors correlated with PoAF. Receiver operating characteristic (ROC) curve was used to evaluate the discrimination of the indicators to predict PoAF.Results: The study enrolled 2920 patients, with a PoAF incidence of 5.2% (95% CI 4.4%-6.0%). In the logistic regression analyses, male sex (OR=1.496, 95% CI 1.056– 2.129, P=0.024), left atrial anteroposterior dimension (LAD) ≥ 40 mm (OR=2.154, 95% CI 1.235– 3.578, P=0.004), hypertension (HTN) without regular treatment (OR=2.044, 95% CI 0.961– 3.921, P=0.044), a history of hyperthyroidism (OR=4.443, 95% CI 0.947– 15.306, P=0.030), surgery of the left upper lobe (compared to other lung lobes) (OR=1.625, 95% CI 1.139– 2.297, P=0.007), postoperative high blood glucose (BG) (OR=2.482, 95% CI 0.912– 5.688, P=0.048), and the time of chest tube removal (per day postoperatively) (OR=1.116, 95% CI 1.038– 1.195, P=0.002) were found to be significantly associated with PoAF. The area under the ROC curve was 0.707 (95% CI 0.519– 0.799). 86.9% patients were successfully converted to sinus rhythm. Compared with the non-PoAF group, the PoAF group had significantly greater risks of prolonged air leakage, postoperative acute coronary syndrome, longer ICU stays, and longer hospital stays.Conclusion: Male sex, LAD≥ 40 mm, HTN without regular treatment, a history of hyperthyroidism, surgery of the left upper lobe, postoperative BG, and the time of chest tube removal were associated with PoAF. These findings may help clinicians identify high-risk patients and take preventive measures to minimize the incidence and adverse prognosis of PoAF.Keywords: video-assisted thoracoscopic surgery, aged, atrial fibrillation, risk factor

Hui Liu,1,2 Xuan Xu,3 Ji Li,3 Zheyu Liu,1 Yuwen Xiong,1 Mengli Yue,4 Pi Liu1 1Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China; 2Gastroenterology Institute of Jiangxi Province, Nanchang, People’s Republic of China; 3Department of Gastroenterology, The People’s Hospital of Longhua, Shenzhen, People’s Republic of China; 4Affiliated Longhua People’s Hospital, The Third School of Clinical Medicine, Southern Medical University, Shenzhen, People’s Republic of ChinaCorrespondence: Pi Liu, Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People’s Republic of China, Tel +86-13507913736, Email liupi126@sina.comPurpose: Capillary leak syndrome (CLS) is an intermediary phase between severe acute pancreatitis (SAP) and multiple organ failure. As a result, CLS is of clinical importance for enhancing the prognosis of SAP. Plakophilin2 (PKP2), an essential constituent of desmosomes, plays a critical role in promoting connections between epithelial cells. However, the function and mechanism of PKP2 in CLS in SAP are not clear at present.Methods: We detected the expression of PKP2 in mice pancreatic tissue by transcriptome sequencing and bioinformatics analysis. PKP2 was overexpressed and knocked down to assess its influence on cell permeability, the cytoskeleton, tight junction molecules, cell adhesion junction molecules, and associated pathways.Results: PKP2 expression was increased in the pancreatic tissues of SAP mice and human umbilical vein endothelial cells (HUVECs) after lipopolysaccharide (LPS) stimulation. PKP2 overexpression not only reduced endothelial cell permeability but also improved cytoskeleton relaxation in response to acute inflammatory stimulation. PKP2 overexpression increased levels of ZO-1, occludin, claudin1, β-catenin, and connexin43. The overexpression of PKP2 in LPS-induced HUVECs counteracted the inhibitory effect of SB203580 (a p38/MAPK signaling pathway inhibitor) on the p38/MAPK signaling pathway, thereby restoring the levels of ZO-1, β-catenin, and claudin1. Additionally, PKP2 suppression eliminated the enhanced levels of ZO-1, β-catenin, occludin, and claudin1 induced by dehydrocorydaline. We predicted that the upstream transcription factor PPARγregulates PKP2 expression, and our findings demonstrate that the PPARγactivator rosiglitazone significantly upregulates PKP2, whereas its antagonist GW9662 down-regulates PKP2. Administration of rosiglitazone significantly reduced the increase in HUVECs permeability stimulated by LPS. Conversely, PKP2 overexpression counteracted the GW9662-induced reduction in ZO-1, phosphorylated p38/p38, and claudin1.Conclusion: The activation of the p38/MAPK signaling pathway by PKP2 mitigates CLS in SAP. PPARγactivator rosiglitazone can up-regulate PKP2. Overall, directing efforts toward PKP2 could prove to be a feasible treatment approach for effectively managing CLS in SAP. Keywords: severe acute pancreatitis, plakophilin2, capillary leak syndrome, tight junction, p38/MAPK signaling pathway

Xin Li,1,&ast; Peng Cui,1,&ast; XingXing Zhao,1 Zhao Liu,1 YanXiang Qi,1 Bo Liu2 1Department of Urology, Baotou Cancer Hospital, Baotou, Inner Mongolia, People’s Republic of China; 2Department of Gynaecological Oncology, Baotou Cancer Hospital, Baotou, Inner Mongolia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Liu, Email keyaxinbt@163.comObjective: To explore the predictive factors and predictive model construction for the progression of prostate cancer bone metastasis to castration resistance.Methods: Clinical data of 286 patients diagnosed with prostate cancer with bone metastasis, initially treated with endocrine therapy, and progressing to metastatic castration resistant prostate cancer (mCRPC) were collected. By comparing the differences in various factors between different groups with fast and slow occurrence of castration-resistant prostate cancer (CRPC). Kaplan-Meier survival analysis and COX multivariate risk proportional regression model were used to compare the differences in the time to progression to CRPC in different groups. The COX multivariate risk proportional regression model was used to evaluate the impact of candidate factors on the time to progression to CRPC and establish a predictive model. The accuracy of the model was then tested using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).Results: The median time for 286 mCRPC patients to progress to CRPC was 17 (9.5– 28.0) months. Multivariate analysis showed that the lowest value of PSA (PSA nadir), the time when PSA dropped to its lowest value (timePSA), and the number of BM, and LDH were independent risk factors for rapid progression to CRPC. Based on the four independent risk factors mentioned above, a prediction model was established, with the optimal prediction model being a random forest with area under curve (AUC) of 0.946[95% CI: 0.901– 0.991] and 0.927[95% CI: 0.864– 0.990] in the training and validation cohort, respectively.Conclusion: After endocrine therapy, the PSA nadir, timePSA, the number of BM, and LDH are the main risk factors for rapid progression to mCRPC in patients with prostate cancer bone metastases. Establishing a CRPC prediction model is helpful for early clinical intervention decision-making.Keywords: metastatic prostate cancer, resistance to castration, PSA minimum value, lactate dehydrogenase, prediction model

Yumei Wu,1– 3,&ast; Chunhua Zeng,1– 3,&ast; Jiajia Lv,1– 3 Hongyu Li,1– 3 Jie Gao,1– 3 Zhidong Liu,4 Zeli Yuan1– 3 1Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 2Key Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, School of Pharmacy, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 3Guizhou International Scientific and Technological Cooperation Base for Medical Photo-Theranostics Technology and Innovative Drug Development, Zunyi Medical University, Zunyi, 563000, People’s Republic of China; 4Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhidong Liu, Tianjin University of Traditional Chinese Medicine, No. 10 Poyanghu Road, Tianjin, Jinghai District, 301617, People’s Republic of China, Email lonerliuzd@163.com Zeli Yuan, Zunyi Medical University, Zunyi, 563000, People’s Republic of China, Email zlyuan@zmu.edu.cnBackground: Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly because of increased toxicity from drug interactions and challenges in achieving the desired spatial and temporal distribution of drug delivery. Optimizing synergistic drug combination ratios to ensure uniform targeting and distribution across space and time, particularly in vivo, is a significant challenge. In this study, cRGD-coated liposomes encapsulating optimized synergistic cepharanthine (CEP; a chemotherapy drug) and IR783 (a phototherapy agent) were developed for combined chemotherapy and photothermal therapy in vitro and in vivo.Methods: An MTT assay was used to evaluate the combination index of CEP and IR783 in five cell lines. The cRGD-encapsulated liposomes were prepared via thin-film hydration, and unencapsulated liposomes served as controls for the loading of CEP and IR783. Fluorescence and photothermal imaging were used to assess the efficacy of CEP and IR783 encapsulated in liposomes at an optimal synergistic ratio, both in vitro and in vivo.Results: The combination indices of CEP and IR783 were determined in five cell lines. As a proof-of-concept, the optimal synergistic ratio (1:2) of CEP to IR783 in 4T1 cells was evaluated in vitro and in vivo. The average diameter of the liposomes was approximately 100 nm. The liposomes effectively retained the encapsulated CEP and IR783 in vitro at the optimal synergistic molar ratio for over 7 d. In vivo fluorescence imaging revealed that the fluorescence signal from cRGD-CEP-IR783-Lip was detectable at the tumor site at 4 h post-injection and peaked at 8 h. In vivo photothermal imaging of tumor-bearing mice indicated an increase in tumor temperature by 32°C within 200 s. Concurrently, cRGD-CEP-IR783-Lip demonstrated a significant therapeutic effect and robust biosafety in the in vivo antitumor experiments.Conclusion: The combination indices of CEP and IR783 were successfully determined in vitro in five cell lines. The cRGD-coated liposomes encapsulated CEP and IR783 at an optimal synergistic ratio, exhibiting enhanced antitumor effects and targeting upon application in vitro and in vivo. This study presents a novel concept and establishes a research framework for synergistic chemotherapy and phototherapy treatment. Keywords: drug delivery, liposomes, synergistic effects, phototherapy

Dazhen Wang,1,&ast; Zhengfeng Zhang,2,&ast; Liu Yang,1 Lu Zhao,1 Ze Liu,1 ChangJie Lou1 1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, People’s Republic of China; 2Department of Hematopathology, The Second Clinical Medical College, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: ChangJie Lou, Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, 150081, People’s Republic of China, Email 601245@hrbmu.edu.cnPurpose: Comparing the efficacy and safety of programmed cell death protein-1 (PD-1) inhibitors combined with tyrosine kinase inhibitors (TKIs) with or without hepatic artery infusion chemotherapy (HAIC) in HBV-related advanced HCC and exploring prognostic predictors of the combined regimen.Patients and Methods: A total of 194 patients diagnosed with HBV-related advanced HCC between 2020 and 2022 were included in the study, including 99 in the HAIC combined with PD-1 inhibitors plus TKIs (HPT group) and 95 in the PD-1 inhibitors plus TKIs (PT group). The efficacy was evaluated according to the tumor response rate and survival, and the safety was evaluated according to the adverse events.Results: The HPT group showed higher overall response rate and disease control rate than the PT group. The median overall survival (OS) of the HPT group and the PT group were 18.10 months and 12.57 months, respectively, and the difference was statistically significant (hazard ratio (HR) = 0.519, 95% confidence interval (CI): 0.374– 0.722, P

Nan Geng,1,&ast; Zhipeng Wu,2– 4,&ast; Zhao Liu,1 Wen Pan,1 Yueke Zhu,1 Hongbo Shi,3 Ying Han,5 Yingmin Ma,2– 4 Bo Liu1 1Department of Emergency Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 3Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 4Beijing Research Center for Respiratory Infectious Diseases, Beijing, 100013, People’s Republic of China; 5Department of Gastroenterology and Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingmin Ma, Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, No. 8, Xi Tou Tiao, Youanmenwai Street, Fengtai District, Beijing City, 100069, People’s Republic of China, Email ma.yingmin@163.com Bo Liu, Department of Emergency Medicine, Beijing Youan Hospital, Capital Medical University, No. 8, Xi Tou Tiao, Youanmenwai Street, Fengtai District, Beijing City, 100069, People’s Republic of China, Email Rippleyayy@sina.comBackground: Research on biomarkers associated with the severity and adverse prognosis of COVID-19 can be beneficial for improving patient outcomes. However, there is limited research on the role of soluble TREM-1 (sTREM-1) in predicting the severity and prognosis of COVID-19 patients.Methods: A total of 115 COVID-19 patients admitted to the emergency department of Beijing Youan Hospital from February to May 2023 were included in the study. Demographic information, laboratory measurements, and blood samples for sTREM-1 levels were collected upon admission.Results: Our study found that sTREM-1 levels in the plasma of COVID-19 patients increased with the severity of the disease (moderate vs mild, p=0.0013; severe vs moderate, p=0.0195). sTREM-1 had good predictive value for disease severity and 28-day mortality (area under the ROC curve was 0.762 and 0.805, respectively). sTREM-1 also exhibited significant correlations with age, body temperature, respiratory rate, PaO2/FiO2, PCT, CRP, and CAR. Ultimately, through multivariate logistic regression analysis, we determined that sTREM-1 (OR 1.008, 95% CI: 1.002– 1.013, p=0.005), HGB (OR 0.966, 95% CI: 0.935– 0.998, p=0.036), D-dimer (OR 1.001, 95% CI: 1.000– 1.001, p=0.009), and CAR (OR 1.761, 95% CI: 1.154– 2.688, p=0.009) were independent predictors of 28-day mortality in COVID-19 patients. The combination of these four markers yielded a strong predictive value for 28-day mortality in COVID-19 cases with an AUC of 0.919 (95% CI: 0.857 − 0.981).Conclusion: sTREM-1 demonstrated good predictive value for disease severity and 28-day mortality, serving as an independent prognostic factor for adverse patient outcomes. In the future, we anticipate conducting large-scale multicenter studies to validate our research findings.Keywords: COVID-19, sTREM-1, inflammation-related markers, disease severity, 28-day mortality

Li Zhang,1,&ast; Menglan Zhou,2,3,&ast; Ziran Wang,2,3,&ast; Hongqiong Zhu,4 Jing Lin,1,5 Minya Lu,2,3 Ying Ge,1 Yingchun Xu,2,3 Taisheng Li,1 Zhengyin Liu1 1Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 3Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 4Department of Infectious Disease, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, People’s Republic of China; 5Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengyin Liu, Department of Infectious Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Number 1, Shuaifuyuan Road, Dongcheng District, Beijing, People’s Republic of China, Email zhengyinl@hotmail.comBackground: In China, due to the large population, infections caused by Nocardia may not be as rare. Unfortunately, there is still inadequate knowledge of the clinical impact caused by Nocardia. This study aimed to compare the clinical characteristics and treatment of localized and disseminated nocardiosis.Methods: The clinical and microbiological data of patients diagnosed with nocardiosis in a tertiary hospital in Beijing from July 2011 to July 2021 were collected and retrospectively analyzed.Results: Among the 54 nocardiosis cases, 34 cases were in the localized infection group, while 20 cases in the disseminated infection group. The proportion of patients with chronic structural lung disease was higher in the localized group (P=0.010). In contrast, patients with disseminated infections were more prone to receive long-term glucocorticoids and/or immunosuppressants (P=0.027). Pulmonary nodules were prominent features of imaging changes in patients with disseminated infections (P=0.027) whereas bronchial dilatation was more common in patients with localized infections (P=0.025). In addition, the disseminated group had longer average hospitalization days relative to the localized group (P=0.016), but there was no significant difference in mortality between them (P=0.942).Conclusion: There were differences in the clinical profiles between patients with localized and disseminated nocardiosis in terms of clinical presentation, infection site, radiological features, treatment, and prognosis. These findings may provide references for the management and treatment of patients with nocardiosis.Keywords: Nocardia, disseminated nocardiosis, immunosuppressive population

Zhipeng Liu,1,&ast; Xinyu Yuan,2,&ast; Yan Huang,3 Zihan Gu,4 Lu Xue,5 Shanshan Xue,6 Jun Wang2 1Information Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 2Emergency Department, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 3Medical College, Yangzhou University, Yangzhou, 225009, People’s Republic of China; 4Nanjing University of Finance & Economics, Nanjing, 210023, People’s Republic of China; 5Department of Critical Care Medicine, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China; 6Institute of Clinical Laboratory, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu Province, 225300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Wang; Shanshan Xue, Email 15061008998@163.com; 245116999@qq.comBackground: Sepsis refers to a life-threatening organ dysfunction which can be resulted from the infection-induced dysregulated host response. A large number of inflammatory cytokines are released to act on the liver, making the liver one of the common target organs for the development of multiple organ dysfunction syndrome (MODS) in patients with sepsis. Sepsis-induced acute liver injury (SALI) can aggravate systemic disease. As a result, it is of great clinical significance to comprehend the molecular biological mechanism of SALI and to identify the markers for evaluating SALI. Interferon-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1, IFIT2) have been recognized as the anti-inflammatory factors that are widely expressed in various organs. The present study was aimed at clarifying the roles of IFIT1 and IFIT2 in the development of SALI.Methods: A two-sample Mendelian randomization (MR) analysis was employed. Summary statistics datas were obtained from GWAS for inflammatory factors [tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], IFIT2, and sepsis as well as liver injury. Independent SNPs were selected as instrumental variables (IVs). Inverse variance weighted (IVW) in the MR analysis was adopted as the primary method for estimating the causal associations of inflammatory factors and IFIT2 with two diseases, and the associations of inflammatory factors with IFIT2. Additionally, weighted median method, MR-Egger and sensitivity analyses were applied in assessing the robustness of the results and ensure the result reliability. Subsequently, 119 healthy volunteers, 116 patients with sepsis and 116 SALI patients were recruited. The ELISA method was employed to quantify the expression levels of TNF-α, IL-1β, and IL-6. Additionally, qRT-PCR was conducted to measure the expression of IFIT1 and IFIT2. Furthermore, the correlations of IFIT1 and IFIT2 with inflammatory factors, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were explored.Results: As shown by the MR analysis, the genetically predisposed sepsis was significantly associated with the risk of IL-1β, with an odds ratio (OR) of 1.069 (95% confidence interval (CI), 1.015– 1.127, p = 0.0119), and negatively associated with the risk of IL-6, with an OR of 0.880 (95% CI: 0.792– 0.979, p= 0.0184). Meanwhile, there were positive causal effects of IL-6 (OR = 1.269, 95% CI: 1.032– 1.561, p= 0.0238), IL-1β (OR = 1.106, 95% CI: 1.010– 1.211, p = 0.0299) and IFIT2 (OR = 1.191, 95% CI: 1.045– 1.359, p = 0.0090) on liver injury. Additionally, there was a positive causal effect of IFIT2 (OR = 1.164, 95% CI: 1.035– 1.309, p= 0.0110) on IL-1β. Upon sensitivity analyses, there was weak evidence of such effects, indicating that the findings of this study were robust and reliable. Our results revealed the elevated levels of TNF-α, IL-1β, and IL-6 in the blood samples of sepsis and SALI patients (p < 0.0001). Conversely, IFIT1 and IFIT2 demonstrated the significantly decreased levels in peripheral blood mononuclear cells (PBMCs) of SALI patients (p < 0.0001). Furthermore, the expression levels of IFIT1 and IFIT2 were both negatively correlated with ALT activity (r = − 0.3426, p = 0.0002; r = − 0.3069, p = 0.0008) and AST activity (r = − 0.2483, p = 0.0072; r = − 0.3261, p = 0.0004), respectively. Moreover, the expression of IFIT1 and IFIT2 was both negatively related to the levels of TNF-α (r = − 0.5027, p < 0.0001; r = − 0.4218, p < 0.0001), IL-1β (r = − 0.3349, p = 0.0002; r = − 0.4070, p < 0.0001) and IL-6 (r = − 0.2734, p = 0.0030; r = − 0.3536, p < 0.0001), respectively.Conclusion: IFIT1 and IFIT2 can serve as the diagnostic markers for sepsis-related liver injury, and IFIT1 and IFIT2 may participate in the pathological process of sepsis-related liver injury by regulating inflammation and liver function.Keywords: acute liver injury, sepsis, IFIT1, IFIT2, inflammation, Mendelian randomization

Xin Tang,1,&ast; Qifu Li,1,&ast; Gaoyangzi Huang,1 Ziwen Chen,2 Ya Huang,1 Xianmei Pei,1 Siwen Zhao,1 Zili Liu,1 Taipin Guo,1 Fanrong Liang2 1School of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China; 2College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Taipin Guo, School of Second Clinical Medicine/The Second Affiliated Hospital, Kunming, People’s Republic of China, Email gtphncs@126.com Fanrong Liang, College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China, Email acuresearch@126.comPurpose: Acute lumbar sprain (ALS) is a common clinical disease characterized by persistent intolerable low back pain and limitation of movement, and quick pain relief and restoration of mobility in a short time are the main needs of patients when they visit the clinic. This study aims to evaluate the immediate efficacy of contralateral acupuncture (CAT) on SI3 combined with active exercise in treating ALS.Methods and Analysis: This study is a randomized controlled trial which will recruit 118 eligible participants aged 18 to 55 years with ALS at the Second Affiliated Hospital of Yunnan University of Chinese Medicine between March 2024 and December 2026. Participants will be randomly assigned to the acupuncture group or the sham-acupuncture group in a 1:1 ratio. The acupuncture group will receive a 10-minute acupuncture treatment combined with active exercise, while the sham-acupuncture group will receive a 10-minute sham acupuncture treatment combined with active exercise. Randomization will use a computer-generated sequence with allocation concealed in opaque envelopes. The primary outcome will be the pain visual analogue scale (VAS) scores after 10 minutes of treatment. Secondary outcomes will include the pain VAS scores at other time points (2, 4, 6, and 8 minutes post-treatment), the lumbar range of motion (ROM) scores at various time points, blinded assessment, the treatment effect expectancy scale, and the rescue analgesia rate. The analysis will follow the intention-to-treat principle. The primary outcome will be analyzed using ANCOVA, and secondary outcomes with repeated measures ANOVA. The rescue analgesia rate will be assessed using either the χ2 test or Fisher’s exact test.Discussion: This study is the first randomized controlled trial to assess the immediate efficacy of CAT in combination with active exercise for ALS. This study will provide a simple, rapid, and effective treatment for the clinical management of ALS.Keywords: acute lumbar sprain, immediate efficacy, contralateral acupuncture, active exercise, randomized controlled trial

Jiejie Guo,1– 3 Yanzi Cao,1 Ting Zhang,2 Chunshuang Xu,1 Zhitao Liu,1,4 Wanyi Li,1 Qinwen Wang1 1Zhejiang Key Laboratory of Pathophysiology, NBU Health Science Center, Ningbo University, Ningbo, People’s Republic of China; 2Department of Clinical Laboratory, The First People’s Hospital of Wenling, Taizhou, People’s Republic of China; 3Department of Neurology, The First People’s Hospital of Wenling, Taizhou, People’s Republic of China; 4Fujian Normal University, Fuzhou, People’s Republic of ChinaCorrespondence: Qinwen Wang, Zhejiang Key Laboratory of Pathophysiology, NBU Health Science Center Ningbo University, Ningbo, People’s Republic of China, Email wangqinwen@nbu.edu.cnBackground: There is growing interest in the role of physical activity in patients with of Alzheimer’s disease (AD), particularly regarding its impact of cognitive function, gut microbiota, metabolites, and neurotrophic factors.Objective: To investigate the impact of multisensory fusion training (MSFT) combined with 7, 8-dihydroxyflavone (DHF) on the behavioral characteristics, protein expression, microbiome, and serum metabolome using the AD model in mice induced with amyloid-β (Aβ).Methods: We assessed cognitive ability, anxiety-like and depression-like behaviors in Aβ mice using behavioral measures. Western blotting was employed to detect the expression of relevant proteins. The 16S rRNA gene sequencing and metabolomics were used to analyze changes in the intestinal microbial composition and serum metabolic profile, respectively, of Aβ mice.Results: The behavioral outcomes indicated that a 4-week intervention combining DHF and MSFT yielded remarkable improvements in cognitive function and reduced anxiety and depression-like behaviors in Aβ mice. In the hippocampus of Aβ mice, the combined intervention increased the levels of BDNF, VGF, PSD-95, Nrf2, p-GSK3β and p-CREB proteins. Analyses of sequence and metabolomic data revealed that Bacteroides and Ruminococcaceae were remarkably more abundant following the combined intervention, influencing the expression of specific metabolites directly linked to the maintenance of neuronal and neurobehavioral functions. These metabolites play a crucial role in vital processes, such as amino acid metabolism, lipid metabolism, and neurotransmitter metabolism in mice.Conclusion: Our study highlighted that MSFT combined with DHF improves cognitive impairment, anxiety, and depression-like behavior in Aβ mice through multiple mechanisms, and further validated the correlation between the gut microbiome and serum metabolome. These findings open up a promising avenue for future investigations into potential treatment strategies for AD.Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, cognitive impairment, acousto-optic stimulation, treadmill exercise

Yu Li,1 Guangren Yue,1 Shuying Yu,1 Zheng Liu,1 Yilin Cao,1– 3 Ximei Wang1 1Department of Plastic and Reconstructive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 2Shanghai Key Laboratory of Tissue Engineering, Department of Plastic and Reconstructive Surgery, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3National Tissue Engineering Center of China, Shanghai, People’s Republic of ChinaCorrespondence: Ximei Wang, Department of Plastic and Reconstructive Surgery, The First Affiliated Hospital of Zhengzhou University, 1st Jianshe Eastern Road, Zhengzhou, 450052, People’s Republic of China, Tel +86 371-66278102, Email tracywang@zzu.edu.cnIntroduction: Autologous stem cell transplantation has emerged as a promising strategy for bone repair. However, the osteogenic potential of mesenchymal stem cells derived from diabetic patients is compromised, possibly due to hyperglycemia-induced senescence. The objective of this study was to assess the preconditioning effects of extracellular vesicles derived from H2O2-stimulated adipose-derived stem cells (ADSCs) and non-modified ADSCs on the osteogenic potential of diabetic bone marrow mesenchymal stem cells (BMSCs).Methods: Sprague-Dawley (SD) rats were experimentally induced into a diabetic state through a high-fat diet followed by an injection of streptozotocin, and diabetic BMSCs were collected from the bone marrow of these rats. Extracellular vesicles (EVs) were isolated from the conditioned media of ADSCs, with or without hydrogen peroxide (H2O2) preconditioning, using density gradient centrifugation. The effects of H2O2 preconditioning on the morphology, marker expression, and particle size of the EVs were analyzed. Furthermore, the impact of EV-pretreatment on the viability, survivability, migration ability, osteogenesis, cellular senescence, and oxidative stress of diabetic BMSCs was examined. Moreover, the expression of the Nrf2/HO-1 pathway was also assessed to explore the underlying mechanism. Additionally, we transplanted EV-pretreated BMSCs into calvarial defects in diabetic rats to assess their in vivo bone formation and anti-senescence capabilities.Results: Our study demonstrated that pretreatment with EVs from ADSCs significantly improved the viability, senescence, and osteogenic differentiation potential of diabetic BMSCs. Moreover, in-vitro experiments revealed that diabetic BMSCs treated with H2O2-activated EVs exhibited increased viability, reduced senescence, and enhanced osteogenic differentiation compared to those treated with non-modified EVs. Furthermore, when transplanted into rat bone defects, diabetic BMSCs treated with H2O2-activated EVs showed improved bone regeneration potential and enhanced anti-senescence function t compared to those treated with non-modified EVs. Both H2O2-activated EVs and non-modified EVs upregulated the expression of the Nrf2/HO-1 pathway in diabetic BMSCs, however, the promoting effect of H2O2-activated EVs was more pronounced than that of non-modified EVs.Conclusion: Extracellular vesicles derived from H2O2-preconditioned ADSCs mitigated senescence in diabetic BMSCs and enhanced their bone regenerative functions via the activation of the Nrf2/HO-1 pathway.Keywords: extracellular vesicles, ADSCs, BMSCs, diabetes mellitus, bone regeneration

Min Liu,1,2 Bo Liu,2 Ziyang Liu,3 Zhen Yang,2 Thomas J Webster,4 Huan Zhou,2 Lei Yang2 1School of Materials Science and Engineering, Hebei University of Technology, Tianjin, People’s Republic of China; 2Center for Health Science and Engineering, Hebei Key Laboratory of Biomaterials and Smart Theranostics, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin, 300131, People’s Republic of China; 3Department of Orthopedics, Tianjin Hospital, Tianjin, People’s Republic of China; 4School of Engineering, Saveetha University, Chennai, IndiaCorrespondence: Huan Zhou; Lei Yang, Center for Health Science and Engineering, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin, 300131, People’s Republic of China, Email zhouhuan@hebut.edu.cn; ylei@hebut.edu.cnIntroduction: Lumbar interbody fusion is widely employed for both acute and chronic spinal diseases interventions. However, large incision created during interbody cage implantation may adversely impair spinal tissue and influence postoperative recovery. The aim of this study was to design a shape memory interbody fusion device suitable for small incision implantation.Methods: In this study, we designed and fabricated an intervertebral fusion cage that utilizes near-infrared (NIR) light-responsive shape memory characteristics. This cage was composed of bisphenol A diglycidyl ether, polyether amine D-230, decylamine and iron oxide nanoparticles. A self-hardening calcium phosphate-starch cement (CSC) was injected internally through the injection channel of the cage for healing outcome improvement.Results: The size of the interbody cage is reduced from 22 mm to 8.8 mm to minimize the incision size. Subsequent NIR light irradiation prompted a swift recovery of the cage shape within 5 min at the lesion site. The biocompatibility of the shape memory composite was validated through in vitro MC3T3-E1 cell (osteoblast-like cells) adhesion and proliferation assays and subcutaneous implantation experiments in rats. CSC was injected into the cage, and the relevant results revealed that CSC is uniformly dispersed within the internal space, along with the cage compressive strength increasing from 12 to 20 MPa.Conclusion: The results from this study thus demonstrated that this integrated approach of using a minimally invasive NIR shape memory spinal fusion cage with CSC has potential for lumbar interbody fusion.Keywords: shape memory, interbody fusion cage, NIR responsive, calcium phosphate cement, minimally invasive

Hongmei Yang,1,&ast; Zhongqi Liu,1,&ast; Fan Liu,1,2,&ast; Haixuan Wu,1 Xiaoyan Huang,1 Rong Huang,1 Phei Er Saw,3,4 Minghui Cao1,2 1Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2Department of Anesthesiology, Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Shanwei, 516600, People’s Republic of China; 3Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 4Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Phei Er Saw; Minghui Cao, Email caipeie@mail.sysu.edu.cn; caomh@mail.sysu.edu.cnBackground: Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia.Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA.Results: Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine (p < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group (p < 0.0001).Conclusion: Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.Keywords: lipid nanoparticle, Tet1, peripheral nerve-targeted, pain management, chronic neuropathic pain

Hanfang Zhou,1 Qingyin Li,1 Zhijun Liu,2 Keman Li,1 Xiaomin Geng,3 Xiaoyi Fang1 1Institute of Developmental Psychology, Beijing Normal University, Beijing, People’s Republic of China; 2School of Education, Hunan University of Science and Technology, Xiangtan, People’s Republic of China; 3State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, People’s Republic of ChinaCorrespondence: Xiaoyi Fang, Institute of Developmental Psychology, Beijing Normal University, No. 19 Xin Jie Kou Wai Street, Hai Dian District, Beijing, 100875, People’s Republic of China, Email fangxy@bnu.edu.cnBackground: The significant influence of family emotional expressiveness (FEE) on adolescents’ face-to-face social interactions is well-established. However, there has been limited investigation into potential links between FEE and adolescents’ online social behaviors, especially cyberbullying bystander behaviors, which are pivotal in cyberbullying incidents. This study aimed to assess the relative importance of different aspects of FEE (positive FEE vs. negative FEE vs. the Positive-to-Negative ratio) in predicting adolescents’ cyberbullying bystander behaviors, and the mediating roles of affective and cognitive empathy in these relationships.Methods: A sample of 1,952 adolescents (Mage = 14.18, SD = 1.33) completed questionnaires, including the Family Emotional Expressiveness Questionnaire, Basic Empathy Scale, and Cyberbullying Bystander Behavior Scale. SPSS 26.0 and Mplus 8.3 were used for analysis.Results: (1) Positive FEE exhibited a positive association with protective behavior and a negative association with indifferent behavior. Conversely, negative FEE showed positive associations with reinforcing and indifferent behaviors. However, the Positive-to-Negative ratio did not exhibit significant associations with any of the three bystander behaviors. (2) Negative FEE emerged as relatively more significant than both positive FEE and the Positive-to-Negative ratio in predicting reinforcing and indifferent behaviors. (3) Affective empathy mediated the relationship between positive FEE and reinforcing behavior, while cognitive empathy mediated the relationship between positive FEE and protective and indifferent behaviors. Moreover, cognitive empathy exerted a more influential role than affective empathy in this mediation process.Conclusion: Various aspects of FEE demonstrated distinct relationships with three cyberbullying bystander behaviors, with affective and cognitive empathy playing an important mediating role in the association. This finding holds substantial implications for the development of cyberbullying prevention strategies. Such strategies could target the reduction of negative emotional expression within adolescent families and the cultivation of both cognitive and affective empathy.Keywords: family emotional expressiveness, positive-to-negative ratio, empathy, cyberbullying bystander behaviors, adolescent

Boyu Zhang,1,&ast; Yajun Bi,2,&ast; Kang Wang,1,&ast; Xingjun Guo,3 Zeming Liu,1 Jia Li,1 Min Wu1 1Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Pediatrics, Dalian Municipal Women and Children’s Medical Center (Group), Dalian Medical University, Dalian, Liaoning Province, 116011, People’s Republic of China; 3Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia Li; Min Wu, Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College 1095 Jiefang Avenue, Wuhan, Hubei, People’s Republic of China, Tel +86 18846818658 ; +86 13554254796, Email 4338311@qq.com; wumin@hust.edu.cnAbstract: Wound healing is a sophisticated and orderly process of cellular interactions in which the body restores tissue architecture and functionality following injury. Healing of chronic diabetic wounds is difficult due to impaired blood circulation, a reduced immune response, and disrupted cellular repair mechanisms, which are often associated with diabetes. Stem cell-derived extracellular vesicles (SC-EVs) hold the regenerative potential, encapsulating a diverse cargo of proteins, RNAs, and cytokines, presenting a safe, bioactivity, and less ethical issues than other treatments. SC-EVs orchestrate multiple regenerative processes by modulating cellular communication, increasing angiogenesis, and promoting the recruitment and differentiation of progenitor cells, thereby potentiating the reparative milieu for diabetic wound healing. Therefore, this review investigated the effects and mechanisms of EVs from various stem cells in diabetic wound healing, as well as their limitations and challenges. Continued exploration of SC-EVs has the potential to revolutionize diabetic wound care. Keywords: diabetes, wound healing, stem cells, EVs, ncRNAs, regeneration

Lang Liu,1,&ast; Binghua Zhang,1,&ast; Zhenwei Zhou,2 Jie Yang,1 Ailin Li,1 Yongji Wu,1 Zeyu Peng,1 Xiangyan Li,2 Zhonghua Liu,3 Xiangyang Leng,1 Changwei Zhao,4 Haisi Dong,2 Wenhai Zhao4 1College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 2Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 3Department of Orthopaedics, The Third Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 4Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haisi Dong, Northeast Asia Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China, Tel/Fax +86 431-18604361976, Email adonghaisi@163.com Wenhai Zhao, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China, Tel/Fax +86 431-86177836, Email zwh9899@163.comBackground: Knee osteoarthritis (KOA) is a persistent degenerative condition characterized by the deterioration of cartilage. The Chinese herbal formula Radix Rehmanniae Praeparata- Angelica Sinensis-Radix Achyranthis Bidentatae (RAR) has often been used in effective prescriptions for KOA as the main functional drug, but its underlying mechanism remains unclear. Therefore, network pharmacology and verification experiments were employed to investigate the impact and mode of action of RAR in the treatment of KOA.Methods: The destabilization of the medial meniscus model (DMM) was utilized to assess the anti-KOA effect of RAR by using gait analysis, micro-computed tomography (Micro-CT), and histology. Primary chondrocytes were extracted from the rib cartilage of a newborn mouse. The protective effects of RAR on OA cells were evaluated using a CCK‐8 assay. The antioxidative effect of RAR was determined by measuring reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione (GSH) production. Furthermore, network pharmacology and molecular docking were utilized to propose possible RAR targets for KOA, which were further verified through experiments.Results: In vivo, RAR significantly ameliorated DMM-induced KOA characteristics, such as subchondral bone sclerosis, cartilage deterioration, gait abnormalities, and the degree of knee swelling. In vitro, RAR stimulated chondrocyte proliferation and the expression of Col2a1, Comp, and Acan. Moreover, RAR treatment significantly reduced ROS accumulation in an OA cell model induced by IL-1β and increased the activity of antioxidant enzymes (SOD and GSH). Network pharmacology analysis combined with molecular docking showed that Mapk1 might be a key therapeutic target. Subsequent research showed that RAR could downregulate Mapk1 mRNA levels in IL-1β-induced chondrocytes and DMM-induced rats.Conclusion: RAR inhibited extracellular matrix (ECM) degradation and oxidative stress response via the MAPK signaling pathway in KOA, and Mapk1 may be a core target.Keywords: knee osteoarthritis, RAR, cartilage degeneration, network pharmacology, Mapk1

Xi Liu,1,&ast; Zhonghan Liu,2,&ast; Yangyang Niu,1,&ast; Kun Zhang,1 Xiaoqin Zhang,1 Chen Yu1 1Department of Nephrology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2Department of Spinal Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chen Yu, Email yuchen@tongji.edu.cnBackground: Patients on maintenance hemodialysis have an increased risk of fracture. However, the relationship between fracture and poor prognosis is not clear.Methods: A total of 182 maintenance hemodialysis patients were enrolled in the study. The relationship between fracture and poor prognosis (cardiovascular events, stroke, malignancy and 5-year all-cause mortality) were analyzed.Results: 21 of 182 patients had a history of fracture at the time of enrollment. 26 patients had a new fracture after enrollment. A total of 57 fractures occurred in 47 patients, the most common fracture site was the rib. Patients with fracture group had a higher proportion of elderly and female, higher serum phosphorus and B-type natriuretic peptide and lower hemoglobin, albumin, and potassium compared with those without fracture. Age (OR=3.809, 95% CI: 1.064– 8.966, p=0.038), hemoglobin (OR=0.961, 95% CI: 0.925– 0.997, p=0.035), and serum phosphorus (OR=3.325, 95% CI:1.104– 10.019, p=0.033) were the independent risk factors of new fractures in MHD patients. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture (p< 0.05). But there was no significant difference in the incidence of acute myocardial infarction or stroke.Conclusion: 25.8% of maintenance hemodialysis patients had at least one fracture, with rib fractures accounting for the highest proportion. Age, hemoglobin and serum phosphorus were the independent risk factors of new fractures. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture, but there was no significant difference in the incidence of acute myocardial infarction and stroke.Plain Language Summary: To determine the incidence of fractures in hemodialysis patients, we conducted this single center, prospective observational study. 182 patients were enrolled. We also recorded the 5-year incidence of acute myocardial infarction(AMI), stroke, malignancy, and mortality.Our results showed that the incidence of fracture in hemodialysis patients was 25.8%. The most common fracture site was the rib. There were significant statistical differences in age, gender, hemoglobin, serum albumin, B-type natriuretic peptide, potassium and phosphorus between patients with and without fractures. Logistic regression analysis suggested that advanced age, anaemia and hyperphosphatemia were independent risk factors for new fractures in hemodialysis patients.We followed 182 patients for 5 years and recorded the incidence of stroke, AMI and malignancy. The rates of AMI and stroke did not differ significantly between the two groups. However, the incidence of malignancy in patients with fractures is significantly higher than that in patients without fractures.In our study, a total of 74 patients died, including 24 deaths in the fracture group and 50 deaths in the non-fracture group. The main causes of death in 74 cases were cardiovascular events. Our study provides some insight into the association between fractures and poor outcomes in hemodialysis patients.Keywords: hemodialysis, fracture, mortality, anemia, hyperphosphatemia

Weijian Zhu,1 Ying He,1 Mufang Huang,1 Shezhu Fu,1 Ziyi Liu,1 Xiaoqi Wang,1 Zhixin Li,1 Xiaoliang Li,1 Jiangming Chen,2 Yangqiu Li3 1Department of Hematology, Zhuhai Clinical Medical College of Jinan University (Zhuhai People’s Hospital), Zhuahai, 519050, People’s Republic of China; 2Department of Haematology, Wuzhou Gongren Hospital, Wuzhou, 543001, People’s Republic of China; 3Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 10632, People’s Republic of ChinaCorrespondence: Yangqiu Li, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, People’s Republic of China, Email yangqiuli@hotmail.comObjective: We evaluated the long-term safety and efficacy of thalidomide in the treatment of transfusion-dependent β-thalassemia (TDT).Methods: Fifty patients with TDT were treated with thalidomide and followed-up for 5 years. Thalidomide at a 50 mg dose was administered once a day after dinner. The dose was increased to 150 mg/d after 3 d if well tolerated. After 1 year of treatment, the hemoglobin (Hb) level was stabilized at its maximum, and thalidomide was gradually reduced and maintained at the minimum dose. The hematological response, transfusion dependence, and haemolytic indicators were assessed.Results: At 9 month of follow-up, 38 (76%) patients achieved an excellent response, 1 (2%) a good response, 4(8%) a minor response, and 7(14%) did not show a response. The overall response rate was 86%. At 9 months, the Hb level increased from 79.0 ± 13.2 g/L at baseline to 99.0 ± 13.7g/L (P< 0.001). Patients who achieved excellent response continued to show an increase in Hb levels during follow-up. At 48 months, the mean Hb level was 98.99 ± 10.3g/L; 21 patients (84.0%) became transfusion independent. Thalidomide was reduced and maintained to 25 mg/d in three of these patients. Moreover, five patients completed 60 months of follow-up, and with a mean Hb level of 99.8 ± 6.7g/L. During follow-up, grade 1– 2 adverse drug reactions were noted; however, no grade 3 or higher adverse event was reported. However, no decrease in hemolytic indicators was observed.Conclusion: Thalidomide was well tolerated in the long term, while it significantly improved Hb levels and reduced the transfusion burden.Keywords: β-thalassemia, transfusion-dependent, thalassemia, thalidomide, foetal hemoglobin

Chang Su,1– 3 Zeyu Wang,4 Zhen Qin,1– 3 Yan Lv,1– 3 Yachen Hou,1– 3 Ge Zhang,1– 3 Mengdie Cheng,1– 3 Xinyue Cui,1– 3 Zhiyu Liu,1– 3 Pengchong Du,1– 3 Tianding Liu,1– 3 Peiyu Yuan,1– 3 Junnan Tang,1– 3 Jinying Zhang1– 3 1Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, People’s Republic of China; 3Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, People’s Republic of China; 4Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Junnan Tang; Jinying Zhang, Department of Cardiology, First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, Henan, 450052, People’s Republic of China, Tel +86 15890696166 ; +86 13503830283, Email fcctangjn@zzu.edu.cn; jyzhang@zzu.edu.cnBackground: The triglyceride-glucose (TYG) index is a novel and reliable marker reflecting insulin resistance. Its predictive ability for cardiovascular disease onset and prognosis has been confirmed. However, for advanced chronic heart failure (acHF) patients, the prognostic value of TYG is challenged due to the often accompanying renal dysfunction (RD). Therefore, this study focuses on patients with aHF accompanied by RD to investigate the predictive value of the TYG index for their prognosis.Methods and Results: 717 acHF with RD patients were included. The acHF diagnosis was based on the 2021 ESC criteria for acHF. RD was defined as the eGFR < 90 mL/(min/1.73 m2). Patients were divided into two groups based on their TYG index values. The primary endpoint was major adverse cardiovascular events (MACEs), and the secondary endpoints is all-cause mortality (ACM). The follow-up duration was 21.58 (17.98– 25.39) months. The optimal cutoff values for predicting MACEs and ACM were determined using ROC curves. Hazard factors for MACEs and ACM were revealed through univariate and multivariate COX regression analyses. According to the univariate COX regression analysis, high TyG index was identified as a risk factor for MACEs (hazard ratio = 5.198; 95% confidence interval [CI], 3.702– 7.298; P < 0.001) and ACM (hazard ratio = 4.461; 95% CI, 2.962– 6.718; P < 0.001). The multivariate COX regression analysis showed that patients in the high TyG group experienced 440.2% MACEs risk increase (95% CI, 3.771– 7.739; P < 0.001) and 406.2% ACM risk increase (95% CI, 3.268– 7.839; P < 0.001). Kaplan-Meier survival analysis revealed that patients with high TyG index levels had an elevated risk of experiencing MACEs and ACM within 30 months.Conclusion: This study found that patients with high TYG index had an increased risk of MACEs and ACM, and the TYG index can serve as an independent predictor for prognosis.Keywords: TyG index, advanced chronic heart failure, renal dysfunction, prognosis factor

Wenyan Sun,1,&ast; Xuetong Zhao,2– 4,&ast; Nicola Dalbeth,5,&ast; Robert Terkeltaub,6 Lingling Cui,1 Zhen Liu,1 Lin Han,1 Can Wang,1 Hui Zhang,1,7 Yiming Bao,2– 4 Changgui Li,1,7 Jie Lu1,7 1Shandong Provincial Key Laboratory of Metabolic Diseases, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2National Genomics Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, 100101, People’s Republic of China; 3CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Science and China National Center for Bioinformation, Beijing, People’s Republic of China; 4University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China; 5Department of Medicine, University of Auckland, Auckland, New Zealand; 6VA San Diego VA Healthcare Center, University of California San Diego, San Diego, CA, USA; 7Institute of Metabolic Diseases, Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Lu, Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China, Email 13127006046@163.com Changgui Li, Shandong Provincial Key Laboratory of Metabolic Diseases, Shandong Provincial Clinical Research Center for Immune Diseases, the Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China, Email changguili@vip.163.comObjective: This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables.Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA< 6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set.Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR.Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.Keywords: gout, febuxostat, urate-lowering therapy, machine learning model

Yinping Feng, Jing Guo, Shuirong Luo, Zunjing Zhang, Zhongda Liu Department of Tuberculosis, Lishui Hospital of Traditional Chinese Medicine Affiliated to Zhejiang University of Traditional Chinese Medicine, Lishui Tuberculosis Clinical Medical Research Center, Lishui, Zhejiang, People’s Republic of ChinaCorrespondence: Zhongda Liu, Email liu_zd0578@126.comObjective: Exploring the risk factors for readmission of elderly patients with pulmonary tuberculosis (PTB) within one month using the propensity score matching(PSM).Methods: A retrospective analysis was conducted on the clinical data of elderly patients with PTB who were admitted to the Tuberculosis Department of Lishui Hospital of Traditional Chinese Medicine from January 2020 to October 2023. The patients were divided into two groups: non-readmission group and readmission group based on whether they were readmitted within one month after discharge. The PSM method was used to match the baseline data of the two groups of patients, and multivariate logistic regression analysis was conducted to explore the risk factors for readmission of elderly patients with PTB within one month after discharge.Results: A total of 1268 hospitalized elderly patients with PTB were included in the study, comprising 977 readmitted patients and 291 newly admitted patients (22.95%). Using the PSM, 288 pairs of patients were successfully matched. Following matching, there were no statistically significant differences between the two groups in terms of gender, age, occupation, body mass index(BMI), past medical history, etc. (all P> 0.05). Multivariate logistic regression analysis indicated that infection, drug-induced liver injury(DILI), acute heart failure(AHF), chronic kidney disease(CKD), and extrapulmonary tuberculosis(EPTB) were all identified as risk factors for readmission of elderly patients with PTB.Conclusion: After controlling for confounding factors through PSM, the study revealed that infection, DILI, AHF, CKD, and EPTB are risk factors for readmission among elderly patients with PTB, highlighting the need for early intervention.Keywords: elderly patients with pulmonary tuberculosis, aged, readmission, propensity score matching, risk factors

Huaming Xu,1 Chunhui Lin,2,3 Hao Tang,4 Rongrong Li,2,3 Zhaoxin Xia,2,3 Yi Zhu,3 Zhen Liu,2,3 Jilu Shen2,3 1The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, People’s Republic of China; 2The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Anhui Public Health Clinical Center, Hefei, People’s Republic of China; 4The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Jilu Shen, Tel +86 151 5515 2963, Email shenjilu@ahmu.edu.cn; 1464675852@qq.comIntroduction: As the last line of defense for clinical treatment, Carbapenem antibiotics are increasingly challenged by multi-drug resistant bacteria containing carbapenemases. The rapid spread of these multidrug-resistant bacteria is the greatest threat to severe global health problems.Methods: To solve the problem of rapid transmission of this multidrug-resistant bacteria, we have developed a rapid detection technology using CRPSPR-Cas12a gene editing based on multiple Recombinase polymerase amplification. This technical method can directly isolate the genes of carbapenemase-containing bacteria from samples, with a relatively short detection time of 30 minutes. The instrument used for the detection is relatively inexpensive. Only a water bath can complete the entire experiment of Recombinase polymerase amplification and trans cleavage. This reaction requires no lid during the entire process while reducing a large amount of aerosol pollution.Results: The detection sensitivity of this method is 1.5 CFU/mL, and the specificity is 100%.Discussion: This multi-scene detection method is suitable for screening populations in wild low-resource environments and large-scale indoor crowds. It can be widely used in hospital infection control and prevention and to provide theoretical insights for clinical diagnosis and treatment.

Pan Gao,1,2 Xinyu Li,1,2 Ziqiu He,1,2 Hongbo Zhang,1,2 Zhi Zhang,1,2 Zonglai Liu1,2 1Department of Urology, Second People’s Hospital of Yichang, Yichang, Hubei Province, People’s Republic of China; 2Department of Urology, Second People’s Hospital of China Three Gorges University, Yichang, Hubei Province, People’s Republic of ChinaCorrespondence: Zonglai Liu, Department of Urology, Second People’s Hospital of Yichang, Second People’s Hospital of China Three Gorges University, 21 Xiling One Road, Yichang, 443000, Hubei Province, People’s Republic of China, Email 85538230@qq.comAbstract: Immune checkpoint inhibitors (ICI) have become a new hope for many patients with advanced cancer by blocking tumor immune escape. Bladder cancer is a common malignant tumor of the urinary tract epithelium that often relapses and metastasizes after surgery, chemotherapy, and radiotherapy. Immunotherapy has dramatically improved patient survival rates and clinical benefits as a new, potentially effective therapy. However, avoidance of various immune-related adverse events (irAEs) remains an implausible idea. ICI-induced myocarditis is different from viral myocarditis, and mortality is still high with the current treatment. We report the case of an 82-year-old female patient with ICI-induced fulminant myocarditis and myasthenia gravis. Although she actively accepted the current mainstream treatment for immune-related myocarditis and myasthenia, she died of heart and respiratory failure. Analyzing and reporting the patient’s disease development process and the changes in related indicators may help peers gain a deeper understanding of immune-related adverse events and reduce the mortality of immune-related myocarditis.Keywords: immune checkpoint inhibitors, immunotherapy, heart failure, multiple organs failure

Xinyong Chen,1,2,&ast; Zhe Chen,3,&ast; Gongchang Ma,2 Jianjun Sha,2 Shan Zhao,2 Zuoqing Liu,2 Nong Chen,2 Huilin Yang1 1Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of China; 2Department of Orthopedics, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200025, People’s Republic of China; 3Department of Orthopedics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nong Chen, Department of Orthopedics, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200025, People’s Republic of China, Email chennong1975@126.com Huilin Yang, Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215000, People’s Republic of China, Email orthdoctor@126.comBackground: Dorsal root ganglia (DRGs) contain sensory neurons that innervate intervertebral discs (IVDs) and may play a critical role in mediating low-back pain (LBP), but the potential pathophysiological mechanism needs to be clarified.Methods: A discogenic LBP model in rats was established by penetration of a lumbar IVD. The severity of LBP was evaluated through behavioral analysis, and the gene and protein expression levels of pro-algesic peptide substance P (SP) and calcitonin gene–related peptide (CGRP) in DRGs were quantified. The level of reactive oxygen species (ROS) in bilateral lumbar DRGs was also quantified using dihydroethidium staining. Subsequently, hydrogen peroxide solution or N-acetyl-L-cysteine was injected into DRGs to evaluate the change in LBP, and gene and protein expression levels of transient receptor potential vanilloid-1 (TRPV1) in DRGs were analyzed. Finally, an inhibitor or activator of TRPV1 was injected into DRGs to observe the change in LBP.Results: The rats had remarkable LBP after disc puncture, manifesting as mechanical and cold allodynia and increased expression of the pro-algesic peptides SP and CGRP in DRGs. Furthermore, there was significant overexpression of ROS in bilateral lumbar DRGs, while manipulation of the level of ROS in DRGs attenuated or aggravated LBP in rats. In addition, excessive ROS in DRGs stimulated upregulation of TRPV1 in DRGs. Finally, activation or inhibition of TRPV1 in DRGs resulted in a significant increase or decrease of discogenic LBP, respectively, suggesting that ROS-induced TRPV1 has a strong correlation with discogenic LBP.Conclusion: Increased ROS in DRGs play a primary pathological role in puncture-induced discogenic LBP, and excessive ROS–induced upregulation of TRPV1 in DRGs may be the underlying pathophysiological mechanism to cause nerve sensitization and discogenic LBP. Therapeutic targeting of ROS or TRPV1 in DRGs may provide a promising method for the treatment of discogenic LBP.Keywords: lower back pain, reactive oxygen species, dorsal root ganglion, transient receptor potential vanilloid-1, substance p, calcitonin gene related peptide, intervertebral disc

Yanlei Wang,&ast; Zhaoxiang Liu,&ast; Wenhui Zhao, Chenxiang Cao, Luqi Xiao, Jianzhong Xiao Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianzhong Xiao, Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, People’s Republic of China, Tel/Fax +8610-5611-9057, Email xjza01150@btch.edu.cnBackground: Von Hippel-Lindau (VHL) syndrome is characterized by tumorous lesions affecting multiple organs. Pancreatic involvement in VHL syndrome can present as endocrine tumors and pancreatic cysts, which can interfere with both exocrine and endocrine functions of the pancreas. Diabetes is an uncommon complication of VHL syndrome.Purpose: This study aims to summarize the various mechanisms of diabetes in VHL syndrome by reporting two cases and conducting a literature review.Methods: We analyzed the clinical and imaging data of two patients with VHL syndrome and diabetes. Additionally, we reviewed the existing literature to explore the clinical diversities and management strategies for VHL syndrome complicated with diabetes.Results: The first patient presented with liver metastasis of pancreatic neuroendocrine tumor and multiple pheochromocytoma. After surgery, the patient’s diabetic control improved, as evidenced by a significant reduction in insulin dosage. This indicates a potential insulin resistance due to elevated metanephrine levels prior to surgery and partial insulin deficiency caused by distal pancreatectomy. The second patient had multiple hemangioblastomas, as well as multiple pancreatic cysts and positive pancreatic islet autoantibodies. Diabetes in this case may be attributed to pancreatic lesions and the coexistence of autoimmune insulitis. A literature review of other patients with VHL combined with diabetes revealed multiple mechanisms, including increased catecholamine levels, pancreatic lesions, surgical removal of pancreatic tissue, endocrine treatment, and possibly the coexistence of autoimmune insulitis.Conclusion: VHL syndrome complicated with diabetes involves diverse mechanisms.Keywords: von Hippel-Lindau syndrome, diabetes, pancreatic neuroendocrine tumor