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Qianhui Zhou,1 Yi Liu,1 Yan Gao,1 Lingli Quan,1 Lin Wang,1 Hao Wang2 1Department of Respiratory and Critical Care Medicine, Zhuzhou Central Hospital, Zhuzhou, 412000, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital, Hengyang Medical School, University of South China, HengYang, Hunan, 421005, People’s Republic of ChinaCorrespondence: Hao Wang, Email wanghao872013@163.comBackground: Lung cancer is the leading cause of cancer deaths worldwide, primarily due to lung adenocarcinoma (LUAD). However, the heterogeneity of programmed cell death results in varied prognostic and predictive outcomes. This study aimed to develop an LUAD evaluation marker based on cuproptosis-related lncRNAs.Methods: First, transcriptome data and clinical data related to LUAD were downloaded from the Cancer Genome Atlas (TCGA), and cuproptosis-related genes were analyzed to identify cuproptosis-related lncRNAs. Univariate, LASSO, and multivariate Cox regression analyses were conducted to construct cuproptosis-associated lncRNA models. LUAD patients were categorized into high-risk and low-risk groups using prognostic risk values. Kaplan-Meier analysis, PCA, GSEA, and nomograms were employed to evaluate and validate the results.Results: 7 cuproptosis-related lncRNAs were identified, and a risk model was created. High-risk tumors exhibited cuproptosis-related gene alterations in 95.54% of cases, while low-risk tumors showed alterations in 85.65% of cases, mainly involving TP53. The risk value outperformed other clinical variables and tumor mutation burden as a predictor of 1-, 3-, and 5-year overall survival. The cuproptosis-related lncRNA-based risk model demonstrated high validity for LUAD evaluation, potentially influencing individualized treatment approaches. Expression analysis of four candidate cuproptosis-related lncRNAs (AL606834.1, AL161431.1, AC007613.1, and LINC02835) in LUAD tissues and adjacent normal tissues revealed significantly higher expression levels of AL606834.1 and AL161431.1 in LUAD tissues, positively correlating with tumor stage, lymph node metastasis, and histopathological grade. Conversely, AC007613.1 and LINC02835 exhibited lower expression levels, negatively correlating with these factors. High expression of AL606834.1 and AL161431.1 indicated poor prognosis, while low expression of AC007613.1 and LINC02835 was associated with unfavorable outcomes. Univariate and multivariate analyses confirmed these lncRNAs as independent risk factors for LUAD prognosis.Conclusion: The 4 cuproptosis-related (lncRNAsAL606834.1, AL161431.1, AC007613.1, and LINC02835) can accurately predict the prognosis of patients with LUAD and may provide new insights into clinical applications and immunotherapy.Keywords: lung adenocarcinoma, tumor mutation load, cuproptosis, long noncoding RNA, immunotherapeutic response

Zhaoli Geng,1– 3 Renping Dong,3 Xinlin Li,1,2 Xinyi Xu,1,2 Lin Chen,1,2 Xu Han,1,2 Dongxu Liu,1,2 Yi Liu1,2 1Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, People’s Republic of China; 2Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, Shandong, 250012, People’s Republic of China; 3Department of Stomatology, Qingdao West Coast New Area People’s Hospital, Qingdao, Shandong, 266400, People’s Republic of ChinaCorrespondence: Yi Liu, Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, No. 44-1 Wenhua Road West, Jinan, Shandong, 250012, People’s Republic of China, Tel +86-531-88381630, Email yiliu@sdu.edu.cnBackground: Implants are widely used in the field of orthopedics and dental sciences. Titanium (TI) and its alloys have become the most widely used implant materials, but implant-associated infection remains a common and serious complication after implant surgery. In addition, titanium exhibits biological inertness, which prevents implants and bone tissue from binding strongly and may cause implants to loosen and fall out. Therefore, preventing implant infection and improving their bone induction ability are important goals.Purpose: To study the antibacterial activity and bone induction ability of titanium–copper alloy implants coated with nanosilver/poly (lactic-co-glycolic acid) (NSPTICU) and provide a new approach for inhibiting implant-associated infection and promoting bone integration.Methods: We first examined the in vitro osteogenic ability of NSPTICU implants by studying the proliferation and differentiation of MC3T3-E1 cells. Furthermore, the ability of NSPTICU implants to induce osteogenic activity in SD rats was studied by micro-computed tomography (micro-CT), hematoxylin-eosin (HE) staining, masson staining, immunohistochemistry and van gieson (VG) staining. The antibacterial activity of NSPTICU in vitro was studied with gram-positive Staphylococcus aureus (Sa) and gram-negative Escherichia coli (E. coli) bacteria. Sa was used as the test bacterium, and the antibacterial ability of NSPTICU implanted in rats was studied by gross view specimen collection, bacterial colony counting, HE staining and Giemsa staining.Results: Alizarin red staining, alkaline phosphatase (ALP) staining, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis showed that NSPTICU promoted the osteogenic differentiation of MC3T3-E1 cells. The in vitro antimicrobial results showed that the NSPTICU implants exhibited better antibacterial properties. Animal experiments showed that NSPTICU can inhibit inflammation and promote the repair of bone defects.Conclusion: NSPTICU has excellent antibacterial and bone induction ability, and has broad application prospects in the treatment of bone defects related to orthopedics and dental sciences.Keywords: nanosilver/PLGA coating, implant infection, antibacterial, osteogenesis, titanium copper alloy

Yong Liu,1 Hui Liu,2 Queqiao Bian,1 Shuhuan Zhang,1 Yanmin Guan3 1Department of Dermatology & STD, the Third Central Hospital of Tianjin; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases; Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin, People’s Republic of China; 2Tianjin Institute of Hepatobiliary Disease, Tianjin, People’s Republic of China; 3Department of Tuberculosis, Tianjin Haihe Hospital, Tianjin, People’s Republic of ChinaCorrespondence: Yong Liu, Department of Dermatology & STD, the Third Central Hospital of Tianjin, No. 83, Jintang Road, Hedong District, Tianjin, 300170, People’s Republic of China, Tel +8602284112488, Email liuyongtj@163.comBackground: Herpes zoster (HZ) typically manifests in the acute phase with distinct blisters and severe neuropathic pain. Remarkably, a subset of patients initially presents with only a mild skin rash and moderate pain that gradually intensifies, following a parabolic pattern. Despite being frequently observed in clinical settings, the underlying causes of this trajectory and its potential connection with post-herpetic neuralgia (PHN) remain unclear.Methods: To investigate this phenomenon in-depth, we conducted a meticulous retrospective study involving 529 eligible HZ patients. All these patients sought medical care at the Third Central Hospital of Tianjin, China, between January 2020 and December 2023.Results: The research identified that 14.6% of the sample (77 patients) experienced pain scores aligning with a parabolic curve. This trend was significantly more prevalent in patients aged 60 and above, accounting for 90.9% of this group, and demonstrated a positive correlation with age. Moreover, 87.0% of these patients had pre-existing medical conditions, highlighting the potential role of comorbidities in influencing the pain trajectory. A concerning 45.5% of patients sought medical attention more than seven days after the onset of symptoms, a delay that could exacerbate neurological damage. Notably, among those following a parabolic pain pattern, 66.2% eventually developed PHN, a considerably higher rate compared to the broader patient population.Conclusion: We emphasize that healthcare practitioners meticulously assess patients who initially report lower pain scores for high-risk factors potentially leading to parabolic pain increases, including being over 60 years old, having comorbid conditions, and delaying medical consultation beyond seven days from symptom onset. Early implementation of supplementary pain management therapies may mitigate the risk of PHN development and enhance the quality of life for patients. This study furnishes clinicians with a deeper understanding of the variations in HZ-related pain trajectories, promising to improve treatment approaches and prognoses for HZ patients while paving the way for enriched clinical practice in the future.Keywords: parabolic pain trajectory, herpes zoster, post-herpetic neuralgia, delayed-onset pain, adjunctive analgesics, early intervention strategies

Bowen Xing,1 Zhengyu Li,1,2 Yuyan Liu,1 Chen Ling,1 Xiaolin Long,1 Hui Xie,3 Fang Feng1 1The First People’s Hospital of Chenzhou City, Chenzhou City, People’s Republic of China; 2Hunan University of Chinese Medicine, Changsha City, People’s Republic of China; 3Chenzhou Municipal Hospital of Traditional Chinese Medicine, Chenzhou City, People’s Republic of ChinaCorrespondence: Hui Xie, Chenzhou Municipal Hospital of Traditional Chinese Medicine, Chenzhou City, 423000, People’s Republic of China, Email 568694981@qq.com Fang Feng The First People’s Hospital of Chenzhou City, Chenzhou City, 423000, People’s Republic of China, Email 272874387@qq.com

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, Email liudeshan@sdu.edu.cn

Beiying Deng,1,2,* Ying Chen,1,2,* Pengzhan He,1,2,* Yinghui Liu,3 Yangbo Li,1,2 Yuli Cai,4 Weiguo Dong1 1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 2Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 3Department of Geriatric, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 4Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiguo Dong, Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 99 Zhangzhidong Road, Wuhan, Hubei Province, 430060, People’s Republic of China, Email dongweiguo@whu.edu.cnBackground: This study aims to elucidate the role of mitochondrial autophagy in metabolic dysfunction-associated steatohepatitis (MASH) by identifying and validating key mitophagy-related genes and diagnostic models with diagnostic potential.Methods: The gene expression profiles and clinical information of MASH patients and healthy controls were obtained from the Gene Expression Omnibus database (GEO). Limma and functional enrichment analysis were used to identify the mitophagy-related differentially expressed genes (mito-DEGs) in MASH patients. Machine learning models were used to select key mito-DEGs and evaluate their efficacy in the early diagnosis of MASH. The expression levels of the key mito-DEGs were validated using datasets and cell models. A nomogram was constructed to assess the risk of MASH progression based on the expression of the key mito-DEGs. The mitophagy-related molecular subtypes of MASH were evaluated.Results: Four mito-DEGs, namely MRAS, RAB7B, RETREG1, and TIGAR were identified. Among the machine learning models employed, the Support Vector Machine demonstrated the highest AUC value of 0.935, while the Light Gradient Boosting model exhibited the highest accuracy (0.9189), kappa (0.7204), and F1-score (0.9508) values. Based on these models, MRAS, RAB7B, and RETREG1 were selected for further analysis. The logistic regression model based on these genes could accurately predict MASH diagnosis. The nomogram model based on these DEGs exhibited excellent prediction performance. The expression levels of the three mito-DEGs were validated in the independent datasets and cell models, and the results were found to be consistent with the findings obtained through bioinformatics analysis. Furthermore, our findings revealed significant differences in gene expression patterns, immune characteristics, biological functions, and enrichment pathways between the mitophagy-related molecular subtypes of MASH. Subtype-specific small-molecule drugs were identified using the CMap database.Conclusion: Our research provides novel insights into the role of mitophagy in MASH and uncovers novel targets for predictive and personalized MASH treatments.Keywords: metabolic dysfunction-associated steatohepatitis, mitophagy, biomarkers, diagnostic model, machine learning

Yifan Liu,1 Yushan Liang,2 Jing Yuhong,3 Peng Xin,1 Jia Li Han,4 Yongle Du,5 Xinru Yu,3 Runhe Zhu,6 Mingxun Zhang,6 Wen Chen,7 Yingjie Ma7 1School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 2School of Rehabilitation Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 3School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 4School of Health Sciences, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 5School of Ophthalmology and Optometry, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 6School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 7First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yingjie Ma; Wen Chen, The First Clinical College, Shandong University of Traditional Chinese Medicine; Reproductive and Genetic Center of Integrative Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 42, Wenhua Road (W), Lixia District, Jinan, 250014, People’s Republic of China, Email 545914553@qq.com; wenchen0515@163.comAbstract: This manuscript offers a comprehensive overview of nanotechnology’s impact on the solubility and bioavailability of poorly soluble drugs, with a focus on BCS Class II and IV drugs. We explore various nanoscale drug delivery systems (NDDSs), including lipid-based, polymer-based, nanoemulsions, nanogels, and inorganic carriers. These systems offer improved drug efficacy, targeting, and reduced side effects. Emphasizing the crucial role of nanoparticle size and surface modifications, the review discusses the advancements in NDDSs for enhanced therapeutic outcomes. Challenges such as production cost and safety are acknowledged, yet the potential of NDDSs in transforming drug delivery methods is highlighted. This contribution underscores the importance of nanotechnology in pharmaceutical engineering, suggesting it as a significant advancement for medical applications and patient care.Keywords: nanotechnology, solubility and bioavailability, poorly soluble drugs, drug delivery systems, pharmaceutical engineering

Junwei Zhan,1 Chengfei Peng,2 Yuxin Liu,1 Zhanhua Bi,1 Guoxiu Lu,1 Shanhu Hao,1 Yanan Tong,1 Guoxu Zhang1 1Department of Nuclear Medicine, General Hospital of Northern Theater Command, Shenyang, 110016, People’s Republic of China; 2Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, 110016, People’s Republic of ChinaCorrespondence: Guoxu Zhang; Yanan Tong, Department of Nuclear Medicine, General Hospital of Northern Theater Command, No. 83, Wenhua Road, Shenyang, 110016, People’s Republic of China, Email zhangguoxu_502@163.com; tongyn1119@foxmail.comObjective: Atrial fibrillation (AF) is a common arrhythmia. This study explored serum miR-29b-3p expression in AF patients and its value in predicting AF recurrence after radiofrequency catheter ablation (RFCA).Methods: Totally 100 AF patients who underwent RFCA were enrolled, with 100 individuals without AF as controls. Serum miR-29b-3p expression in participants was determined using RT-qPCR. The correlation between miR-29b-3p and atrial fibrosis markers (FGF-21/FGF-23) was assessed by Pearson analysis. The diagnostic efficacy of serum miR-29b-3p and FGF-21/FGF-23 in predicting AF recurrence after RFCA was analyzed by the receiver operating characteristic (ROC) curves. The Kaplan-Meier method was adopted to evaluate the effect of miR-29b-3p expression on the incidence of AF recurrence after RFCA. The independent risk factors for AF recurrence after RFCA were analyzed by logistic regression analysis.Results: Serum miR-29b-3p was poorly expressed in AF patients. After RFCA, AF patients showed elevated serum miR-29b-3p expression. Serum miR-29b-3p expression in AF patients negatively correlated with serum FGF-21 and FGF-23 concentrations. The cut-off values of serum miR-29b-3p, FGF-21, and FGF-23 in identifying AF recurrence were 0.860 (sensitivity: 100.00%, specificity: 39.71%), 222.2 pg/mL (sensitivity: 96.88%, specificity: 32.35%) and 216.3 ng/mL (sensitivity: 53.13%, specificity: 70.59%), respectively. Patients with low miR-29b-3p expression had a significantly higher incidence of AF recurrence than patients with high miR-29b-3p expression. Serum miR-29b-3p expression was one of the independent risk factors for AF recurrence after RFCA.Conclusion: Low miR-29b-3p expression in AF patients has certain predictive values and is one of the independent risk factors for AF recurrence after RFCA.Keywords: miR-29b-3p, atrial fibrillation, radiofrequency catheter ablation, recurrence, fibrosis marker, logistic regression analysis

Yanchao Liu,1 Jianhui Li,2 Hainan Wen,1 Cuixin Qiang,3 Shoujun Xie,1 Jianhong Zhao3,4 1Department of Clinical Laboratory, The Affiliated Hospital of Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China; 2Department of Preventive Medicine, Chengde Medical University, Chengde, Hebei, 067000, People’s Republic of China; 3Hebei Provincial Center for Clinical Laboratories, Shijiazhuang, Hebei, 050000, People’s Republic of China; 4Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of ChinaCorrespondence: Jianhong Zhao, Email zhaojh_2002@hebmu.edu.cnObjective: To compare the epidemiological characteristics and drug resistance of Burkholderia cepacia isolated from blood cultures, and to provide data support and a scientific basis for the clinical treatment and detection of hospital infections.Methods: The Hebei Province Antimicrobial Surveillance Network received 349 B. cepacia strains isolated from blood cultures reported by 83 hospitals, from 2016 to 2021. These strains were identified by MALDI-TOF MS and, the antibiotic sensitivity tests were carried out using the VITEK 2 COMPACT system. The 2023 Institute of Clinical and Laboratory Standardization drug-susceptibility breakpoints were used for drug susceptibility testing and the data were analyzed using WHONET5.6 software.Results: A total of 349 B. cepacia strains were isolated from 2016 to 2021, including 68 strains from secondary hospitals and 281 strains from tertiary hospitals. The ratios of male: female patients with B. cepacia bloodstream infections in all hospitals, secondary hospitals, and tertiary hospitals were 1.49:1 (209/140), 2.09:1 (46/22), and 1.38:1 (163/118), respectively. Most B. cepacia strains were isolated in intensive care units (ICUs), followed by internal medicine departments, accounting for 49.57% (173/349) and 22.92% (80/349), respectively. Regarding the age distribution, most patients were elderly (> 65 years, 57.59%, 201/349), with numbers of patients gradually declining with decreasing of age. The resistance rates for levofloxacin, ceftazidime, and sulfamethoxazole decreased over the 6-year period (P< 0.05), while there were no significant changes in the resistance rates for meropenem, chloramphenicol, and minocycline (P> 0.05). There was no significant difference in drug-resistance rates between secondary and tertiary hospitals (P> 0.05).Conclusion: Attention should be paid to bloodstream infections caused by B. cepacia, especially elderly patients and patients admitted to the ICU. The difficult treatment characteristics of B. cepacia bloodstream infections mean that laboratories and clinicians should pay careful attention to drug resistance to provide a basis for their prevention and empirical treatment.Keywords: B. cepacia, antimicrobial resistance, secondary hospital, tertiary hospital, multicenter investigation

Wanying Wu,1,2,&ast; Congzhuo Jia,1,2,&ast; Xiayan Xu,1– 3 Yibo He,1,2 Yun Xie,1,2,4 Yang Zhou,1,2 Hongyu Lu,1,2 Jin Liu,1,2 Jiyan Chen,1,2 Yong Liu1,2 1Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 2Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People’s Republic of China; 3School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China; 4School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiyan Chen; Yong Liu, Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China, Tel +86 2083827812-10528, Fax +86 2083851483, Email chenjiyandr@126.com; liuyong@gdph.org.cnBackground: Inflammation contributes to the initiation and advancement of both coronary atherosclerosis and type 2 diabetes mellitus (T2DM). Recent evidence has underscored the platelet-to-HDL-cholesterol ratio (PHR) as a promising inflammatory biomarker closely linked to the severity of coronary artery disease (CAD). Nevertheless, the risk of adverse clinical outcomes remains unclear among CAD patients with varying PHR levels and glycemic status.Methods: A total of 56,316 CAD patients were enrolled, primarily focusing on mortality outcomes. Patients were categorized into four subgroups based on median baseline PHR values and glycemic status: lower PHR (PHR-L) and higher PHR (PHR-H) with or without T2DM. Cox proportional hazard model and subgroup analysis were employed to investigate the association between PHR and glycemic status with mortality.Results: Over a median 5.32-year follow-up, 8909 (15.8%) patients experienced all-cause mortality, with 3873 (6.9%) deaths attributed to cardiovascular causes. Compared to individuals in PHR-L/non-DM, those in PHR-H/non-DM, PHR-L/DM and PHR-H/DM groups exhibited a higher risk of all-cause death [adjusted hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.06– 1.18; HR 1.21, 95% CI 1.14– 1.29; HR 1.43, 95% CI 1.34– 1.52, respectively], as well as cardiac mortality [HR 1.19, 95% CI 1.08– 1.30; HR 1.58, 95% CI 1.44– 1.74; HR 1.89, 95% CI 1.72– 2.07, respectively]. Cox proportional hazard model also revealed the highest mortality risk among patients in PHR-H/DM compared to other groups (P < 0.05). Restricted cubic spline regression analysis revealed a positive linear association between PHR and all-cause as well as cardiac mortality (P for non-linearity > 0.05) after adjustment. Additionally, subgroup analysis indicated consistent effects on cardiac mortality within diverse subsets.Conclusion: In this real-world observational cohort analysis, elevated PHR levels joint with T2DM were related to adverse long-term clinical outcomes in CAD patients. PHR levels may serve as a valuable tool for identifying high-risk individuals within this specific group.Trial Registration: The Cardiorenal ImprovemeNt II registry NCT05050877.Keywords: platelet-to-HDL-cholesterol ratio, coronary artery disease, diabetes, all-cause mortality, cardiovascular mortality

Dongmei Zou,1,&ast; Yanqiong Liu,2,&ast; Youwen Gong,3 Xueqing Zhang,4 Jieqiong Liu,4 Jinhua Shen4 1Department of Cardiovascular Surgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde city), Changde, People’s Republic of China; 2Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, People’s Republic of China; 3Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, People’s Republic of China; 4Department of Nursing, Changde Hospital, Xiangya School of Medicine, Central South University (The first People’s hospital of Changde city), Changde, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Youwen Gong, Department of Neurosurgery, Changde Hospital, Xiangya School of Medicine, Central South University (The first People’s hospital of Changde city), Changde, People’s Republic of China, Email 1755144149@qq.com Xueqing Zhang, Department of Nursing, Changde Hospital, Xiangya School of Medicine, Central South University (The first People’s hospital of Changde city), Changde, People’s Republic of China, Email 382731326@qq.comPurpose: This study investigated the current state of self-efficacy and the association between self-perceived burden (SPB) and health-related quality of life (HRQoL) among Chinese older-adult inpatients.Methods: A cross-sectional study was conducted using convenience sampling to survey Chinese older-adult inpatients. Data regarding demographic characteristics, self-efficacy, SPB, and HRQoL were collected. Pearson’s correlation analysis was used to examine the correlations among the research variables. SPSS® Statistics V26.0, and SPSS® PROCESS Macro Model 4 were used to analyze the available data. The bootstrap method was used to analyze the mediating role of self-efficacy.Results: Survey participants included 514 older-adult inpatients, with a mean age of 72.28± 5.58 years. Self-efficacy (r=0.471, p< 0.01) was positively correlated with HRQoL, whereas self-efficacy (r=− 0.891, p< 0.01) and HRQoL (r=− 0.516, p< 0.01) were negatively correlated with SPB. The mediating effect analysis revealed that self-efficacy either completely or partially mediated the effect of SPB on HRQoL, with the indirect effect accounting for 30.2% of the total.Conclusion: This study provides a mediating model suggesting that SPB exerts both direct and indirect effects on the HRQoL of older-adult inpatients through self-efficacy.Keywords: aging, Chinese, negative emotions, self-efficacy, health-related quality of life, mediating effects

Yanhua Liu,1,2,&ast; Fuxing Li,1,2,&ast; Youling Fang,2,3 Qiaoshi Zhong,1,2 Yanping Xiao,1,2 Yunwei Zheng,1,2 Junqi Zhu,2,3 Chuwen Zhao,2,3 Xingwei Cao,1,2 Jianqiu Xiong,4 Longhua Hu1,2 1The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, Nanchang, People’s Republic of China; 2Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang, People’s Republic of China; 3School of Public Health, Nanchang University, Jiangxi, Nanchang, People’s Republic of China; 4Department of Nursing, the Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianqiu Xiong, Department of Nursing, The Second Affiliated Hospital of Nanchang University, Mingde Road No. 1, Jiangxi, Nanchang, 330006, People’s Republic of China, Email 1773014059@qq.com Longhua Hu, Department of Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Mingde Road No. 1, Jiangxi, Nanchang, 330006, People’s Republic of China, Email longhuahu@163.comObjective: This research aimed to analyze the clinical characteristics, prognosis, and antimicrobial treatment of bloodstream infections (BSI) caused by Enterobacter cloacae complex (ECC).Methods: The clinical data of patients with bloodstream infections caused by Enterobacter cloacae complex from April 2017 to June 2023 were collected retrospectively. These data were then analyzed in subgroups based on the detection results of extended-spectrum β-lactamase (ESBL), 30-day mortality, and the type of antimicrobial agent used (β-lactam/β-lactamase inhibitor combinations (BLICs) or carbapenems).Results: The proportion of ESBL-producing Enterobacter cloacae complex was 32.5% (37/114). Meanwhile, ICU admission, receiving surgical treatment within 3 months, and biliary tract infection were identified as risk factors for ESBL-producing ECC-BSI. Additionally, immunocompromised status and Sequential Organ Failure Assessment (SOFA) score ≥ 6.0 were identified as independent risk factors of 30-day mortality in patients with ECC-BSI (n = 108). Further analysis in BSI patients caused by non-ESBL-producing ECC revealed that patients treated with BLICs (n = 45) had lower SOFA scores and lower incidence of hypoproteinemia and sepsis compared with patients treated with carbapenems (n = 20). Moreover, in non-ESBL-producing ECC-BSI patients, the univariate Cox regression analysis indicated a significantly lower 30-day mortality rate in patients treated with BLICs compared to those treated with carbapenems (hazard ratios (HR) [95% CI] 0.190 [0.055– 0.662], P = 0.009; adjusted HR [95% CI] 0.106 [0.013– 0.863], P = 0.036).Conclusion: This study investigated the factors influencing the susceptibility to infection by ESBL-producing strains and risk factors for 30-day mortality in ECC-BSI patients. The results revealed that ESBL-negative ECC-BSI patients treated with BLICs exhibited significantly lower 30-day mortality compared to those treated with carbapenems. BLICs were found to be more effective in ECC-BSI patients with milder disease (ESBL-negative and SOFA ≤ 6.0).Keywords: Enterobacter cloacae complex, extended-spectrum β-lactamase, bloodstream infection, risk factors, β-lactam/β- lactamase inhibitor combinations, carbapenems

Xiaoyi Tang,1,2,&ast; Yijia Liu,1,2,&ast; Mengxin Zhao,3,&ast; Lei He,3 Jiahao Guo,3 Tian Wang,3 Wei Li,3 Jiaqi Zhao1 1Department of Ultrasound, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434, People’s Republic of China; 2Department of Ultrasound, the Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai, 200003, People’s Republic of China; 3Department of Nanomedicine, Naval Medical University, Shanghai & School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200433, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Li; Jiaqi Zhao, Email liwei@smmu.edu.cn; ultrasoundczzjq@163.comPurpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention.Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery.Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18± 1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA’s potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure’s efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation.Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.Keywords: ultrasonography, nanoscale contrast agent, nanotechnology, musculoskeletal ultrasound, photothermal imaging, microcirculatory perfusion

Liyuan Qiao,1,2,&ast; Shulin Ding,2,&ast; Wanrui Ma,1 Chuanzhi Xu,3 Xiaoqing Zhang,3 Yuxi Liu,1,2 Chonghua Wan1,2 1The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan, people’s republic of china; 2Key Laboratory for Quality of Life and Psychological Assessment and Intervention, School of Humanities and Management, Guangdong Medical University, Dongguan, people’s republic of china; 3School of Public Health, Kunming Medical University, Kunming, people’s republic of china&ast;These authors contributed equally to this workCorrespondence: Yuxi Liu; Chonghua Wan, Email yuxiliu123@126.com; wanchh@hotmail.comObjective: Coronary heart disease (CHD) is a common and frequent disease with a long and incurable course, and the quality of life of patients is severely reduced. This study was to develop and validate a quality of life scale for patients with CHD based on the Chinese context.Methods: The scale QLICD-CHD (V2.0) was developed based on the QLICD-CHD (V1.0), using a programmed decision procedures. Based on the data measuring QoL 3 times before and after treatments from 189 patients with CHD, the psychometric properties of the scale were evaluated with respect to validity, reliability and responsiveness employing correlation analysis, multi-trait scaling analysis, structural equation modeling, t-test and also G-study and D-study of generalizability theory analysis. The SF-36 scale was used as the criterion to evaluate the criterion-related validity. Paired t tests were conducted to evaluate the responsiveness on each domain/facet as well as the total of the scale, with Standardized Response Mean (SRM) being calculated.Results: The QLICD-CHD (V2.0) has been developed with 42 items in 4 domains. The Cronbach’s α of the general module, the specific module and the total scale were 0.91, 0.92 and 0.91 respectively. The overall score and the test-retest reliability coefficients in all domains are higher than 0.60, except for the specific module. Correlation and factor analysis confirmed good construct validity and criterion-related validity. After treatments, the overall score and score of all domains have statistically significant changes (P< 0.01). The SRM of domain-level score ranges from 0.27 to 0.50. Generalizability Theory further confirm the reliability of the scale through more accurate variance component studies.Conclusion: The QLICD-CHD (V2.0) could be used as a useful instrument in assessing QoL for patients with CHD, with good psychometric properties.Keywords: quality of life, classical test theory, standardized response mean, psychometric properties, generalizability theory

Yan Jin,1 Yiju Wang,2 Shusen Liu,3 Sifang Niu,4 Hao Sun,1 Yan Liu,5 Ning Liu6 1School of Clinical Medicine, Jining Medical University, Jining, Shandong, 272002, People’s Republic of China; 2School of Mental Health, Jining Medical University, Jining, Shandong, 272002, People’s Republic of China; 3School of Pharmacy, Harbin University of Commerce, Harbin, Heilongjiang, 150076, People’s Republic of China; 4School of Public Health, Binzhou Medical University, Binzhou, Shandong, 264003, People’s Republic of China; 5School of Public Health, Jining Medical University, Jining, Shandong, 272002, People’s Republic of China; 6School of Basic Medicine, Jining Medical University, Jining, Shandong, 272067, People’s Republic of ChinaCorrespondence: Yan Liu; Ning Liu, Email hakunaly@163.com; 631864@qq.comAim: Stressful life events have a significant impact on the mental health of college students. Depression, as a prevalent psychological issue, has garnered attention in the field of college student mental health and is closely linked to it. Additionally, parenting style is identified as an important factor influencing the development of college students’ mental health. Therefore, this study aims to explore the relationship between these three factors.Methods: A total of 8079 first-year college students from two medical universities in Shandong Province, China were surveyed. The Beck Depression Inventory was utilized to evaluate depressive symptoms among the college students, while the Adolescent Self-rating Life Events Checklist and the Egna Minnen Beträfande Uppfostran were employed to gather data. Subsequently, the SPSS macro program PROCESS was utilized to analyze both the mediating and moderating effects. All statistical analyses were conducted using SPSS 26.0.Results: The study found a detection rate of 6.3% for depressive symptoms among college students. The correlation analysis of this study showed that the stressful life events of college students were significantly positively correlated with depressive symptoms (r=0.261, p< 0.01). Each dimension of parenting style was associated with depressive symptoms in different degrees and directions. At the same time, parenting styles of all sizes play a partial mediating role between stressful life events and depressive symptoms in college students, gender plays a crucial regulatory role in this mediation.Conclusion: Stressful life events experienced by college students have a significant impact on their mental health. Early intervention through positive parenting styles from parents may prove to be beneficial in promoting the development of good mental health among college students.Keywords: college students, stressful life events, depressive symptoms, parenting style, gender

Min Zhou,1,&ast; Yuping Liu,2,&ast; Xue Fang,1 Zhezhen Jiang,1 Wang Zhang,1 Xin Wang1 1Department of Orthopaedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan City, People’s Republic of China; 2Sichuan University West China Second University Hospital, Department of Anesthesiology, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Wang, Department of Orthopedics Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan Ctiy, Hubei Province, 430000, People’s Republic of China, Tel +86-027-67812557, Email wangxinznyy@whu.edu.cnPurpose: Polyhexanide is a safe and effective wound care antiseptic commonly used in clinics as wound rinsing solution and gel. However, the efficacy of Polyhexanide in treatment of wound infected with MRSA (methicillin-resistant Staphylococcus aureus) is unknown. The aim of this study is to assess the effectiveness of polyhexanide with povidone iodine in treating wound infected with MRSA.Patients and Methods: A prospective analysis of 62 patients with wound infections, who were admitted to our department from 2016 to 2020, was conducted in order to assess the efficacy of different treatment approaches. The patients were divided into two groups: the experimental group and the control group. In the experimental group, 30 patients underwent treatment with a combination of diluted povidone iodine and polyhexanide immersion. Conversely, in the control group, 32 patients received treatment with diluted povidone iodine along with systemic antibiotic therapy. The time required for dressing changes, bacterial clearance rates, and the Bates-Jasen wound assessment tool (BWAT) scores were utilized as indicators to evaluate the effectiveness of the treatments.Results: In our study, the findings indicated that the experimental group exhibited a lesser number of days for the bacteria culture to turn negative compared to the control group, with statistical significance (p< 0.05). Furthermore, the decline in the BWAT score was significantly greater in the experimental group than in the control group (p< 0.05). However, no significant differences were observed in terms of dressing times and wound coverage between the two groups (p> 0.05).Conclusion: Polyhexanide combined with povidone iodine can effectively remove MRSA infection in wounds and reduce antibiotic dosages.Keywords: methicillin-resistant staphylococcus aureus, wound, polyhexanide

Yongyi Xie,1,&ast; Nanhui Wu,1,&ast; Suwei Tang,1,&ast; Zhiyu Zhou,1 Jiashe Chen,1 Jie Li,1 Fei Wu,1 Mingyuan Xu,1 Xiaoxiang Xu,1 Yeqiang Liu,1 Xin Ma1,2 1Shanghai Skin Disease Hospital, Institute of Dermatology, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yeqiang Liu; Xin Ma, Shanghai Skin Disease Hospital, Institute of Dermatology, Baode Road 1278 Street, Shanghai, 200433, People’s Republic of China, Email 1500156@tongji.edu.cn; Nicole.ma@me.comAbstract: The endoplasmic reticulum (ER) is the main site of protein synthesis, transport, and modification. Its abnormal status has now emerged as an established cause of many pathological processes, such as tumors and autoimmune diseases. Recent studies also demonstrated that the defective functions of ER may lead to pigmentary diseases. Vitiligo is a depigmenting ailment skin disorder whose pathogenesis is now found to be associated with ER. However, the detailed mechanism is still unclear. In this review, we try to link the association between ER with its inter- and intra-organellar interactions in vitiligo pathogenesis and focus on the function, mechanism, and clinical potential of ER with vitiligo. Expand ER is found in melanocytes of vitiligo and ER stress (ERS) might be a bridge between oxidative stress and innate and adaptive immunity. Meanwhile, the tight association between ER and mitochondria or melanosomes in organelles levels, as well as genes and cytokines, is the new paradigm in the pathogenesis of vitiligo. This undoubtedly adds a new aspect to the understanding of vitiligo, facilitating the design of targeted therapies for vitiligo.Keywords: vitiligo, endoplasmic reticulum, organelles, cellular interactions, oxidative stress

Bingcong Zhao,1,2 Zhigang Li,3 Chuan Shi,4 Yan Liu,5 Yang Sun,3 Bin Li,1,2 Jie Zhang,6 Zhizhong Gong,7 Yuanzheng Wang,8 Xuehong Ma,9 Xinjing Yang,10 Huili Jiang,3 Yuanbo Fu,1,2 Xin Wang,1,2 Yang Li,6 Hengchia Liu,6 Tuya Bao,3 Yutong Fei11– 13 1Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, People’s Republic of China; 3School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Psychological Assessment Center, Peking University Sixth Hospital, Beijing, People’s Republic of China; 5Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 6Department of Psychosomatic Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 7Division of Medical Affairs, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 8Department of Integrative TCM and Western Medicine, Peking University First Hospital, Beijing, People’s Republic of China; 9Department of Acupuncture & Moxibustion, Dongfang Hospital, the Second Clinical Medical College of Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 10Department of Traditional Chinese Medicine, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China; 11Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 12Institute of Excellence in Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 13Beijing GRADE Centre, Beijing, People’s Republic of ChinaCorrespondence: Tuya Bao, School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of China, Email tuyab@263.net Yutong Fei, Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of China, Email feiyt@bucm.edu.cnPurpose: Anxious depression (AD) is a common, distinct depression subtype. This exploratory subgroup analysis aimed to explore the effects of acupuncture as an add-on therapy of selective serotonin reuptake inhibitors (SSRIs) for patients with AD or non-anxious depression (NAD).Patients and Methods: Four hundred and sixty-five patients with moderate-to-severe depression from the AcuSDep pragmatic trial were included in analysis. Patients were randomly assigned to receive MA+SSRIs, EA+SSRIs, or SSRIs alone (1:1:1) for six weeks. AD was defined by using dimensional criteria. The measurement instruments included 17-items Hamilton Depression Scale (HAMD-17), Self-Rating Depression Scale (SDS), Clinical Global Impression (CGI), Rating Scale for Side Effects (SERS), and WHO Quality of Life-BREF (WHOQOL-BREF). Comparison between AD and NAD subgroups and comparisons between groups within either AD or NAD subgroups were conducted.Results: Eighty percent of the patients met the criteria for AD. The AD subgroup had poorer clinical manifestations and treatment outcomes compared to those of the NAD subgroup. For AD patients, the HAMD response rate, remission rate, early onset rate, and the score changes on each scale at most measurement points on the two acupuncture groups were significantly better than the SSRIs group. For NAD patients, the HAMD early onset rates of the two acupuncture groups were significantly better than the SSRIs group.Conclusion: For AD subtype patients, either MA or EA add-on SSRIs showed comprehensive improvements, with small-to-medium effect sizes. For NAD subtype patients, both the add-on acupuncture could accelerate the response to SSRIs treatment. The study contributed to the existing literature by providing insights into the potential benefits of acupuncture in combination with SSRIs, especially for patients with AD subtypes. Due to its limited nature as a post hoc subgroup analysis, prospectively designed, high-quality trials are warranted.Clinical Trials Registration: ChiCTR-TRC-08000297.Keywords: anxious depression, non-anxious depression, acupuncture, SSRIs, subgroup analysis

Gang Fan,1,&ast; Jingfen Lu,2,&ast; Jinhui Zha,3,&ast; Weiming Guo,1 Yifei Zhang,4 Yuxin Liu,5 Liyuan Zhang1 1Department of Urology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518052, People’s Republic of China; 2The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 3Shenzhen University, Shenzhen, 518000, People’s Republic of China; 4The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People’s Republic of China; 5College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liyuan Zhang; Gang Fan, Department of Urology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000, People’s Republic of China, Email liyuan.zhang@uszh.org.cn; gang.fan.med@qq.comAbstract: The maintenance of normal vascular function and homeostasis is largely dependent on the signaling mechanisms that occur within and between cells of the vasculature. TGF-β-activated kinase 1 (TAK1), a multifaceted signaling molecule, has been shown to play critical roles in various tissue types. Although the precise function of TAK1 in the vasculature remains largely unknown, emerging evidence suggests its potential involvement in both physiological and pathological processes. A comprehensive search strategy was employed to identify relevant studies, PubMed, Web of Science, and other relevant databases were systematically searched using keywords related to TAK1, TABs and MAP3K7.In this review, we discussed the role of TAK1 in vascular signaling, with a focus on its function, activation, and related signaling pathways. Specifically, we highlight the TA1-TABs complex is a key factor, regulating vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) involved in the processes of inflammation, vascular proliferation and angiogenesis. This mini review aims to elucidate the evidence supporting TAK1 signaling in the vasculature, in order to better comprehend its beneficial and potential harmful effects upon TAK1 activation in vascular tissue.Keywords: TGF-β-activated kinase 1, vascular disease, mitogen-activated protein kinase, transforming growth factor-β, smooth muscle cell, endothelial cell

Yun Liu,1,2 Timo Hamm,3 Thomas Ralf Eichinger,3 Walter Kamm,3 Heike Andrea Wieland,3 Brigitta Loretz,1 Anna KH Hirsch,2,4 Sangeun Lee,1,2 Claus-Michael Lehr1,2 1Department of Drug Delivery Across Biological Barriers, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; 2Department of Pharmacy, Saarland University, Saarbrücken, Germany; 3Department of Research and Development, Sanofi-Aventis Deutschland GmbH, Frankfurt Am Main, Germany; 4Department of Drug Design and Optimisation, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, GermanyCorrespondence: Claus-Michael Lehr, Department of Drug Delivery Across Biological Barriers, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany, Tel +49 681 98806-1000, Fax +49 681 98806 1009, Email Claus-Michael.Lehr@helmholtz-hips.de Sangeun Lee, Department of Pharmacy, Saarland University, Saarbrücken, Germany, Tel +49 681 302 4764, Fax +49 681 302 2028, Email Sangeun.Lee@uni-saarland.deBackground: Therapeutic proteins and peptides offer great advantages compared to traditional synthetic molecular drugs. However, stable protein loading and precise control of protein release pose significant challenges due to the extensive range of physicochemical properties inherent to proteins. The development of a comprehensive protein delivery strategy becomes imperative accounting for the diverse nature of therapeutic proteins.Methods: Biodynamers are amphiphilic proteoid dynamic polymers consisting of amino acid derivatives connected through pH-responsive dynamic covalent chemistry. Taking advantage of the amphiphilic nature of the biodynamers, PNCs and DEs were possible to be prepared and investigated to compare the delivery efficiency in drug loading, stability, and cell uptake.Results: As a result, the optimized PNCs showed 3-fold encapsulation (< 90%) and 5-fold loading capacity (30%) compared to DE-NPs. PNCs enhanced the delivery efficiency into the cells but aggregated easily on the cell membrane due to the limited stability. Although DE-NPs were limited in loading capacity compared to PNCs, they exhibit superior adaptability in stability and capacity for delivering a wider range of proteins compared to PNCs.Conclusion: Our study highlights the potential of formulating both PNCs and DE-NPs using the same biodynamers, providing a comparative view on protein delivery efficacy using formulation methods. Keywords: amphiphilic polymer, nanocomplex, double emulsion, pH-responsive, protein delivery, dynamic covalent chemistry

Ruifang Shi,1,&ast; Fan Yang,1,&ast; Hongli Wu,2 Yonggang Liu1 1Department of Pathology, Tianjin Institute of Hepatology, Tianjin Second People’s Hospital, Tianjin, 300192, People’s Republic of China; 2Department of Clinical Lab, Tianjin Institute of Hepatology, Tianjin Second People’s Hospital, Tianjin, 300192, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonggang Liu, Department of Pathology, Tianjin Institute of Hepatology, Tianjin Second People’s Hospital, No. 7, Sudi South Road, Nankai District, Tianjin, 300192, People’s Republic of China, Tel +86 22 27426025, Email liuyonggang_2023@163.comObjective: To analyse clinical manifestations of unexplained abnormal liver function and perform hepatobiliary histopathology procedures on patients to evaluate the value of liver biopsy in diagnosing the aetiology of unexplained abnormal liver function.Methods: A convenience sampling method was used to retrospectively collect the data of patients who were diagnosed with unexplained abnormal liver function and who received liver biopsy in the Pathology Department of Tianjin Second People’s Hospital, China, between March 2022 and July 2023 to analyse liver pathology and clinical manifestations.Results: A total of 1302 patients were included in this study, which mainly included 11 diseases: autoimmune liver disease (74 cases, 5.68%), drug-induced liver injury (DILI) (204 cases, 15.67%), cancer (237 cases, 18.20%), non-alcoholic fatty liver disease (104 cases, 7.99%), non-alcoholic steatohepatitis (74 cases, 5.68%), viral hepatitis (490 cases, 37.63%), other types of hepatitis (30 cases, 2.30%), cholestatic liver disease (17 cases, 1.31%), alcoholic liver disease (15 cases, 1.15%), hepatic cyst (5 cases, 0.38%) and Gilbert syndrome (4 cases, 0.31%). The success rate of liver biopsy sampling was 100%, and (1.52 ± 0.130) tissue strips were sampled. The average operating time was 11.52 minutes. The percutaneous liver biopsy did not significantly increase short-term liver function index values (serum γ-glutamyl transpeptidase, total bilirubin, alanine transaminase, aspartate aminotransferase, alkaline phosphatase). Ninety-two patients had a small amount of liver subcapsular fluid, but there was no progress after medical treatment.Conclusion: Ultrasound-guided percutaneous liver biopsy has value in the diagnosis of unexplained abnormal liver function. Viral hepatitis, cancer and DILI are the most common causes of unexplained abnormal liver function. Liver biopsy does not aggravate the organic and functional impairment of the liver.Keywords: unexplained abnormal liver function, clinical manifestations, liver biopsy, pathology

Minmin Han,1,2,&ast; Xiaoming Cao,3,&ast; Jian Zhang,1,2 Xifeng Yang,1,2 Yi Zhang,4,5 Yunfeng Liu1,2 1Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China; 2First Clinical Medical College, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China; 3Department of Urology, First Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of China; 4Department of Pharmacology, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China; 5Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, 030000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yunfeng Liu, Department of Endocrinology, First Hospital of Shanxi Medical University, No. 85, Jiefang Nan Road, Taiyuan, 030000, People’s Republic of China, Tel +86-18703416196, Fax +86-351-4639756, Email nectarliu@163.com Yi Zhang, Department of Pharmacology, Shanxi Medical University, No. 56, Xinjian Nan Road, Taiyuan, 030000, People’s Republic of China, Tel +86-18835102847, Fax +86-351-4135971, Email yizhang313@163.comPurpose: This study aimed to investigate the glycometabolism, fat mass, and lean mass in primary aldosteronism (PA) during disease progression.Patients and Methods: Patients diagnosed with PA and healthy controls (HCs) were enrolled. A flash glucose monitoring system (FGMS) and dual-energy X-ray absorptiometry (DEXA) were used to measure glucose variability and glucose target rate along with fat mass and lean mass. Comparative analysis of FGMS- or DEXA-derived parameters along with correlation analyses between these parameters and PA progression were performed.Results: Increased glucose variability and poor glucose target rate, along with an increased proportion of truncal fat mass, and decreased proportion of appendicular lean mass, were identified in PA group compared to those in HCs. Plasma aldosterone concentration was positively correlated with glucose variability and poor glucose target rate. Plasma renin concentration was positively correlated with the proportion of truncal fat mass and lean mass, and negatively correlated with the proportion of appendicular fat mass. Aldosterone-to-renin ratio was negatively correlated with the proportion of truncal fat mass and lean mass, and positively correlated with the proportion of appendicular fat mass.Conclusion: Patients with PA presented significant differences in glycometabolism, fat mass, and lean mass compared with HCs, and these alterations correlated with PA progression.Keywords: glucose variability, fat mass, lean mass, aldosterone, renin, ARR, correlation analysis

Yongxu Lin,1,2 Yaling Liu,3 Qiuyan Lin,1,2 Mingrong Wang,1,2 Pingying Jiang,1,2 Kaiyi Mao,1,2 Fenglin Chen,1,2 Jian Ding,3 Dan Li1,2 1Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 2Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, People’s Republic of China; 3Department of Gastroenterology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, People’s Republic of ChinaCorrespondence: Dan Li, No. 29 Xinquan Road, Fuzhou, 350001, People’s Republic of China, Email doctorlidan99@fjmu.edu.cn Jian Ding, No. 20 Chazhong Road, Fuzhou, 350005, People’s Republic of China, Email docdingjian@163.comPurpose: Early detection of hyperlipidemic acute pancreatitis (HLAP) with exacerbation tendency is crucial for clinical decision-making and improving prognosis. The aim of this study was to establish a reliable model for the early prediction of HLAP severity.Patients and Methods: A total of 225 patients with first-episode HLAP who were admitted to Fujian Medical University Union Hospital from June 2012 to June 2023 were included. Patients were divided into mild acute pancreatitis (MAP) or moderate-severe acute pancreatitis and severe acute pancreatitis (MSAP+SAP) groups. Independent predictors for progression to MSAP or SAP were identified through univariate analysis and least absolute shrinkage and selection operator regression. A nomogram was established through multivariate logistic regression analysis to predict this progression. The calibration, receiver operating characteristic(ROC), and clinical decision curves were employed to evaluate the model’s consistency, differentiation, and clinical applicability. Clinical data of 93 patients with first-episode HLAP who were admitted to the First Affiliated Hospital of Fujian Medical University from October 2015 to October 2022 were collected for external validation.Results: White blood cell count, lactate dehydrogenase, albumin, serum creatinine, serum calcium, D-Dimer were identified as independent predictors for progression to MSAP or SAP in patients with HLAP and used to establish a predictive nomogram. The internally verified Harrell consistency index (C-index) was 0.908 (95% CI 0.867– 0.948) and the externally verified C-index was 0.950 (95% CI 0.910– 0.990). The calibration, ROC, and clinical decision curves showed this nomogram’s good predictive ability.Conclusion: We have established a nomogram that can help identify HLAP patients who are likely to develop MSAP or SAP at an early stage, with high discrimination and accuracy.Keywords: early prediction, nomogram, hyperlipidemic acute pancreatitis, risk factor, prognosis

Yuanli Liu,1 Chunqing Deng2 1The First Clinical Medical School, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of China; 2Department of Infectious Diseases, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, People’s Republic of ChinaCorrespondence: Chunqing Deng, Department of Infectious Diseases, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, 030000, People’s Republic of China, Tel +8613546459087, Email 13546459087@163.comBackground: Visceral leishmaniasis (VL), also known as kala-azar, is caused by an intracellular parasite transmitted to humans by the bite of a sand fly, and with the source of the infection mainly being dogs. The main features of the disease are irregular fever, weight loss, hepatosplenomegaly and anaemia. Diagnosis relies mainly on bone marrow aspiration tests to find Leishman-Donovan(LD) bodies. And we report the case without febrile symptoms and hepatitis C virus antibody was probably false positive.Case Presentation: The case was a 74-year-old male residing in Yangquan City, Shanxi Province, a VL endemic area. He presented with generalised malaise, hepatosplenomegaly and scarring pigmentation on the skin as a result of scratching. Laboratory tests showed pancytopenia, positive hepatitis C virus antibody (HCV-Ab), positive direct anti-human globulin test (DAT), positive anti-cardiolipin antibody IgG, IgM (+), and increased immunoglobulin IgG. Symptomatic treatments such as hepatoprotection and blood transfusion were given, but the patient’s symptoms still persisted and his spleen and liver further enlarged. Further repeat tests were performed and found to be negative for hepatitis C virus antibodies and antigens. The patient was eventually found to be infected with Leishmania protozoa by rk39 rapid diagnostic test and metagenomic next-generation sequencing(mNGS). And the patient quickly relieved after one course of treatment with sodium stibogluconate.Conclusion: Patients with VL may cause abnormalities in the immune system, leading to false positives for various antibodies without clear febrile symptoms, resulting in misdiagnosis or delayed diagnosis. It is important to consider VL in cases where there is a significant hepatosplenomegaly with a relevant epidemiological history. If the diagnosis cannot be confirmed through bone marrow aspiration and the patient is not suitable for splenic aspiration, the rk39 test can be used for initial exclusion and further verified through mNGS.Keywords: visceral leishmaniasis, symptoms, false-positive antibodies, metagenomic next-generation sequencing, case report

Yixin Liu,1 Feifei Ren,1 Shan Li,1 Xiangchen Li,1 Dongyan Shi,2 Zhiqing Zhang1 1Department of Pharmacy, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Department of Clinical Laboratory, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Zhiqing Zhang, Department of pharmacy, the Second Hospital of Hebei Medical University, 215, Heping Road, Xinhua District, Shijiazhuang, Hebei, People’s Republic of China, Email 26500007@hebmu.edu.cn Dongyan Shi, Department of clinical laboratory, the Second Hospital of Hebei Medical University, 215, Heping Road, Xinhua District, Shijiazhuang, Hebei, People’s Republic of China, Email shidongyan73@126.comObjective: To define the antifungal activity of n-butylphthalide alone or in combination with fluconazole in Candida glabrata and Candida tropicalis.Methods: The antifungal activity of n-butylphthalide alone and in combination with fluconazole was investigated by the classical broth microdilution method and the time-killing curve method. The QRT-PCR method was used to determine gene expressions changes of mitochondrial respiratory chain enzymes, drug efflux pumps and drug target enzymes in Candida glabrata and Candida tropicalis after n-butylphthalide treatment.Results: The MIC values of n-butylphthalide against Candida glabrata and Candida tropicalis ranged from 16 to 64 μg·mL-1. The FICI value of the combination of n-butylphthalide and fluconazole against drug-resistant Candida glabrata and Candida tropicalis ranged from 0.5001 to 0.5315 with partial synergism. Time-killing curves showed that 256 μg·mL-1 n-butylphthalide significantly inhibited the growth of drug-resistant colonies of Candida glabrata and Candida tropicalis, and 128 μg·mL-1 n-butylphthalide combined with 1 μg·mL-1 fluconazole had an additive effect. N-butylphthalide could alter the expression of mitochondrial respiratory chain enzymes COX1, COX2, COX3, and CYTB genes in Candida glabrata and Candida tropicalis (P< 0.05) and downregulate the expression of the drug efflux pump genes CDR1 and CDR2 in drug-resistant Candida glabrata to 3.36% and 3.65%, respectively (P< 0.001), but did not affect the drug target enzyme ERG11 in drug-resistant Candida tropicalis.Conclusion: N-butylphthalide had antifungal activity against Candida glabrata and Candida tropicalis. N-butylphthalide improved the activity of fluconazole against drug-resistant Candida glabrata by affecting the expression of mitochondrial respiratory chain enzyme genes and reversing the high expression of drug efflux pump genes CDR1 and CDR2.Keywords: n-butylphthalide, fluconazole, drug resistance, Candida glabrata, Candida tropicalis, potentiation

Zhengjun Ma,1 Yanmei Zhang,1 Yupu Zhu,2 Minxuan Cui,2 Yutao Liu,2 Yun-You Duan,1 Li Fan,2 Li Zhang1 1Department of Ultrasound Medicine, Tangdu Hospital, Air Force Medical University, Xi’an, People’s Republic of China; 2Department of Pharmaceutical Chemistry and Analysis, School of Pharmacy, Air Force Medical University, Xi’an, People’s Republic of ChinaCorrespondence: Li Fan; Li Zhang, Email xxfanny@fmmu.edu.cn; lilyzhang319_20@hotmail.comIntroduction: Recently, nanobubbles (NBs) have gained significant traction in the field of tumor diagnosis and treatment owing to their distinctive advantages. However, the application of NBs is limited due to their restricted size and singular reflection section, resulting in low ultrasonic reflection.Methods: We synthesized a nano-scale ultrasound contrast agent (IR783-SiO2NPs@NB) by encapsulating SiO2 nanoparticles in an IR783-labeled lipid shell using an improved film hydration method. We characterized its physicochemical properties, examined its microscopic morphology, evaluated its stability and cytotoxicity, and assessed its contrast-enhanced ultrasound imaging capability both in vitro and in vivo.Results: The results show that IR783-SiO2NPs@NB had a “donut-type” composite microstructure, exhibited uniform particle size distribution (637.2 ± 86.4 nm), demonstrated excellent stability (30 min), high biocompatibility, remarkable tumor specific binding efficiency (99.78%), and an exceptional contrast-enhanced ultrasound imaging capability.Conclusion: Our newly developed multiple scattering NBs with tumor targeting capacity have excellent contrast-enhanced imaging capability, and they show relatively long contrast enhancement duration in solid tumors, thus providing a new approach to the structural design of NBs.Keywords: ultrasound contrast agents, nanobubbles, CEUS, scattering cross-section, SiO2 NPs

Lijuan Zhang,1 Zhe Wang,2 Yingge Liu,1 Xiaobao Zhang,1 Yong Wu1 1Department of Anesthesiology, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu, People’s Republic of ChinaCorrespondence: Yong Wu, Department of Anesthesiology, Lianyungang Clinical College of Nanjing Medical University, No. 6 East Zhenhua Road, Lianyungang, Jiangsu, 222061, People’s Republic of China, Tel +8618961325621, Email 18961325621@163.comPurpose: Remimazolam tosilate is a novel ultrafast-acting benzodiazepine that has a rapid emergence even after continuous infusion when using flumazenil. So far, relatively few articles are still focusing on the quality of recovery after general anesthesia with remimazolam, especially in day surgery. This study aimed to compare the early postoperative quality of recovery of remimazolam tosilate with flumazenil and propofol in patients undergoing day surgery.Patients and Methods: 137 patients scheduled for day surgery were randomly divided into the remimazolam tosilate or propofol group. The primary endpoint was the incidence of overall recovery assessed with the early postoperative quality of recovery scale (PostopQRS) on postoperative day 1 (POD 1). The Richmond Agitation-Sedation Scale (RASS) scores in the post-anesthesia care unit (PACU), extubation time, postoperative recovery profiles, and perioperative data were documented. Any adverse events were recorded.Results: The incidence of overall recovery on POD1 was 47.7% in the remimazolam tosilate group and 65.1% in the propofol group (odds ratio, 0.52; 95% confidence interval (CI) 0.26 to 1.06; P = 0.072). In general, the overall recovery of the PostopQRS increased over time, and its interaction between time and group was significant (P = 0.003). Among the five dimensions of PostopQRS, there exist statistical differences between groups including emotional state and cognitive recovery. Upon arrival at the PACU, the remimazolam group was more sedated and took longer to recover to a RASS score similar to propofol. The frequency of application of vasoactive drugs during anesthesia was similar in both groups (P = 0.119). Despite rapid emergence with remimazolam after flumazenil reversal, re-sedation (10.8%) or somnolence (60%) in the PACU was observed, and the length of PACU stay in patients treated with remimazolam tosilate was longer than that of the propofol (35 min vs 30 min, P< 0.001).Conclusion: General anesthesia with remimazolam tosilate in conjunction with flumazenil reversal permits rapid recovery of consciousness in day surgery, but there was a notable occurrence of re-sedation or somnolence observed in PACU.Keywords: remimazolam tosilate, flumazenil, propofol, day surgery, quality of recovery

Xin-Mei Hu,1,&ast; Can-Can Wang,1,&ast; Yu Xiao,1 Yu Liu,1 Hong-Ri Huang,2 Peng Jiang,1 Ying-Kai Wang,1 Yun-Jin Lin,1 Liang-Cheng Li,3 Zhong-Quan Qi1 1Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Research and Development, Guangxi Taimei Rensheng Biotechnology Co., Ltd, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhong-Quan Qi, Guangxi University, Da-Xue-Dong Road No. 100, Xixiangtang District, Nanning, Guangxi Zhuang Autonomous Region, 530004, People’s Republic of China, Tel +8613806001271, Email yxyyz@gxu.edu.cn Liang-Cheng Li, Xiamen University, No. 4221-115, Rm 355, Xiang’an District, Xiang’an, Xiamen Fujian Province, 361102, People’s Republic of China, Tel +8618359206906, Email lchli2013@xmu.edu.cnPurpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future.Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection.Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group.Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.Keywords: exosomes, cynomolgus monkeys, safety, immunotoxicity

Xiang Liu,1,&ast; Zhipeng Wei,2,&ast; Long Ting,1,&ast; Xuming Liu,3 Yongqiang Shu,1 Huang Ling,1 Lifeng Li,1 Yumeng Liu,1 Guojin Xia,1 Dechang Peng,1 Haijun Li1 1Department of Radiology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, People’s Republic of China; 2Department of Radiology, the Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, People’s Republic of China; 3Department of Radiology, Wenzhou People’s Hospital, Wenzhou, Zhejiang, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dechang Peng; Haijun Li, Email pengdcdoctor@163.com; haijunli1990@163.comIntroduction: Continuous positive airway pressure (CPAP) therapy improves clinical symptoms in patients with obstructive sleep apnea (OSA); however, the mechanism of this clinical improvement and how it may be associated with the restoration of white matter (WM) structures in the brain is unclear. Therefore, this study investigated the relationship between the structural recovery of brain WM and improvements in cognitive function and emotion after long-term (12 months) CPAP treatment in patients with OSA.Methods: We collected data from 17 patients with OSA before and 12 months after CPAP treatment, including sleep monitoring, clinical assessment, and diffusion tensor imaging (DTI) magnetic resonance imaging.Results: We observed a partial reversible recovery of brain WM (mean and radial diffusion coefficients) after treatment. This recovery involved the commissural fibers (cingulum, body of corpus callosum), projection fibers (retrolenticular part of the internal capsule, posterior thalamic radiation, posterior limb of the internal capsule, superior corona radiata, posterior corona radiata), association fibers (external capsule, superior longitudinal fasciculus, inferior longitudinal fasciculus), and other regions. In addition, the improvements in WM fibers in one part of the brain significantly were correlated with the Hamilton Anxiety Scale and Hamilton Depression Scale scores.Discussion: Our results suggest that reversible recovery of reduced brain WM integrity due to OSA may require longer CPAP treatment. Moreover, changes in the integrity of the commissural fibers were associated with emotion regulation. These restored WM areas may explain the cognitive and mood improvements observed after OSA treatment.Keywords: obstructive sleep apnea, continuous positive airway pressure, diffusion tensor imaging, tract-based spatial statistics

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

Yinyu Zhao,1,2 Nan Guo,1,3 Yidan Zhu,1,2 Jingyuan Shang,4 Jiali Chen,1,3 Xingxian Luo,1 Yi Liu,1 Xiaohong Zhang,1 Lin Huang1 1Department of Pharmacy, Peking University People’s Hospital, Beijing, People’s Republic of China; 2School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 3School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 4Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pharmacy, Peking University Cancer Hospital and Institute, Beijing, People’s Republic of ChinaCorrespondence: Xiaohong Zhang; Lin Huang, Department of Pharmacy, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China, Email zhangxiaohong@pkuph.edu.cn; huanglin@pkuph.edu.cnAbstract: Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.Keywords: venetoclax, BCL-2 inhibitor, population pharmacokinetics, PPK model, systematic review

Qian Chen,1,2 Chengyin Yu,1,2 Qingqing Wu,1,2 Rong Song,1,2 Ye Liu,1,2 Sheng Feng,3 Chen Yu,1,2 Jingying Jia1,2 1Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People’s Republic of China; 3Jiangsu Hengrui Pharmaceuticals Co., Ltd, Lianyungang, Jiangsu, People’s Republic of ChinaCorrespondence: Jingying Jia, Center Laboratory, Shanghai Xuhui Central Hospital, No. 966, Huaihai Road (M), Shanghai, People’s Republic of China, Tel/Fax +86-21-54030254, Email jyjia@shxh-centerlab.comPurpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ.Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated.Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80– 1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported.Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing.Trial Registration: ClinicalTrials.gov NCT06083116.Keywords: henagliflozin, drug-drug interaction, hydrochlorothiazide, pharmacokinetics, tolerability, pharmacodynamics, selective sodium-glucose cotransporter 2

Yuanhang Pan,1,&ast; Di Zhao,1,&ast; Xinbo Zhang,1,&ast; Na Yuan,1 Lei Yang,1 Yuanyuan Jia,2 Yanzhao Guo,3 Ze Chen,1 Zezhi Wang,1 Shuyi Qu,1 Junxiang Bao,4 Yonghong Liu1 1Department of Neurology, Xijing Air Force Medical University, Xi’an, People’s Republic of China; 2Encephalopathy Department No.2, Baoji Hospital of Traditional Chinese Medicine, Baoji, People’s Republic of China; 3Encephalopathy Department No.10, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, People’s Republic of China; 4Department of Aerospace Hygiene, Air Force Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghong Liu, Department of Neurology, Xijing hospital, Air Force Medical University, Xi’an, People’s Republic of China, Tel +86 13991236602, Email liuyhong@fmmu.edu.cn Junxiang Bao, Department of Aerospace Hygiene, Air Force Medical University, Xi’an, People’s Republic of China, Tel +86 02984711241, Email baojunx@fmmu.edu.cnBackground: Excessive daytime sleepiness (EDS) forms a prevalent symptom of obstructive sleep apnea (OSA) and narcolepsy type 1 (NT1), while the latter might always be overlooked. Machine learning (ML) models can enable the early detection of these conditions, which has never been applied for diagnosis of NT1.Objective: The study aimed to develop ML prediction models to help non-sleep specialist clinicians identify high probability of comorbid NT1 in patients with OSA early.Methods: Totally, clinical features of 246 patients with OSA in three sleep centers were collected and analyzed for the development of nine ML models. LASSO regression was used for feature selection. Various metrics such as the area under the receiver operating curve (AUC), calibration curve, and decision curve analysis (DCA) were employed to evaluate and compare the performance of these ML models. Model interpretability was demonstrated by Shapley Additive explanations (SHAP).Results: Based on the analysis of AUC, DCA, and calibration curves, the Gradient Boosting Machine (GBM) model demonstrated superior performance compared to other machine learning (ML) models. The top five features used in the GBM model, ranked by feature importance, were age of onset, total limb movements index, sleep latency, non-REM (Rapid Eye Movement) sleep stage 2 and severity of OSA.Conclusion: The study yielded a simple and feasible screening ML-based model for the early identification of NT1 in patients with OSA, which warrants further verification in more extensive clinical practices.Keywords: obstructive sleep apnea, narcolepsy, machine learning, prediction model, sleep disorder

Yu Liu,&ast; Hongying Guo,&ast; Wei Yuan, Ying Zou, Zhiping Qian, Xue Mei, Liujuan Ji, Jiefei Wang, Yuyi Zhang Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuyi Zhang, Email zhangyuyi@shaphc.orgBackground: Talaromyces marneffei (TM) is the third most prevalent opportunistic infection in HIV-positive patients after tuberculosis and cryptococcosis. However, such infection of non-HIV individuals has rarely been reported.Case Presentation: We describe a very rare case of a 52-year-old male who presented with a single space-occupying lesion on the right lung and was eventually diagnosed with pulmonary TM infection. The patient was HIV-negative and had liver cirrhosis with portal vein thrombosis. Lung tissue next-generation sequencing (NGS) revealed TM infection. We successfully treated the patient with voriconazole for 8 weeks and observed lesion absorption via subsequent CT. The patient consumed wild bamboo rats two months before admission. Mutations related to congenital immune deficiency were not detected by whole-exome sequencing.Conclusion: Early and timely diagnosis is critical for improving patient prognosis. NGS plays a vital role in the diagnosis of pulmonary TM infection in patients. To our knowledge, this is the first published case of pulmonary TM infection in an HIV-negative patient with liver cirrhosis.Keywords: Talaromyces marneffei, pulmonary infection, HIV-negative, PVT

Yujian Shao,1,2 Yonglu Chen,2 Mingyue Zhu,3 Yuanyuan Liu,2 Chen Fang,3 Minjun Wang,2 Peng Sun,3 Weiling Fu,2 Jing Huang,3 Shimei Sheng,2 Yanshan Huang2 1Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd, Hangzhou, Zhejiang, People’s Republic of China; 3First Research Institute, Zhejiang Heze Pharmaceutical Technology Co., Ltd, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Yanshan Huang, Department of Innovative Drug Discovery and Development, Zhejiang Doer Biologics Co., Ltd, Hangzhou, Zhejiang, People’s Republic of China, Email yanshanhuang@doerbio.comIntroduction: Diabetes and obesity are momentous risk factors threatening people’s lives and health. Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss. Co-agonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss. Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it.Methods: The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro. The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys. The OGTTs were performed in Sprague‑Dawley (SD) rats. The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic (db/db) mice for 4 weeks. The effects of anti-obesity and improving metabolism of DR10627 were evaluated by repeated administration of DR10627 in diet-induced obesity (DIO) mice for 57 days.Results: DR10627 had the capacity to activate both GLP-1R and GIPR in vitro. The terminal half-life of DR10627 was found to be approximately 4.19– 5.8 h in cynomolgus monkeys. DR10627 had a great improvement in oral glucose tolerance in SD rats. Moreover, DR10627 had a potent glucose-lowering effect in db/db mice, and the hypoglycemic effect of 18 nmol/kg DR10627 was better than that of 50 nmol/kg liraglutide. In addition, 10 and 30 nmol/kg DR10627 possessed the ability of potentiating the weight-loss, lipid-lowing efficacy and improving metabolism to a greater extent than 80 nmol/kg liraglutide.Conclusion: Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and db/db mice, and substantial body weight reduction and metabolism improvement in DIO mice. DR10627 is a promising agent deserving further investigation for the treatment of type 2 diabetes and obesity.Keywords: glucagon-like peptide-1, gastric inhibitory polypeptide receptor, obesity, type 2 diabetes, inflammation

Wenlong Nie,&ast; Yun Liu,&ast; Jinshuai Lan, Ting Li, Yitian He, Zhe Li, Tong Zhang, Yue Ding School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tong Zhang; Yue Ding, Email zhangtongshutcm@hotmail.com; Dingyue-2001@hotmail.comBackground: Natural nanoparticles have been found to exist in traditional Chinese medicine (TCM) decoctions. However, whether natural nanoparticles can influence the oral bioavailability of active compounds has not been elucidated. Using Xie-Bai-San decoction (XBSD) as an example, the purpose of this study was to isolate, characterize and elucidate the mechanism of the nanoparticles (N-XBSD) in XBSD, and further to explore whether the bioavailability of the main active compounds could be enhanced by N-XBSD.Methods: N-XBSD were isolated from XBSD, and investigated its characterization and study of its formation mechanism, and evaluation of its ability to enhance bioavailability of active compounds.Results: The N-XBSD was successfully isolated with the average particle size of 104.53 nm, PDI of 0.27 and zeta potential of − 5.14 mV. Meanwhile, all the eight active compounds were most presented in N-XBSD. Kukoamine B could self-assemble with mulberroside A or liquiritin to form nanoparticles, respectively. And the FT-IR and HRMS results indicated the possible binding of the ammonium group of kukoamine B with the phenolic hydroxyl group of mulberroside A or liquiritin, respectively. The established UPLC-MS/MS method was accurate and reliable and met the quantitative requirements. The pharmacokinetic behaviors of the N-XBSD and decoction were similar in rats. Most notably, compared to that of free drugs, the Cmax, AUC0-∞, AUC0-t, T1/2 and MRT0-∞ values of index compounds were the higher in N-XBSD, with a slower plasma clearance rate in rats.Conclusion: The major active compounds of XBSD were mainly distributed in N-XBSD, and N-XBSD was formed through self-assembly among active compounds. N-XBSD could obviously promote the bioavailability of active compounds, indicating natural nanoparticles of decoctions play an important role in therapeutic effects. Keywords: nanoparticles, enhancing bioavailability, comparative pharmacokinetics, UPLC-MS/MS, Xie-Bai-San decoction

Lei Yuan,&ast; Lan Min Lai,&ast; Xinyu Zhu, Zhao Rui, Yang Liu, Qiang Chen Department of Clinical laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang Chen, Email 674389899@qq.comBackground: The HACEK group comprises Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae, are Gram-negative bacteria that are slow-growing and fastidious. These organisms are common causes of culture-negative endocarditis. However, brain abscesses caused by Haemophilus aphrophilus and E. corrodens have been rarely reported. The case we describe, which was promptly identified and successfully treated, will be meaningful for the diagnosis and treatment of such infectious diseases.Case Presentation: Herein, we report a case of brain abscess in a young man who was infected with Haemophilus aphrophilus and E. corrodens. The patient was admitted to the hospital with sudden onset of vomiting, coma, and fever. Magnetic resonance imaging (MRI) of the brain and cerebrospinal fluid cell counts suggested cerebral abscess, he underwent drainage of the abscess and empirical antimicrobial therapy of meropenem (2 g every 8 hours) and linezolid (0.6 g every 12 hours) for more than 10 days without significant improvement. Metagenomic next-generation sequencing (mNGS) of drainage fluid and matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS) detection for isolated bacteria from samples suggested the presence of H. aphrophilus and E. corrodens. After 7 weeks of ceftriaxone (2 g every 12 hours) and meropenem (2 g every 8 hours) intravenously, the patient was discharged with a normal temperature and brain MRI showed improvement of the lesion.Conclusion: Similar cases reported in previous studies were always associated with bacterial blood dissemination after dental surgery or myocarditis; however, the patient in our case had no any associated risk factors. As far as we know, this is the only case of central nervous system infection caused by H. aphrophilus and E. corrodens that has utilized combined mNGS and MALDI-TOF MS in the diagnosis.Keywords: Haemophilus aphrophilus, Eikenella corrodens, HACEK, brain abscess

Jiaman Yang,1,2,&ast; Yulin Xie,1,2,&ast; Zhikuan Xia,1,&ast; Shuaifei Ji,3,&ast; Xin Yang,1 Danxia Yue,1 Yuanyuan Liu,1,3 Rongya Yang,1– 3 Yunlong Fan1,3 1Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China; 2The Second School of Clinical Medicine, SouThern Medical University, Guangzhou, 510599, People’s Republic of China; 3Chinese PLA Medical School, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Rongya Yang, Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, No. 5, Nanmencang Alley, Dongsi Shitiao, Dongcheng District, Beijing, 100700, People’s Republic of China, Email YangRY301hospital@163.com Yunlong Fan, Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, No. 5, Nanmencang alley, Dongsi Shitiao, Dongcheng District, Beijing, 100700, People’s Republic of China, Email FanYL301hospital@163.comBackground: Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes.Methods: HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes (Cpt1b, Acadm, and Acadl).Results: Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration.Conclusion: This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo. Keywords: HucMSC-Exo, neutrophils, phenotype switching, cutaneous wound healing, tissue restoration

Qilin Han,1,2 Yifan Li,3 Yao Liu,1 Xuehan Zhu,1 Qiqi An,4 Yameng Li,5 Tingting Wang,5 Yuzhen Zhang,1,2 Yingying Li,5 Weiwei Fang,1,2 Ningning Tao,1,&ast; Huaichen Li1,2,&ast; 1Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 2Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences), Jinan, Shandong, 250031, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Xingyi People’s Hospital, Qianxinan, Guizhou, 561499, People’s Republic of China; 5Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ningning Tao, Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China, Email 826794467@qq.com Huaichen Li, Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwuweiqi Road, Huaiyin District, Jinan, Shandong, 250021, People’s Republic of China, Email lihuaichen@163.comPurpose: To analyze the time trends in the notification rates of registered tuberculosis (TB) and bacteriologically confirmed TB in Shandong Province. And analyze the changes in TB treatment outcomes during 2005– 2021.Patients and Methods: The information of TB patients registered in the Shandong Information Center for Disease Control and Prevention (CDC) was collected during 2005– 2021. We calculated the notification rates of registered TB and bacteriologically confirmed TB. Moreover, we calculated the year-to-year change rate of TB in treatment outcomes before and after COVID-19. The time trends were analyzed using the joinpoint regression method and illustrated as the annual percentage change (APC) of notification rates.Results: A total of 236,898 cases of TB were diagnosed during 2005– 2021, of which 51.11% were bacteriologically confirmed cases. Since 2008, the notification rates of registered TB have declined. The notification rates of bacteriologically confirmed TB had been declining during 2005– 2016, then remained stable after 2016. In subgroup, the notification rates of both registered TB and bacteriologically confirmed TB were higher among men, rural residents, and people aged ≥ 60 years. Compared with clinically confirmed TB, bacteriologically confirmed TB has shown higher rates of poor outcomes since 2008 and higher case fatality rate since 2005. The rate of poor outcomes remained stable during 2008– 2019. However, after the COVID-19 outbreak, the rate of poor outcomes and case fatality rate of TB has risen significantly.Conclusion: After unremitting efforts to fight against TB, the notification rates of registered TB and bacteriologically confirmed TB declined in Shandong Province. The rate of poor outcomes remained stable during 2008– 2019, then rise significantly after the COVID-19 outbreak. In the context of the long-term existence of COVID-19, further efforts should be made in TB diagnosis and treatment among high-risk population, especially with regard to males, rural residents and older adults.Keywords: tuberculosis, joinpoint regression, time trends, COVID-19

Mengjiao Yang,1,2,&ast; Yang Liu,1,&ast; Yangyang Zhao,3,&ast; Ziwei Wang,4 Jie He,5 Yali Wang,2 Tokie Anme6 1Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan; 2Department of Cardiovascular Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, People’s Republic of China; 3Department of Blood Transfusion, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, People’s Republic of China; 5Department of Nursing, Affiliated Hospital of North Sichuan Medical College, Nanchong City, Sichuan Province, People’s Republic of China; 6Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan&ast;These authors contributed equally to this workCorrespondence: Tokie Anme, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 3058577, Japan, Tel\Fax +81-29-853-3436, Email tokieanme@gmail.comPurpose: This study aimed to explore the correlation of frailty status with disease characteristics and patient-reported outcomes (PROs) in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and determine the sensitivity and specificity of modified COPD PRO scale (mCOPD-PRO) for detecting frailty.Patients and Methods: This cross-sectional study surveyed 315 inpatients with AECOPD from a tertiary hospital in China from August 2022 to June 2023. Patient frailty and PROs were assessed using the validated FRAIL scale and mCOPD-PRO, respectively. Spearman’s ρ was used to assess the relevance of lung disease indicators commonly used in clinical practice, and ordinal logistic regression analyses were used to identify the variables associated with frailty status. The validity of mCOPD-PRO in discriminating frail or non-frail individuals was determined using the receiver operating characteristic curve.Results: The participants (N=302, mean age 72.4± 9.1 years) were predominantly males (73.2%). Among them, 43 (14.3%) patients were not frail, whereas 123 (40.7%) and 136 (45.0%) patients were pre-frail and frail, respectively. The FRAIL scale was moderately correlated with the mCOPD-PRO scores (Spearman’s rank correlation coefficient [Rs]=0.52, P< 0.01) for all dimensions (Rs=0.43– 0.49, P< 0.01). Patients residing in rural areas (odds ratio [OR], 1.67; 95% confidence interval [95% CI], 1.01– 2.76) and with higher mCOPD-PRO scores (OR, 4.78; 95% CI, 2.75– 8.32) were more likely to be frail. Physically active patients (OR, 0.42; 95% CI, 0.21– 0.84) were less likely to be frail. In addition, mCOPD-PRO had good discriminate validity for detecting frailty (area under the curve=0.78), with a sensitivity and specificity of 84.6% and 60.8%, respectively. The optimal probability threshold for mCOPD-PRO was ≥ 1.52 points.Conclusion: In patients with AECOPD, frailty is closely related to PROs and disease characteristics. Additionally, the mCOPD-PRO score can distinguish well between frail and non-frail patients. Our findings provide support for interventions targeting frail populations with AECOPD.Plain Language Summary: Patients with chronic obstructive pulmonary disease often have concomitant frailty that may lead to disease deterioration such as acute exacerbations, hospital readmissions, disability, and premature death. Patient-reported outcomes are often used in clinical practice to measure patients’ disease characteristics and overall status. Whether patients’ frailty state is associated with patient-reported outcomes and if so, which factors are associated with frailty remain unclear. This study, conducted in China, examined their relationship as well as identified factors associated with frailty states. 302 hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease completed a questionnaire answering questions about disease severity, frailty state, anxiety, and depression. The findings suggest that people who live in rural areas, self-reported more severe overall conditions, and are physically inactive are more likely to be frail. Patient-reported outcomes can distinguish between frail and non-frail patients. Therefore, patient-reported outcomes can be used to assess the extent of frailty; early screening of AECOPD combined frailty population and implementation of interventions can help mitigate the adverse effects of frailty.Keywords: frailty, COPD, COPD exacerbation, patient-report outcome, aging

Bo Huang,&ast; Xin Li,&ast; Xinxin Zhang, Shiwei Li, Yue Liu, Mengjuan Zhang, Jingqiu Cui Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jingqiu Cui, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China, Tel +86 13920765604, Email cuijingqiu@tmu.edu.cnPurpose: People with hyperuricemia (HUA) are often related to metabolic disorders such as diabetes, metabolic syndrome (MetS), and obesity. However, the correlation between excretion of uric acid and these diseases is unclear. Our study aimed to explore the relationship between uric acid excretion and type 2 diabetes (T2D).Methods: A total of 228 HUA patients from Tianjin Medical University General Hospital from 2022 to 2023 were included in this study. We collected demographic, biochemical, and anthropometric data on each subject. Urine uric acid excretion (UUAE) was calculated enzymatically from a single urine collection that lasted 24 hours. And fractional excretion of uric acid (FEUA) was calculated from serum uric acid and creatinine and uric acid and creatinine. Binary logistic regression modeling assessed the association between uric acid excretion and T2D.Results: Of the 228 subjects, 13.4% had T2D and 48.7% had obesity. The obesity group had a lower FEUA (p< 0.05) and a higher UUAE compared to the control group (p< 0.05). And FEUA had a stronger correlation with the risk of T2D (p< 0.001). Also, there was a negative association between BMI and FEUA and a positive link between BMI and UUAE in the outpatients.Conclusion: Increased FEUA levels were significantly associated with T2D in HUA patients. Therefore, routine calculating of FEUA is essential for proper diagnosis and appropriate treatment T2D of in HUA patients. Keywords: urine uric acid excretion, hyperuricemia, obesity, Type 2 diabetes, fractional excretion of urate

Chao Zuo,1 Yi Liu,1 Ziqiang Wang,2 Jing Cheng,1 Dongli Yang,1 Huasong Gong,1 Yu Wang,3 Yongchao Qiao1 1Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People’s Republic of China; 2Research Center of Clinical Laboratory Science, Bengbu Medical College, Bengbu, Anhui, People’s Republic of China; 3Department of Geriatrics, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, People’s Republic of ChinaCorrespondence: Yongchao Qiao, Department of Clinical Laboratory, Affiliated Hospital of Guilin Medical University, Le Qun Road 15, Guilin, Guangxi, 541001, People’s Republic of China, Email qiaoyc@glmc.edu.cn Yu Wang, Department of Geriatrics, Affiliated Hospital of Guilin Medical University, Le Qun Road 15, Guilin, Guangxi, 541001, People’s Republic of China, Tel +86 773 2822730, Email wangyu101101@163.comIntroduction: This study aimed to investigate the association of Nicotinamide phosphoribosyl transferase (NAMPT) rs61330082 polymorphism with co-morbid hypertension (HTN) and the progression of hypertension in Chinese patients with type 2 diabetes mellitus (T2DM).Methods: A total of 453 T2DM patients were genotyped for the polymorphism of rs61330082 using SNP-scan high-throughput technology. These patients were divided into T2DM group (261 patients) and T2DM combined with hypertension group (T2MH, 192 patients). The T2MH group was further categorized into Grade I, Grade II, and Grade III based on the results of the Hypertension Grade Score. Peripheral blood plasma urea, plasma creatinine, renin-angiotensin system (RAS) indexes, and lipid biochemistry indexes were measured in patients and analyzed in relation to NAMTP polymorphisms.Results: We found that the presence of the NAMPT rs61330082-AA genotype was associated with a significantly increased risk of developing higher-grade hypertension in patients with T2MH. In addition, the A allele of the NAMPT rs61330082 gene displayed more associated in developing a higher grade of hypertension compared to the G allele. Also, the level of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) increased with hypertension grade in the NAMPT rs61330082-GG genotype.Conclusion: NAMPT rs61330082 polymorphism was significantly associated with the progression of hypertension grade in T2MH patients and also affected plasma creatinine and LDL-c levels.Keywords: NAMPT, polymorphism, T2DM, hypertension classification

Min Wu,1,2,&ast; Sining Zeng,3,&ast; Yi Zhang,1,2,&ast; Yanru Liu,1,2 Bingbing Li,1,2 Xuemei Yi,1,2 Yuling Shi,1,2 Xiaoping Zhu3 1Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China; 2Institute of Psoriasis, Tongji University School of Medicine, Shanghai, 200443, People’s Republic of China; 3Nursing Department, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoping Zhu, Nursing Department, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Middle Road, Jing’an District, Shanghai, People’s Republic of China, Tel +86-021-66300588, Fax +86-021-66307542, Email xiaopingzhu0424@163.com Yuling Shi, Department of Dermatology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 1278 Baode Road, Jing’an District, Shanghai, People’s Republic of China, Tel +86-021-36803020, Fax +86-021-36803021, Email shiyuling1973@tongji.edu.cnBackground: Psoriasis is a chronic autoimmune inflammatory skin condition characterized by erythema, papules, and scales. It imposes a heavy psychological and social strain on both patients and their families. Surprisingly, there’s limited research delving into the disease burden and coping strategies of spouses contending with psoriasis.Objective: The objective is to explore the disease burden faced and coping strategies utilized by spouses of individuals living with psoriasis. This exploration aims to offer insights crucial for devising mental health support and intervention strategies.Methods: The research methodology employed in this study was phenomenological, a qualitative approach. A total of fifteen spouses of patients with psoriasis were selected using an objective sampling method for in-depth, semi-structured interviews. Thematic analysis was then applied to the recorded interview data to derive meaningful themes.Results: This study has identified and analyzed three core themes concerning the disease burden and coping strategies of spouses of patients with psoriasis: Overwhelming disease burden; Lack of support system; Coping strategies (Problem - centered coping strategies: Proactive acquisition of disease knowledge; Active confrontation of illness - related issues; Behavioral habit alteration; and Emotional - centered coping strategies: Active acceptance and normalization; Passive acceptance and internalized stigma; Avoidance of disease - related problems).Conclusion: This study adds valuable insights into comprehending the disease burden encountered by spouses of patients with psoriasis and sheds light on the coping strategies they employ. Healthcare providers should proactively recognize and address the burden experienced by spouses early on. Establishing a robust support network is crucial, and promoting adaptive coping strategies can significantly aid spouses in effectively navigating and managing the complexities associated with psoriasis.Keywords: psoriasis, spouse, disease burden, coping strategies, qualitative research

Hua-Jing Yuan,1 Hua-Chen Jiao,2 Xiu-Juan Liu,2 Hao Hao,2 Yang Liu,2 Yi-Tao Xue,2 Yan Li2 1Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014, People’s Republic of China; 2Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, 250014, People’s Republic of ChinaCorrespondence: Yi-Tao Xue; Yan Li, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shanshi East Road, Lixia District, Jinan City, Shandong Province, People’s Republic of China, Tel +86-531-82602943 ; +86-531-68611662, Email xytsdzydfy@126.com; liyan88130@163.comPurpose: The association between serum uric acid (SUA) and atrial fibrillation (AF) has been widely focused on and studied in recent years. However, the exact association between SUA and AF is unclear, and the effect of gender on the association between SUA levels and AF has been controversial. This study aimed to investigate the association between SUA levels and non-valvular AF (NVAF) and the potential effect of gender on it.Patients and Methods: A total of 866 NVAF patients (463 males, age 69.44 ± 8.07 years) and 646 sex-matched control patients in sinus rhythm, with no history of arrhythmia were included in this study. t-test, ANOVA, and chi-square test were used for baseline data analysis. The receiver operating characteristic curve, logistic regression and Pearson correlation analysis were used for correlation analysis.Results: Compared to controls, NVAF patients exhibited higher SUA (P< 0.001). After adjusting for confounders of NVAF, SUA remained significantly associated with NVAF, regardless of gender (OR= 1.31, 95% CI 1.18– 1.43, P< 0.001). SUA demonstrated higher predictability and sensitivity in predicting the occurrence of female NVAF compared to male (area under the curve was 0.68 (95% CI 0.64– 0.72, P< 0.001), sensitivity 87.3%), with the optimal cut-off point identified as 5.72 mg/dL. Furthermore, SUA levels correlated with APOA1, Scr and NT-proBNP in NVAF patients. SUA levels varied significantly among NVAF subtypes.Conclusion: High SUA levels were independently associated with NVAF, regardless of gender. SUA exhibited higher predictability and sensitivity in predicting the occurrence of NVAF in females compared to males. High SUA levels may affect other NVAF-related factors and participate in the pathophysiological process of NVAF.Keywords: serum uric acid, non-valvular atrial fibrillation, gender difference, retrospective study, predictive indicators

Yue Chen,1,&ast; Aili Gao,1,&ast; Yanan Ke,1 Xin Zhou,1 Li Lin,2 Sha Lu,2 Yumei Liu1 1Department of Dermatology, Guangzhou Dermatology Hospital, Guangzhou, 510095, People’s Republic of China; 2Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yumei Liu, Director of Department of Dermatology, Guangzhou Dermatology Hospital, Guangzhou, People’s Republic of China, Tel/Fax +86- 20-83593472, Email liuyumei1109@163.comAbstract: Protothecosis, an infrequent human infection, is caused by achlorophyllic algae belonging to the genus Prototheca, particularly Prototheca wickerhamii. The skin stands as the most commonly affected organ. This report documents a case involving an 82-year-old male with Protothecosis. Histopathological analysis revealed granulomatous inflammation in the dermis, exhibiting necrotic features and hosting numerous non-budding spherical organisms. These organisms were positively stained using methenamine silver and periodic acid–Schiff stains, confirming identification as P. wickerhamii after validation through tissue culture and sequencing procedures. Initially, the patient received oral itraconazole at a dosage of 200 mg daily, accompanied by topical 1% naftifine-0.25% ketoconazole cream for a duration of 4 weeks, resulting in significant improvement. Subsequently, due to gastrointestinal discomfort presumably linked to itraconazole, terbinafine was administered. Over a span of 3 months, the patient received oral terbinafine at a dosage of 250 mg/day alongside the application of topical 1% naftifine-0.25% ketoconazole cream, leading to complete healing of the skin lesion, leaving behind a fibrotic scar.Keywords: protothecosis, Prototheca wickerhamii, terbinafine

Jiarun Mi, Xinyu Du, Yilixiati Aili, Mingkun Li, Yuanli Liu School of Health Policy and Management, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, People’s Republic of ChinaCorrespondence: Yuanli Liu, School of Health Policy and Management, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongdansantiao, Dongcheng District, Beijing, 100730, People’s Republic of China, Tel +86-13522592907, Email liuyuanli_pumc@163.comBackground: Trust is a major factor affecting patient-physician relationship and healthcare quality. However, there has been a lack of comprehensive study on the extent of and major factors affecting patient trust in healthcare providers of China, the world’s largest developing country. The objective of this study is to elucidate the current status of outpatient trust in physicians in China and its influencing factors, providing empirical evidence to enhance doctor-patient trust and improve doctor-patient relationships.Methods: Between December 2017 and January 2018, 28,760 patients seeking care at the outpatient departments of 136 tertiary hospitals were interviewed, where they were asked to rate their trust in physicians. We applied a multilevel logistic regression model to explore the association between patients trust and characteristics of hospitals, physicians and patient characteristics. We conducted a series of sensitivity analysis to check the robustness of our findings.Results: Among 28,760 participants included in this study, 91.54% expressed trust in their physicians, while 7.52% showed moderate trust. Only 0.94% expressly distrusted or strongly distrusted their physicians. Outpatients of hospitals with convenient payment, volunteer guidance and enough seats available in the rest and waiting area showed higher levels of trust. Physicians who had a senior title, showed patience and protection of the patient’s privacy were more likely to be trusted by their patients in the outpatient setting. Compared to their female counterparts, male outpatients showed a higher degree of trust.Conclusion: While this study highlights an overall high level of Trust in physicians (TIP) among patients in China’s tertiary hospitals, it is found to vary with patient demographic factors as well as provider’s attributes. Hospitals with a more keen sense of protecting patients privacy and better meeting patients’ need for efficient and caring service provision process appeared to yield a higher level of trust.Keywords: trust in physicians, national survey, outpatients

Xiaoyue Feng,&ast; Jianli Shang,&ast; Zhengping Gu, Xingyi Luo, Yong Chen, Youting Liu Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Youting Liu, Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, 102699, People’s Republic of China, Tel +86 1 851 025 6963, Email YtLiu.adpt@outlook.comAbstract: Lactic acid is the most widely occurring natural organic acid in nature. It not only exhibits mild and safe properties but also possesses multiple physiological activities, such as antibacterial effects, immune regulation, and promotion of wound healing, making it one of the most popular chemical peeling agents. Chemical peels are commonly used in the field of aesthetic dermatology as a non-invasive therapeutic approach. This research aims to provide valuable references for clinical dermatologists by summarizing the characteristics of lactic acid, elucidating its mechanism of action in peeling, and investigating the clinical applications of this compound. Furthermore, it anticipates the potential for lactic acid to be the most suitable chemical peeling agent for Chinese skin.Keywords: lactic acid, physiological activities, clinical applications, Chinese skin

Ling Lv,1 Xin Zhang,1 Yajun Liu,1 Xutong Zhu,2 Ruihan Pan,1 Lifa Huang1 1Department of Neurosurgery, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, People’s Republic of China; 2The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Lifa Huang, Department of Neurosurgery, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), No. 54 Youdian Road, Hangzhou, 310006, People’s Republic of China, Tel/Fax +86-57186620251, Email jazzle@163.comPurpose: Dysregulated liquid-liquid phase separation (LLPS) instigates tumorigenesis through biomolecular condensate dysfunction. However, the association between LLPS-associated genes and glioma remains underexplored.Patients and Methods: Differentially expressed genes (DEGs) of glioma were obtained from the GSE50161 dataset, including 34 glioma and 13 normal samples. We analyzed differentially expressed LLPS-related genes in glioma from public databases. These genes informed refined molecular subtyping on the TCGA-glioma dataset. CIBERSORT assessed immune cell infiltration across three subclusters. A prognostic model was devised using univariate and lasso Cox regressions on intersecting genes. Prognostic gene expression was validated in glioma cells via RT-qPCR.Results: A total of 673 differentially expressed LLPS-associated genes were identified in glioma. Three distinct molecular subtypes (C1, C2, and C3) of glioma were obtained with a marked variance in the expression of immune checkpoint genes PD1 and PDL1. Differences in immune cell infiltration were observed across subtypes. In addition, a tri-gene prognostic signature (TAGLN2, NTNG2, and IGF2BP2) was derived with significant survival differences between high and low-risk groups. The prognostic model displayed impressive AUC values for 1, 3, and 5-year survival in both training and validation sets. Further analysis highlighted a notable correlation between the three prognostic genes and immune cells in glioma samples. Furthermore, we found the upregulation of TAGLN2 and IGF2BP2 and the downregulation of NTNG2 in glioma tumors and cells.Conclusion: This study innovatively uncovers the significant role of LLPS-related genes in glioma tumor grading and prognosis. The constructed tri-gene prognostic model holds promise for enhancing personalized prognosis assessments and optimizing immunotherapy strategies for glioma patients.Keywords: liquid-liquid phase separation, glioma, prognostic model, molecular subtype, immune cell infiltration

Liuping Cui,1,2 Ran Liu,1 Fubo Zhou,1 Yumei Liu,1 Bing Tian,1 Ying Chen,2,&ast; Yingqi Xing1,3,4,&ast; 1Department of Vascular Ultrasound, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Beijing Diagnostic Center of Vascular Ultrasound, Beijing, People’s Republic of China; 4Center of Vascular Ultrasound, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingqi Xing, Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing, Xicheng District, 100053, People’s Republic of China, Tel +86-18610047846, Email xingyq2009@sina.comPurpose: Intraplaque neovascularization, assessed using contrast-enhanced ultrasound (CEUS), is associated with ischemic stroke. It remains unclear whether detection of intraplaque neovascularization combined with color Doppler ultrasound (CDUS) provides additional value compared with CDUS alone in assessing ischemic stroke risk. Therefore, we investigated the clinical value of combined CEUS, CDUS, and clinical features for ischemic stroke risk stratification.Patients and Methods: We recruited 360 patients with ≥ 50% carotid stenosis between January 2019 and September 2022. Patients were examined using CDUS and CEUS. Covariates associated with ischemic stroke were identified using multivariate logistic regression analysis. The discrimination and calibration were verified using the C-statistic and Hosmer–Lemeshow test. The incremental value of intraplaque neovascularization in the assessment of ischemic stroke was analyzed using the Delong test.Results: We analyzed the data of 162 symptomatic and 159 asymptomatic patients who satisfied the inclusion and exclusion criteria, respectively. Based on multivariate logistic regression analysis, we constructed a nomogram using intraplaque neovascularization, degree of carotid stenosis, plaque hypoechoicity, and smoking status, with a C-statistic of 0.719 (95% confidence interval [CI]: 0.666– 0.768) and a Hosmer–Lemeshow test p value of 0.261. The net reclassification index of the nomogram was 0.249 (95% CI: 0.138– 0.359), and the integrated discrimination improvement was 0.053 (95% CI: 0.029– 0.079). Adding intraplaque neovascularization to the combination of CDUS and clinical features (0.672; 95% CI: 0.617– 0.723) increased the C-statistics (p=0.028).Conclusion: Further assessment of intraplaque neovascularization after CDUS may help more accurately identify patients at risk of ischemic stroke. Combining multiparametric carotid ultrasound and clinical features may help improve the risk stratification of patients with ischemic stroke with ≥ 50% carotid stenosis.Plain Language Summary: We studied whether using contrast-enhanced ultrasound (CEUS) to detect intraplaque neovascularization could help better determine the risk of ischemic stroke. We compared the combined use of color Doppler ultrasound (CDUS) and CEUS with CDUS alone in patients with more than 50% carotid narrowing. Our findings showed that combining clinical details, CDUS, and CEUS was more effective (0.719 vs 0.672). This means that CEUS provides extra insight when gauging ischemic stroke risk compared with CDUS alone. This could help in accurately identifying patients at high risk of stroke. However, more extensive studies are needed to fully understand the role of these tests in the evaluation of stroke risk. Keywords: atherosclerosis, contrast-enhanced ultrasound, vulnerable plaque, carotid ultrasound

Xulei Sui,1 Peipei Feng,1 Xiaoyuan Sun,1 Peng Liang,1 Ying Liu,2 Guowei Zhang3 1Department of Radiology, Yantaishan Hospital, Yantai City, 264001, People’s Republic of China; 2Department of Pathology, Yantaishan Hospital (East Courtyard), Yantai City, 264003, People’s Republic of China; 3Department of Radiology, Yantaishan Hospital (East Courtyard), Yantai City, 264003, People’s Republic of ChinaCorrespondence: Guowei Zhang, Department of Radiology, Yantaishan Hospital (East Courtyard), No. 10087 Keji Avenue, Laishan District, Yantai City, 264003, People’s Republic of China, Tel +86-0535-6602048, Email zhangguoweiyt@163.comPurpose: This study determined the digital mammography and ultrasonography imaging features of pure invasive micropapillary carcinoma of the breast (PIMPC) and the correlation with pathologic features.Patients Methods: Nineteen patients diagnosed with PIMPC at Yantaishan Hospital from October 2015 to February 2022 were included in the study group. Forty patients with breast masses diagnosed as nonspecific invasive ductal carcinoma of the breast (NIDC) from July to December 2021 were included in the control group. Digital mammography and ultrasonography features were compared between the two groups.Results: Patients with PIMPC had a younger age profile compared to patients with NIDC (P=0.017). Moreover, PIMPC masses were smaller than NIDC masses (P=0.040). Imaging features analysis revealed significant differences in age groups (< 45 years: χ²=5.971, P=0.044) and the presence of spiculations or the crab claw sign (χ²=8.583, P=0.004) between patients with PIMPC and NIDC. However, there were no statistically significant differences in the presence of calcifications, blood flow grading, pathologic molecular subtypes between the study and control groups. The Ki-67 proliferative index (χ²=1.052, P=0.389), vascular invasion (χ²=2.263, P=0.197), and lymph node metastasis (χ²=1.968, P=0.386) showed no significant differences between PIMPC and NIDC patients.Conclusion: PIMPC imaging features show specificity, such as tiny breast masses, spiculated edges, or crab claw-like patterns, and malignant signs appeared when the lesion was < 2 cm in diameter. PIMPC mainly occurs in middle-aged women 45– 59 y of age. Patients with PIMPC and NIDC of the breast are frequently associated with lymph node metastases and greater than one-half of the cases (74%) were shown to have a Ki-67 index > 30%, suggesting a significant risk of recurrence and metastasis. Early therapeutic care for these patients is crucial. These results warrant further validation with additional samples from several centers due to the limited single-center sample size in the current study.Keywords: pure invasive micropapillary breast carcinoma, digital mammography, ultrasonography, breast cancer, pathologic features