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Zixiang Geng,1,2,* Tiancheng Sun,1,2,* Jie Yu,1,2,* Ning Wang,1,2 Qiang Jiang,1,2 Peige Wang,1,2 Guangyue Yang,1,2 Yifei Li,3 Yue Ding,4 Jiange Zhang,5 Guoqiang Lin,5 Yongfang Zhao1,2 1Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 5The Research Center of Chiral Drugs, Innovation Research Institute of Traditional, Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zixiang Geng, Institute of Traumatology and Orthopedics, Shanghai Academy of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Email gengzx@foxmail.com Yongfang Zhao, Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email zhaoyongfang@shutcm.edu.cnBackground: Cinobufagin, the primary active compound in toad venom, is commonly used for anti-tumor, anti-inflammatory, and analgesic purposes. However, its specific bone-protective effects remain uncertain. This research aims to ascertain the bone-protective properties of cinobufagin and investigate underlying mechanisms.Methods: Mice were ovariectomized to establish an osteoporosis model, followed by intraperitoneal injections of cinobufagin and cinobufagin-treated RAW.264.7-derived exosomes for therapy. MicroCT, HE staining, and TRAP staining were employed to evaluate bone mass and therapeutic outcomes, while mRNA sequencing and immunoblotting were utilized to assess markers of bone metabolism, inflammation, and lipid peroxidation. Osteoblast and osteoclast precursor cells were differentiated to observe the impact of cinobufagin-treated exosomes derived from RAW264.7 cells on bone metabolism. Exosomes characteristics were studied using transmission electron microscopy and particle size analysis, and miRNA binding targets in exosomes were determined by luciferase reporting.Results: In ovariectomized mice, cinobufagin and cinobufagin-treated exosomes from RAW264.7 cells increased trabecular bone density and mass in the femur, while also decreasing inflammation and lipid peroxidation. The effect was reversed by an exosomes inhibitor. In vitro experiments revealed that cinobufagin-treated exosomes from RAW264.7 cells enhanced osteogenic and suppressed osteoclast differentiation, possibly linked to Upregulated miR-3102-5p in RAW-derived exosomes. MiR-3102-5p targets the 3′UTR region of alox15, thereby suppressing its expression and reducing the lipid peroxidation process in osteoblasts.Conclusion: Overall, this study clarified cinobufagin’s bone-protective effects and revealed that cinobufagin can enhance the delivery of miR-3102-5p targeting alox15 through macrophage-derived exosomes, demonstrating anti-lipid peroxidation and anti-inflammatory effects. Keywords: osteoporosis, cinobufagin, exosomes, miR-3102-5p

Chenrui Zhao,1,2,* Yuanyuan Ding,2,* Yihan Huang,2 Chao Wang,2 Bin Guo,1 Tao Zhang2 1Department of Anesthesiology, Xi’an Honghui Hospital, Xi’an Jiaotong University, Xi’an, 710054, People’s Republic of China; 2College of Pharmacy, Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bin Guo, Department of Anesthesiology, Xi’an Honghui Hospital, Xi’an Jiaotong University, Xi’an, 710054, People’s Republic of China, Email xuan_310755@sina.comBackground: CMRF35-like molecule-1 (CLM-1) is a receptor of the CD300 family that inhibits MRGPRX2-mediated mast cell degranulation. Understanding the role and mechanism of CLM-1 agonist has significant implications for the treatment of allergic disease. Quercetin is a natural small molecule compound derived from plants and vegetables that has been shown to prevent histamine release by immune cells.Objective: This study aims to examine the inhibitory effects of quercetin on MRGPRX2-mediated mast cell degranulation via CLM-1.Results: We found that C48/80 stimulation resulted in significantly increased release of β-hexosaminidase, histamine and Ca2+ in CLM-1-knockdown LAD2 cells than in NC-LAD2 cells. Surface plasmon resonance (SPR) and molecular docking analyses revealed high-affinity binding between quercetin and CLM-1 (KD = 2.962× 10− 5 mol/L) mediated by the formation of hydrogen bonds. In addition, quercetin can selectively bind to CLM-1 on mast cells, leading to SHP-1 phosphorylation and subsequent inhibition of downstream MyD88/IKK/NF-κB signaling. Furthermore, activation of CLM-1 modulated the surface expression of MRGPRX2 by inhibiting F-actin, leading to internalization of the MRGPRX2 receptor via the PI3K/AKT/ Rac1/Cdc42 pathway.Conclusion: Quercetin is a promising treatment for allergic diseases by acting as a CLM-1 agonist that inhibits MRGPRX2-mediated mast cell degranulation. Keywords: quercetin, CLM-1, inhibition, MRGPRX2, mast cell degranulation

Zhaochang Jiang,1 Haohao Lu,2 Beibei Gao,3 Jinyu Huang,3 Yu Ding4 1Department of Pathology, Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2Zhejiang Center of Laboratory Animals, Hangzhou Medical College, Hangzhou, Zhejiang, 310063, People’s Republic of China; 3Department of Cardiology, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, 310006, People’s Republic of China; 4Department of Clinical Laboratory, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, 310006, People’s Republic of ChinaCorrespondence: Yu Ding, Department of Clinical Laboratory, Hangzhou First People’s Hospital, Hangzhou, Zhejiang, 310006, People’s Republic of China, Email dingyu_zj@126.comPurpose: Coronary microembolization (CME) can result in cardiac dysfunction, severe arrhythmias, and a reduced coronary flow reserve. Impairment of mitochondrial energy metabolism has been implicated in the progression and pathogenesis of CME; however, its role remains largely undetermined. This study aimed to explore alterations in mitochondria-related genes in CME.Methods: A rat model of CME was successfully established by injecting plastic microspheres into the left ventricle. The cardiac tissues of the two groups were sequenced and mitochondrial functions were assessed.Results: Using RNA-Seq, together with GO and KEGG enrichment analyses, we identified 3822 differentially expressed genes (DEGs) in CME rats compared to control rats, and 101 DEGs were mitochondria-related genes. Notably, 36 DEGs were up-regulated and 65 DEGs were down-regulated (CME vs control). In particular, the oxidative phosphorylation (OXPHOS) and mitochondrial electron transport were obviously down-regulated in the CME group. Functional analysis revealed that CME mice exhibited marked reductions in ATP and mitochondrial membrane potential (MMP), by contrast, the production of reactive oxygen species (ROS) was much higher in CME mice than in controls. Protein–protein interaction (PPI) and quantitative PCR (qPCR) validation suggested that eight hub genes including Cmpk2, Isg15, Acsl1, Etfb, Ndufa8, Adhfe1, Gabarapl1 and Acot13 were down-regulated in CME, whereas Aldh18a1 and Hspa5 were up-regulated.Conclusion: Our findings suggest that dysfunctions in mitochondrial activity and metabolism are important mechanisms for CME, and mitochondria-related DEGs may be potential therapeutic targets for CME.Keywords: CME, rat model, RNA-Sequence, DEGs, OXPHOS, energy metabolism

Jing Yu,1,2 Yanzi Ding,1,2 Xue Zhang,1,2 Shuhong Tai,1,2 Chengwen Zhang,1,2 Cailin Liu,3 Enwu Yuan,1,2 Yitao Duan1,2 1Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 2Zhengzhou Key Laboratory for in vitro Diagnosis of Hypertensive Disorders of Pregnancy, Zhengzhou, Henan, 450052, People’s Republic of China; 3Department of Laboratory Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaCorrespondence: Yitao Duan; Enwu Yuan, Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University, No. 7 Front Kangfu Street, Zhengzhou, Henan, 450052, People’s Republic of China, Email duanyitao@zzu.edu.cn; yuanenwu@126.comPurpose: Understanding the horizontal transfer of resistance genes, such as blaNDM-5, is pivotal in developing strategies to control the spread of resistance. In this study, we isolated two bacterial strains, Escherichia coli (designated GYB01) and Klebsiella pneumoniae (designated GYB02), from a single patient. The aim of our research is to explore the biological characteristics of these strains and to investigate the interspecies horizontal transfer of blaNDM-5.Materials and Methods: Strain identification and antimicrobial susceptibility testing were conducted using the Vitek 2 system. Both GYB01 and GYB02 were sequenced with the Illumina HiSeq platform. Bioinformatics analysis tools, including multilocus sequence typing, PlasmidFinder, ResFinder, and others, were utilized to analyze the strains. Additionally, conjugation assays and Galleria mellonella infection assays were employed to assess the strains.Results: The isolates exhibited similar antimicrobial resistance profiles and both harbored the blaNDM-5 gene within the IncFIA plasmids (pGYB01-2, 165.8 kb and pGYB02-2, 211.6 kb, respectively). These plasmids (pGYB01-2 and pGYB02-2) shared over 99% homology, suggesting a common ancestral origin. Conjugation experiments confirmed the transferability of the blaNDM-5 carrying IncFIA plasmids among Enterobacteriaceae. GYB02 possessed an iucACD-iutA gene cluster, exhibited high virulence, and tested positive in the string test.Conclusion: Our findings provide direct evidence of potential in vivo interspecies transfer of a multidrug-resistant plasmid, thus enriching our understanding of the mechanisms driving multidrug resistance (MDR) and aiding in the formulation of containment and treatment strategies.Keywords: CRE, NDM-5 carbapenemase, IncFIA plasmid, interspecies horizontal transfer

Yiping Wang,1 Zhiqing Hu,2,3 Yueming Ding,2,3 Yanjun Sun,2,3 Rui Meng,1 Yuan He1– 3 1School of Nursing, Nanjing Medical University, Nanjing, People’s Republic of China; 2Institute of Medical Humanities, Nanjing Medical University, Nanjing, People’s Republic of China; 3School of Marxism, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Yuan He, School of Nursing, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, People’s Republic of China, Email heyuan@njmu.edu.cnObjective: Our study aimed to examine the association between delay discounting (DD) and body mass index (BMI) in individuals with hypertension. Additionally, we sought to explore and compare the potential mediating effects of self-efficacy, physical activity and sedentary behavior in this association.Methods: A cross-sectional survey was conducted in two cities in the Jiangsu province of China, specifically Nanjing and Yangzhou, from March to June 2023. A total of 972 hypertensive patients completed the questionnaire (Mage = 64.7 years, SDage = 8.2 years, 54.2% female). Participants engaged in a money choice experiment on computers, provided their height and weight, and completed the International Physical Activity Questionnaire-Short Form (IPAQ-SF) and General Self-Efficacy Scale (GSES). The experimental program was generated using the programming software E-Prime version 2.0. Multiple hierarchical regression analysis was conducted to identify potential covariates. Two serial mediation models were conducted using PROCESS macro 4.1 in SPSS 27.0. Physical activity and sedentary behavior were designated as M2 to investigate and contrast their respective mediating effects in the association between delay discounting and body mass index.Results: Self-efficacy, physical activity, and sedentary behavior served as mediators in the relationship between delay discounting and BMI. Self-efficacy accounted for 14.9% and 14.3% of the total effect in Models 1 and 2, respectively, while physical activity and sedentary behavior each accounted for 14.9% and 9.5% of the total effect, respectively. The serial mediation effects of self-efficacy and physical activity, as well as self-efficacy and sedentary behavior, were significant (B = 0.01, 95% CI [0.01, 0.02]; B = 0.01, 95% CI [0.002, 0.01]), collectively contributing 2.1% and 2.4% of the total effect. Sedentary behavior played a smaller mediating role compared to physical activity in this association.Conclusion: The results indicated that self-efficacy, physical activity and sedentary behavior could act as mediators in the association between delay discounting and BMI, thus potentially mitigating the risk of obesity in hypertensive individuals.Keywords: delay discounting, obesity, physical activity, sedentary behavior, self-efficacy, hypertension

Yueming Ding,1 Huiying Zhang,1 Zhiqing Hu,1 Yanjun Sun,1 Yiping Wang,2 Baolong Ding,3 Guofeng Yue,4 Yuan He1,5 1Institute of Medical Humanities, School of Marxism, Nanjing Medical University, Nanjing, People’s Republic of China; 2School of Nursing, Nanjing Medical University, Nanjing, People’s Republic of China; 3School of Pharmacy, Nanjing Medical University, Nanjing, People’s Republic of China; 4School of Health Policy and Management, Nanjing Medical University, Nanjing, People’s Republic of China; 5Research Center for Social Risk Management of Major Public Health Events (Key Research Base of Philosophy and Social Sciences of Universities in Jiangsu), Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Yuan He, Institute of Medical Humanities, School of Marxism, School of Nursing, Research Center for Social Risk Management of Major Public Health Events (Key Research Base of Philosophy and Social Sciences of Universities in Jiangsu), Nanjing Medical University, Nanjing, 211166, People’s Republic of China, Email heyuan@njmu.edu.cn Guofeng Yue, School of Health Policy and Management, Nanjing Medical University, Nanjing, 211166, People’s Republic of China, Email gfyue@njmu.edu.cnBackground: Improving health-related quality of life (HRQoL) among hypertensive individuals has emerged as a significant public health issue. However, current research has ignored the individual heterogeneity of perceived social support (PSS) among hypertensive patients. The potential mechanism of delay discounting (DD), living alone, and PSS on HRQoL remains unclear, and further exploration is required.Aim: This study aimed to ascertain PSS profiles among hypertensive patients and examine the hypotheses that DD mediates the relationship between PSS and HRQoL and that this mediating process is moderated by living alone in hypertensive patients.Methods: A cross-sectional study was carried out in Jiangsu, China. In total, 1815 hypertensive patients completed socio-demographic and HRQoL questionnaires, a PSS scale, and a DD task. Data analyses included a latent profile analysis, χ2-test, Spearman correlation analysis, and PROCESS macro for regression analysis.Results: Four potential PSS profiles were identified: lowest (3.2%), moderate–low (26.6%), moderate–high (42.4%), and highest (27.8%). DD mediated the association between PSS and HRQoL. The first half of this mediating process was moderated by living alone.Conclusion: Our findings indicated that PSS, DD, and living alone significantly influence the HRQoL of individuals with hypertension. Healthcare professionals should consider variations in PSS among hypertensive patients and implement interventions to reduce DD by enhancing PSS, in order to improve the HRQoL of this population.Keywords: perceived social support, delay discounting, health-related quality of life, living alone, hypertensive patients, latent profile analysis

Liyan Sun,1 Jinshuai Lan,1,2 Zhe Li,1,2 Ruifeng Zeng,1,2 Yi Shen,1 Tong Zhang,1,2 Yue Ding1– 3 1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3National Innovation Platform for Medical Industry-Education Integration, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of ChinaCorrespondence: Yue Ding; Tong Zhang, Email dingyue-2001@hotmail.com; zhangtongshutcm@hotmail.comAbstract: Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. This review introduced the expansive spectrum of BBR’s anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery. Berberine (BBR), recognized as an oncotherapeutic phytochemical, exhibits its anti-cancer properties via multiple molecular pathways. However, its clinical application is hindered by suboptimal tumor accumulation, rapid systemic elimination, and diminished bioactive concentration owing to extensive metabolic degradation. To circumvent these limitations, the strategic employment of nanocarriers and other drugs in combination with BBR is emerging as a focus to potentiate its anti-cancer efficacy. Nano-delivery systems increase drug concentration at the tumor site by improving pharmacological activity and tissue distribution, enhancing drug bioavailability. Organic nanocarriers have advantages for berberine delivery including biocompatibility, encapsulation, and controlled release of the drug. While the advantages of inorganic nanocarriers for berberine delivery mainly lie in their efficient loading ability of the drug and their slow release ability of the drug. This review introduced the expansive spectrum of BBR’s anti-cancer activities, BBR and other drugs co-loaded nanocarriers for anti-cancer treatments, and evaluated the synergistic augmentation of these amalgamated modalities. The aim is to provide an overview of BBR for cancer treatment based on nano-delivery.Keywords: berberine, anti-cancer, nano drug delivery system, combination therapy

Shanshan Wu,1,2,* Shuren Wang,3,* Yonghong Ding,2 Zongwang Zhang1,2 1Department of Anesthesiology, Liaocheng People’s Hospital, Shandong University, Liaocheng, People’s Republic of China; 2Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, People’s Republic of China; 3Department of Anesthesiology, Dongchangfu District Maternal and Child Health Hospital, Liaocheng, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zongwang Zhang, Department of Anesthesiology, Liaocheng People’s Hospital, Shandong University, Liaocheng, People’s Republic of China, Tel +86-13346256809, Email zwzhang68@sina.comObjective: Postoperative pain is a common complication in endoscopic submucosal dissection (ESD) patients. This study aimed to develop and validate predictive models for postoperative pain associated ESD.Methods: We retrospectively constructed a development cohort comprising 2162 patients who underwent ESD at our hospital between January 2015 and April 2022. The dataset was randomly divided into a training set (n = 1541) and a validation set (n = 621) in a 7:3 ratio. The bidirectional stepwise regression with Akaike’s information criterion (AIC) and multivariate logistic regression analysis were used to screen the predictors of post-ESD pain and construct three nomograms. We evaluated the model’s discrimination, precision and clinical benefit through receiver operating characteristic (ROC) curves, calibration plots, Hosmer–Lemeshow (HL) goodness-of-fit test and decision curve analysis (DCA) in internal validation.Results: The proportion of patients developing postoperative pain in the training and testing data set was 25.6% and 28.5%, respectively. Three nomograms were constructed according to the final logistic regression models. The clinical prediction models for preoperative risks, preoperative and intraoperative risks, and perioperative risks consisted of seven, nine and six independent predictors, respectively, after bidirectional stepwise elimination. The models demonstrated the AUC of 0.794 (95% CI 0.768– 0.820), 0.823 (95% CI 0.799– 0.847) and 0.817 (95% CI 0.792– 0.842) in the training cohort and 0.702 (95% CI 0.655– 0.748), 0.705 (95% CI 0.659– 0.752) and 0.747 (95% CI 0.703– 0.790) in the validation cohort. The calibration plot, HL and DCA demonstrated the model’s favorable clinical applicability.Conclusion: We developed and validated three robust nomogram models, which might identify patients at risk of post-ESD pain and promising for clinical applications.Keywords: endoscopic submucosal dissection, postoperative pain, nomograms

Lianjie Miao, Songwei Feng, Bo Ding, Ke Zhang, Yue Ding, Yang Shen Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of ChinaCorrespondence: Yang Shen, Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, 210096, People’s Republic of China, Email shenyang@seu.edu.cnPurpose: The aim of this study was to analyze the survival of patients with endometrial cancer diagnosed after a prior cancer and identify risk factors of endometrial cancer death in this population.Methods: Totally 1371 women diagnosed with second primary endometrial cancer (SPEC) between 2004 and 2015 were identified using the SEER database. Clinicopathological characteristics were collected, and Fine and Gray regression model was employed to assess the impact of treatment for the first primary cancer (FPC) and SPEC on the mortality of endometrial cancer patients. After propensity score matching (PSM), patients diagnosed with single primary endometrial cancer and SPEC between 2004 and 2015 were included as the second cohort. Kaplan-Meier and Cox survival risk models were used to assess the influence of previous cancer history on survival.Results: Patients previously diagnosed as lung cancer exhibited the lowest overall survival (OS). A diagnostic interval of ≥ 3 years was significantly associated with higher mortality from SPEC compared with that < 3 years. Surgical treatment for SPEC was linked to a reduced risk of endometrial cancer-specific mortality (ECSM) and non-ECSM. Conversely, radiotherapy and chemotherapy were associated with an increased risk of ECSM. The 1-, 3-, and 5-year OS rates of patients with SPEC were significantly lower than those with single primary endometrial cancer whether before or after PSM. Univariate and multivariate analyses further demonstrated that endometrial cancer, either as FPC or SPEC, was independently associated with an increased risk for endometrial cancer-specific survival (ECSS) and OS.Conclusion: Chemotherapy and radiotherapy for SPEC can elevate the risk of ECSM. Whether as FPC or SPEC, endometrial cancer is demonstrated to be a significant independent risk factor for ECSS and OS.Keywords: second primary cancer, endometrial cancer, risk factor, overall survival, SEER database

Yongfeng Lao,1,2 Yanan Bai,1,2 Xin Guan,1,2 Jian Wang,1,2 Yanan Wang,1,2 Rongxin Li,1,2 Yongqiang Ding,1,2 Zhilong Dong1,2 1Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 2Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, Gansu, People’s Republic of ChinaCorrespondence: Zhilong Dong, Department of Urology, The Second Hospital of Lanzhou University, No. 82, Cuiyingmen, Chengguan District, Lanzhou, Gansu, People’s Republic of China, Email dzl1997.student@sina.comIntroduction: Although sertraline has been widely used for chronic prostatitis (CP), the mechanisms are unclear. Herein, we explored the mechanisms of sertraline in treating CP.Methods: Network pharmacology methods were used to explore the potential targets and molecular mechanisms. LPS was used to stimulate RWPE-1 cells to construct an in vitro model of CP. An experimental autoimmune prostatitis (EAP) mice model was built. CCK-8 assay, EdU assay, BrdU detection, and Tunel assay were performed to evaluate the proliferation and apoptosis process of cells or tissues, respectively. DCFH-DA and Fluo-4 fluorescence probes were used to detect intracellular ROS and calcium concentrations. Von Frey filaments and open-field tests were utilized to evaluate pain response and depressive-like behavior of mice. Histopathology was evaluated through hematoxylin and eosin staining. RT-qPCR, Western blot, immunofluorescence, and immunohistochemistry were utilized to evaluate the transcription, expression, and location of related proteins. Molecular dynamics (MD) simulation and surface plasmon resonance (SPR) assay were performed to measure the binding capacity of sertraline and related proteins.Results: Through a network pharmacology analysis, 27 potential targets of sertraline for CP were obtained, and 5 key targets (CHRM1, ADRA1B, HTR2B, HTR2A, and TRPV1) were finally identified. Functional experiments suggested that TRPV1 was involved in the proliferation, apoptosis inhibition, and ROS production of LPS-induced RWPE-1 cells. In vitro experiments showed that sertraline significantly inhibited cell proliferation, ROS generation, and transcription of inflammation cytokines of LPS-induced RWPE-1 cells. Additionally, sertraline markedly promoted the apoptosis level of LPS-stimulated RWPE-1 cells and elevated the expression level of BAX while reducing the expression levels of Bcl2 and Caspase-3. MD simulation and SPR assay confirmed the direct binding of sertraline to TRPV1. Moreover, sertraline significantly down-regulated the expression level of TRPV1 and inhibited calcium influx of LPS-induced RWPE-1 cells. TRPV1 agonist (Capsaicin) significantly restored the effects on proliferation, apoptosis, ROS production, and calcium influx of sertraline on LPS-induced RWPE-1 cells. Mice experiments demonstrated that sertraline treatment could reduce pain response, improve depression-like symptoms, and relieve local prostate inflammation of EAP mice, as well as down-regulated the expression level of TRPV1, inhibit the proliferation, and promote apoptosis of prostate tissues in EAP mice.Discussion: The results revealed the anti-inflammatory effect of sertraline for RWPE-1 cells and EAP mice, and the potential mechanism was regulating the TRPV1 channel. It indicated that sertraline might serve as a complementary anti-inflammatory agent for CP.Keywords: chronic prostatitis, sertraline, RWPE-1, mice, TRPV1

Xundi Bao,1 Shuo Liang,1 Jun Li,1 Qian Ye,1 Dandan Wu,1 Shu Wang,2 Yue Li,1 Yunsheng Ding,1 Jie Liu3 1Clinical Laboratory, Anhui Provincial Chest Hospital (Provincial Institute of Tuberculosis Control), Hefei, Anhui, People’s Republic of China; 2Department of Science and Education, Anhui Provincial Chest Hospital (Provincial Institute of Tuberculosis Control), Hefei, Anhui, People’s Republic of China; 3Tuberculosis Control Institute, Anhui Provincial Chest Hospital (Provincial Institute of Tuberculosis Control), Hefei, Anhui, People’s Republic of ChinaCorrespondence: Xundi Bao, Clinical laboratory, Anhui Provincial Chest Hospital (Provincial Institute of Tuberculosis Control), No. 397, Jixi Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86-13866774716, Email baoxundi@163.comObjective: To preliminarily assess the prevalence and control effect of tuberculosis and drug-resistant tuberculosis (TB) in Anhui province, and analyze the trends in the changing drug resistance spectrum of Mycobacterium tuberculosis (Mtb) isolated in Anhui province from 2016 to 2022.Methods: From 2016 to 2022, a total of 2336 culture-positive tuberculosis strains were collected from four drug resistance monitoring sites. Patient demographic information was collected and drug susceptibility testing was conducted.Results: Among the 2336 Mycobacterium tuberculosis complex strains, 1788 (76.54%) were from male patients and 548 (23.46%) were from female patients. The majority were of Han ethnicity, from rural areas, and employed in agriculture, with 12.54% (285/2273) having diabetes. A total of 1893 (81.04%) strains were sensitive to all six anti-TB drugs tested, and 443 (18.96%) strains were resistant to at least one or more anti-TB drugs. The drug resistance rate for patients undergoing initial treatment was 16.80% (348/2071), and 35.85% (95/265) for those receiving retreatment. Among the six anti-TB drugs, the resistance rates from highest to lowest were: INH (10.55%, 236/2336), SM (8.18%, 183/2336), OFX (6.53%, 146/2336), RFP (5.95%, 133/2336), EMB (2.37%, 53/2336), KM (1.97%, 44/2336). Significant differences were observed in MDR strains across different ages, types, with or without diabetes, and geographical sources (χ 2=14.895,76.534,6.032,5.109, all P< 0.05).Conclusion: The tuberculosis prevention and control measures have controlled the drug resistance rate of Mycobacterium tuberculosis to a certain extent. However, there are still statistical differences in drug resistance rates among TB patients with different categories, age groups, regions, and diabetic diseases. Early detection and prompt treatment of patients with drug-resistant TB remain critical to controlling the spread of this disease.Keywords: tuberculosis, mycobacterium, drug resistance, surveillance, population distribution, characteristic analysis

Donghao Wang,1,&ast; Yuting Zhang,1,&ast; Qiming Gan,1,&ast; Xiaofen Su,1,&ast; Haojie Zhang,1,2,&ast; Yanyan Zhou,1 Zhiyang Zhuang,1 Jingcun Wang,1 Yutong Ding,1 Dongxing Zhao,1 Nuofu Zhang1 1State Key Laboratory of Respiratory Disease, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, National Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2The Clinical Medicine Department, Henan University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nuofu Zhang; Dongxing Zhao, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, National Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Tel +86-13600460056 ; +86-13650901411, Email nfzhanggird@163.com; rieast@163.comObjective: Compared to low arousal threshold (AT), high AT is an easily overlooked characteristic for obstructive sleep apnea (OSA) severity estimation. This study aims to evaluate the relationship between high AT, hypertension and diabetes in OSA, compared to those with apnea–hypopnea index (AHI).Methods: A total of 3400 adults diagnosed with OSA were retrospectively recruited. Propensity score matching (PSM) was conducted to further categorize these patients into the low and high AT groups based on the strategy established by previous literature. The different degrees of AHI and quantified AT (AT score) were subsequently measured. The correlation of AT and AHI with the occurrence of various comorbidities in OSA was estimated by logistic regression analysis with odds ratio (OR).Results: After PSM, 938 pairs of patients arose. The median AT score of high and low AT group was 21.7 and 12.2 scores, and the adjusted OR of high AT for hypertension and diabetes was 1.31 (95% CI = 1.07– 1.62, P < 0.01) and 1.45 (95% CI = 1.01– 2.08, P < 0.05), respectively. Compared to low AT score group, the OR significantly increased in patients with very high AT score (30 ≤ AT score), especially for diabetes (OR = 1.79, 95% CI = 1.02– 3.13, P < 0.05). The significant association was not observed in AHI with increasing prevalent diabetes.Conclusion: Higher AT is significantly associated with increased prevalence of hypertension and diabetes in patients with OSA. Compared with AHI, AT score is a potentially comprehensive indicator for better evaluating the relationship between OSA and related comorbidities.Keywords: obstructive sleep apnea, arousal threshold, apnea–hypopnea index, hypertension, diabetes

Zhangrui Zeng,1,&ast; Yueshuai Wei,1,&ast; Caihong Ye,1 Yuan Jiang,1 Chunlin Feng,1 Tongtong Guo,1 Min Song,1 Yinhuan Ding,1 Ping Zhan,2 Jinbo Liu1 1Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, People’s Republic of China; 2Department of Gynaecology, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinbo Liu, Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, People’s Republic of China, Te/Fax +86 0830 3165730, Email liujb7203@swmu.edu.cnPurpose: The isolation rate of carbapenem-resistant Enterobacter cloacae complex (CREC) is continuously increasing. The aims of this study were to investigate the molecular characteristics and risk factors associated with CREC infections.Methods: Bacterial species were identified using the matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) (Bruker Daltonik GmbH, Bremen, Germany), and the hsp60 gene was utilized for further typing. Antimicrobial susceptibilities were assessed through the MicroScan WalkAway 96 Plus system (Siemens, Germany) and the microbroth dilution method. Antimicrobial resistance genes were screened through polymerase chain reaction (PCR), while the homologous relationship was assessed using multilocus sequence typing (MLST). Conjugation experiments were performed to verify whether the plasmid could be transferred. Additionally, logistic regression model was employed to analyze risk factors for CREC infections.Results: 32 strains of CREC bacteria were isolated during the study, yet only 20 were retained for preservation. While the isolates demonstrated resistance to the majority of antibiotics, they exhibited high sensitivity to polymyxin B and tigecycline. All isolates carried the blaNDM resistance gene, including 13 blaNDM-1 isolates and 7 blaNDM-5 isolates. MLST homology analysis revealed the presence of seven known ST types and one new ST type. Conjugation experiments confirmed that 13 isolates were capable of transferring the blaNDM resistance gene to Escherichia coli strain EC600. Single-factor analysis identified multiple primary risk factors for CREC infection, but multivariate analysis did not reveal independent risk factors.Conclusion: This study investigates the molecular characteristics and risk factors associated with CREC infections. The detection rate of CREC strains in our hospital is continuously rising and homology analysis suggested that strains might spread in our hospital, emphasizing the importance of implementing effective preventive measures to control the horizontal transmission of plasmid-mediated antimicrobial resistance genes.Keywords: carbapenem-resistant, Enterobacter cloacae complex, antimicrobial resistance, molecular characteristics, risk factors

Yuanyuan Ding,&ast; Linjiang Chen,&ast; Jing Xu, Yuhan Feng, Qiong Liu Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiong Liu, Department of Ophthalmology, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, Baiyun District, Guangzhou, Guangdong Province, 510515, People’s Republic of China, Tel +86-13922442109, Email nanfanglq2023@163.comObjective: Diabetic retinopathy (DR) can cause permanent blindness with unstated pathogenesis. We aim to find novel biomarkers and explore the mechanism of apoptotic protease activating factor 1 (APAF1) in DR.Methods: Differential expression genes (DEGs) were screened based on GSE60436 dataset to find hub genes involved in pyroptosis after comprehensive bioinformatics analysis. DR mice model was constructed by streptozotocin injection. The pathological structure of retina was observed using hematoxylin-eosin staining. The enzyme-linked immunosorbent assay was applied to assess inflammatory factors, vascular endothelial growth factor (VEGF), and oxidative stress. The mRNA and protein expression levels were detected using quantitative real-time polymerase-chain reaction and Western blot. Cell counting kit and flow cytometry were employed to detect proliferation and apoptosis in high glucose-induced ARPE-19 cells.Results: Total 71 pyroptosis-related DEGs were screened. BIRC2, CXCL8, APAF1, PPARG, TP53, and CYCS were identified as hub genes of DR. APAF1 was selected as a potential regulator of DR, which was up-regulated in DR mice. APAF1 silencing alleviated retinopathy and inhibited pyroptosis in DR mice with decreased levels of inflammatory factors, VEGF, and oxidative stress. Moreover, APAF1 silencing promoted proliferation while inhibiting apoptosis and caspase-3/GSDME-dependent pyroptosis with a decrease in TNF-α, IL-1β, IL-18, and lactate dehydrogenase in high glucose-induced ARPE-19 cells. Additionally, caspase-3 activator reversed the promotion effect on proliferation and inhibitory effect on apoptosis and pyroptosis after APAF1 silencing in high glucose-induced ARPE-19 cells.Conclusion: APAF1 is a novel biomarker for DR and APAF1 silencing inhibits the development of DR by suppressing caspase-3/GSDME-dependent pyroptosis.Keywords: diabetic retinopathy, APAF1, caspase-3, GSDME, pyroptosis

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

Xuejiao Yu,1 Sheng Li,2 Qinxian Guo,3 Jianhang Leng,3 Yu Ding3 1Department of Clinical Laboratory, Quzhou People’s Hospital, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, Zhejiang Province, 324000, People’s Republic of China; 2Department of Otolaryngology, Quzhou People’s Hospital, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, Zhejiang Province, 324000, People’s Republic of China; 3Central Laboratory, Hangzhou First People’s Hospital, Hangzhou, Zhejiang Province, 310006, People’s Republic of ChinaCorrespondence: Xuejiao Yu, Department of Clinical Laboratory, Quzhou People’s Hospital, the Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, People’s Republic of China, Email ajkc5701@163.com Yu Ding, Central Laboratory, Hangzhou First People’s Hospital, Hangzhou City, Zhejiang Province, 310006, People’s Republic of China, Email dingyu_zj@126.comPurpose: This study aimed to examine the frequencies of mt-tRNAGlu variants in 180 pediatric patients with non-syndromic hearing loss (NSHL) and 100 controls.Methods: Sanger sequencing was performed to screen for mt-tRNAGlu variants. These mitochondrial DNA (mtDNA) pathogenic mutations were further assessed using phylogenetic conservation and haplogroup analyses. We also traced the origins of the family history of probands carrying potential pathogenic mtDNA mutations. Mitochondrial functions including mtDNA content, ATP and reactive oxygen species (ROS) were examined in cells derived from patients carrying the mt-tRNAGlu A14692G and CO1/tRNASer(UCN) G7444A variants and controls.Results: We identified four possible pathogenic variants: m.T14709C, m.A14683G, m.A14692G and m.A14693G, which were found in NSHL patients but not in controls. Genetic counseling suggested that one child with the m.A14692G variant had a family history of NSHL. Sequence analysis of mtDNA suggested the presence of the CO1/tRNASer(UCN) G7444A and mt-tRNAGlu A14692G variants. Molecular analysis suggested that, compared with the controls, patients with these variants exhibited much lower mtDNA copy numbers, ATP production, whereas ROS levels increased (p< 0.05 for all), suggesting that the m.A14692G and m.G7444A variants led to mitochondrial dysfunction.Conclusion: mt-tRNAGlu variants are important risk factors for NSHL.Plain Language Summary: The main aim of our study was to explore the association between the mt-tRNAGlu variants and hearing loss. We found that m.T14709C, m.A14683G, m.A14692G and m.A14693G variants were associated with hearing impairments, these variants localized at extremely conserved nucleotides of mt-tRNAGlu and may result a failure in tRNA metabolism, furthermore, patients with mt-tRNAGlu variants exhibited much lower levels of mtDNA copy number, ATP as compared with controls, whereas ROS increased. As a result, mt-tRNAGlu variants may serve as biomarkers for mitochondrial deafness, and screening for tRNAGlu variants is recommended for early detection and diagnosis of mitochondrial deafness.Keywords: deafness, mitochondrial tRNAGlu variants, pediatrics, tRNA metabolism

Meilan Xian,1,2,&ast; Jiaoyuan Xu,1,3,&ast; Yamei Zheng,4 Lei Zhang,4 Jie Zhao,4 Jie Chen,1 Siguang Li,1 Lingsang Lin,1 Yi Zhong,4 Zehua Yang,4 Tian Xie,4 Linhui Huang,4 Yipeng Ding1,4 1Department of General Practice, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou, Hainan, 570311, People’s Republic of China; 2Department of General Diseases, Hainan Chengmei Hospital, Haikou, Hainan, 570300, People’s Republic of China; 3Department of General Clinic, Longbo Health Hospital, Lingao County, Hainan, 571800, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, 570311, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yipeng Ding; Linhui Huang, Department of General Practice, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, No. 19, Xiuhua Road, Xiuying District, Haikou, Hainan, 570311, People’s Republic of China, Email ypding@yeah.net; rochelle-11@163.comBackground: Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder in pulmonology. Chuanbeimu (CBM) is a traditional Chinese medicinal herb for treating COPD and has been widely utilized in clinical practice. However, the mechanism of CBM in the treatment of COPD remains incompletely understood. This study aims to investigate the underlying therapeutic mechanism of CBM for COPD using network pharmacology and experimental approaches.Methods: Active ingredients and their targets were obtained from the Traditional Chinese Medicine Systems Pharmacology database. COPD-associated targets were retrieved from the GeneCards database. The common targets for CBM and COPD were identified through Venn diagram analysis. Protein-protein interaction (PPI) networks and disease-herb-ingredient-target networks were constructed. Subsequently, the results of the network pharmacology were validated by molecular docking and in vitro experiments.Results: Seven active ingredients and 32 potential targets for CBM were identified as closely associated with COPD. The results of the disease-herb-ingredient-target network and PPI network showed that peimisine emerged as the core ingredient, and SRC, ADRB2, MMP2, and NOS3 were the potential targets for CBM in treating COPD. Molecular docking analysis confirmed that peimisine exhibited high binding affinity with SRC, ADRB2, MMP2, and NOS3. In vitro experiments demonstrated that peimisine significantly upregulated the expression of ADRB2 and NOS3 and downregulated the expression of SRC and MMP2.Conclusion: These findings indicate that CBM may modulate the expression of SRC, ADRB2, MMP2, and NOS3, thereby exerting a protective effect against COPD.Keywords: chuanbeimu, molecular docking, network pharmacology, experiment verification, chronic obstructive pulmonary disease

Kongjia Wang,1 Shufei Wang,2 Yixin Ding,3 Zengshun Kou,1 Bo Jiang,1 Sichuan Hou1 1Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, People’s Republic of China; 2College of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 3Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Bo Jiang; Sichuan Hou, Email jiangboqdy@126.com; housichuandoctor@126.comBackground: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with increased susceptibility to cancer, including bladder urothelial carcinoma (BLCA). This study investigates the shared molecular mechanisms and gene signatures between SLE and BLCA, shedding light on potential biomarkers and therapeutic targets.Methods: We compiled gene datasets related to SLE and BLCA from various databases and identified common genes. Differential gene expression analysis, protein-protein interaction networks, and hub gene identification were performed. We studied functional enrichment, immune infiltration, and transcription factor/miRNA regulation networks. We also explored gene-disease interactions and protein-chemical/drug networks. Hub gene expression levels and diagnostic values were validated in TCGA and GEO databases. Prognostic analysis was performed on the core gene MMP9 in the TCGA-BLCA database to study its prognostic value. Finally, the mRNA expression of MMP9 was verified in bladder cancer cell lines and BLCA patient blood. The diagnostic value of MMP9 for BLCA was verified by receiver operating characteristic(ROC) curve analysis of the expression of MMP9 in patients’ blood.Results: We identified 524 common genes between SLE and BLCA, enriched in pathways related to apoptosis and cytokine regulation. Immune infiltration analysis for two diseases. Transcription factors and microRNAs were implicated in regulating these common genes. The gene-disease network linked hub genes with various diseases, emphasizing their roles in autoimmune disease and cancer. Protein-chemical/drug networks highlighted potential treatment options. Finally, our study found that MMP9 is a potential therapeutic target with diagnostic and prognostic value and Immune-related biomarkers in patients with BLCA and SLE.Conclusion: Our study reveals shared molecular mechanisms, genetic signatures, and immune infiltrates between SLE and BLCA. MMP9 emerges as a potential diagnostic and prognostic biomarker in BLCA, warranting further investigation. These findings provide insights into the pathogenesis of SLE-associated BLCA and may guide future research and therapeutic strategies.Keywords: systemic lupus erythematosus, bladder urothelial carcinoma, gene signatures, immune response, MMP9

Donghao Wang,1,&ast; Yating Chen,1,&ast; Yutong Ding,1,&ast; Yongkang Tang,1,&ast; Xiaofen Su,1,&ast; Shiwei Li,1 Haojie Zhang,1,2 Yanyan Zhou,1 Zhiyang Zhuang,1 Qiming Gan,1 Jingcun Wang,1 Yuting Zhang,1 Dongxing Zhao,1 Nuofu Zhang1 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510160, People’s Republic of China; 2The Clinical Medicine Department, Henan University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Nuofu Zhang, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510160, People’s Republic of China, Tel +86-13600460056, Email nfzhanggird@163.comBackground: Obstructive sleep apnea (OSA) is a common chronic disease with various comorbidities. The cardiometabolic index (CMI) reflects visceral fat tissue distribution and function, assessing the risk of obesity-related conditions such as metabolic syndrome (MetS) and stroke, which are strongly connected to OSA. The relationship between CMI with OSA and OSA combined with MetS (OMS) remains unclear. This study aims to evaluate the screening value of CMI for OSA and OMS, compared to the lipid accumulation product (LAP).Methods: A total of 280 participants who underwent polysomnography were finally included, with the measurements of metabolic-related laboratory test results such as total cholesterol and triglyceride. Receiver operating curve (ROC) analysis and calculation of the area under the curve (AUC) were conducted to assess the screening potential of CMI, LAP, and the logistic regression models established based on them for OSA and OMS. The Youden index, sensitivity, and specificity were used to determine the optimal cutoff points.Results: ROC curve analysis revealed that the AUCs for CMI in screening OSA and OMS were 0.808 and 0.797, and the optimal cutoff values were 0.71 (sensitivity 0.797, specificity 0.776) and 0.89 (sensitivity 0.830, specificity 0.662), respectively, showing higher Youden index than LAP. The AUCs of screening models based on CMI for OSA and OMS were 0.887 and 0.824, respectively.Conclusion: CMI and LAP can effectively screen for OSA and OMS, while CMI has more practical cutoff values for identifying the diseased states. Screening models based on CMI demonstrate a high discriminatory ability for OSA and OMS, which needs verification in a large-scale population.Keywords: obstructive sleep apnea, metabolic syndrome, cardiometabolic index, lipid accumulation products, screening model

Lingbo Bi,&ast; Chaofan Wang,&ast; Yimei Du,&ast; Changpei Lu, Min Zhao, Yunbu Ding, Weiling Sun, Weixin Fan Department of Dermatology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weixin Fan; Weiling Sun, Department of Dermatology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, People’s Republic of China, Tel +86-13327805737 ; +86-13813955963, Email swl0560@sina.com; hairmanfwx@163.comPurpose: To investigate whether increased levels of lipids-related metabolites (LRMs) result in androgenic alopecia (AGA).Patients and Methods: A two-sample Mendelian randomization (MR) study was designed, and single nucleotide polymorphisms (SNPs) respectively related to nine LRMs were selected from the genome-wide association study (GWAS) dataset. An MR analysis was performed to assess the causal association between LRMs and AGA.Results: Through the fixed-effect inverse variance weighting (IVW) method, MR analysis indicated that Apolipoprotein B (ApoB), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) had a causal relationship with AGA. No obvious heterogeneity or pleiotropy was observed.Conclusion: The risk of AGA increases significantly when the serum levels of ApoB, LDL, and VLDL increase. This causal relationship is solid and free of interference from confounding factors.Keywords: androgenic alopecia, apolipoprotein B, VLDL, LDL

Baofeng Wang,1,2,&ast; Jiang Wang,2,&ast; Tongyu Sun,2 Yilin Ding,2 Shasha Li,3 Hengxiao Lu2 1School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, People’s Republic of China; 2Department of Thoracic Surgery, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China; 3Clinic, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hengxiao Lu, Department of Thoracic Surgery, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China, Email luhengxiao1000@126.comPurpose: Lu’s approach for video-assisted thoracoscopic surgery (LVATS), which derives from Uniportal Video-Assisted Thoracoscopic Surgery(UVATS), is a novel surgical approach for VATS and carries out micro-innovation for lung cancer resection. The objective of this study is to elucidate the safety, feasibility, and efficacy of this novel surgical approach.Patients and Methods: The clinical data of patients with non-small cell lung cancer (NSCLC) who underwent a curative thoracoscopic lobectomy between Mar. 2021 and Mar. 2022, were retrospectively collected and analyzed. Patients were divided into the LVATS group and the UVATS group. Propensity score matching (PSM) was used to reduce selection bias and create two comparable groups. Perioperative variables were compared, and a p-value < 0.05 was deemed statistically significant.Results: A total of 182 patients were identified, among whom 86 patients underwent LVATS and 96 UVATS. Propensity matching produced 62 pairs in this retrospective study. There were no deaths during perioperative period. Patients in the LVATS group experienced a shorter operation time (88 (75, 106) VS 122 (97, 144) min, P < 0.001), less intraoperative blood loss (20 (20, 30) VS 25 (20, 50) mL, P = 0.021), shorten incision length (2.50 (2.50, 2.50) VS 3.00 (3.00, 3.50) cm, P < 0.001), and more drainage volume (460 (310, 660) VS 345 (225, 600) mL, P = 0.041) than patients in the UVATS group. There was not significant difference in the lymph node stations dissected (5 (4, 5) VS 5 (4, 5), P = 0.436), drainage duration (3 (3, 4) VS 3 (3, 4) days, P =0.743), length of postoperative hospital stay (4 (4, 5) VS 4 (4, 6) days, P = 0.608), VAS on the POD1 (4 (4, 4) VS 4 (4, 4), P=0.058) and POD3 (3 (3, 4) VS 4 (3, 4), P=0.219), and incidence of postoperative complications (P=0.521) between the two groups.Conclusion: Lu’s approach for video-assisted thoracoscopic lobectomy is safe and feasible, potentially reducing surgery time, incision length, and intraoperative blood loss.Keywords: non-small cell lung cancer, uniportal video-assisted thoracoscopic surgery, Lu’s approach for VATS, lobectomy

Yan Ding,1,&ast; Banqin Wang,2,&ast; Yongjun Liu,1 Shengjie Dong,1 Xuri Sun,1 Zhilin Cao,1 Leisheng Wang1 1Department of Orthopedics, Yantaishan Hospital, Yantai, People’s Republic of China; 2Department of Blood Transfusion, Shandong Provincial Qianfoshan Hospital Affiliated with Shandong First Medical University, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Leisheng Wang, Department of Orthopedics, Yantaishan Hospital, No. 10087 Keji Road, Yantai, 264003, People’s Republic of China, Tel +86-13792566016 ; +86-0535-6863898, Email 37724148@qq.comPurpose: Percutaneous pedicle screw fixation is a common minimally invasive treatment for traumatic thoracolumbar and lumbar fractures; however, research on hardware removal after successful healing is limited. We aimed to introduce a rapid, safe, minimally invasive, and cost-effective method for percutaneous pedicle screw removal.Patients and Methods: We conducted a retrospective analysis of demographic (age, sex, body mass index, alcohol use, and current smoking), clinical (hypertension and diabetes mellitus), surgical (affected levels, number of screws, time of surgery, and blood loss), and treatment cost characteristics of 92 patients who had undergone percutaneous pedicle screw removal between May 2016 and February 2023. The first 57 patients underwent the conventional method, and the remaining 35 underwent the modified method. Independent-sample t-tests and chi-square tests were used to compare continuous and categorical variables, respectively, between the two groups.Results: No significant differences were observed in the demographic parameters, complications, or affected levels between the groups. However, the average surgical time (P=0.000) was significantly shorter, and the average blood loss volume (P=0.002) and total cost (P=0.000) were significantly lower in the modified group than in the conventional group.Conclusion: Compared with the conventional method, our modified method can shorten the surgical time, reduce blood loss, and reduce the total cost of treatment. It is a quick and safe minimally invasive method that does not require additional surgical instruments and is suitable for implementation in primary hospitals.Keywords: bone screw, device, Kirschner wire, surgery, control

Caixia Yang,1,2,&ast; Yuan Ding,1,2,&ast; Zhengwei Mao,3 Weilin Wang1,2 1Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China; 3MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhengwei Mao, Department of Polymer Science and Engineering, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, People’s Republic of China, Tel +86057187783820, Fax +86057187068001, Email zwmao@zju.edu.cn Weilin Wang, Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang, 310009, People’s Republic of China, Email wam@zju.edu.cnAbstract: The overall cancer incidence and death toll have been increasing worldwide. However, the conventional therapies have some obvious limitations, such as non-specific targeting, systemic toxic effects, especially the multidrug resistance (MDR) of tumors, in which, autophagy plays a vital role. Therefore, there is an urgent need for new treatments to reduce adverse reactions, improve the treatment efficacy and expand their therapeutic indications more effectively and accurately. Combination therapy based on autophagy regulators is a very feasible and important method to overcome tumor resistance and sensitize anti-tumor drugs. However, the less improved efficacy, more systemic toxicity and other problems limit its clinical application. Nanotechnology provides a good way to overcome this limitation. Co-delivery of autophagy regulators combined with anti-tumor drugs through nanoplatforms provides a good therapeutic strategy for the treatment of tumors, especially drug-resistant tumors. Notably, the nanomaterials with autophagy regulatory properties have broad therapeutic prospects as carrier platforms, especially in adjuvant therapy. However, further research is still necessary to overcome the difficulties such as the safety, biocompatibility, and side effects of nanomedicine. In addition, clinical research is also indispensable to confirm its application in tumor treatment.Keywords: autophagy, tumor resistance, nanotechnology, combination therapy, co-delivery

Yuping Ding,1,2 Guiqiang Wang,3,4 Quanjun Deng,1,2 Mei Yang,1,2 Jinghua Li,5 Zuoyu Wang,1,2 Haiyan Niu,1,2 Shihai Xia1,2 1Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, 300162, People’s Republic of China; 2Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, Tianjin, 300162, People’s Republic of China; 3Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, People’s Republic of China; 4Department of Infectious Diseases, Peking University International Hospital, Beijing, People’s Republic of China; 5Department of Endocrinology and Hematology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, 300162, People’s Republic of ChinaCorrespondence: Shihai Xia, Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, 220, Chenglin Road, Dongli, Tianjin, 300162, People’s Republic of China, Email xshhcx@sina.comBackground: Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are closely related conditions.Aim: This study investigated a group of individuals with NAFLD to evaluate if liver fibrosis, identified by FibroScan, correlated with T2DM.Methods: 154 NAFLD patients obtained FibroScan, liver ultrasonography (US), and a thorough assessment of clinical implications and chemical biomarkers.Results: In comparison to the NAFLD without T2DM group, the hemoglobin A1c(HBA1c)(mmol/mol%), homeostasis model of assessment for insulin resistance index (HOMA-IR), gamma-glutamyl transferase (GGT), fibrosis indices, and liver stiffness measurement (LSM) values were all considerably higher in the NAFLD with T2DM group. Patients with NAFLD and T2DM had considerably lower serum uric acid(SUA) levels than those with NAFLD alone.Those with severe fibrosis (79.3%, 23/29) in the NAFLD group showed a greater frequency of T2DM than those with mild fibrosis (45.6%, 21/46) or no fibrosis (27.85%, 22/79) (P=0.000). LSM value and elements of the metabolic syndrome (MetS) were independent risk factors for incident T2DM among NAFLD patients (OR=1.466, 95% CI [1.139-1.888], P=0.003; and OR=0.273, 95% CI [0.081-0.916], P=0.036).Conclusion: FibroScan can identify significant fibrosis, which is independently linked to a higher prevalence of T2DM. As a result, it is crucial to make use of this technology to predict T2DM in NAFLD patients.Keywords: liver stiffness measurement, NAFLD, T2DM, risk factors, early warning

Shangren Qin,1 Xiaoyan Ni,2 Ye Ding3 1School of Public Health, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 2Cangqian Street Community Health Service Center, Hangzhou, Zhejiang, People’s Republic of China; 3School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Ye Ding, School of Public Health, Hangzhou Medical College, 8 Yikang Street, Hangzhou, 311399, People’s Republic of China, Tel +86-571-87692813, Email dingye729@126.comconvenienBackground: There have been few studies concerning delayed medical attention among middle-aged and older adults, and in-depth analyses of delay duration and symptoms have been lacking.Methods: In this cross-sectional study exploiting a face-to-face questionnaire survey, we investigated delays in seeing a doctor among ≥ 45-year-old people in Zhejiang, China over the past year, and analyzed relevant influencing factors through logistics regression.Results: A total of 1034 people aged ≥ 45 years were enrolled, whose overall occurrence of delay in seeing a doctor was 28.24% (23.00% for older adults aged ≥ 60 years). Factors like the presence of 2 chronic diseases, intense social loneliness, and more health care needs contributed to the occurrence of delay in seeing a doctor (OR (95% CI) = 2.102 (1.252– 3.529); OR (95% CI) = 1.030 (1.002– 1.059); OR (95% CI) = 1.049 (1.002– 1.099). Contrastively, factors like convenient access to medical care and good self-reported health status inhibited such occurrence OR (95% CI) = 0.321 (0.199– 0.519); OR (95% CI) = 0.369 (0.183– 0.745). The foremost reason was wanting to wait and see if the problem would get better on its own (117, 40.07%). Respiratory system disease (14.90%), dental problems (13.82%), and cardiac disease (13.61%) constituted the top 3 types of diseases whose treatments were delayed. Additionally, for the majority of older adults, the delay duration was 1– 2 weeks (99, 33.90%), and the economic burden was the cause of the longest delay in seeing a doctor among middle-aged and older adults.Conclusion: To alleviate the problem of delay in seeing a doctor among middle-aged and older adults, their families and society should enhance care for them and reduce their sense of social loneliness. Emphasis should be placed by the government on helping middle-aged and older adults with financial difficulties so that their medical convenience can be improved.Keywords: middle-aged, older adults, delaying doctor visits, China, cross-sectional study

Hongxia Wang,1,&ast; Fating Zhou,2,&ast; Zhilin Li,1 Yulan Ding,1 Qian Wen,1 Quanxing Tang1 1Department of General Practice, People’s Hospital of Deyang City, Deyang, Sichuan, People’s Republic of China; 2Emergency Department, Chongqing Emergency Medical Center, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongxia Wang, Department of General Practice, People’s Hospital of Deyang City, Deyang, Sichuan, People’s Republic of China, Email HongXia.W@hotmail.comBackground: Streptococcus constellatus rarely causes pyopneumothorax, which is a serious state and requires a surgery. However, not every patient can tolerate surgery and individualized solutions are needed. Furthermore, many known situations are risk factors of S. constellatus infection, but S. constellatus pyopneumothorax associated with Hashimoto’s thyroiditis has not been reported.Case Presentation: We present the case of a 74-year-old male with multiple encapsulated pyopneumothorax caused by S. constellatus. Given his respiratory failure, we provided two-stage percutaneous right empyema radiography for catheter drainage in the radiology interventional department instead of surgery. Moreover, an occult Hashimoto’s thyroiditis was discovered in the patient, which was possibly associated with S. constellatus pyopneumothorax. Levothyroxine was administered to improve his situation.Conclusion: To our knowledge, it is the first case described in this context. We provided an alternative treatment for S. constellatus encapsulated pyopneumothorax in patient who might not tolerate surgery. We also revealed the possible relationship between S. constellatus pyopneumothorax and Hashimoto’s thyroiditis.Keywords: radiology interventional, Streptococcus constellatus, pyopneumothorax, Hashimoto’s thyroiditis

Zheming Zhang,1,2,&ast; Haoda Yu,1,2,&ast; Qi Wang,3 Yu Ding,1,2 Ziteng Wang,1,2 Songyun Zhao,1 Tao Bian1,2 1Wuxi Medical Center of Nanjing Medical University, Wuxi, People’s Republic of China; 2Department of Respiratory Medicine, Wuxi People’s Hospital, Nanjing Medical University, Wuxi, People’s Republic of China; 3Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tao Bian; Songyun Zhao, Email btaophd@sina.com; 2021122190@stu.njmu.edu.cnBackground: This study aims to investigate the association between immune cells and the development of COPD, while providing a new method for the diagnosis of COPD according to the changes in immune microenvironment.Methods: In this study, the “CIBERSORT” algorithm was used to estimate the tissue infiltration of 22 types of immune cells in GSE20257 and GSE10006. The “limma” package was used for differentially expressed analysis. The key modules associated with vital immune cells were identified using WGCNA. GO and KEGG enrichment analysis revealed the biological functions of the candidate genes. Ultimately, a novel diagnostic prediction model was constructed via machine learning methods and multivariate logistic regression analysis based on GSE20257. Furthermore, we examined the stability of the model on one internal test set (GSE10006), three external test sets (GSE8545, GSE57148 and GSE76925), one single-cell transcriptome dataset (GSE167295), macrophages (THP-M cells) and lung tissue from COPD patients.Results: M0 macrophages (AUC > 0.7 in GSE20257 and GSE10006) were considered as the most important immune cells through exploring the immune microenvironment landscapes in COPD patients and healthy controls. The differentially expressed genes from GSE20257 and GSE10006 were divided into six and five modules via WGCNA, respectively. The green module in GSE20257 (cor = 0.41, P < 0.001) and the brown module in GSE10006 (cor = 0.67, P < 0.001) were highly correlated with M0 macrophages and were selected as key modules. Forty-one intersected genes obtained from two modules were primarily involved in regulation of cytokine production, regulation of innate immune response, specific granule, phagosome, lysosome, ferroptosis, and other biological processes. On the basis of the candidate genetic markers further characterized via the “Boruta” and “LASSO” algorithm for COPD, a diagnostic model comprising CLEC5A, FTL and SLC2A3 was constructed, which could accurately distinguish COPD patients from healthy controls in multiple datasets. GSE20257 as the training set has an AUC of 0.916. The AUCs of the internal test set and three external test sets were 0.873, 0.932, 0.675 and 0.688, respectively. Single-cell sequencing analysis suggested that CLEC5A, FTL and SLC2A3 were expressed in macrophages from COPD patients. The expressions of CLEC5A, FTL and SLC2A3 were up-regulated in THP-M cells and lung tissue from COPD patients.Conclusion: According to the variations of immune microenvironment in COPD patients, we constructed and validated a novel macrophage M0-associated diagnostic model with satisfactory predictive value. CLEC5A, FTL and SLC2A3 are expected to be promising targets of immunotherapy in COPD.Keywords: COPD, CLEC5A, FTL, SLC2A3, immune infiltration, WGCNA, machine learning, multivariate logistic regression

Zhaoyinqian Li,1– 3,&ast; Tingting Li,1– 4,&ast; Jingyang Tang,1– 3 Li Huang,1– 3 Yinhuan Ding,1– 3 Zhangrui Zeng,1– 3 Jinbo Liu1– 3 1Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 2Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Luzhou, People’s Republic of China; 3Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, People’s Republic of China; 4Department of Laboratory Medicine, West China Fourth Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinbo Liu, Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Tel/Fax +86 08303165730, Email liujb7203@swmu.edu.cnIntroduction: The prevalence of diabetic foot ulcers (DFUs) is increasing, leading to a huge financial burden and human suffering. Furthermore, antibiotic resistance is an urgent problem in the realm of clinical practice. Antimicrobial peptides are an effective and feasible strategy for combating infections caused by drug-resistant bacteria. Therefore, we investigated the in vitro antimicrobial ability of the lipopeptide surfactin, either alone or in combination with conventional antibiotics, against the standard and clinical strains of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), isolated from patients with DFUs.Methods: The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of surfactin on the selected strains were evaluated by a microbroth dilution technique. The growth curves of the selected strains with and without surfactin were measured, and transmission electron microscopy was used to observe the structure of surfactin-treated bacterial cells. The biofilm inhibitory abilities of surfactin were assessed by crystal violet staining. The antimicrobial interactions between surfactin and conventional antibiotics were established using a checkerboard assay, as well as determining the mutant prevention concentration. The inhibitory effect of surfactin on penicillinase was tested by iodometry.Results: The MIC and MBC values of surfactin ranged from 512 to 1024 μg/mL and 1024 to 2048 μg/mL, respectively. Moreover, surfactin significantly prevented the S. aureus biofilm formation and displayed limited toxicity on human red blood cells. The synergies between surfactin and ampicillin, oxacillin, and tetracycline against S. aureus were revealed. In vitro resistance was not readily produced by surfactin. The action of surfactin may be by disrupting bacterial cell membranes and inhibiting penicillinase.Conclusion: Surfactin appears to be a potential option for the treatment of DFUs infected with MRSA, as it is capable of improving antimicrobial activities and can be used alone or in combination with conventional antibiotics to prevent or postpone the emergence of resistance.Keywords: surfactin, antimicrobial peptides, diabetic foot ulcers, methicillin-resistant Staphylococcus aureus, synergistic effect

Mingyang Ren,1 Xianhong Yang,2 Yan Teng,2 Wei Lu,2 Yang Ding,2 Xiaohua Tao2 1Department of Graduate School, Bengbu Medical College, Bengbu, People’s Republic of China; 2Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, People’s Republic of ChinaCorrespondence: Xiaohua Tao, Email txhtxh@sina.comAbstract: Granulomatous rosacea (GR) is a rare inflammatory skin disease characterized by persistent, hard, yellow, brown, red, or flesh-colored papules, plaques, or nodules on the face. Limited data are available on patients treated for GR, with only case reports and case series published. Herein, we describe the case of a 53-year-old woman who presented to the hospital with persistent red to brown and pink patches on both cheeks accompanied by a burning sensation for one month. Histopathological examination of a cutaneous biopsy revealed granulomatous inflammation in focal areas. Both acid-fast and Periodic acid-Schiff staining were negative. The patient was diagnosed with GR based on her clinical presentation and laboratory test results. She was treated with abrocitinib, a JAK-1 inhibitor, for 20 weeks. This resulted in substantial improvement in her rash and the associated burning sensation. Subsequent follow-up visits indicated no adverse effects or relapses. Additionally, a literature review was conducted to compare with the current case, which concluded that abrocitinib is a viable treatment option for GR, exhibiting a relatively high safety profile with minimal side effects.Keywords: JAK inhibitor, granulomatous rosacea, abrocitinib, efficacy

Yixin Ding,1,&ast; Kongjia Wang,2,&ast; Shufen Zhao,1 Yu Li,3 Wensheng Qiu,1 Chunyang Zhu,1 Yan Wang,1 Chen Dong,1 Jiani Liu,1 Yangyang Lu,1 Weiwei Qi1 1Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Urology, Qingdao Municipal Hospital, Qingdao University, Qingdao, People’s Republic of China; 3Department of Gastrointestinal Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Weiwei Qi, Email qwwqdfy@126.comPurpose: Kinetochore scaffold 1 (KNL1), a crucial protein during cell mitosis participating in cell division, was widely expressed in multiple kinds of cancers. However, the expression profile, the effect on cell biological function, tumor immune microenvironment, and predictive value of clinical prognosis in pan-cancer of KNL1 still require a comprehensive inquiry.Methods: The mRNA and protein expression profile of KNL1 was validated in pan-cancer using different databases. Six algorithms were used to explore the correlation between KNL1 and immune infiltration and the relationship between KNL1 and tumor mutation burden (TMB), microsatellite instability (MSI), and TIDE score were calculated. The diagnostic and clinical prognostic predictive ability of KNL1 was assessed. Differentially expressed genes (DEGs) of KNL1 were screened out and function enrichment analyses were performed in pancreatic adenocarcinoma (PAAD), stomach adenocarcinoma (STAD), and bladder urothelial carcinoma (BLCA). Finally, 8 cases of pancreatic adenocarcinoma tissues and paired adjacent tissues were collected for immunohistochemical (IHC) staining and the histological score (H-score) was calculated. Real-time PCR was performed in gastric cancer and bladder cancer cell lines.Results: KNL1 was abnormally upregulated in more than half of cancers across different databases. IHC and real-time PCR verified the up-regulated expression in cancer tissues in PAAD, gastric cancer, and BLCA. The satisfactory diagnostic value of KNL1 was indicated in 30 cancers and high KNL1 expression was associated with poorer overall survival (OS) in 12 cancers. The prognostic role of KNL1 as a predictive biomarker of PAAD was clarified. KNL1 played an active part in the cell cycle and cell proliferation. Moreover, KNL1 was likely to mold the Th2-dominant suppressive tumor immune microenvironment and was associated with TMB, MSI, and immune checkpoint-related genes in pan-cancer.Conclusion: Our study elucidated the anomalous expression of KNL1 and revealed that KNL1 was a promising prognostic biomarker in pan-cancer.Keywords: KNL1, bioinformatics, pan-cancer, immune infiltration, prognosis, clinical prognostic model

Yuping Ding,1,2 Quanjun Deng,1,2 Mei Yang,1,2 Haiyan Niu,1,2 Zuoyu Wang,1,2 Shihai Xia1,2 1Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, 300162, People’s Republic of China; 2Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, Tianjin, 300162, People’s Republic of ChinaCorrespondence: Shihai Xia, Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force; Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, 220, Chenglin Road, Dongli, Tianjin, 300162, People’s Republic of China, Email xshhcx@sina.comAbstract: Obesity,and metabolic dysfunction-associated fatty liver disease (MAFLD) have reached epidemic proportions globally. Obesity and MAFLD frequently coexist and act synergistically to increase the risk of adverse clinical outcomes (both hepatic and extrahepatic). Type 2 diabetes mellitus (T2DM) is the most important risk factor for rapid progression of steatohepatitis and advanced fibrosis. Conversely, the later stages of MAFLD are associated with an increased risk of T2DM incident. According to the proposed criteria, MAFLD is diagnosed in patients with liver steatosis and in at least one in three: overweight or obese, T2DM, or signs of metabolic dysregulation if they are of normal weight. However, the clinical classification and correlation between obesity and MAFLD is more complex than expected. In addition, treatment for obesity and MAFLD are associated with a reduced risk of T2DM, suggesting that liver-based treatments could reduce the risk of developing T2DM. This review describes the clinical classification of obesity and MAFLD, discusses the clinical features of various types of obesity and MAFLD, emphasizes the role of visceral obesity and insulin resistance (IR) in the development of MAFLD,and summarizes the existing treatments for obesity and MAFLD that reduce the risk of developing T2DM.Keywords: obesity, metabolic dysfunction-associated fatty liver disease, phenotypes, type 2 diabetes mellitus, treatment, weight loss

Yan Teng,1,&ast; Mingyang Ren,2,&ast; Yang Ding,1 Xianhong Yang,1 Yibin Fan,1 Xiaohua Tao1 1Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China; 2Graduate School of Clinical Medicine, Bengbu Medical School, Bengbu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaohua Tao; Yibin Fan, Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang provincial people’s hospital, People’s Hospital of Hangzhou Medical College, Tel +86-13505811700 ; +86-18806538451, Email taoxiaohua@hmc.edu.cn; fanyibin@hmc.edu.cnAbstract: Perioral dermatitis (POD) is a chronic inflammatory skin disease that primarily affects females between the ages of 16 and 45. Conventional therapies face the challenge of limited efficacy and a high recurrence rate. In this report, we present the case of a 26-year-old male patient with POD who was successfully treated using the Janus kinase (JAK) inhibitor, abrocitinib. This treatment exhibited both good efficacy and safety. Abrocitinib, as a JAK inhibitor, holds promise as a potential therapy for cases of POD that might be resistant to conventional therapies.Keywords: JAK inhibitors, abrocitinib, perioral dermatitis

Chen He,1– 3,&ast; Huiyan Ding,4,&ast; Lubo Li,5 Jing Chen,6 Xiaofei Mo,1– 3 Yinan Ding,4 Wenjing Chen,4 Qiusha Tang,4 Yuetao Wang1– 3 1Department of Nuclear Medicine, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People’s Republic of China; 2Institute of Clinical Translation of Nuclear Medicine and Molecular Imaging, Soochow University, Changzhou, Jiangsu Province, People’s Republic of China; 3Changzhou Clinical Medical Center, Changzhou, Jiangsu, People’s Republic of China; 4Medical School of Southeast University, Nanjing, People’s Republic of China; 5The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People’s Republic of China; 6Taikang Xianlin Drum Tower Hospital, Nanjing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiusha Tang; Yuetao Wang, Email panyixi-tqs@163.com; yuetao-w@163.comBackground: Radiation therapy (RT) is commonly used to treat glioblastoma, but its immunomodulatory effect on tumors, through mechanisms such as immunogenic cell death (ICD), is relatively weak. Gold nanoparticles (AuNPs) have been suggested as potential radio-sensitizers, but it is unclear if they can enhance radiation-induced ICD. This study aimed to investigate the potential of AuNPs to improve the effectiveness of radiation-induced ICD.Methods: G422 cells were treated with a combination of AuNPs and RT to induce cell death. Various assays were conducted to assess cell death, surface expression of CRT, and release of HMGB1 and ATP. In vitro co-culture experiments with bone marrow-derived dendritic cells (BMDCs) were performed to analyze the immunogenicity of dying cancer cells. Flow cytometry was used to measure the maturation rate of BMDCs. An in vivo mouse tumor prophylactic vaccination model was employed to assess immunogenicity.Results: The study findings presented here confirm that the combination of radiotherapy (RT) with AuNPs can induce a stronger ICD effect on glioblastoma cells compared to using RT alone. Specifically, treatment with AuNPs combined with RT resulted in the emission of crucial damage-associated molecular patterns (DAMPs) such as CRT, HMGB1 (479.41± 165.34pg/mL vs 216.04± 178.16 pg/mL, &ast;P< 0.05) and ATP (The release of ATP in the AuNPs + RT group was 1.2 times higher than in the RT group, &ast;P< 0.05). The proportion of BMDC maturation rate was higher in the group treated with AuNPs and RT compared to the group treated with RT alone. (32.53± 0.52% vs 25.03± 0.28%,&ast;&ast;&ast;P < 0.001). In the tumor vaccine experiment, dying tumor cells treated with AuNPs and RT effectively inhibited tumor growth in mice when exposed to living tumor cells.Conclusion: These results indicate that AuNPs have the ability to enhance RT-induced ICD.Keywords: Immunogenic cell death, Gold nanoparticles, Radiation therapy, Glioblastoma

Jialu Sun,1 Yijun Shi,1 Yaowei Ding,1 Siqi Wang,1 Lingye Qian,2 Xin Luan,1 Guoge Li,1 Yuxin Chen,1 Xiaotong Li,1 Hong Lv,1,3,4 Guanghui Zheng,1,3,4,&ast; Guojun Zhang1,3,4,&ast; 1Laboratory, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Laboratory, Beijing An Zhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 3NMPA Key Laboratory for Quality Control of in vitro Diagnostics, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Engineering Research Center of Immunological Reagents Clinical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guanghui Zheng; Guojun Zhang, Beijing Tiantan Hospital, NO. 119 Nansihuan West Road, Fengtai District, Beijing, People’s Republic of China, Tel +86 18600148997 ; +86 13811792425, Email zgh999@yeah.net; guojun.zhang@ccmu.edu.cnBackground: To investigate the factors associated with follow-up CSF cultures (FUCCs) in post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis and the effect of FUCCs on treatment management and patient outcomes.Methods: This single-centered retrospective cohort study enrolled post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis at a tertiary-care university hospital between 2012 and 2022. The risk factors for 28-day mortality were evaluated using multivariate Cox analysis. FUCC-related risk factors were also analyzed.Results: Among the 844 enrolled patients, 504 (59.7%) underwent FUCC, and FUCC was found to be associated with lower rates of both all-cause (hazard ratio (HR) 0.391; 95% confidence interval (CI), 0.235– 0.651; p< 0.001) and attributable mortality (HR 0.463; 95% CI, 0.239– 0.897; p=0.023) in Post-neurosurgical patients diagnosed with Gram-negative bacterial meningitis/encephalitis. Moreover, the results of the study underscored that patients with persistent gram-negative bacterial meningitis/encephalitis had a lower all-cause/attributable short-term survival rate according to 28-day mortality Kaplan–Meier analysis (P=0.001/0.006).Conclusion: Performing FUCC has been demonstrated to lower mortality rates in Post-neurosurgical patients suffering from Gram-negative bacterial meningitis/encephalitis. The higher mortality rate observed in patients with persistent gram-negative bacterial meningitis/encephalitis suggests that performing FUCC is a crucial component of proper patient care and management, and is therefore recommended for use by clinicians as a standard practice. This finding underscores the significance of consistent implementation of FUCC in the management and prognosis of patients with Post-neurosurgical infections.Keywords: gram-negative bacterial meningitis/encephalitis, follow-up cerebrospinal fluid cultures, all-cause 28-day mortality, persistent meningitis/encephalitis, risk factors

Fei Zhang,1 Yicen Ding,1 Bohan Zhang,1 Mengju He,1 Zhijiang Wang,2 Chunbo Lu,3 Yani Kang1 1School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Pharmaceutical Engineering, Zhejiang Pharmaceutical University, Ningbo, People’s Republic of China; 3Department of Obstetrics and Gynecology, Qiuai Central Health Center, Ningbo, People’s Republic of ChinaCorrespondence: Chunbo Lu, Department of Obstetrics and Gynecology, Qiuai Central Health Center, Ningbo, 315100, People’s Republic of China, Tel +86-13567881644, Email lucbnb@126.com Yani Kang, School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai, 200240, People’s Republic of China, Tel +86-13661848623, Email kangyani@sjtu.eduPurpose: This study aimed to identify differentially methylated genes (DMGs) and differentially expressed genes (DEGs) to investigate new biomarkers for the diagnosis and treatment of polycystic ovary syndrome (PCOS).Methods: To explore the potential biomarkers of PCOS diagnosis and treatment, we performed methyl-binding domain sequencing (MBD-seq) and RNA sequencing (RNA-seq) on ovarian granulosa cells (GCs) from PCOS patients and healthy controls. MBD-seq was also performed on the ovarian tissue of constructed prenatally androgenized (PNA) mice. Differential methylation and expression analysis were implemented to identify DMGs and DEGs, respectively. The identified gene was further verified by real-time quantitative PCR (RT-qPCR) and methylation-specific PCR (MSP) in clinical samples. Furthermore, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) was carried out on PCOS patients and healthy controls to identify differential lipid metabolites.Results: Compared to the control group, 13,526 DMGs related to the promoter region and 2429 DEGs were found. The function analysis of DMGs and DEGs showed that they were mainly enriched in glycerophospholipid, ovarian steroidogenesis, and other lipid metabolic pathways. Moreover, 5753 genes in DMGs related to the promoter region were screened in the constructed PNA mice. Integrating the DMGs data from PCOS patients and PNA mice, we identified the following 8 genes: CDC42EP4, ERMN, EZR, PIK3R1, ARHGEF18, NECTIN2, TSC2, and TACSTD2. RT-qPCR and MSP verification results showed that the methylation and expression of TACSTD2 were consistent with sequencing data. Additionally, 15 differential lipid metabolites were shown in the serum of PCOS patients. The differential lipids were involved in glycerophospholipid and glycerolipid metabolism.Conclusion: Using integration of methylome and lipid metabolites profiling we identified 8 potential epigenetic markers and 15 potential lipid metabolite markers for PCOS. Our results suggest that aberrant DNA methylation and lipid metabolite disorders may provide novel insights into the diagnosis and etiology of PCOS.Keywords: polycystic ovary syndrome, DNA methylation, transcriptome, lipid metabolites, granulosa cell

Xianhong Yang,1 Yunlin Ren,1,2 Huachu Liu,1,3 Yan Ten,1 Yang Ding,1 Shasha Fan,1 Xiaohua Tao,1 Wei Lu1 1Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, 310014, People’s Republic of China; 2Department of Dermatology and Venereology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China; 3Department of Dermatology and Venereology, The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Zhong Shan Hospital), Hangzhou, 310009, People’s Republic of ChinaCorrespondence: Xiaohua Tao; Wei Lu, Email txhtxh@sina.com; miniluwei@163.comAbstract: We report a case of 32-year-old patient who presented with painless erythematous plaque gradually ulcerated for 9 years. He had a history of pulmonary tuberculosis 12 years ago and was cured by the treatment of 2HRZE/4HR. The laboratory examination of t-spot and PPD skin test was positive. Histopathology examinations of left cervical lymph node as well as skin revealed granulomatous inflammation with caseous necrosis. A diagnosis of scrofuloderma was made. Negative sputum culture and chest CT scan results excluded pulmonary tuberculosis. The patient was treated with a standard antituberculosis therapy and recovered well after 5 months’ follow-up. Scrofuloderma is a rare manifestation of mycobacterial infection. Early diagnosis and treatment are very important.Keywords: case report, cutaneous tuberculosis, scrofuloderma, caseous necrosis

Qigang Huang, Yingwei Ding, Chao Fang, Hao Wang, Laifa Kong Department of Emergency Medicine, Zhejiang University Medical College Affiliated Jinhua Hospital, Jinhua, Zhejiang, People’s Republic of ChinaCorrespondence: Laifa Kong, Department of Emergency Medicine, Zhejiang University Medical College Affiliated Jinhua Hospital, Jinhua, Zhejiang, People’s Republic of China, Email h1585897@163.comAbstract: Sepsis is a syndrome in multi-organ dysfunction triggered by a deleterious immunological reaction of the body to a condition caused by infection, surgery, or trauma. Currently, sepsis is thought to be primarily associated with abnormal immune responses resulting in organ microcirculatory disturbances, cellular mitochondrial dysfunction, and induced cell death, although the exact pathogenesis of sepsis is still inconclusive. In recent years, the role of abnormal metabolism of trace nutrients in the pathogenesis of sepsis has been investigated. Ferroptosis is a type of cell death that relies on iron and is characterized by unique morphological, biochemical, and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily driven by lipid peroxidation. Ferroptosis cells may be immunogenic, amplify inflammatory responses, cause more cell death, and ultimately induce multi-organ failure. An increasing number of studies have indicated the significance of ferroptosis in sepsis and its role in reducing inflammation. The effectiveness of sepsis treatment has been demonstrated by the use of drugs that specifically target molecules associated with the ferroptosis pathway, including ferroptosis inhibitors. Nevertheless, there is a scarcity of studies investigating the multi-organ dysfunction caused by ferroptosis in sepsis. This article presents a summary and evaluation of recent progress in the role of ferroptosis through molecularly regulated mechanisms and its potential mechanisms of action in the multi-organ dysfunction associated with sepsis. It also discusses the current challenges and prospects in understanding the connection between sepsis and ferroptosis, and proposes innovative ideas and strategies for the treatment of sepsis.Keywords: sepsis, ferroptosis, organ damage, lipid peroxidation, treatment

Zhongping Duan,1 Jinling Dong,1 Ying Liu,2 Haiyang Zhou,2 Shuli Duan,2 Weihong Liu,3 Rico Liang,3 Yue Ding3 1Fourth Department of Hepatology Center, Beijing You’an Hospital, Capital Medical University, Beijing, People’s Republic of China; 2iGandan, the Portal for All Liver Disease Caring, Beijing, People’s Republic of China; 3Brii Biosciences Inc., Beijing, People’s Republic of ChinaCorrespondence: Rico Liang, Brii Biosciences Inc, 3F, Building 7, Zhongguancun Dongsheng International Science Park, No. 1 North. Yongtaizhuang Road, Haidian District, Beijing, 100192, People’s Republic of China, Tel/Fax +86 10 6587 6121, Email Rico.Liang@briibio.comPurpose: HBV functional cure is an optimal treatment goal for chronic hepatitis B (CHB) at present and numerous new drugs aiming for HBV functional cure are in development. We carried out an internet-based survey to understand the treatment status, unmet needs, awareness of HBV functional cure and attitude toward related clinical trials among CHB patients in China.Patients and Methods: An internet-based anonymous survey was conducted on CHB patients who reside in mainland China. Determinants of awareness and attitude were identified by logistic regression models.Results: Of the 1220 CHB patients who completed the survey questionnaire, 11.1% (135/1220) were aware of HBV functional cure and 50.2% (612/1220) answered “definitely will” to participate in related clinical trials. Participants who knew their HBsAg level (HBsAg< 1500 IU/mL: OR=3.03, 95% CI: 1.87– 4.92; HBsAg≥ 1500 IU/mL: OR=2.57, 95% CI: 1.35– 4.88), who expected to achieve HBsAg loss with treatment (OR=1.63, 95% CI: 1.07– 2.50) and who were dissatisfied with current treatment due to the failure of achieving HBsAg loss (OR=1.67, 95% CI: 1.10– 2.53) had better awareness of HBV functional cure. Participants who had HBsAg level less than 1500 IU/mL (OR=1.45, 95% CI: 1.05– 1.99), treatment with pegylated interferon alpha with or without nucleos(t)ide (OR=1.68, 95% CI: 1.11– 2.53) and better awareness of HBV functional cure (OR=1.62, 95% CI: 1.01– 2.61) were more likely to say “definitely will” to participate in related clinical trials.Conclusion: Chinese CHB patients reported a low awareness of HBV functional cure. Although CHB patients in China reported a low rate of HBV functional cure awareness, they had a high acceptance of related clinical trials.Keywords: CHB, HBV functional cure, awareness, related clinical trials

Weijia Wang,1– 3 Xiaojing Kang,1– 3 Yuan Ding,1– 3 Lidan Mao,1– 3 Abudureyimu Dilinuer,1– 3 Wenzheng Li1– 3 1Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, People’s Republic of China; 2Xinjiang Clinical Research Center for Dermatologic Diseases, Urumqi, People’s Republic of China; 3Xinjiang Key Laboratory of Dermatology Research (XJYS1707), Urumqi, People’s Republic of ChinaCorrespondence: Xiaojing Kang, Department of Dermatology and Venereology, People’s Hospital of Xinjiang Uygur Autonomous Region, No. 91 Tianchi Road, Tianshan District, Urumqi, People’s Republic of China, Email drkangxj666@163.comBackground: IgG4-related disease (IgG4-RD) is a rare fibroinflammatory disease that has a high tendency to misdiagnosis in clinics.Case Presentation: A 48-year-old man developed a rash with progressive itching 3 years ago after hormone therapy for an ocular “inflammatory pseudotumor”. The disease condition of this patient involved multiple organs which involved the skin. The patient was misdiagnosed with other diseases during the period of hospitalization, leading to poor therapeutic effects and repeated skin lesions. The dermatopathological report indicated plasma cell proliferative disorder, with IgG4/IgG exceeding 40% and abnormally elevated serum IgG4 levels. After the patient was diagnosed with IgG4-RD, a series of treatments improved skin lesions, relieved other symptoms, and decreased serum IgG4 levels.Conclusion: IgG4-RD is a highly misdiagnosed disease that deserves the attention of physicians. The patient we reported could be considered a representative case of IgG4-RD that presents with skin lesions. For patients with suspected IgG4-RD, serum IgG4 testing should be performed, and further imaging, serological tests, and pathology examinations are needed to exclude malignancy, infection, and autoimmune diseases.Keywords: IgG4-RD, fibro-inflammatory, dermatopathological, misdiagnosis, diagnosis, treatment

Yajie Ding,1,&ast; Zongzhe Tang,1,&ast; Ru Zhang,1 Mengting Zhang,1 Qing Guan,1 Liuxin Zhang,2 Hongliang Wang,3 Yue Chen,1 Wei Zhang,4 Jie Wang1 1Department of Fundamental and Community Nursing, School of Nursing, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (SAR), People’s Republic of China; 3Department of General Practice, Ninghai Road Community Health Service Center, Nanjing, Jiangsu, People’s Republic of China; 4Department of Epidemiology, Shanghai Cancer Institute, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie Wang, Department of Fundamental and Community Nursing, School of Nursing, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, People’s Republic of China, Tel +86-25-86869557, Fax +86-25-86868501, Email wangjienjmu@126.comPurpose: Protein kinase B (PKB/AKT) has shown a high profile in the research of metabolic diseases. This research sought to determine whether the AKT1 gene’s single nucleotide polymorphisms (SNPs) and the risk of developing non-alcoholic fatty liver disease (NAFLD) were related.Patients and Methods: Recruited in this case–control study were 2693 subjects, including 815 with NAFLD and 1878 without NAFLD. Three SNPs of AKT1 (rs2494732, rs2494752 and rs1130233) were genotyped. To examine the correlation between SNPs and NAFLD susceptibility, logistic regression was performed.Results: After adjusting for sex, age, triglyceride and glucose, AKT1 rs2494732-C (all P < 0.05 in co-dominant model, dominant model and additive model) and rs2494752-G (P < 0.05 in co-dominant model) were linked to a lower risk of NAFLD. The combined effect of both SNPs on NAFLD risk was statistically significant, showing a dose dependence (Ptrend = 0.010). Sex, body mass index, hypertension, hyperglycemia, hypertriglyceridemia, high-density lipoprotein-cholesterol, alanine aminotransferase, and beneficial alleles were all significant predictors of NAFLD risk (all P < 0.05). The prediction model achieved good discrimination, with an area under the receiver operating characteristic curve of 0.779. The Hosmer–Lemeshow test suggested an inadequate calibration of the model (χ2 = 21.073, P = 0.007).Conclusion: AKT1 rs2494732 and rs2494752 may be related to Chinese NAFLD susceptibility. The prediction model combining both SNPs with clinical factors displays a strong ability to discriminate NAFLD patients. Both SNPs may be exploited to design new models for early screening of NAFLD high-risk population.Graphical Abstract: Keywords: NAFLD, susceptibility, AKT1 gene, polymorphism, risk screening

Xingyu Mu,1,&ast; Wen Li,2,&ast; Ming Zhang,2 Changxiao Yang,2 Xianxu Yang,2 Dan Li,2 Yan Ding3 1The First Clinical College of Hainan Medical University, Haikou, Hainan, People’s Republic of China; 2Department of Dermatology, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 3Department of Dermatology, Affiliated Dermatology Hospital of Hainan Medical University, The Fifth People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dan Li, Department of Dermatology, The Fifth People’s Hospital of Hainan Province, No. 8 Longhua Road, Longhua District, Haikou, Hainan, People’s Republic of China, Tel +8613807656023, Email hn1380765@163.com Yan Ding, Department of Dermatology, Affiliated Dermatology Hospital of Hainan Medical University, The Fifth People’s Hospital of Hainan Province, No. 8 Longhua Road, Longhua District, Haikou, Hainan, People’s Republic of China, Tel +8618689980361, Email annymilk@126.comAbstract: Eruptive pruritic papular porokeratosis (EPPP) is a rare subtype of porokeratosis that presents as an acute exacerbation of an annular papule with a distinct peripheral hyperkeratotic ridge border and severe pruritus. EPPP is mainly reported in elderly East Asian men. Its etiology and pathogenesis are unknown. We hereby present a case report of EPPP in a 68-year-old Chinese male with persistent circumscribed papules on the extremities, accompanied by severe pruritus for one year. After the patient was given conventional medication, a new rash appeared on the patient’s extremities and he felt intense itching in the area of the rash. The patient was switched to oral tofacitinib treatment. The patient felt that the pruritus had largely disappeared after one month of oral dosing, leaving only brown pigmentation on the erythema of the extremities. The patient has been off the drug for 2 months. There was no pruritus or new rash during the follow-up period.Keywords: eruptive pruritic papular porokeratosis, porokeratosis, tofacitinib

Sheng Zhao, Wei Zhang, Linfei Zhang, Jing Zhang, Jinghang Li, Linjie Si, Yi Ding, Mingke Li, Yuanyuan Song Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, People’s Republic of ChinaCorrespondence: Sheng Zhao, Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, People’s Republic of China, Tel +86-25-83714511ext 3107, Fax +86-25-83718836, Email drzhaosheng@126.comAbstract: Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) is usually life threatening and difficult to treat. Contezolid is a newly approved oxazolidinone antimicrobial agent showing potent activity against MRSA. We successfully treated a case of refractory IE caused by MRSA with contezolid in a 41-year-old male patient. The patient was admitted due to recurrent fever and chills for more than 10 days. He had chronic renal failure for more than 10 years and under ongoing hemodialysis. The diagnosis of IE was confirmed by echocardiography and positive blood culture of MRSA. Antimicrobial therapy with vancomycin combined with moxifloxacin, and daptomycin combined with cefoperazone-sulbactam failed in the first 27 days. Moreover, the patient had to take oral anticoagulant after removal of tricuspid valve vegetation and tricuspid valve replacement. Contezolid 800 mg was added orally every 12 hours, to replace vancomycin, for its anti-MRSA activity and good safety profile. Temperature normalized after the contezolid add-on treatment for 15 days. No relapse of infection or drug-related adverse reaction was reported at 3-month follow-up since the diagnosis of IE. This successful experience serves as motivation for a well-designed clinical trial to confirm the utility of contezolid in managing IE.Keywords: infective endocarditis, methicillin-resistantStaphylococcus aureus, contezolid, chronic renal failure

Qianjia Sun,1,2,&ast; Tingjing Zhang,3,&ast; Laeeqa Manji,4 Yashu Liu,1,2 Qing Chang,1,2 Yuhong Zhao,1,2 Yang Ding,5,6 Yang Xia1,2 1Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China; 2Key Laboratory of Precision Medical Research on Major Chronic Disease, Shenyang, People’s Republic of China; 3School of Public Health, Wannan Medical College, Wuhu, People’s Republic of China; 4International Educational School, China Medical University, Shenyang, People’s Republic of China; 5Department of Infectious Diseases, Shengjing Hospital of China Medical University, China Medical University, Shenyang, People’s Republic of China; 6Diagnosis and Treatment Centre for Liver Diseases of Liaoning Province, Shenyang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Xia, Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, People’s Republic of China, Tel +86 24-96615-13650, Email xytmu507@126.com; yxia@cmu.edu.cn Yang Ding, Department of Infectious Diseases, Shengjing Hospital of China Medical University, No. 36, San Hao Street, Shenyang, Liaoning, 110004, People’s Republic of China, Tel +86 24-96615-62211, Email yding0903@sina.comObjective: Recent epidemiological evidence shows that there is an association between serum uric acid (SUA) levels and nonalcoholic fatty liver disease (NAFLD). The purpose of this meta-analysis is to summarize all available evidence and assess the associations between SUA levels and NAFLD.Methods: Using two databases, Web of Science and PubMed, observational studies were applied from the establishment of the databases to June 2022. We used a random effect model to construct the pooled odds ratio (OR) and 95% confidence interval (CI) to appraise the association between SUA levels and NAFLD. The Begg’s test was conducted to appraise publication bias.Results: A total of 50 studies were included, involving 2,079,710 participants (719,013 NAFLD patients). The prevalence and incidence rates (95% CIs) of NAFLD in the patients with hyperuricemia were 65% (57– 73%) and 31% (20– 41%), respectively. Compared to participants with lower levels of SUA, the pooled OR (95% CI) of NAFLD in those with higher levels of SUA was 1.88 (95% CI: 1.76– 2.00). In the subgroup analyses, we found that SUA levels were positively associated with NAFLD in all subgroups, according to study design, study quality, sample size, sex, comparison, age, or country.Conclusion: This meta-analysis shows that increased SUA levels are positively associated with NAFLD. The results suggested that reducing SUA levels can be a potential strategy for the prevention of NAFLD.Registration Number: PROSPERO-CRD42022358431.Keywords: serum uric acid, nonalcoholic fatty liver disease, meta-analysis, updated

Yan Teng,1 Danfeng Xu,1 Xianhong Yang,1 Hui Tang,2 Xiaohua Tao,1 Yibin Fan,1,&ast; Yang Ding1,&ast; 1Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China; 2Graduate School of Clinical Medicine, Bengbu Medical College, Bengbu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Ding; Yibin Fan, Center for Plastic & Reconstructive Surgery, Department of Dermatology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China, Tel +86-13732261339 ; +86-13505811700, Email dingyang@hmc.edu.cn; taoxiaohua@hmc.edu.cnAbstract: Unlike apoptosis, pyroptosis, necroptosis, and ferroptosis are recently identified modes of programmed cell death (PCD) with unique molecular pathways. Increasing evidence has indicated that these PCD modes play a crucial role in the pathogenesis of various non-malignant dermatoses (a group of cutaneous disorders), including infective dermatoses, immune-related dermatoses, allergic dermatoses, benign proliferative dermatoses, etc. Moreover, their molecular mechanisms have been suggested as potential therapeutic targets for the prevention and treatment of these dermatoses. In this article, we aim to review and summarize the molecular mechanisms of pyroptosis, necroptosis, and ferroptosis and their roles in the pathogenesis of some non-malignant dermatoses.Keywords: pyroptosis, necroptosis, ferroptosis, molecular mechanisms, non-malignant dermatoses

Yanhong Ding,1,&ast; Cheng Pu,2,&ast; Xiao Zhang,3 Gaoyan Tang,1 Fengjuan Zhang,3 Guohua Yu1 1Department of Medical Oncology, the First Affiliated Hospital of Weifang Medical University, Weifang, 261032, People’s Republic of China; 2Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang District, 611130, People’s Republic of China; 3Department of Microbiology, Weifang Center for Disease Control and Prevention, Weifang, 261061, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohua Yu, Email ghyry@126.comPurpose: HIV-infected immunological non-responders (INRs) failed to achieve the normalization of CD4+ T cell counts despite their undetectable viral load. INRs have an increased risk of clinical progressions of Acquired Immunodeficiency Syndrome (AIDS) and non-AIDS events, accompanied by higher mortality rates than immunological responders (IRs). This study aimed to discover the genes, which help to distinguish INRs from IRs and explore the possible mechanism of INRs.Methods: Screening DEGs between INRs and IRs using GEO microarray dataset GSE143742. DEG biological functions were investigated using GO and KEGG analysis. DEGs and WGCNA linked modules were intersected to find common genes. Key genes were identified using SVM-RFE and LASSO regression models. ROC analysis was done to evaluate key gene diagnostic effectiveness using GEO database dataset GSE106792. Cytoscape created a miRNA-mRNA-TF network for diagnostic genes. CIBERSORT and flow cytometry examined the INRs and IRs immune microenvironments. In 10 INR and 10 IR clinical samples, diagnostic gene expression was verified by RT-qPCR and Western blot.Results: We obtained 190 DEGs between the INR group and IR group. Functional enrichment analysis found a significant enrichment in mitochondria and apoptosis-related pathways. CD69 and ZNF207 were identified as potential diagnostic genes. CD69 and ZNF207 shared a transcription factor, NCOR1, in the miRNA-mRNA-TF network. Immune microenvironment analysis by CIBERSORT showed that IRs had a higher level of resting memory CD4+ T cells, lower level of activated memory CD4+ T cells and resting dendritic cells than INRs, as confirmed by flow cytometry analysis. In addition, CD69 and ZNF207 were correlated with immune cells. Experiments confirmed the expression of the diagnostic genes in INRs and IRs.Conclusion: CD69 and ZNF207 were identified as potential diagnostic genes to discriminate INRs from IRs. Our findings offered new clues to diagnostic and therapeutic targets for INRs.Keywords: HIV, immunological non-responder, immunological responder, diagnostic genes, bioinformatic analysis

Liqian Yin,1 Yansheng Ding,2 Yang Wang,3 Chengdong Wang,2 Kuisheng Sun,1 Liquan Wang3 1College of Medical Laboratory Medicine, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 2Clinical Laboratory, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China; 3Breast Surgery Center, Weifang People’s Hospital, Weifang, Shandong, People’s Republic of ChinaCorrespondence: Liquan Wang, Breast Surgery Center, Weifang People’s Hospital, NO. 151 Guangwen Road, Weifang, Shandong, 261000, People’s Republic of China, Email rxwk1990@126.comBackground: MicroRNAs influence the growth and metastasis of breast cancer (BC) by regulating their target genes. Our study aims to screen and identify miRNAs that are closely related to the development of breast cancer, and explore the role of these miRNAs and their target genes in breast cancer.Methods: Bioinformatics tools were applied to screen breast cancer-associated miRNAs and predict their potential target genes. Serum miRNAs were measured using RT-PCR. The correlation between miRNA expression and different clinicopathological features of BC patients was analyzed. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value. GEPIA, Kaplan-Meier Plotter, TIMER, and TISIDB databases were used to validate the expression levels and their prognostic value, as well as their target gene associated with immune infiltrating cells and immune checkpoints.Results: Breast cancer-associated serum miR-338-3p and miR-501-3p were screened and verified for the first time. Serum miR-501-3p was elevated in BC and was closely linked to the ki-67 index and histological grade. CDKN2C, as a potential target gene of miR-501-3p, was enriched in the cGMP-PKG signaling pathway. Serum miR-338-3p was reduced in BC and was strongly linked to lymph node metastasis and histological grading. ACTR2, CDH1, COL1A1, RBBP5, RRM1, and TPM3, as potential target genes of miR-338-3p, were enriched in MAPK, PI3K-Akt, and RAS signaling pathways. These target genes were found to be linked to breast cancer prognosis, immune infiltrating cells, and immune checkpoint inhibitors. Analysis of ROC curve showed that serum miR-501-3p combined with serum miR-338-3p had a high diagnostic value in breast cancer (AUC: 0.89, 95% CI: 0.821– 0.958).Conclusion: Serum miR-501-3p combined with serum miR-338-3p show obvious clinical significance in the diagnosis and prognosis of breast cancer, which suggests that they may act as novel diagnostic biomarkers for breast cancer.Keywords: breast cancer, miR-501-3p, miR-338-3p, serum biomarker, bioinformatics analysis

Yichuan Ding,1– 3,&ast; Sihui Tang,1,2,4,&ast; Zihan Zhou,1– 3 Hui Wei,1– 3 Wanchun Yang1– 3 1Department of Respiratory and Critical Care Medicine, the Second People’s Hospital of Hefei, Hefei, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Hefei Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China; 3The Fifth Clinical College of Anhui Medical University, Hefei, People’s Republic of China; 4Department of Respiratory and Critical Care Medicine, the Second People’s Hospital of Hefei Affiliated to Bengbu Medical University, Bengbu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wanchun Yang, Department of Respiratory and Critical Care Medicine, the Second People’s Hospital of Hefei, Hefei, Anhui, 230011, People’s Republic of China, Tel +8662965684, Fax +8662965684, Email 1225399339@qq.comPurpose: To investigate the potential of plasma microRNA-150-5p (miR-150-5p) as a biomarker for chronic obstructive pulmonary disease (COPD) and its relationship with clinical indicators such as pulmonary function.Patients and Methods: Fifty-nine patients with COPD and twenty-six healthy control individuals were recruited in the Second People’s Hospital of Hefei from September 2021 to September 2022. The plasma expression level of miR-150-5p was measured by quantitative real-time polymerase chain reaction.Results: The miR-150-5p level in the COPD group was significantly lower than that in the control group, and the relative expression was lower in patients with severe airflow limitation than those with mild limitation. Plasma miR-150-5p levels were positively correlated with pulmonary function indicators and negatively correlated with the white blood cell count and C-reactive protein level. The receiver operating characteristic curve suggested that plasma miR-150-5p had predictive value for COPD (area under curve = 0.819, sensitivity 64.4%, specificity 92.3%).Conclusion: MiR-150-5p can be useful for the diagnosis and disease assessment of COPD, and has value as a biomarker for COPD.Keywords: chronic obstructive pulmonary disease, miR-150-5p, biomarker, miRNA

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

Xiao-Chao Dong,1 Chang Liu,1 Guang-Chao Zhuo,2 Yu Ding2 1Department of Gynecology and Obstetrics, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Central Laboratory, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Yu Ding, Central Laboratory, Hangzhou First People’s Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, People’s Republic of China, Tel/Fax +86-571-5600-5600, Email dingyu_zj@126.comAbstract: Polycystic ovary syndrome (PCOS) is the most common heterogeneous endocrine disease that affecting females in reproductive age. Insulin resistance (IR), an important molecular basis for PCOS, accounts for at least 75% of women carrying this syndrome. Although there have been many studies on PCOS-IR, the detailed mechanisms are not fully understood. As essential hub for energy generation, mitochondria are critical to insulin secretion and normal function, whereas mutations in mitochondrial DNA (mtDNA) result in mitochondrial dysfunctions contributing to the pathophysiology of PCOS-IR via the regulation of balance of oxidative stress (OS), energy deficiency, or hormone metabolism. In the current review, we summarize the clinical and molecular features of PCOS-IR and discuss molecular mechanisms related to mtDNA mutations.Keywords: PCOS-IR, mitochondrial dysfunction, mtDNA mutations

Han Li,1,&ast; Yinan Ding,2,&ast; Jiayan Huang,1 Yanyan Zhao,1 Wei Chen,3 Qiusha Tang,2 Yanli An,4 Rong Chen,5 Chunmei Hu1 1Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Medical School of Southeast University, Nanjing, People’s Republic of China; 3Department of Clinical Research Center, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 4Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People’s Republic of China; 5Department of Oncology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunmei Hu, Department of tuberculosis, the Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing, 210009, People’s Republic of China, Email njyy003@njucm.edu.cnBackground: Central nervous system tuberculosis (CNS-TB) is the most devastating form of extrapulmonary tuberculosis. Rifampin (RIF) is a first-line antimicrobial agent with potent bactericidal action. Nonetheless, the blood-brain barrier (BBB) limits the therapeutic effects on CNS-TB. Exosomes, however, can facilitate drug movements across the BBB. In addition, exosomes show high biocompatibility and drug-loading capacity. They can also be modified to increase drug delivery efficacy. In this study, we loaded RIF into exosomes and modified the exosomes with a brain-targeting peptide to improve BBB permeability of RIF; we named these exosomes ANG-Exo-RIF.Methods: Exosomes were isolated from the culture medium of BMSCs by differential ultracentrifugation and loaded RIF by electroporation and modified ANG by chemical reaction. To characterize ANG-Exo-RIF, Western blot (WB), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were performed. Bend.3 cells were incubated with DiI labeled ANG-Exo-RIF and then fluorescent microscopy and flow cytometry were used to evaluate the targeting ability of ANG-Exo-RIF in vitro. Fluorescence imaging and frozen section were used to evaluate the targeting ability of ANG-Exo-RIF in vivo. MIC and MBC were determined through microplate alamar blue assay (MABA).Results: A novel exosome-based nanoparticle was developed. Compared with untargeted exosomes, the targeted exosomes exhibited high targeting capacity and permeability in vitro and in vivo. The MIC and MBC of ANG-Exo-RIF were 0.25 μg/mL, which were sufficient to meet the clinical needs.Conclusion: In summary, excellent targeting ability, high antitubercular activity and biocompatibility endow ANG-Exo-RIF with potential for use in future translation-aimed research and provide hope for an effective CNS-TB treatment.Graphical Abstract: Keywords: exosome, central nervous system tuberculosis, blood-brain barrier, rifampin