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Hanxiang Gong,1,2,* Tao Zhang,1,* Xi Wang,1 Baoxin Chen,3 Baoling Wu,1 Shufang Zhao1 1Faculty of Humanities and Social Sciences, Macao Polytechnic University, Macao, 999078, People’s Republic of China; 2The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, People’s Republic of China; 3Pingshan Hospital, Southern Medical University, Shenzhen, Guangdong, 518118, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi Wang, Faculty of Humanities and Social Sciences, Macao Polytechnic University, Macao, 999078, People’s Republic of China, Tel +86-18029928803, Fax +86-853-28718003, Email xwang@mpu.edu.moPurpose: This study explores regional differences, dynamic evolution, and influencing factors of medical service levels in Guangzhou under the Health China Strategy to provide a basis for improving service quality and reducing disparities.Patients and Methods: An evaluation system was constructed using the entropy weight TOPSIS method. The Dagum Gini coefficient analyzed regional differences, Kernel density estimation assessed service levels’ distribution, and Tobit regression explored influencing factors. Data were collected from the “Guangzhou Statistical Yearbook”, Guangzhou Health Commission reports, and government work reports from 2017 to 2022.Results: The study shows that from 2017 to 2022, there were significant differences in medical service levels among different regions of Guangzhou, with higher service quality in central urban areas compared to remote and peripheral areas. The application of the entropy weight method revealed the importance of indicators such as medical business costs and the number of registered nurses per thousand population in evaluating service quality. According to the Dagum Gini coefficient decomposition method, regional differences in medical services in Guangzhou are the main factor causing uneven overall development quality. Kernel density estimation indicates a bimodal distribution of medical service quality, suggesting heterogeneity in service quality and an increasing trend in low-quality service areas. The Tobit model confirms that factors such as medical institution drug costs, bed occupancy rate, and medical human resources have a positive impact on improving service quality.Conclusion: This study uniquely integrates the entropy weight TOPSIS method, Dagum Gini coefficient decomposition, and Kernel density estimation to dissect regional disparities in Guangzhou’s medical services, offering a novel perspective on healthcare evolution under the Health China Strategy. The findings provide an innovative framework for optimizing resource allocation and enhancing service quality, guiding balanced development across regions.Keywords: Healthcare evaluation, Service quality disparities, Dynamic distribution, Resource optimization, Medical resource allocation

Yuhao Zhao,&ast; Shun Zhao,&ast; Yuchen Shi, Qin Ma, Ze Zheng, Ping Wang, Jinghua Liu Center for Coronary Artery Disease (CCAD), Beijing Anzhen Hospital, Capital Medical University, and Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Wang; Jinghua Liu, Email wang_ping@vip.sina.com; liujinghua@vip.sina.comBackground: There is limited research on the long-term prognosis of percutaneous coronary intervention (PCI) in coronary chronic total occlusion (CTO) patients who have previously undergone coronary artery bypass grafting (CABG). Additionally, the prognostic value of a novel systemic immune inflammation index (SII) in this specific patient population remains unclear.Methods: To adjust for differences in baseline features and minimize bias, 335 pairs of patients with or without prior CABG undergone PCI were obtained after probability score matching (PSM) in a single-center cohort. The clinical characteristics were collected, and the primary outcomes were major cardiovascular events (MACE), which included all-cause death, nonfatal MI and unplanned revascularization, were recorded during the follow-up period after discharge. The group with prior CABG were divided according to the median level of SII: Lower SII group (SII ≤ 570.10, N = 167) and higher SII group (SII ≥ 570.10, N = 168).Results: The SII values were significantly higher in the prior CABG group than in the without prior CABG group [570.10 (444.60, 814.12) vs 519.65 (446.86, 565.84), P < 0.001, respectively]. The survival Kaplan–Meier analysis showed that patients with prior CABG was significantly associated with a higher risk of MACE than patients without prior CABG (P = 0.016) in the long-term follow-up. As SII levels increased, the cumulative risk of MACE became significantly higher in the patients with prior CABG (P = 0.023) stratified by the median value of SII. The Cox proportional hazards regression model analysis indicated that the level of SII (hazard ratio = 2.035, 95% CI, 1.103– 3.753, P = 0.023) emerged as independent predictors of MACE. The restricted cubic spline (RCS) analysis illustrated that the HR for MACE increased with increasing SII.Conclusion: SII is a reliable predictor of long-term cardiovascular events after PCI in CTO patients with prior CABG, suggesting that SII may be helpful in identifying high-risk patients who need more aggressive treatment and follow‐up strategies.Keywords: systemic immune inflammation index, coronary chronic total occlusion, coronary artery bypass grafting, percutaneous coronary intervention, major adverse cardiovascular events

Qinglu Yang,1,&ast; Ruitong Li,2,&ast; Yigen Hong,1 Hongsheng Liu,3 Chuyao Jian,1 Shaofeng Zhao1 1Department of Rehabilitation Medicine, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, People’s Republic of China; 2Department of Psychology and Human Development, IOE, UCL’s Faculty of Education and Society, University College London, London, WC1H 0AL, UK; 3Guangdong Huayi Biomedical Science and Technology Center, Guangzhou, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chuyao Jian; Shaofeng Zhao, Email jianchy3@mail.sysu.edu.cn; shaofengzhao88@163.comBackground: Ischemic stroke is a medical emergency for which effective treatment remains inadequate. Curcumin (Cur) is a natural polyphenolic compound that is regarded as a potent neuroprotective agent. Compared to synthetic pharmaceuticals, Cur possesses minimal side effects and exhibits multiple mechanisms of action, offering significant advantages in the treatment of ischemic stroke. However, drawbacks such as poor water solubility and transmembrane permeability limit the efficacy of Cur. In recent years, nano-delivery systems have attracted great interest in the field of stroke therapy as an effective method to improve drug solubility and cross the blood-brain barrier (BBB).Methods: In this study, a novel nanomedicine (Cur@GAR NPs) for ischemic stroke treatment was developed based on Cur-loaded gelatin nanoparticles (Cur@Gel NPs) that were then functionalized and modified with rabies virus glycoprotein (RVG29) to target brain tissue. The stability, antimicrobial properties, antioxidant properties, neuroprotective effects, neuronal cell uptake, and biocompatibility of Cur@GAR NPs were investigated in vitro. The in vivo therapeutic effect of Cur@GAR NPs on ischemic stroke was investigated in a middle cerebral artery occlusion (MCAO) rat model using the Morris water maze test and the open field test, and the potential mechanism of action was further investigated by histological analysis.Results: The resulting Cur@GAR NPs improved the solubility of Cur and exhibited good dispersion. In vitro studies have shown that Cur@GAR NPs exhibit great antimicrobial properties, antioxidant properties and intracellular reactive oxygen species (ROS) protection. Notably, RVG29 significantly enhanced the uptake of Cur@GAR NPs by SH-SY5Y cells. Furthermore, in vivo studies verified the role of Cur@GAR NPs in reducing nerve damage and supporting neurological recovery. In the MCAO rat model, Cur@GAR NPs significantly attenuated neuroinflammation, reduced neuronal apoptosis and restored behavioral functions to a great extent.Conclusion: Together these findings implied that Cur@GAR NPs could provide a novel and promising approach for effective ischemic stroke treatment. Keywords: ischemic stroke, nanomedicine, anti-inflammatory, antioxidant, targeted delivery

Min Li,1,2 Song Zhao,2 Yan Liu,1 Qian Wang,2 Yongzhe Chen,2 Yaru Zhou1 1Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of Nephrology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaCorrespondence: Yaru Zhou, Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, Ziqiang Road 139, Hebei, 050051, People’s Republic of China, Tel +86-0311-88603031, Email zyrydsy@hebmu.edu.cnBackground: Diabetes kidney disease (DKD) is a common complication of diabetes and is currently considered the primary cause of end-stage renal disease. Ferroptosis has been found to participate in the development of DKD. However, no ferroptosis-related markers have been evaluated in human DKD samples. This study aimed to examine the ferroptosis-related pathological alterations in DKD samples.Methods: This study enrolled patients with DKD at the Third Hospital of Hebei Medical University between January 2018 and December 2022, of whom 30 were diagnosed with DKD and 10 with non-DKD (CON). Clinical data of patients were collected, and hematoxylin-eosin staining (H&E), PASM, and immunohistochemical staining were performed to evaluate pathological changes and the expression of ferroptosis-related proteins, including GPX4, ACSL4, Nrf2, TfR1, FTH, and FTL.Results: Compared with the CON group, patients with DKD exhibited significantly elevated serum creatinine levels and reduced eGFR (P < 0.05). Iron content and the expression of the ferroptosis-related protein ACSL4 were significantly increased, while the expression of Nrf2 was significantly decreased in the renal tissues of patients with DKD (P all < 0.05). There were no differences in the expression of GPX4, TfR1, FTH, or FTL between the two groups. Nrf2 and ACSL4 expression were influential factors in the occurrence of DKD and both exhibited diagnostic value for DKD. Nrf2 was a protective factor (OR, < 1), whereas ACSL4 was a risk factor (OR, > 1).Conclusion: Ferroptosis-promoting gene profile was identified in DKD renal samples, indicating that ferroptosis may participate in the pathogenesis of DKD. The expression levels of Nrf2 and ASCL4 in the kidneys are related to the severity and progression of DKD.Keywords: diabetes kidney disease, ferroptosis, iron overload, lipid peroxidation

Shangtao Wang,1 Chenghao Zhu,1 Shurui Zhang,1 Siyu Ma,1 Baoshan Li,1 Shengbo Zhao,2 Wei Zhang,3 Zhirong Sun1 1School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Ningqiang Tianma Research Institution Limited Liability Company, Hanzhong, Shaanxi, People’s Republic of China; 3Ningqiang County Traditional Chinese Medicinal Industry Development Center, Hanzhong, Shaanxi, People’s Republic of ChinaCorrespondence: Zhirong Sun, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Northeast Corner of the Intersection of Yangguang South Street and Baiyang East Road, Fangshan District, Beijing, 102401, People’s Republic of China, Email szrbucm67@163.comBackground: Hypertension (HTN) is closely related to endothelial damage. While tianma (TM) and gouqizi (GQZ) have the potential to be effective in the treatment of HTN in traditional Chinese medicine, their main active ingredients and whether its exert synergistic effects and the underlying mechanisms of synergistic effects are still unclear.Objective: This study screened the active ingredients of TM and GQZ, investigated the synergistic effects of the active ingredients and explored possible mechanisms.Methods: The potential targets and mechanisms of TM and GQZ were screened using network pharmacology, and gastrodin (GAS) and gallic acid (GA) were identified as compounds with significant antihypertensive activity. The synergistic effects of the combination of GAS and GA was assessed by measuring biomarkers of AngII-induced human umbilical vein endothelial cell (HUVECs) dysfunction model. Furthermore, the anti-apoptotic and anti-inflammatory effects were evaluated by measuring inflammatory cytokine secretion, and apoptosis-related markers. Finally, key targets of the sphingolipid signaling pathway were experimentally validated by Western blotting.Results: In network pharmacology, the herb-pair exerted a synergetic effect by regulating sphingolipid pathways. The GAS and GA exerted synergistic protective effects in AngII-induced HUVECs injury by improving Nitric Oxide Content (NO) levels, alleviating lactate Endothelin-1 (ET-1), and Thromboxane B2 (TX-B2) release, reducing the secretion of inflammatory factors like interleukin-6 (IL-6), interleukin-1β (IL-1β), Tumor Necrosis Factor Alpha (TNF-α)), decreasing the pro-apoptotic protein BAX, and increasing the anti-apoptotic protein BCL-2. Furthermore, the results showed that the GAS and GA combination could elevate the level of S1PR1 and inhibit the expression of ROCK2 and the phosphorylation of NF-κB, which are key targets involved in sphingolipid pathways.Conclusion: Our study revealed that the combination of GAS and GA could suppress inflammation and apoptosis, which are highly correlated with sphingolipid signaling pathways, making it a potential candidate for the treatment of HTN. Keywords: gastrodin, gallic acid, synergistic effects, inflammation, apoptosis, sphingolipid pathways

Zhenghua Cao,1 Shengkun Zhao,1 Shaodan Hu,2 Tong Wu,3 Feng Sun,2 LI Shi2 1Changchun University of Traditional Chinese Medicine, Changchun, Jilin, People’s Republic of China; 2Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, Jilin, People’s Republic of China; 3Geriatric Department, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, Jiangsu, People’s Republic of ChinaCorrespondence: LI Shi, Email shili0648@163.comPurpose: To employ bioinformatics and machine learning to predict the characteristics of immune cells and genes associated with the inflammatory response and ferroptosis in chronic obstructive pulmonary disease (COPD) patients and to aid in the development of targeted traditional Chinese medicine (TCM). Mendelian randomization analysis elucidates the causal relationships among immune cells, genes, and COPD, offering novel insights for the early diagnosis, prevention, and treatment of COPD. This approach also provides a fresh perspective on the use of traditional Chinese medicine for treating COPD.Methods: R software was used to extract COPD-related data from the Gene Expression Omnibus (GEO) database, differentially expressed genes were identified for enrichment analysis, and WGCNA was used to pinpoint genes within relevant modules associated with COPD. This analysis included determining genes linked to the inflammatory response in COPD patients and analyzing their correlation with ferroptosis. Further steps involved filtering core genes, constructing TF-miRNA‒mRNA network diagrams, and employing three types of machine learning to predict the core miRNAs, key immune cells, and characteristic genes of COPD patients. This process also delves into their correlations, single-gene GSEA, and diagnostic model predictions. Reverse inference complemented by molecular docking was used to predict compounds and traditional Chinese medicines for treating COPD; Mendelian randomization was applied to explore the causal relationships among immune cells, genes, and COPD.Results: We identified 2443 differential genes associated with COPD through the GEO database, along with 8435 genes relevant to WGCNA and 1226 inflammation-related genes. A total of 141 genes related to the inflammatory response in COPD patients were identified, and 37 core genes related to ferroptosis were selected for further enrichment analysis and analysis. The core miRNAs predicted for COPD include hsa-miR-543, hsa-miR-181c, and hsa-miR-200a, among others. The key immune cells identified were plasma cells, activated memory CD4 T cells, gamma delta T cells, activated NK cells, M2 macrophages, and eosinophils. Characteristic genes included EGF, PLG, PTPN22, and NR4A1. A total of 78 compounds and 437 traditional Chinese medicines were predicted. Mendelian randomization analysis revealed a causal relationship between 36 types of immune cells and COPD, whereas no causal relationship was found between the core genes and COPD.Conclusion: A definitive causal relationship exists between immune cells and COPD, while the prediction of core miRNAs, key immune cells, characteristic genes, and targeted traditional Chinese medicines offers novel insights for the early diagnosis, prevention, and treatment of COPD.Keywords: bioinformatics analysis, Mendelian randomization, machine learning, COPD, characteristic genes, targeted traditional Chinese medicine, early diagnosis

Zaifeng Si,1,2,&ast; Shengmei Zhao,3,&ast; Yingying Hao,3 Qian Wang,3 Yanfa Zhong,2 Yue Liu,3 Ran Chen,3 Yan Jin,3 Zhiming Lu1,3 1Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Clinical Laboratory, Dezhou Municipal Hospital of Traditional Chinese Medicine, Dezhou, Shandong, People’s Republic of China; 3Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Jin; Zhiming Lu, Email sdjinyan@163.com; luzhiming@sdu.edu.cnBackground: Enterobacter cloacae complex (ECC), which includes major nosocomial pathogens, causes urinary, respiratory, and bloodstream infections in humans, for which colistin is one of the last-line drugs.Objective: This study aimed to analyse the epidemiology and resistance mechanisms of colistin-resistant Enterobacter cloacae complex (ECC) strains isolated from Shandong, China.Methods: Two hundred non-repetitive ECC strains were collected from a tertiary hospital in Shandong Province, China, from June 2020 to June 2022. Whole-genome sequencing and bioinformatics analyses were performed to understand the molecular epidemiology of the colistin-resistant ECC strains. The nucleotide sequences of heat shock protein (hsp60) were analyzed by using BLAST search to classify ECC. The gene expression levels of ramA, soxS, acrA, acrB, phoP, and phoQ were assessed using RT-qPCR. MALDI-TOF MS was used to analyse the modification of lipid A.Results: Twenty-three colistin-resistant strains were detected among the 200 ECC clinical strains (11.5%). The hsp60 cluster analysis revealed that 20 of the 23 ECC strains belonged to heterogeneous resistance clusters. Variants of mgrB, phoPQ, and pmrAB, particularly phoQ and pmrB, were detected in the 23 ECC strains. The soxS and acrA genes were significantly overexpressed in all 23 colistin-resistant ECC strains (P < 0.05). Additionally, all 23 ECC strains contained modified lipid A related to colistin resistance, which showed five ion peaks at m/z 1876, 1920, 1955, 2114, and 2158. Among the 23 ECC strains, 6 strains possessed a phosphoethanolamine (pETN) moiety, 16 strains possessed a 4-amino-4-deoxy-L-arabinose (−L-Ara4N) moiety, and one strain had both pETN and −L-Ara4N moieties.Conclusion: This study suggests that diverse colistin resistance existed in ECC, including unknown resistance mechanisms, exist in ECC. Mechanistic investigations of colistin resistance are warranted to optimise colistin use in clinical settings and minimise the emergence of resistance.Keywords: Enterobacter cloacae complex, ECC, epidemiology, colistin, resistance mechanism

Honggang Zhang,1 Huiling Li,1 Shuangjun Zhao,2 Fangping Bao1,2 1Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 2The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu, Zhejiang Province, People’s Republic of ChinaCorrespondence: Fangping Bao, Email baofp@zju.edu.cnAbstract: Remimazolam is a novel ultra-short-acting benzodiazepine with a unique pharmacokinetic profile that makes it an attractive option for use in general anesthesia. This review paper provides an in-depth analysis of remimazolam’s applications in the field of general anesthesia, focusing on its pharmacological properties, clinical efficacy, safety profile, and potential advantages compared to other anesthetic agents. Remimazolam acts on GABAa receptors, offering rapid onset and recovery times due to its unique metabolic pathway involving tissue esterases. Clinical trials have demonstrated its efficacy in procedural sedation and general anesthesia, showing a favorable safety profile with minimal cardiovascular and respiratory depression. Compared to traditional anesthetics such as propofol, remimazolam presents distinct advantages, including predictable pharmacokinetics, reduced risk of prolonged sedation, and a reliable safety margin. These attributes position remimazolam as a promising agent in various clinical settings. The purpose of this review is to synthesize current evidence on remimazolam and discuss its potential to improve clinical outcomes in anesthesia practice.Keywords: remimazolam, clinical efficacy, general anesthesia, safety profile, respiratory depression

Zijuan Ma,1,&ast; Yunge Fan,1,&ast; Zhijun Yu,1 Wenxuan Wu,1 Xiangting Zhang,1 Huolian Li,1 Shaochen Zhao,2 Yang Li,3 Yuanyuan Li,4 Dongfang Wang,1 Fang Fan1 1Center for Studies of Psychological Application, School of Psychology, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, People’s Republic of China; 2Research Center for Guangdong-Hong Kong-Macao Policing Model Innovation, China People’s Police University, Guangzhou, People’s Republic of China; 3Department of Educational Psychology, Faculty of Education, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 4Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongfang Wang; Fang Fan, School of Psychology, South China Normal University, Shipai Road, Guangzhou, 510631, People’s Republic of China, Email wdfpsyc@126.com; fangfan@scnu.edu.cnPurpose: Although experimental psychopathology using PET, EEG, and fMRI is at the forefront of understanding the underlying mechanisms of sleep inertia, many questions concerning causality remain unanswerable due to ethical constraints and the use of small and heterogeneous samples in experimental methods. There is a pressing need for a novel perspective in a large and relatively homogeneous population to fully capture and elucidate longitudinal processes and dynamic causality that culminate in episodes of sleep inertia over time. Therefore, this study aimed to reveal the causal relationships between symptoms of sleep inertia across its distinct patterns.Patients and Methods: A total of 1636 intern nurses participated in the first survey (94.1% validity rate), then 1277 intern nurses were followed up (82.9% tracing rate). Symptoms of sleep inertia were self-reported using the Sleep Inertia Questionnaire. The cross-lagged panel network models were used to examine unique longitudinal relationships between symptoms of sleep inertia across distinct trajectories.Results: Four distinct trajectories of sleep inertia were established. Additionally, we found differences in those symptoms with the highest influence on other symptoms at the subsequent point across the networks of four trajectories, particularly, “Difficulty in concentrating” in the persistent-high group and “Feeling tense” in the deteriorating groups.Conclusion: The current study highlights changes in sleep inertia based on the long-term course over time. Notably, symptoms of “Difficulty in concentrating” and “Feeling tense” are imperative to address these specific symptoms within subpopulations.Keywords: sleep inertia, change patterns, network structures, intern nurse, shift work

Yixin Li,1– 6,&ast; Qi Sun,2,3,7,&ast; Lingjia Hao,1,8 Han Shan,2,3,7 Zixi Jiang,1– 6 Ying Wang,1– 6 Zeyu Chen,2,3,7 Wu Zhu,1– 6 Shuang Zhao1– 6 1Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 2Furong Laboratory (Precision Medicine), Changsha, 410008, People’s Republic of China; 3National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 4Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 5Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 6National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China; 7School of Mechanical and Electrical Engineering, Central South University, Changsha, 410083, People’s Republic of China; 8Xiangya School of Medicine, Central South University, Changsha, 410083, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuang Zhao; Wu Zhu, Department of Dermatology, Xiangya Hospital of Central South University, 87 Xiangya Road, Kaifu District, Changsha, Hunan Province, People’s Republic of China, Email shuangxy@csu.edu.cn; zhuwuxy@csu.edu.cnIntroduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time.Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment.Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model.Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.Keywords: liposome, pathological scar, 5-fluorouracil, fibroblast

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

Zheping Chen,1,&ast; Changli Gao,1,2,&ast; Yingchao Zhang,1,3 Yongxu Gao,1,4 Le Zhang,1 Shanshan Zhao,1 He Zhang,1 Xin Zhao,1 Yanwu Jin1 1Department of Anesthesiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Anesthesiology, Laoling People Hospital, Laoling, People’s Republic of China; 3Department of Anesthesiology, Shouguang People Hospital, Weifang, People’s Republic of China; 4Department of Anesthesiology, Jinan Third People’s Hospital, Laoling, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanwu Jin, Department of Anesthesiology, the Second Hospital, Cheeloo College of Medicine, Shandong University, 247 Bei Yuan Street, Jinan, 250033, People’s Republic of China, Tel +86-17660085535, Email jinyanwu_aa@163.comBackground: Thoracic paravertebral block (TPVB) analgesia can be prolonged by local anesthetic adjuvants such as dexmedetomidine. This study aimed to evaluate the two administration routes of dexmedetomidine on acute pain and chronic neuropathic pain (NeuP) prevention compared with no dexmedetomidine.Methods: A total of 216 patients were randomized to receive TPVB using 0.4% ropivacaine alone (R Group), with perineural dexmedetomidine 0.5 μg·kg− 1 (RD0.5 Group) or 1.0 μg·kg− 1 (RD1.0 Group), or intravenous (IV) dexmedetomidine 0.5 μg·kg− 1·h− 1 (RDiv Group). The primary outcome was the incidence of chronic NeuP, defined as a Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain score > 12 points at 3-month after surgery.Results: (1) For the primary outcome, RD0.5 Group and RD1.0 Group demonstrated a decreased incidence of chronic NeuP at 3-month after surgery; (2) Compared with R Group, RDiv Group, RD0.5 Group, and RD1.0 Group can reduce VAS scores at rest and movement and Prince-Henry Pain scores at 12 and 24-h after surgery, the consumption of oral morphine equivalent (OME) and improve QOD-15 at POD1; (3) Compared with RDiv Group, RD0.5 Group and RD1.0 Group can reduce VAS scores at rest and movement and Prince-Henry Pain scores at 12 and 24-h after surgery, the consumption of postoperative OME and improve QOD-15 at POD1; (4) Compared with RD0.5 Group, RD1.0 Group effectively reduced VAS scores at rest at 12 and 24-h after surgery, VAS scores in movement and Prince-Henry Pain scores at 12-h after surgery. However, RD1.0 Group showed an increased incidence of drowsiness.Conclusion: Perineural or IV dexmedetomidine are similarly effective in reducing acute pain, but only perineural dexmedetomidine reduced chronic NeuP. Moreover, considering postoperative complications such as drowsiness, perineural dexmedetomidine (0.5 μg·kg− 1) may be a more appropriate choice.Clinical Trial Registration: Chinese Clinical Trial Registry (ChiCTR2200058982).Keywords: dexmedetomidine, thoracic paravertebral nerve block, neuropathic pain, thoracoscopic surgery

Dan Qi,1– 9 Xi Zhang,1– 8 Fangli Li,10 Shengrui Zhao,2– 8 Qiumin Wang,1– 8 Wen Liu,2– 8 Lei Yan,1– 8 Yanbo Du1– 8 1State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, Shandong, People’s Republic of China; 2National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, People’s Republic of China; 3Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, Shandong, People’s Republic of China; 4Shandong Technology Innovation Center for Reproductive Health, Jinan, Shandong, People’s Republic of China; 5Shandong Provincial Clinical Research Center for Reproductive Health, Jinan, Shandong, People’s Republic of China; 6Shandong Key Laboratory of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 7Research Unit of Gametogenesis and Health of ART-Offspring, Chinese Academy of Medical Sciences (No. 2021RU001), Jinan, Shandong, People’s Republic of China; 8Medical Integration and Practice Center, Shandong University, Jinan, Shandong, People’s Republic of China; 9Weifang People’s Hospital, Weifang, Shandong, People’s Republic of China; 10Department of Gynecology and Obstetrics, Public Health Clinical Center Affiliated to Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yanbo Du, Center for Reproductive Medicine, Shandong University, Jinan, 250012, Shandong, People’s Republic of China, Tel +86 1 301 173 4515, Email duyanboivf@163.comPurpose: The objective of this study was to assess reproductive outcomes of D6 blastocysts transferred on day 6 in comparison to those transferred on day 7 of progesterone exposure in frozen-thawed embryo transfer cycles.Patients and Methods: This retrospective cohort study included 2029 D6 single blastocysts from the first frozen-thawed embryo transfer cycles of patients at the Hospital for Reproductive Medicine Affiliated to Shandong University from February 2017 to January 2020. Participants were divided into Group A (blastocyst transferred on the 6th day of progesterone exposure, n=1634) and Group B (blastocyst transferred on the 7th day of progesterone exposure, n=395).Results: The live birth rate was comparable between Group A and Group B (38.7% versus 38.7%, P=0.999). Subgroup analysis revealed a significantly higher preterm birth rate in D6 single blastocysts transferred on the 7th day than in those transferred on the 6th day of progesterone exposure for natural cycle frozen-thawed embryo transfer (5.2% versus 11.3%, P=0.020). After adjustment for potential confounders, the differences in the preterm birth rate in natural cycles persisted (adjusted odds ratio 2.347, 95% confidence interval 1.129– 4.877, P=0.022).Conclusion: In frozen-thawed embryo transfer cycles, transferring on the 6th or 7th day of progesterone exposure of D6 blastocysts did not affect the live birth rate; however, when a natural cycle protocol is adopted, the possible preterm risk of transferring D6 blastocysts on the 7th day of progesterone exposure should be noted.Keywords: frozen-thawed embryo transfer, blastocyst transfer, endometrium preparation, live birth rate

Zhitao Zhang, Huan Lan, Shuai Zhao Department of Galactophore, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian Province, 350001, People’s Republic of ChinaCorrespondence: Shuai Zhao, Department of Galactophore, Fujian Maternity and Child Health Hospital, No. 18 Daoshan Road, Gulou District, Fuzhou City, Fujian Province, 350001, People’s Republic of China, Email zhaoshuaizh@21cn.comObjective: To analyze the diagnostic value of quantitative features in multimodal magnetic resonance imaging (MRI) images to construct a radio-omics model for breast cancer.Methods: Ninety-five patients with breast-related diseases from January 2020 to January 2021 were grouped into the benign group (n=57) and malignant group (n=38) according to the pathological findings. All cases were randomized as the training group (n=66) and validation group (n=29) in a 7:3 ratio based on the examination time. All subjects were examined by T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE), and apparent diffusion coefficient (ADC) multimodality MRI. The MRI findings were analyzed against pathological findings. A diagnostic breast cancer radiomics model was constructed. The diagnostic efficacy of the model in the validation group was analyzed, and the diagnostic efficacy was analyzed via the ROC curve.Results: Fibroadenoma accounted for 49.12% of benign breast diseases, and invasive ductal carcinoma accounted for 73.68% of malignant breast diseases. The sensitivity of T1WI, T2WI, DWI, ADC, and DCE in diagnosing breast cancer was 61.14%, 66.67%, 73.30%, 78.95%, and 85.96%, using the four-fold table method. The area under the curves (AUCs) of T1WI, T2WI, DWI, ADC, and DCE for diagnosing breast cancer were 0.715, 0.769, 0.785, 0.835, and 0.792, respectively. The AUCs of plain scan, diffuse, enhanced, plain scan + diffuse, plain scan + enhanced, enhanced + diffuse, and plain scan + enhanced + diffuse for diagnosing breast cancer were 0.746, 0.798, 0.816, 0.839, 0.890, 0.906, and 0.927, respectively.Conclusion: The construction of a radio-omics model by quantitative features in multimodal MRI images was valuable in the diagnosis of breast cancer. The value of radio-omics models such as plain scan + enhanced + diffuse was higher than the other models in diagnosing breast cancer and could be widely applied in clinical practice.Keywords: MRI, quantitative features, imaging histology, model, breast cancer, diagnosis

Nan Du,1 Xiaolei Wang,1 Zhaohui Wang,2 Hongwei Liu,1 Hui Liu,1 Hongfang Duan,1 Shaozhi Zhao,1 Santasree Banerjee,3 Xinwen Zhang1 1Department of Medical Genetics, Xi’an People’s Hospital (Xi’an Fourth Hospital), Xi’an, Shaanxi, 710004, People’s Republic of China; 2Center for Children Health Care, Xi’an People’s Hospital (Xi’an Fourth Hospital), Xi’an, Shaanxi, 710004, People’s Republic of China; 3Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, People’s Republic of ChinaCorrespondence: Xinwen Zhang, Department of Medical Genetics, Xi’an People’s Hospital (Xi’an Fourth Hospital), 21 Jiefang Road, Xi’an, Shaanxi, 710004, People’s Republic of China, Tel +86- 13992809311, Email xianxinwen@163.com Santasree Banerjee, Department of Genetics, College of Basic Medical Sciences, Jilin University, No. 126 Xinmin Street, Changchun, Jilin, 130021, People’s Republic of China, Tel +86-13823715105, Email santasree.banerjee@yahoo.comBackground: Charcot–Marie–Tooth disease (CMT) is a heterogeneous group of disorders involving peripheral nervous system. Charcot–Marie–Tooth disease 4B1 (CMT4B1) is a rare subtype of CMT. CMT4B1 is an axonal demyelinating polyneuropathy with an autosomal recessive mode of inheritance. Patients with CMT4B1 usually manifested with dysfunction of the motor and sensory systems which leads to gradual and progressive muscular weakness and atrophy, starting from the peroneal muscles and finally affecting the distal muscles. Germline mutations in MTMR2 gene causes CMT4B1.Material and Methods: In this study, we investigated a 4-year-old Chinese boy with gradual and progressive weakness and atrophy of both proximal and distal muscles. The proband’s parents did not show any abnormalities. Whole-exome sequencing and Sanger sequencing were performed.Results: Whole-exome sequencing identified a novel homozygous nonsense mutation (c.118A>T; p.Lys40&ast;) in exon 2 of MTMR2 gene in the proband. This novel mutation leads to the formation of a truncated MTMR2 protein of 39 amino acids instead of the wild- type MTMR2 protein of 643 amino acids. This mutation is predicted to cause the complete loss of the PH-GRAM domain, phosphatase domain, coiled-coil domain, and PDZ-binding motif of the MTMR2 protein. Sanger sequencing revealed that the proband’s parents carried the mutation in a heterozygous state. This mutation was absent in 100 healthy control individuals.Conclusion: This study reports the first mutation in MTMR2 associated with CMT4B1 in a Chinese population. Our study also showed the importance of whole-exome sequencing in identifying candidate genes and disease-causing variants in patients with CMT4B1.Keywords: Charcot–Marie–Tooth disease, MTMR2 gene, novel mutation, homozygous, whole-exome sequencing

Yuanyuan Wang,1 Ruibo Guo,2 Ming Zou,1 Lingling Jiang,1 Liang Kong,2 Sen Zhao,1 Xuan Zhang,1 Wei Wang,1 Baoli Xu1 1Department of Pharmacy, Affiliated Zhongshan Hospital of Dalian University, Dalian, People’s Republic of China; 2School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, People’s Republic of ChinaCorrespondence: Baoli Xu, Department of Pharmacy, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Dalian, 116001, Liaoning, People’s Republic of China, Tel +86411 6289 3215, Email xubaoli1981@hotmail.comIntroduction: Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that involves synovitis, cartilage destruction, and even joint damage. Traditional agents used for RA therapy remain unsatisfactory because of their low efficiency and obvious adverse effects. Therefore, we here established RA microenvironment-responsive targeted micelles that can respond to the increase in reactive oxygen species (ROS) levels in the joint and improve macrophage-specific targeting of loaded drugs.Methods: We here prepared ROS-responsive folate-modified curcumin micelles (TK-FA-Cur-Ms) in which thioketal (TK) was used as a ROS-responsive linker for modifying polyethylene glycol 5000 (PEG5000) on the micellar surface. When micelles were in the ROS-overexpressing inflammatory microenvironment, the PEG5000 hydration layer was shed, and the targeting ligand FA was exposed, thereby enhancing cellular uptake by macrophages through active targeting. The targeting, ROS sensitivity and anti-inflammatory properties of the micelles were assessed in vitro. Collagen-induced arthritis (CIA) rats model was utilized to investigate the targeting, expression of serum inflammatory factors and histology change of the articular cartilage by micelles in vivo.Results: TK-FA-Cur-Ms had a particle size of 90.07 ± 3.44 nm, which decreased to 78.87 ± 2.41 nm after incubation with H2O2. The micelles exhibited in vitro targeting of RAW264.7 cells and significantly inhibited inflammatory cytokine levels. Pharmacodynamic studies have revealed that TK-FA-Cur-Ms prolonged the drug circulation and exhibited augmented cartilage-protective and anti-inflammatory effects in vivo.Conclusion: The unique ROS-responsive targeted micelles with targeting, ROS sensitivity and anti-inflammatory properties were successfully prepared and may offer an effective therapeutic strategy against RA.Keywords: rheumatoid arthritis, ROS-responsive, curcumin, folate, micelles

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

Lirong Zhang,1 Shaocong Zhao,1 Zhongbing Yang,2 Hua Zheng,3 Mingxing Lei4,5 1Department of Physical Education, Xiamen University of Technology, Xiamen, Fujian, 361024, People’s Republic of China; 2School of Physical Education, Guizhou Normal University, Guizhou, 550025, People’s Republic of China; 3College of Physical Education and Health Sciences, Chongqing Normal University, Chongqing, 401331, People’s Republic of China; 4National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, 100039, People’s Republic of China; 5Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, 100039, People’s Republic of ChinaCorrespondence: Hua Zheng, College of Physical Education and Health Sciences, Chongqing Normal University, No. 37, Middle Road, University Town, Shapingba District, Chongqing, 401331, People’s Republic of China, Tel +86+15923028254, Email 20130296@cqnu.edu.cn Mingxing Lei, Department of Orthopedic Surgery, Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China, Tel +86+18811772189, Email leimingxing@301hospital.com.cnBackground: Sleep problems are prevalent among university students, yet there is a lack of effective models to assess the risk of sleep disturbance. Artificial intelligence (AI) provides an opportunity to develop a platform for evaluating the risk. This study aims to develop and validate an AI platform to stratify the risk of experiencing sleep disturbance for university students.Methods: A total of 2243 university students were included, with 1882 students from five universities comprising the model derivation group and 361 students from two additional universities forming the external validation group. Six machine learning techniques, including extreme gradient boosting machine (eXGBM), decision tree (DT), k-nearest neighbor (KNN), random forest (RF), neural network (NN), and support vector machine (SVM), were employed to train models using the same set of features. The models’ prediction performance was assessed based on discrimination and calibration, and feature importance was determined using Shapley Additive exPlanations (SHAP) analysis.Results: The prevalence of sleep disturbance was 44.69% in the model derivation group and 49.58% in the external validation group. Among the developed models, eXGBM exhibited superior performance, surpassing other models in metrics such as area under the curve (0.779, 95% CI: 0.728– 0.830), accuracy (0.710), precision (0.737), F1 score (0.692), Brier score (0.193), and log loss (0.569). Calibration and decision curve analyses demonstrated favorable calibration ability and clinical net benefits, respectively. SHAP analysis identified five key features: stress score, severity of depression, vegetable consumption, age, and sedentary time. The AI platform was made available online at https://sleepdisturbancestudents-xakgzwectsw85cagdgkax9.streamlit.app/, enabling users to calculate individualized risk of sleep disturbance.Conclusion: Sleep disturbance is prevalent among university students. This study presents an AI model capable of identifying students at high risk for sleep disturbance. The AI platform offers a valuable resource to guide interventions and improve sleep outcomes for university students.Keywords: university students, sleep disturbance, machine learning, artificial intelligence, feature importance

Shaoqi Zong,1,2,&ast; Guokai Huang,1,3,&ast; Bo Pan,1,&ast; Shasha Zhao,4 Changquan Ling,1,3 Binbin Cheng1,3 1Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai, 200043, People’s Republic of China; 2Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, People’s Republic of China; 3Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai, 200043, People’s Republic of China; 4Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Binbin Cheng, Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, 168 Changhai Road, Shanghai, 200043, People’s Republic of China, Email cbb8202@smmu.edu.cn Changquan Ling, Faculty of Traditional Chinese Medicine, Naval Medical University, 800 Xiangyin Road, Shanghai, 200043, People’s Republic of China, Email changquanling@smmu.edu.cnPurpose: Transcatheter arterial chemoembolization (TACE) is commonly used in the treatment of hepatocellular carcinoma (HCC). However, not all patients respond to this treatment. TACE typically leads to hypoxia in the tumor microenvironment. Therefore, we aimed to construct a prognostic model based on hypoxia-related differentially expressed microRNA (miRNAs) in hepatocellular carcinoma (HCC) and to investigate the potential target mRNAs for predicting TACE response.Methods: The hypoxia-related miRNAs (HRMs) were identified in liver cancer cells, then global test was performed to further select the miRNAs which were associated with recurrence and vascular invasion. A prognostic model was constructed based on multivariate Cox regression analysis; qRT-PCR analysis was used to validate the differentially expressed miRNAs in HCC cell lines under hypoxic condition. We further identified the putative target genes of the miRNAs and investigate the relationship between the target genes and TACE response, immune cells infiltration.Results: We established a HRMs prognostic model for HCC patients, containing two miRNAs (miR-638, miR-501-5p), the patients with high-HRMs score showed worse survival in discovery and validation cohort; qRT-PCR analysis confirmed that these two miRNAs are up-regulated in hepatoma cells under hypoxic condition. Furthermore, four putative target genes of these two miRNAs were identified (ADH1B, CTH, FTCD, RCL1), which were significantly associated with TACE response, immune score, immunosuppressive immune cells infiltration, PDCD1 and CTLA4.Conclusion: The HCC-HRMs signature may be utilized as a promising prognostic factor and may have implications for guiding TACE and immune therapy.Keywords: hypoxia, miRNA, signature, hepatocellular carcinoma, prognosis

Yu Gao,1 Min Fan,1 Yu Li,1 Shaochen Zhao,2 Wei Chen,1 Donghuan Zhang,1 Xifu Zheng1,3 1School of Psychology, South China Normal University, Guangzhou, 510663, People’s Republic of China; 2Guangdong-Hongkong-Macao Policing Model Innovation Research Center, China People’s Police University, Guangzhou, 510663, People’s Republic of China; 3Key Laboratory of Brain, Cognition, and Education Sciences, Ministry of Education, Guangzhou, 510663, People’s Republic of ChinaCorrespondence: Xifu Zheng, School of Psychology, South China Normal University, Guangzhou, 510663, People’s Republic of China, Email zhengxifu@m.scnu.edu.cnObjective: The study aimed to examine the roles of anxiety and intolerance of uncertainty (IU) in conditioned fear learning under an uncertain context induced by the contingency reversal of the association between the conditioned stimulus and the unconditioned stimulus (CS-US).Methods: The study sample comprised 53 participants, randomly divided into two groups: a non-instruction group and an instruction group. The experimental procedure encompassed five stages: pre-acquisition, acquisition, generalization, reversal acquisition, and reversal generalization. Our study primarily focused on analyzing a moderated mediation model.Results: In the instructed group, we observed that the reversed fear generalization response was directly influenced by the pre-reversal fear generalization response, while also being indirectly mediated by the IU factor. However, in the non-instructed group, we did not find a significant mediating effect of IU. Moreover, we noted that the mediation of IU was contingent on the instructional information. It is noteworthy that anxiety did not exhibit a discernible role in conditioned fear within the uncertainty condition in our study.Conclusion: The findings provide novel insights into fear-related phenomena, emphasizing the intricate interplay between individual traits and fear generalization under conditions of uncertainty. They contribute to understanding the mechanisms of emotional and cognitive interactions in uncertain conditions.Keywords: associations learning, fear generalization, instructional learning, moderated mediation model

Jiawei He,&ast; Danyang Jing,&ast; Shen Zhao, Meili Duan Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shen Zhao; Meili Duan, Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Betijing, 100050, People’s Republic of China, Tel +86-15960008819 ; +86-18811695963, Email jzkzhaoshen@163.com; dmeili@ccmu.edu.cnPurpose: To investigate the role of B cell receptor associated protein 31 (BAP31) in the pathogenesis of sepsis.Methods: Cecal ligation and puncture (CLP)-induced C57BL/6J mice, and LPS-challenged endothelial cells (HUVECs) were established to mimic a sepsis animal model and a sepsis cell model, respectively. Cre/LoxP and shRNA methods were used for BAP31 knockdown in vivo and in vitro respectively. Neutrophils/macrophages-endothelial cocultures were used to evaluate neutrophils or macrophages infiltration and adhesion to endothelial cells. Cox proportional hazards model was used to evaluate the survival time of mice. Western blotting (WB) and Quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect toll-like receptor (TLR) signaling pathway, transforming growth factor β activated kinase 1 (TAK1) signaling pathway and phosphoinositide-3 kinases-protein kinase B (PI3K/AKT) signaling pathway.Results: Deletion of BAP31 reduced CLP-induced mortality of mice, histological damage with less interstitial edema, and neutrophils and macrophages infiltration. IHC and IF showed that BAP31 knockdown significantly decreases the expressions of ICAM1 and VCAM1 both in vivo and in vitro. Coculture showed that LPS-induced neutrophils or macrophages adhesion to endothelial cells was significantly weakened in BAP31 knockdown cells. In addition, BAP31 knockdown of endothelial cells decreased the expression of CD80 and CD86 on the surface of macrophages as well as interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) during sepsis. Mechanistically, LPS-induced the activation of TLR4, MyD88 and TRAF6, and the phosphorylation of TAK1, PI3K, AKT, IκBα and IKKα/β, resulting in activation of nuclear factor kappa B (NF-κB) p65 in endothelial cells. However, BAP31 knockdown significantly reversed the expressions of associated proteins.Conclusion: BAP31 up-regulated the expressions of ICAM1 and VCAM1 in endothelial cells leading to sepsis-associated organ injury. This may be involved in activation of TLR signaling pathway, TAK1 pathway, and PI3K-AKT signaling pathway.Keywords: BAP31, sepsis, macrophages, endothelial cells, NF-κB

Enyi Zhu,1,2,&ast; Ming Zhong,3,&ast; Tiantian Liang,4,&ast; Yu Liu,3,&ast; Keping Wu,1,2 Zhijuan Zhang,1,2 Shuping Zhao,1,2 Hui Guan,5 Jiasi Chen,6 Li-Zhen Zhang,7 Yimin Zhang1,2 1The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, 510000, People’s Republic of China; 2Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, Guangdong, 510000, People’s Republic of China; 3Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 517108, People’s Republic of China; 4Nephrology Division, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, People’s Republic of China; 5Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, People’s Republic of China; 6Department of Nephrology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510030, People’s Republic of China; 7Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yimin Zhang, The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, People’s Republic of China, Email zhangyim@mail.sysu.edu.cn Li-Zhen Zhang, Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China, Email zhanglzh3@mail2.sysu.edu.cnObjective: Diabetic nephropathy (DN) represents the principal cause of end-stage renal diseases worldwide, lacking effective therapies. Fatty acid (FA) serves as the primary energy source in the kidney and its dysregulation is frequently observed in DN. Nevertheless, the roles of FA metabolism in the occurrence and progression of DN have not been fully elucidated.Methods: Three DN datasets (GSE96804/GSE30528/GSE104948) were obtained and combined. Differentially expressed FA metabolism-related genes were identified and subjected to DN classification using “ConsensusClusterPlus”. DN subtypes-associated modules were discovered by “WGCNA”, and module genes underwent functional enrichment analysis. The immune landscapes and potential drugs were analyzed using “CIBERSORT” and “CMAP”, respectively. Candidate diagnostic biomarkers of DN were screened using machine learning algorithms. A prediction model was constructed, and the performance was assessed using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The online tool “Nephroseq v5” was conducted to reveal the clinical significance of the candidate diagnostic biomarkers in patients with DN. A DN mouse model was established to verify the biomarkers’ expression.Results: According to 39 dysregulated FA metabolism-related genes, DN samples were divided into two molecular subtypes. Patients in Cluster B exhibited worse outcomes with a different immune landscape compared with those in Cluster A. Ten potential small-molecular drugs were predicted to treat DN in Cluster B. The diagnostic model based on PRKAR2B/ANXA1 was created with ideal predictive values in early and advanced stages of DN. The correlation analysis revealed significant association between PRKAR2B/ANXA1 and clinical characteristics. The DN mouse model validated the expression patterns of PRKAR2B/ANXA1.Conclusion: Our study provides new insights into the role of FA metabolism in the classification, immunological pathogenesis, early diagnosis, and precise therapy of DN.Keywords: diabetic nephropathy, fatty acid metabolism, molecular subtypes, immune landscape, pharmacotherapy, diagnostic model

Sicheng Zhao, Tingyan Wu, Mingjing Fu, Zhe Zhang Department of Dermatology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou, People’s Republic of ChinaCorrespondence: Sicheng Zhao, Department of Dermatology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, No. 118 Wansheng Street, Suzhou Industrial Park, Suzhou, Jiangsu, 215028, People’s Republic of China, Email zscba@163.comBackground: Psoriasis is a chronic inflammatory skin disease characterized by erythema, papules, and plaques. Adiponectin (ADIPOQ) is an important protein hormone secreted by adipose tissue. Here, we aimed to explore the expression of ADIPOQ in psoriasis patients and the moderation effect of histone lactylation on ADIPOQ.Methods: The GSE78097 data set was downloaded from GEO database to analyze the differentially expressed genes (DEGs) in psoriasis. A total of 36 psoriasis patients were recruited to obtain the skin samples. The ADIPOQ protein levels, global lactylation and histone lactylation (H3K18lac) levels were detected by Western blot assay. Chromatin immunoprecipitation (CHIP) assay was performed to detect the combination between H3K18lac and promoter regions of the ADIPOQ. The receiver operating curve (ROC) analysis was used to evaluate the diagnostic value of ADIPOQ in psoriasis.Results: ADIPOQ was decreased in the skin tissues of psoriasis patients. In addition, the global lactylation and H3K18lac levels were significantly decreased in the skin tissues of psoriasis patients. In HaCaT cells, promoting the global lactylation and H3K18lac levels increased the ADIPOQ protein levels, while si-LDHA transfection decreased the ADIPOQ protein levels. The CHIP results indicated that lactylation promoted the binding of promoter regions of the ADIPOQ and H3K18lac. Finally, the ROC analysis showed that ADIPOQ exhibited diagnostic value in psoriasis.Conclusion: This study demonstrated ADIPOQ was decreased in the skin tissues of psoriasis patients, and ADIPOQ has diagnostic value for psoriasis. Furthermore, down-regulation of H3K18lac levels inhibited the transcription of ADIPOQ, which was the key factor of decrease of ADIPOQ levels in psoriasis patients.Keywords: psoriasis, ADIPOQ, histone, lactylation

Lingchun Zhang,1,&ast; Yani Ma,2,&ast; Chenglong Zhao,1 Shujuan Zhao,1 Lulu Zhao,3 Yuxin Yang,4 Yuhan Wang,5 Haiyang Meng,6 Jun Sun1 1Department of Pharmacy, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, People’s Republic of China; 2Department of Pharmacy, the First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Department of Pharmacy, Gongyi People’s Hospital, Zhengzhou, People’s Republic of China; 4Department of Pharmacy, Anyang Ophthalmic Hospital, Anyang, People’s Republic of China; 5Department of Pharmacy, Henan Integrative Medicine Hospital, Zhengzhou, People’s Republic of China; 6Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Sun, Department of Pharmacy, Henan Provincial People’s Hospital, No. 7 Weiwu Road, Zhengzhou, People’s Republic of China, Tel +86 13683827203, Email Jun_84@163.comPurpose: Carbapenem-Resistant Klebsiella pneumoniae (CRKP) is a significant public health threat, because it is associated with substantial morbidity and mortality. However, the risk factors associated with treatment failure of ceftazidime-avibactam (CAZ-AVI) and the need for CAZ-AVI-based combination remain unclear.Methods: We conducted a retrospective study of critically ill patients (age: > 18 years) diagnosed with CRKP infections and treated with CAZ-AVI for at least 24 h between June 2020 and December 2022 at Henan Provincial People’s Hospital.Results: This study included a total of 103 patients who received CAZ-AVI. Of these, 91 (88.3%) patients received the standard dosage of 2.5 g every q8h, while only 20 (19.4%) received monotherapy. The Kaplan–Meier curves showed that the all-cause 30-day mortality was significantly higher among patients who experienced septic shock than those who did not. There was no significant difference in mortality between monotherapy and combination therapy. Dose reduction of CAZ-AVI was associated with a significantly increased mortality rate. Independent risk factors for the 30-day mortality included higher APACHE II score (HR: 1.084, 95% CI: 1.024– 1.147, p = 0.005) and lower lymphocyte count (HR: 0.247, 95% CI: 0.093– 0.655, p = 0.005). Conversely, a combination therapy regimen containing carbapenems was associated with lower mortality (HR: 0.273, 95% CI: 0.086– 0.869, p = 0.028).Conclusion: Our study suggests that CAZ-AVI provides clinical benefits in terms of survival and clinical response in critically ill patients with CRKP infection. A higher APACHE II score and lower lymphocyte count were associated with 30-day mortality, while the combination therapy regimen containing carbapenems was the only protective factor. CAZ-AVI dose reduction was associated with an increased mortality rate. Futher large-scale studies are needed to validate these findings.Keywords: carbapenem-resistant Klebsiella pneumoniae, ceftazidime-avibactam, retrospective study, combination therapy

Shuxing Zhu, Yaqing Liu, Xiuli Wang, Liang Wang, Jinru Li, Xiaoming Xue, Zhao Li, Jiaxin Liu, Xin Liu, Shuang Zhao Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of ChinaCorrespondence: Shuang Zhao, Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86 13613210924, Email zhaoshuang810924@163.comBackground: Postoperative delirium (POD) is of great concern as a complication of surgery in older adult patients. Sedation strategies influence the development of POD. This study compared how sedation strategies administered during spinal anesthesia influenced POD in patients aged ≥ 65 years undergoing elective surgery for hip fracture repair.Patients and Methods: A randomized clinical trial was conducted from 1 August 2021 to 30 June 2022 at a single academic medical center. Two hundred and twenty-six patients were randomly divided into four groups: lighter sedation with propofol (LP), heavier sedation with propofol (HP), lighter sedation with dexmedetomidine (LD), and heavier sedation with dexmedetomidine (HD). The incidence of delirium was the primary outcome and was assessed daily by the blinded Confusion Assessment Method.Results: There was a significant association between dexmedetomidine (LD+HD group) and a lower incidence of delirium (11.9% [13/109] vs the propofol group (23.6% [26/110]; Risk ratio, 0.51; 95% CI, 0.274 to 0.929; p=0.024). In the propofol group, heavier sedation had a higher rate of POD (32.7% [18/55] vs the lighter sedation group (14.5% [8/55]; Risk ratio, 2.25; 95% CI, 1.069 to 4.736; p=0.025).Conclusion: Dexmedetomidine was associated with a lower incidence of delirium than that with propofol among older patients with hip fractures. In patients that received propofol, heavier sedation was associated with high incidence of POD.Keywords: aged, anesthetics, hip surgery, propofol, spinal anesthesia

Ning Xu,1,&ast; Guanzheng Cui,1,&ast; Shengyin Zhao,1 Yu Li,1 Qian Liu,2 Xuchang Liu,1 Chuanliang Zhao,3 Rongjie Feng,1 Mingjie Kuang,1 Shijie Han1 1Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong, 250014, People’s Republic of China; 2Department of Pain, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 3Department of Orthopedic Surgery, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shijie Han; Mingjie Kuang, Department of Orthopedic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250014, People’s Republic of China, Email hanshijie@sdfmu.edu.cn; doctorkmj@tmu.edu.cnIntroduction: Osteoporosis is a common bone disease in which the bone loses density and strength and is prone to fracture. Bone marrow mesenchymal stem cells (BMSCs) are important in bone-related diseases. Exosomes, as mediators of cell communication, have potential in cell processes. Previous studies have focused on muscle factors’ regulation of bone remodeling, but research on exosomes is lacking.Methods: In order to confirm the therapeutic effect of mechanically stimulated myocytes (C2C12) derived exosomes (Exosome-MS) on the Glucocorticoid-induced osteoporosis(GIOP) compared with unmechanically stimulated myocytes (C2C12) derived exosomes (Exosomes), we established a dexamethasone-induced osteoporosis model in vivo and in vitro. Cell viability and proliferation were assessed using CCK8 and EDU assays. Osteogenic potential was evaluated through Western blotting, real-time PCR, alkaline phosphatase activity assay, and alizarin red staining. Differential expression of miRNAs was determined by high-throughput sequencing. The regulatory mechanism of miR-92a-3p on cell proliferation and osteogenic differentiation via the PTEN/AKT pathway was investigated using real-time PCR, luciferase reporter gene assay, Western blotting, and immunofluorescence. The therapeutic effects of exosomes were evaluated in vivo using microCT, HE staining, Masson staining, and immunohistochemistry.Results: In this study, we found that exosomes derived from mechanical stress had a positive impact on the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs). Importantly, we demonstrated that miR-92a-3p mimics could reverse dexamethasone-induced osteoporosis in vitro and in vivo, indicating that mechanical stress-induced mouse myoblast-derived exosomes could promote osteogenesis and prevent the occurrence and progression of osteoporosis in mice through miR-92a-3p/PTEN/AKT signaling pathway.Conclusion: Exosomes derived from mechanical stress-induced myoblasts can promote the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells through miR-92a-3p/PTEN/AKT signaling pathway, and can have a therapeutic effect on glucocorticoid-induced osteoporosis in mice in vivo. Keywords: Human bone marrow mesenchymal stem cells, Mechanical stimulation, Exosome, miR-92a-3p, AKT signaling

Jing Wang, Changqin Xu, Hongwei Xu, Ruixia Wang, Tong Su, Shulei Zhao Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, People’s Republic of ChinaCorrespondence: Shulei Zhao, Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Road, Jinan, 250021, People’s Republic of China, Email wenzhu24@126.comPurpose: To explore the molecular mechanisms of intestinal injury and treatment by analyzing changes in cellular heterogeneity and composition in rat ileal tissue during injury and treatment processes.Methods: We constructed a rat model of SAP and evaluated treatment with an injected of monoacylglycerol lipase (MAGL) inhibitor (JZL184) solution using three experimental groups: healthy male Sprague-Dawley (SD) rats injected with vehicle (CON), male SD SAP model rats injected with vehicle (SAP), and male SAP rats injected with JZL184. We obtained and prepared a single-cell suspension of ileal tissue of each rat for single-cell transcriptome sequencing.Results: This project classified changes in cellular heterogeneity and composition in rat ileal tissue during SAP-induced intestinal injury and MAGL treatment. We found that the number of fibroblast clusters was decreased in the SAP group relative to the CON group, and increased after JZL184 treatment. Further analysis of differences in gene expression between cell clusters in each group reveals that fibroblasts had the greatest number of differentially expressed genes. Most notably, expression of genes involved in communication between cells was found to vary during SAP-induced intestinal injury and JZL184 treatment. Among these changes, the degree of difference in expression of genes involved in communication between fibroblasts and other cells was the highest, indicating that fibroblasts in rat ileal tissue affect intestinal injury and repair through cell-to-cell communication. In addition, our results reveal that differentially expressed RNA-binding proteins in fibroblasts may affect their functions in intestinal injury and treatment by affecting the expression of genes regulating communication between cells.Conclusion: These findings emphasize the importance of understanding the interactions between fibroblasts and other cells in the context of intestinal injury, providing valuable insights for further exploring molecular mechanisms and insight for discovering new treatment targets and strategies.Keywords: single-cell RNA sequencing, cell heterogeneity, fibroblasts, monoacylglycerol lipase, intestinal injury, RNA-binding protein, severe acute pancreatitis

Yiwei Zhao,&ast; Zechao Qu,&ast; Songchuan Zhao, Yong Zhang, Yining Gong, Bo Zhang, Xiangcheng Gao, Dong Wang, Liang Yan Department of Spine Surgery, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liang Yan, Department of Spine Surgery, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, People’s Republic of China, Email yanliangdr5583@163.comAbstract: The maintenance of bone homeostasis is dynamically regulated by osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Abnormal differentiation of osteoclast and insufficient osteoblast production can cause bone diseases such as osteoporosis. As one of the highly conserved catabolic pathways in eukaryotic cells, autophagy plays an important role in maintaining cell homeostasis, stress injury repair, proliferation and differentiation. Numerous studies have found that autophagy activity is essential for the survival, differentiation and function of bone cells, and that regulation of autophagy can affect the metabolism of osteoblasts and osteoclasts, thus affecting bone homeostasis. Therefore, using autophagy as a theme, this review outlines the basic process of autophagy, the relationship between autophagy and osteoblasts and osteoclasts, and summarizes the latest research progress of common autophagic signaling pathways in osteoblasts and osteoclasts. The regulatory effects of protein molecules and natural compounds on the autophagy pathway of osteoblasts and osteoclasts discovered in current research are summarized and discussed. This will help to further clarify the mechanism of osteoporosis, understand the relationship between autophagy and osteoporosis, and propose new therapeutic strategies and new ideas for anti-osteoporosis.Keywords: osteoporosis, osteoblast, osteoclast, autophagy signaling pathway, natural compounds

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

Simin Min,1,2 Weiting Tao,1 Yuchen Miao,3 Yan Li,4 Tianyu Wu,5 Xiaoyu He,6 Yijing Zhang,7 Bangye Liu,7 Zixin Meng,7 Ke Han,1 Saisai Liu,1 Li Li,1 Jie Chen,1 Shidi Zhao,1 Junjie Zhang,3 Xiaonan Zhang1 1Bengbu Medical College Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 2Suzhou Hospital of Anhui Medical University, Suzhou, Anhui, 234000, People’s Republic of China; 3Department of Chemistry, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 4School of Medicine and Health Engineering, Changzhou University, Changzhou, Jiangsu, 213164, People’s Republic of China; 5School of Public Health, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 6Department of Rheumatology and Immunology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of China; 7School of Clinical Medicine, Bengbu Medical College, Bengbu, Anhui, 233030, People’s Republic of ChinaCorrespondence: Xiaonan Zhang, Department of Pathophysiology, Bengbu Medical College, 2600 Donghai Avinue, Longzihu District, Bengbu, Anhui, People’s Republic of China, Tel +86-13609827842, Fax +86-552-3175283, Email zhangxn@bbmc.edu.cn Junjie Zhang, Department of Chemistry, Bengbu Medical College, 2600 Donghai Avinue, Longzihu District, Bengbu, Anhui, People’s Republic of China, Tel +86-16655208659, Fax +86-552-3175257, Email zhangjj@bbmc.edu.cnBackground: The respiratory system is intensely damaged by acute lung injury (ALI). The anti-inflammatory effects of tetramethylpyrazine (TMP) against ALI have been confirmed, but it exhibits a short half-life. miR-194-5p could directly target Rac1, but the internalization rate of miRNA cells was low.Purpose: To explore the potential of the soft mesoporous organic silica nanoplatform (NPs) as carriers for delivery of TMP and miR-194-5p through the tail vein.Methods: NPs@TMP and NPs@PEI@miR-194-5p were added to the HUVEC cell-lines, in vitro, to observe the cell uptake and cytotoxic effects. In vivo experiments were conducted by injecting fluorescently labeled NPs through the tail vein and tracking distribution. Therapeutic and toxic side-effects were analyzed systemically.Results: In vitro study exhibited that NPs have no toxic effect on HUVECs within the experimental parameters and have excellent cellular uptake. The IVIS Spectrum Imaging System shows that NPs accumulate mainly in the lungs. NPs@TMP treatment can improved oxidative stress and inflammation levels in ALI mice and inhibited the TLR4/NLRP3/caspase 1 pathway. NPs@PEI@miR-194-5p can inhibit the Rac1/ZO-1/occludin pathway and improved endothelial cell permeability in ALI mice. The co-treatment of NPs@TMP and NPs@PEI@miR-194-5p can significantly improved the survival rates of the mice, reduced pulmonary capillary permeability and improved pathological injury in ALI mice.Innovation: This study combined traditional Chinese medicine, bioinformatics, cellular molecular biology and nanobiomedicine to study the pathogenesis and treatment of ALI. The rate of cellular internalization was improved by changing the shape and hardness of nanoparticles. NPs@TMP and NPs@PEI@miR-194-5p combined application can significantly improve the survival condition and pathological injury of mice.Conclusion: NPs loaded with TMP and miR-194-5p showed a greater therapeutic effect in ALI mice. Keywords: NPs@TMP, NPs@PEI@miR-194-5p, tight junction, pulmonary capillary, endothelial cells, inflammation, acute lung injury

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

Si-Yu Long,&ast; Lin Shang,&ast; Huijuan Shi, Siqi Zhao, Jiali Cao, Yanling He Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, National Clinical Research Center for Skin and Immune Diseases, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiali Cao; Yanling He, Department of Dermatology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 10020, People’s Republic of China, Email cnsk2008@126.com; hylchaoyang@163.comBackground: Psoriasis is a global health concern as a chronic inflammatory skin disease. Endothelial dysfunction has been implicated in psoriasis pathogenesis.Objective: This study aims to explore the scientific literature on the relationship between psoriasis and endothelial cells using bibliometric analysis, identifying research trends and public interest in this topic.Methods: We analyzed articles on the topic of endothelial cells and psoriasis in the Web of Science (WoS) Core Collection from 1987 to 2022, examining their distribution by publication year, country, organization, author, and journal. We used bibliometric software, including CiteSpace and R package bibliometrix, to visualize co-authorship relations, keyword citation burst analysis, co citation networks, keyword time zone map, burst references and cluster analysis.Results: Our analysis included 993 publications. The bibliometric analysis revealed a steady increase in the number of publications on psoriasis and endothelial cells over the past decade. The United States was the leading contributor to this field. The Journal of Investigative Dermatology was the most high-yield publication journal. Burst references analysis identified key articles that have significantly influenced the field, including studies on the role of endothelial dysfunction in psoriasis pathogenesis and the association between psoriasis severity and cardiovascular outcomes. 9 clusters were grouped in the key-word citation network. “Expression”, “inflammation”, “endothelial growth factor” and “angiogenesis” were the research focuses, while “cardiovascular disease”, “atherosclerosis”, “endothelial dysfunction”, and “oxidative stress” might be the future research hotspots.Conclusion: This bibliometric analysis sheds light on the growing acknowledgement of the involvement of endothelial cells in psoriasis, with the United States taking the lead. It also emphasizes the necessity for additional research to unravel the underlying mechanisms connecting psoriasis, endothelial dysfunction, and cardiovascular comorbidities. Ultimately, this research will contribute to the development of enhanced management strategies for psoriasis patients.Keywords: bibliometric analysis, endothelial cells, psoriasis, inflammation, cardiovascular risk, molecular mechanisms

Subei Zhao, Zheng Yang, Meng Yu, Linyu Xiang, Yuhuan Lv, Chunyan Tian, Rong Li Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of ChinaCorrespondence: Rong Li, Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, People’s Republic of China, Tel +86 13508385198, Email rongli@hospital.cqmu.edu.cnPurpose: Subclinical inflammation may be involved in the pathogenesis of diabetic cardiac autonomic neuropathy (DCAN). The purpose of the study is to explore the relationship between novel inflammation biomarkers fibrinogen-albumin ratio (FAR), fibrinogen-prealbumin ratio (FPR), and DCAN in type 2 diabetes mellitus (T2DM).Patients and Methods: A total of 715 T2DM patients were enrolled in this retrospective study, divided into non-DCAN (n=565) and DCAN (n=150) groups by Ewing’s test. Serum fibrinogen, albumin, prealbumin, routine inflammatory and other biochemical markers were measured.Results: Patients with versus without DCAN had higher FAR (10.29 ± 4.83 vs 7.22 ± 2.56 g/g, P < 0.001) and FPR (2.19 ± 1.85 vs 1.43 ± 0.93 g/mg, P < 0.001). As FAR and FPR quartiles increased, the incidence of DCAN increased (Quartile 1 vs Quartile 4: 8.4 vs 42.7%, 9.6 vs 39.2%, respectively, P < 0.001), heart rate variability parameters decreased (P < 0.001); the incidence of diabetic nephropathy, retinopathy and peripheral neuropathy tended to be higher and inflammation factors were more active (P < 0.01). FAR (OR, 95% CI: 1.16, 1.08– 1.25, P < 0.001) and FPR (OR, 95% CI: 1.22, 1.03– 1.44, P = 0.021) were independent determinants of DCAN; the risk of DCAN increased by approximately 65% and 27% with each increase in the standard deviation (SD) of FAR (OR per SD, 95% CI: 1.65, 1.29– 2.11, P < 0.001) and FPR (OR per SD, 95% CI: 1.27, 1.04– 1.56, P = 0.021).Conclusion: FAR and FPR are independent risk factors and may influence DCAN development through inflammation.Keywords: type 2 diabetes mellitus, diabetic cardiac autonomic neuropathy, inflammation, fibrinogen-albumin ratio, fibrinogen-prealbumin ratio

Zhifeng Li,1,2 Ting Guo,3 Susu Zhao,4 Mei Lin2 1Medical School of Nantong University, Nantong, Jiangsu, People’s Republic of China; 2Clinical Laboratory, Taizhou People’s Hospital (Affiliated Hospital 5 of Nantong University), Taizhou, Jiangsu, People’s Republic of China; 3Research Center of Clinical Medicine, Taizhou People’s Hospital (Affiliated Hospital 5 of Nantong University), Taizhou, Jiangsu, People’s Republic of China; 4Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Mei Lin, Tel +86-052389890037, Email trylm@ntu.edu.cnPurpose: Improving the treatment of triple-negative breast cancer (TNBC) is a serious challenge today. The primary objective of this study was to construct MUC1-C shRNA@ Fe3O4 magnetic nanoparticles (MNPs) and investigate their potential therapeutic benefits in alternating magnetic fields (AMF) on TNBC.Methods: Firstly, we verified the high expression of MUC1 in TNBC and synthesized specific MUC1-C shRNA plasmids (MUC1-C shRNA). Then, we prepared and characterized MUC1-C shRNA@Fe3O4 MNPs and confirmed their MUC1-C gene silencing effect and magneto-thermal conversion ability in AMF. Moreover, the inhibitory effects on TNBC in vitro and in vivo were observed as well as biosafety. Finally, the protein levels of BCL-2-associated X protein (Bax), cleaved-caspase3, glutathione peroxidase inhibitor 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), and ferritin heavy chain 1 (FTH1) in TNBC cells and tissues were examined, and it was speculated that apoptosis and ferroptosis were involved in the synergistic treatment.Results: MUC1-C shRNA@ Fe3O4 MNPs have a size of ~75 nm, with an encapsulation rate of (29.78± 0.63) %, showing excellent gene therapy and magnetic hyperthermia functions. Under a constant AMF (3Kw) and a set concentration (200μg mL− 1), the nanoparticles could be rapidly warmed up within 20 minutes and stabilized at about 43 °C. It could be uptaken by TNBC cells through endocytosis and significantly inhibit their proliferation and migration, with a growth inhibition rate of 79.22% for TNBC tumors. After treatment, GPX4, NRF2, and FTH1 expression levels in TNBC cells and tumor tissues were suppressed, while Bax and cleaved-caspase3 were increased. As key therapeutic measures, gene therapy, and magnetic hyperthermia have shown a synergistic effect in this treatment strategy, with a combined index (q index) of 1.23.Conclusion: In conclusion, we developed MUC1-C shRNA@Fe3O4 MNPs with magnetic hyperthermia and gene therapy functions, which have shown satisfactory therapeutic effects on TNBC without significant side effects. This study provides a potential option for the precision treatment of TNBC.Keywords: triple-negative breast cancer, nanoparticle, MUC1, hyperthermia, ferroptosis

Shuang Song,1,2,&ast; Shulong Zhao,2,&ast; Wei Wang,1 Fei Jiang,2 Jingfang Sun,2 Ping Ma,1,2 Haiquan Kang2 1Medical Technology School, Xuzhou Medical University, Xuzhou, People’s Republic of China; 2Department of Clinical Laboratory, Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haiquan Kang, Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China, Tel +86-516 85802759, Email hqk811029@163.com Ping Ma, Medical Technology School, Xuzhou Medical University, Department of Laboratory Medicine, Xuzhou, People’s Republic of China, Tel +86-516 85807017, Email pingm62@aliyun.comBackground: The prevalence of carbapenem-resistant hypervirulent Klebsiella pneumoniae (hv-CRKP) is a serious public threat globally. Here, we performed clinical, molecular, and phenotypic monitoring of hv-CRKP strains isolated from the intensive care unit (ICU) to offer evidence for prevention and control in hospitals.Methods: Data analysis of ICU patients suffering from ventilator-associated pneumonia (VAP) because of hv-CRKP infection, admitted at the Chinese Teaching Hospital between March 2019 and September 2021 was performed. Patients’ antibiotic-resistance genes, virulence-associated genes, and capsular serotypes of these isolates were detected. Homology analysis of the strains was performed by MLST and PFGE. Six different strains were tested for their virulence traits using the serum killing test and the Galleria mellonella infection assay. For whole genome sequencing, KP3 was selected as a representative strain.Results: Clinical data of 19 hv-CRKP-VAP patients were collected and their hv-CRKP were isolated, including 10 of ST11-KL64, 4 of ST15-KL112, 2 of ST11-KL47, 1 of ST15-KL19, 1 of ST17-KL140, and 1 of ST48-KL62. Four ST15 and 8 ST11 isolates revealed high homology, respectively. Most strains carried the carbapenemase gene blaKPC-2 (14/19, 73.68%), followed by blaOXA-232 (4/19, 21.05%). All strains were resistant to almost all the antibiotics except polymyxin and tigacycline. Ten patients were treated with polymyxin or tigacycline based on their susceptibility results, and unfortunately 6 patients died. All strains exhibited a hyper-viscous phenotype, and the majority (17/19, 89.47%) of them contained rmpA and rmpA2. The serum killing test showed that KP9 was resistant to normal healthy serum, others were intermediately or highly sensitive. G. mellonella larvae infection assay suggested that the strains in this study were hypervirulent.Conclusion: This study highlights the dominant strain and molecular epidemiology of hv-CRKP in a hospital in China. We should pay more attention to the effect of hv-CRKP on VAP, strengthen monitoring and control transmission.Keywords: Klebsiella pneumoniae, hypervirulent, carbapenem-resistant, ventilator-associated pneumonia

Cong Chen,1,&ast; Jian Liu,2,&ast; Zhuxin Gu,1 Yanjun Sun,1 Wenwu Lu,3 Xiaokan Liu,4 Kang Chen,1 Tianzhi Ma,5 Suming Zhao,1 Hui Zhao1 1Department of Interventional & Vascular Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 2Dalian Medical University and Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 3Department of Medical Ultrasound, Affiliated Hospital of Nantong University, Nantong, 226001, People’s Republic of China; 4Department of Interventional Radiology, Affiliated Hospital 2 of Nantong University, Nantong, 226001, People’s Republic of China; 5Nanjing University of Aeronautics and Astronautics, Nanjing, 210000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Suming Zhao; Hui Zhao, The Affiliated Hospital of Nantong University, No. 20, Xisi Road, Chongchuan District, Nantong City, Jiangsu Province, People’s Republic of China, Tel +86-513-85052071, Email 5201120@ntu.edu.cn; zhaohui8868@sina.comBackground: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Patients with HCC choose postoperative adjuvant transarterial chemoembolization (PA-TACE) after surgical resection to reduce the risk of recurrence. However, many of them have recurrence within a short period.Methods: In this retrospective analysis, a total of 173 patients who underwent PA-TACE between September 2016 and March 2020 were recruited. Radiomic features were derived from the arterial and venous phases of each patient. Early recurrence (ER)-related radiomics features of HCC and the spleen were selected to build two rad-scores using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Logistic regression was applied to establish the Radiation (Rad)_score by combining the two regions. We constructed a nomogram containing clinical information and dual-region rad-scores, which was evaluated in terms of discrimination, calibration, and clinical usefulness.Results: All three radiological scores showed good performance for ER prediction. The combined Rad_score performed the best, with an area under the curve (AUC) of 0.853 (95% confidence interval [CI], 0.783– 0.908) in the training set and 0.929 (95% CI, 0.789– 0.988) in the validation set. Multivariate analysis identified total bilirubin (TBIL) and the combined Rad_score as independent prognostic factors for ER. The nomogram was found to be clinically valuable, as determined by the decision curves (DCA) and clinical impact curves (CIC).Conclusion: A multimodal dual-region radiomics model combining HCC and the spleen is an independent prognostic tool for ER. The combination of dual-region radiomics features and clinicopathological factors has a good clinical application value.Keywords: hepatocellular carcinoma, radiomics, nomogram, transcatheter arterial chemoembolization, computed tomography

Shangping Zhao,1 Guanxiu Tang,2 Pan Liu,1 Qingyong Wang,3 Guohui Li,1 Zhaoyun Ding1 1Laboratory for Big Data and Decision, National University of Defense Technology, ChangSha, Hunan, People’s Republic of China; 2The Nursing Department, The Third Xiangya Hospital of Central South University, ChangSha, Hunan, People’s Republic of China; 3School of Information and Computer, Anhui Agricultural University, Hefei, Anhui, People’s Republic of ChinaCorrespondence: Zhaoyun Ding, Laboratory for Big Data and Decision, National University of Defense Technology, No. 109 Deya Road, Kaifu District, ChangSha, Hunan, 410003, People’s Republic of China, Tel +86 17607310865, Fax +86 731 88618837, Email dingzhaoyun1983@163.comPurpose: Mortality risk prediction helps clinicians make better decisions in patient healthcare. However, existing severity scoring systems or algorithms used in intensive care units (ICUs) often rely on laborious manual collection of complex variables and lack sufficient validation in diverse clinical environments, thus limiting their practical applicability. This study aims to evaluate the performance of machine learning models that utilize routinely collected clinical data for short-term mortality risk prediction.Patients and Methods: Using the eICU Collaborative Research Database, we identified a cohort of 12,393 ICU patients, who were randomly divided into a training group and a validation group at a ratio of 9:1. The models utilized routine variables obtained from regular medical workflows, including age, gender, physiological measurements, and usage of vasoactive medications within a 24-hour period prior to patient discharge. Four different machine learning algorithms, namely logistic regression, random forest, extreme gradient boosting (XGboost), and artificial neural network were employed to develop the mortality risk prediction model. We compared the discrimination and calibration performance of these models in assessing mortality risk within 1-week time window.Results: Among the tested models, the XGBoost algorithm demonstrated the highest performance, with an area under the receiver operating characteristic curve (AUROC) of 0.9702, an area under precision and recall curves (AUPRC) of 0.8517, and a favorable Brier score of 0.0259 for 24-hour mortality risk prediction. Although the model’s performance decreased when considering larger time windows, it still achieved a comparable AUROC of 0.9184 and AUPRC of 0.5519 for 3-day mortality risk prediction.Conclusion: The findings demonstrate the feasibility of developing a highly accurate and well-calibrated model based on the XGBoost algorithm for short-term mortality risk prediction with easily accessible and interpretative data. These results enhance confidence in the application of the machine learning model to clinical practice.Keywords: intensive care unit, XGBoost, routinely collected data, short-term mortality risk

Xiang-Zhe Shi,1,2 Sheng Zhao,3 Yan Wang,1,2 Meng-Yao Wang,1,2 Su-Wen Su,1,2 Yan-Zhao Wu,3 Chen Xiong1,2 1The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 2The Key Laboratory of Pharmacology and Toxicology for New Drugs, Department of Pharmacology, Hebei Medical University, Shijiazhung, 050017, People’s Republic of China; 3Department of Otorhinolaryngology-Head and Neck Surgery, 4th Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of ChinaCorrespondence: Chen Xiong; Yan-Zhao Wu, Email bearmorning@sina.com; wyz315@163.comIntroduction: Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid carcinoma. Doxorubicin (DOX) is the only drug approved for anaplastic thyroid cancer treatment, but its clinical use is restricted due to irreversible tissue toxicity. Berberine (BER), an isoquinoline alkaloid extracted from Coptidis Rhizoma, has been proposed to have antitumor activity in many cancers. However, the underlying mechanisms by which BER regulates apoptosis and autophagy in ATC remain unclear. Thus, the present study aimed to assess the therapeutic effect of BER in human ATC cell lines CAL-62 and BHT-101 as well as the underlying mechanisms. In addition, we assessed the antitumor effects of a combination of BER and DOX in ATC cells.Methods: The cell viability of CAL-62 and BTH-101 with treatment of BER for different hours was measured by CCK-8 assay, and cell apoptosis was assessed by clone formation assay and flow cytometric analysis. The protein levels of apoptosis protein, autophagy-related proteins and PI3K/AKT/mTORpathway were determined Using Western blot. Autophagy in cells was observed with GFP-LC3 plasmid using confocal fluorescent microscopy. Flow cytometry was used to detect intracellular ROS.Results: The present results showed that BER significantly inhibited cell growth and induced apoptosis in ATC cells. BER treatment also significantly upregulated the expression of LC3B-II and increased the number of GFP-LC3 puncta in ATC cells. Inhibition of autophagy by 3-methyladenine (3-MA) suppressed BER-induced autophagic cell death. Moreover, BER induced the generation of reactive oxygen species (ROS). Mechanistically, we demonstrated that BER regulated the autophagy and apoptosis of human ATC cells through the PI3K/AKT/mTOR pathways. Furthermore, BER and DOX cooperated to promote apoptosis and autophagy in ATC cells.Conclusion: Taken together, the present findings indicated that BER induces apoptosis and autophagic cell death by activating ROS and regulating the PI3K/AKT/mTOR signaling pathway.Keywords: anaplastic thyroid carcinoma, berberine, autophagy, apoptosis, PI3K/AKT/mTOR, reactive oxygen species

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

Yichen Wang,1,&ast; Tao Zhou,2,&ast; Shanshan Zhao,1,&ast; Ning Li,3 Siwen Sun,1 Man Li1 1Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China; 3Department of Foreign Language, Dalian Medical University, Dalian, 116050, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Man Li; Siwen Sun, Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China, Tel +86-17709873580 ; +86-17709891126, Email man_li@dmu.edu.cn; ssw0728@163.comPurpose: Malignant pleural effusion (MPE) is a severe complication in patients with advanced cancer that is associated with a poor prognosis. Breast cancer is the second leading cause of MPE after lung cancer. We therefore aim to describe clinical characteristics of the patients with MPE combined with breast cancer and construct a machine learning-based model for predicting the prognosis of such patients.Methods: This study is a retrospective and observational study. Least absolute shrinkage and selection operator (LASSO) and univariate Cox regression analyses were applied to identify eight key clinical variables, and a nomogram model was established. Model performance was evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analyses.Results: 196 patients with both MPE and breast cancer (143 in the training group and 53 in the ex-ternal validation group) were analyzed in this study. The median overall survival in two cohorts was 16.20 months and 11.37 months. Based on the ROC curves for 3-, 6-, and 12-month survival, the areas under the curves were 0.824, 0.824, and 0.818 in the training set and 0.777, 0.790, and 0.715 in the validation set, respectively. In the follow-up analysis, both systemic and intrapleural chemotherapy significantly increased survival in the high-risk group compared to the low-risk group.Conclusion: Collectively, MPE confers a poor prognosis in breast cancer patients. We have developed a first-ever survival prediction model for breast cancer patients with newly diagnosed MPE and validated the model using an independent cohort.Keywords: malignant pleural effusion, breast cancer, prognostic model, LASSO, pleural metastases, survival analysis

Song Guo,1,&ast; Di Zhang,2,&ast; Shan Zhao,1 Huan Zhang,1 Yijuan Sun,3 Li Yan1 1Gynecology Department, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, People’s Republic of China; 2Obstetrics Department, Shandong Provincial Third Hospital, Jinan, Shandong Province, People’s Republic of China; 3Shanghai Ji Ai Genetics & In vitro Fertilization Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yijuan Sun, Shanghai Ji Ai Genetics & IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, NO. 352 Dalin Road, Shanghai, 200011, People’s Republic of China, Tel +86-21-6345-5468, Fax +86-21-33180478, Email xiaowei2987415@163.com Li Yan, Gynecology Department, The First Affiliated Hospital of Shandong First Medical University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, People’s Republic of China, Tel +86-531-89268763, Fax +86-531-82963647, Email yanliqy@163.comBackground: It is well established that female fertility declines with age, primarily because of loss of ovarian function. However, few studies have clarified the relationship between increasing age and endometrial receptivity. Here, we aimed to study the impact of age on endometrial receptivity, meanwhile, we examined the expression of endometrial mesenchymal stem cell (eMSC) surface markers (CD146 and PDGF-Rβ), essential for endometrial development and re-growth, in different age groups.Methods: Participants were enrolled in this study between October 2020 and July 2021. All 31 patients were divided into three age groups; early (30– 39 years old, n=10), intermediate (40– 49 years old, n=12) and advanced (≥ 50 years old, n=9). We assessed localization and expression of CD146 and PDGF-Rβ by immunofluorescence and further analyzed selected endometrial receptivity markers (Homeobox A10 HOXA10, leukemia inhibitory factor LIF and osteopontin) and steroid hormone receptors by immunohistochemistry.Results: There were no significant differences in expression of HOXA10 and OPN (p> 0.05) among the three groups. However, we found a significant difference in LIF expression between the early and advanced age groups, with higher expression noted in the latter group (p=0.02). Similarly, estrogen receptor (ER) and progesterone receptor (PR) expression were significantly increased (p=0.01 and p=0.01, respectively) in the advanced age group compared with the early age group. There were no significant difference in CD146 and PDGF-Rβ expression among the three groups (p> 0.05).Conclusion: These results suggest that the age of the patient does not influence their endometrial receptivity. So, this study serves to increase our understanding of the impact of age and eMSCs on endometrial receptivity and expands the etiology of age-related infertility.Keywords: age, endometrial receptivity, endometrial mesenchymal stem cells

Xin Liu,1,&ast; Miao Tang,2,&ast; Tian-Yi He,1 Shuang Zhao,1 Hui-Zhou Li,1 Zhao Li,1 Yue-Xian Guo,3 Xiu-Li Wang1 1Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People’s Republic of China; 3Department of Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiu-Li Wang, Department of Anesthesiology, The Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-13313019968, Email wangxl311@126.comObjective: This study aimed to investigate the effect of resveratrol (Res) on paclitaxel (PTX)-induced cognitive impairment and elucidate the underlying molecular mechanisms.Methods: Morris Water Maze (MWM) test was used to evaluate the mice’s spatial learning and memory abilities. Western blotting was applied to detect protein expression of receptor-interacting protein (RIP3), mixed lineage kinase domain-like protein (MLKL), silencing information regulator 2 related enzyme 1 (SIRT1), peroxisome proliferator activated receptor coactivator-1 (PGC-1α), NADPH oxidase 2 (NOX2), NOX4, postsynaptic density zone 95 (PSD95), arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Immunofluorescence of RIP3, MLKL, Arg-1, Iba-1 and iNOS was conducted to observe the apoptosis of hippocampal cells and the polarization of microglia. qRT-PCR was performed to detect BDNF mRNA expressions. DHE staining was used to assess the level of oxidative stress response. Golgi-Cox staining and dendritic spine counting were applied to visualize synaptic structural plasticity. Postsynaptic density was performed by transmission electron microscope. ELISA was used to detect the contents of tumour necrosis factor alpha (TNF-α), IL-1β, IL-4, and IL-10.Results: PTX-induced cognitive impairment model was constructed after the application of PTX, represented as longer latency to platform and less platform crossing times over the whole period in PTX group. After Res treatment, the above indicators were reversed, indicating that cognitive function was improved. Moreover, Res reduced neuronal apoptosis and oxidative stress through SIRT1/PGC-1α pathway in mice, manifesting as down-regulated expression of RIP3, MLKL, NOX2 and NOX4. Meanwhile, Res increased the density of dendritic spines and the expression of PSD95 and BDNF, thereby ameliorating the PTX induced synaptic damage. Besides, M2 microglia was in the majority, eliciting the expression of anti-inflammatory cytokines IL-4 and IL-10 after Res treatment in PTX+Res group, while immunofluorescence images results demonstrated an decrease in the proportion of M2 microglia a following SIRT1 inhibitor EX-527.Conclusion: Res improves PTX-induced cognitive impairment in mice by activating SIRT1/PGC-1α pathways to regulate neuronal state and microglia cell polarization.Keywords: resveratrol, paclitaxel, SIRT1/PGC-1α, microglia, M2 polarization

Qifu Li,1,&ast; Yi Lu,2,&ast; Xinghe Zhang,1 Ziwen Chen,3 Jialei Feng,4 Xuanxiang Zeng,1 Siwen Zhao,1 Gaoyangzi Huang,1 Li Li,5 Chonghui Xing,6 Fanrong Liang,3 Taipin Guo1 1School of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China; 2The Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Kunming, People’s Republic of China; 4Institute for History of Medicine and Medical Literature, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 5The Third Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China; 6The Sports Trauma Specialist Hospital of Yunnan Province, Kunming, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Taipin Guo, School of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, People’s Republic of China, Email gtphncs@126.com Fanrong Liang, School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China, Email acuresearch@126.comBackground: Acupoint catgut embedding (ACE) has been proven to be effective and safe in the treatment of obesity, but few studies have been conducted involving its central mechanisms. Our previous study has demonstrated the effectiveness of Shu-Mu ACE in the treatment of abdominal obesity (AO). However, the neurological mechanism of Shu-Mu ACE for weight loss has not yet been elucidated. The mechanism of the combination of the Shu and Mu acupoints may be related to the central integrative effects of the brain. This paper aims to explore the potential neural mechanisms of Shu-Mu ACE in female patients with AO.Methods and Analysis: A total of 100 eligible female AO patients and 20 healthy female subjects will be recruited for this study. 100 AO patients will be randomly allocated to five groups: Shu-Mu ACE (Group A), Shu ACE (Group B), Mu ACE (Group C), sham ACE (Group D), and waiting-list (Group E). Treatment will be administrated once every two weeks for 12 weeks. The body mass index (BMI), waist circumference (WC), Visual Analog Scales (VAS) of appetite, Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) will be utilized to evaluate the clinical efficacy. Outcomes will be assessed at baseline and at each time point of treatment. Multimodal MRI will be performed at baseline and after 12-week treatment and the results will be used to investigate the neural mechanisms of ACE for obesity. Neurological changes and clinical data will be analysed for correlation.Discussions: This study hypothesized that Shu-Mu ACE therapy has a synergistic effect and may treat AO by modulating the neuropathological alterations in the brain. Our findings will demonstrate the neurological mechanism of AO treated by “Shu-Mu” Acupoint Catgut Embedding and compatibility relation.Trial Registration: This trial is registered at the Chinese Clinical Trial Registration Center (No. ChiCTR2100048920).Keywords: acupoint catgut embedding, female, abdominal obesity, Shu-Mu acupoints, compatibility relation, study protocol, neurological mechanism

Yuhuan Lv, Zheng Yang, Linyu Xiang, Meng Yu, Subei Zhao, Xiaoru Zhang, Rong Li Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Rong Li, The Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, YouYi Road 1&num;, Yuzhong District, Chongqing, People’s Republic of China, Email rongli@hospital.cqmu.edu.cnBackground: As an early manifestation of diabetic peripheral neuropathy (DPN), sudomotor dysfunction significantly increases the risk of diabetic foot ulcer. The pathogenesis of sudomotor dysfunction is still unclear. Lower limb ischemia may be related to sudomotor dysfunction, but few studies have explored it. The purpose of this study is to explore the relationship between sudomotor function and comprehensive lower limb arterial ischemia including large arteries, small arteries and microvascular in type 2 diabetes mellitus (T2DM).Patients and Methods: 511 T2DM patients were enrolled in this cross-sectional study. Sudomotor function was assessed qualitatively and quantitatively by Neuropad. Lower limb arterial ischemia was defined as any abnormality of the ankle brachial index (ABI), toe brachial index (TBI) or transcutaneous oxygen tension (TcPO2).Results: In this study, 75.1% of patients had sudomotor dysfunction. Compared with normal sudomotor function, patients with sudomotor dysfunction had a higher incidence of lower limb arterial ischemia (51.2% vs 36.2%, p = 0.004). Similarly, compared with the non-arterial ischemia group, the proportion of sudomotor disorders was higher in the arterial ischemia group (p = 0.004). Low TBI and low TcPO2 groups also had a higher proportion of sudomotor disorders (all p < 0.05).Compare with normal groups, low ABI, low TBI, and low TcPO2 groups had lower Slop4 which quantitatively reflecting Neuropad discoloration. Arterial ischemia was an independent risk factor for sudomotor dysfunction [OR = 1.754, p = 0.024]. Low TcPO2 also independently increased the risk of sudomotor disorders [OR = 2.231, p = 0.026].Conclusion: Lower limb arterial ischemia is an independent risk factor of sudomotor dysfunction. Especially below the ankle (BTA) small arteries and microvascular ischemia may also be involved in the occurrence of sudomotor disorders.Keywords: sudomotor function, lower limb arterial ischemia, ankle brachial index, toe brachial index, transcutaneous oxygen tension

Shuang Li,1,2,&ast; Yanwen Xu,2,&ast; Yuhang Wu,2,&ast; Heyu Huang,2 Chen Sun,2 Shanshan Xu,2 Huajun Li,2 Xi Zhang,3 Shiyong Zhao,4 Lisu Huang1,2 1Department of Infectious Diseases, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Infectious Diseases, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Clinical Research Unit, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Infectious Diseases, Hangzhou Children’s Hospital, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lisu Huang, Department of Infectious Diseases, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 3333 Binsheng Road, Hangzhou, Zhejiang Province, 310052, People’s Republic of China, Email lisuhuang@zju.edu.cn Shiyong Zhao, Department of Infectious Diseases, Hangzhou Children’s Hospital, 195 Wenhui Road, Hangzhou, Zhejiang Provinve, 310005, People’s Republic of China, Email jhzsyhj@163.comPurpose: Heparin-binding protein (HBP) is a novel biomarker for inflammatory diseases. This study aimed to investigate the role of serum HBP in community-acquired pneumonia (CAP) in children and the association of HBP with the severity and prognosis.Patients and Methods: A total of 125 children with CAP admitted to the hospital were enrolled in this retrospective study. We analyzed the differences in clinical characteristics and examination findings between patients with different levels of HBP. The severe or complicated CAP was defined as having severe radiographic findings and/or systemic manifestations. Receiver operator characteristic (ROC) curves detected the performance of biomarkers in identifying patients with severe or complicated pneumonia. The multivariate logistic regression models assessed the association between HBP levels and the severity and prognosis. Finally, we constructed a predictive model based on HBP.Results: The rate of severe or complicated CAP for patients with upper-quartile HBP concentration (≥ 60 ng/mL) was 54.8%, significantly higher than that of patients with lower HBP concentration (26.6%). The level of HBP is substantially correlated with neutrophil counts, C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A protein (r = 0.31, 0.26, 0.36, and 0.26, respectively). HBP achieved the highest level of discrimination for severe or complicated CAP among the biomarkers. Higher HBP concentration (≥ 60 ng/mL) was associated with a three-fold higher risk of severe or complicated CAP (adjusted odds ratio = 3.11, p < 0.05). A predictive model including four characteristics (HBP, lactate dehydrogenase, age and non-viral infection) for predicting severe or complicated CAP (with area under the ROC curve = 0.75) was built to create a nomogram.Conclusion: Substantially elevated serum HBP is significantly associated with severe or complicated CAP and poor prognosis in children. This finding warrants further investigation of the function of HBP in the pathogenesis of CAP.Keywords: pneumonia, biomarker, heparin-binding protein, children

Shuya Zhao,1 Yunyang Zhang,2 Yun Chen,3 Xianghui Xing,1 Yu Wang,1 Guofeng Wu4 1Department of Pediatric Dentistry, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China; 2Center of Modem Analysis, Nanjing University, Nanjing, People’s Republic of China; 3Department of Pediatric Dentistry, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Prosthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of ChinaCorrespondence: Guofeng Wu; Xianghui Xing, Email wgffmmu@sina.com; dr.xing@qq.comPurpose: To evaluate the effects of dentin pretreatment with chitosan-loaded oleuropein nanoparticles (CONPs) on the durability of resin–dentin bonding interfaces.Methods: Eighty freshly extracted non-carious human third molars were randomly divided into four groups (n = 20 each): a de-ionized water (DW) group, a chitosan (CS) group, a chlorhexidine (CHX) group and a CONP group. The dentin in the DW, CS, CHX, and CONP groups were pretreated with de-ionized water, 1.0 mg/L CS solution, 2% chlorhexidine solution, and CONP suspension (prepared with 100 mg/L oleuropein), respectively, followed by the universal adhesive and resin composites. The bonded teeth of each group were randomly divided into two subgroups: an immediate subgroup and an aged subgroup. The bonded teeth of each group were then cut into the bonded beams. We measured their microtensile bond strength (μTBS), observed the characteristics of bonding interface by atomic force microscope, calculated the percentage of silver particles in a selected area for interfacial nanoleakage analysis, and evaluated the endogenous gelatinase activity within the bonding interface for in-situ zymogram analysis. Data were analyzed with two-way ANOVA and LSD multiple comparison test (P < 0.05).Results: Regardless of after 24 h or after thermocycling, CONP exhibited better μTBS (P < 0.05) than the other three groups except that there was not a statistical significance (P > 0.05) in the CONP and CHX groups after 24 h. Besides, the CONP group presented significantly higher modulus of elasticity in the hybrid layers (P < 0.05), lower expression of nanoleakage (P < 0.05), and better inhibitory effect of matrix metalloproteinases than the other three groups before and after thermocycling.Conclusion: Altogether, the CONPs had the potential to act as a dentin primer, which could effectively improve the dentin-resin binding durability.Keywords: atomic force microscopy, dentin, matrix metalloproteinases, microtensile bond strength, nanoleakage

Jingya Zhang,1 Siqi Zhao,1 Xinzhu Xing,1 Lin Shang,1 Jiali Cao,1 Yanling He1,2 1Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2National Clinical Research Center for Skin and Immune Diseases, Branch in Beijing Chaoyang Hospital, Beijing, People’s Republic of ChinaCorrespondence: Yanling He, Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, 8 Gongti South Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel/Fax +86-10-85231889, Email hylchaoyang@163.comAbstract: Psoriasis is an autoimmune disease that is characterized by discolored, scaled patches of skin. Clinically, it is found that psychological factors often induce or aggravate the disease. Current research suggests that the pathogenesis of psoriasis involves the nervous and immune systems. This article reviews how neuropeptides secreted by nerve fibers affect dendritic cells in psoriasis. In this review, we describe that the neuropeptides calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide can act on dendritic cells and participate in the pathogenesis of psoriasis. These neuropeptides can affect the secretion of interleukin (IL)-12 and IL-23 by dendritic cells, which stimulate T helper (Th)1, Th17, and Th22 cells to produce immune responses and cause the manifestation of psoriasis. The application of neuropeptide inhibitors can improve the skin lesions of psoriasis, which has been confirmed in clinical trials. Therefore, neuroimmune response may be a new direction to develop new drug treatments and perspectives in the development of psoriasis.Keywords: psoriasis, dendritic cell, calcitonin gene-related peptide, substance P, vasoactive intestinal peptide

Hui Li,1,2,&ast; Tao Liu,1,2,&ast; Jingjing Sun,1,2 Shuai Zhao,1,2 Xin Wang,1,2 Wei Luo,1,2 Ruyi Luo,1,2 Weiyun Shen,1,2 Cong Luo,1,2 Di Fu3 1Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, People’s Republic of China; 3Department of Anesthesiology, the XiangYa Hospital, Central South University, ChangSha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Di Fu, Department of Anesthesiology, the XiangYa Hospital, Central South University, Xiangya Road No. 86, Changsha, Hunan Province, 410011, People’s Republic of China, Tel/Fax +86 85295987, Email xyyyfudi@csu.edu.cnBackground: The spinal cord expresses brain-derived neurotrophic factor precursor (proBDNF) and its receptor pan neurotrophin receptor 75 (p75NTR). However, the role of spinal proBDNF signaling in the pathogenesis of inflammatory pain remains unknown.Methods: Rats were locally injected with complete Freund’s adjuvant (CFA) to induce inflammatory pain. The proBDNF signal expression was detected by double-labeled immunofluorescence. ProBDNF protein, p75NTR extracellular domain (p75NTR-ECD), or monoclonal anti-proBDNF (McAb-proB) were administrated by intrathecal injection to investigate their effects on pain behavior. Paw withdrawal thermal latency (PWL) and paw withdrawal mechanical threshold (PWT) were performed to evaluate pain behavior. Immunoblotting, immunohistochemistry, and immunofluorescence were used to assess inflammation-induced biochemical changes.Results: CFA induced a rapid increase in proBDNF in the ipsilateral spinal cord, and immunofluorescence revealed that CFA-enhanced proBDNF was expressed in NeuN positive neurons and GFAP positive astrocytes. The administration of furin cleavage-resistant proBDNF via intrathecal injection (I.t.) significantly decreased the PWT and PWL, whereas McAb-proB by I.t. alleviated CFA-induced pain-like hypersensitivity in rats. Meanwhile, CFA administration triggered the activation of p75NTR and its downstream signaling extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor (NF)-kappaB p65 in the spinal cord. I.t. administration of p75NTR-ECD suppressed CFA-induced pain and neuroinflammation, including the expression of p-ERK1/2, p-p65, and the gene expression of tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6).Conclusion: Our study reveals that the activated proBDNF/p75NTRsignaling in the spinal cord contributes to the development of CFA-induced inflammatory pain. McAb-proB and p75NTR-ECD appear to be promising therapeutic agents for inflammatory pain.Keywords: brain-derived neurotrophic factor precursor, inflammatory pain, spinal cord, neuron, pan neurotrophin receptor 75

Cui Shao,1,&ast; Mengxue Sun,2,&ast; Wanwen Liu,2 Shaoyang Zhao,1 Yang Liu,2 Yuna Chen,1 Shu-Nung Liang,2 Haoyu Yuan,2 Huacheng Sui,2 Baohua Wang,1 Saimei Li1 1Department of Endocrinology, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Baohua Wang; Saimei Li, Department of Endocrinology, First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China, Tel +8613580515855 ; +8615818159018, Fax +86 20-36588726, Email wangbaohua@gzucm.edu.cn; lsm@gzucm.edu.cnPurpose: We aimed to assess the efficacy of the Jiang Tang San Huang (JTSH) tablet for the treatment of patients with type 2 diabetes mellitus (T2DM).Methods: All data for this retrospective cohort study were acquired from the outpatient clinic database of our institution, and all enrolled patients received JTSH tablet for at least two months. Overall, 147 patients were included in the analysis. The primary outcome was patient-reported outcomes on the efficacy of the JTSH tablets using a questionnaire survey. Correlation analysis evaluated the duration of JTSH tablet administration and glycemic control in patients with T2DM. The secondary outcome measures included: changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-hour postprandial blood glucose, homeostasis model assessment of insulin resistance index (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) after 2 months of treatment with JTSH tablets.Results: Overall,120 patients (81.63%) reported a JTSH tablet treatment satisfaction score of ≥ 60 points, and believed that JTSH tablets had satisfactory hypoglycemic effects and could improve symptoms. The average duration of JTSH tablet treatment was 2.57± 1.45 years. Overall, 111 patients achieved good blood glucose control, while 36 patients had poor glycemic control. Multivariate logistic regression model analysis showed that taking JTSH tablets for 1 year might reduce the risk of poor hypoglycemic effect by 17.00% (Risk ratio=0.830, 95% confidence interval:0.578, 1.021, P=0.066). Compared with the baseline data, the levels of HbA1c, FPG and HOMA-IR decreased significantly and HOMA-β levels increased significantly (P< 0.05).Conclusion: Good blood glucose control may be positively correlated with the duration of JTSH tablets administration. Patients with T2DM were satisfied with the anti-diabetic effects of JTSH tablets, which can significantly reduce blood glucose and insulin resistance, and improve the function of islet cells.Keywords: type 2 diabetes mellitus, Jiang Tang San Huang tablet, patient-reported outcomes, blood glucose control, multiple logistic regression

Haipeng Wang,1,2,&ast; Shichao Zhao,3,&ast; Qian Liu,4 Jinyu Wang,3 Beibei Yuan5 1Centre for Health Management and Policy Research, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2NHC Key Laboratory of Health Economics and Policy Research, Shandong University, Jinan, People’s Republic of China; 3School of Public Administration, Shandong Normal University, Jinan, People’s Republic of China; 4School of Social Development and Public Policy, Beijing Normal University, Beijing, People’s Republic of China; 5China Center for Health Development Studies, Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Beibei Yuan, China Center for Health Development Studies, Peking University, Box 505, 38 Xue Yuan Road, Haidian District, Beijing, 100191, People’s Republic of China, Email beibeiyuan@bjmu.edu.cnObjective: This study aims to explore the association between financial incentives and job performance of primary care providers (PCPs) from a nationally representative survey in China.Methods: This is a cross-sectional study conducted in six provinces of China in 2019. A sample of 1388 PCPs participated in the survey was selected using a stratified cluster sampling method. A self-administered questionnaire composed of socio-demographic, work-related characteristics, financial incentives received by PCPs and their job performance was used. The association between financial incentives and job performance are analyzed using logistic regression model. The significance level for statistics is set at P < 0.05.Results: The PCPs with higher real income level have lower contextual performance (OR = 0.67, p < 0.01) and learning performance (OR = 0.63, p < 0.01) than those with lower real income level. The PCPs with the expectation of income rising above 50% have lower contextual performance (OR = 0.66, p < 0.05) than those with the expectation of income rising above 20%. The PCPs with preference for monetary income have lower task performance (OR = 0.62, p < 0.01), contextual performance (OR = 0.55, p < 0.01) and learning performance (OR = 0.57, p < 0.01) than those without lower preference for monetary income. The percent of performance-based income has no significant effect on all the three dimensions of job performance.Conclusion: Financial incentive was regarded as the most important motivating factor of PCPs in China, but existing financial incentives received by PCPs could not improve their job performance. The findings can be attributed to the unsatisfying total income level, “intrinsic motivation crowding out” effect, and the poorly designed performance-based salary system for PCPs. Policy attention is called for to continuing efforts and system reform to increase the total income level for PCPs in China, and improve the performance-based salary system to better motivate PCPs and improve their job performance.Keywords: financial incentive, job performance, primary care providers, China