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Quan Hu,1,* Yingxiao Li,2,* Zhaochen Lin,3 Hao Zhang,4 Haoyue Chen,4 Cui Chao,3 Chuanliang Zhao5 1Department of Neurosurgery, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 2Department of Gynecology, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 3Hydrogen Medical Research Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 4Department of Rehabilitation Medical Center, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China; 5Department of Orthopedics, the Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuanliang Zhao, Department of Orthopedics, The Affiliated Taian City Central Hospital of Qingdao University, Tai’an City, Shandong, 271000, People’s Republic of China, Tel +8615621539631, Email zhaochuanliang2003@163.comAbstract: Hydrogen, which is a novel biomedical molecule, is currently the subject of extensive research involving animal experiments and in vitro cell experiments, and it is gradually being applied in clinical settings. Hydrogen has been proven to possess anti-inflammatory, selective antioxidant, and antiapoptotic effects, thus exhibiting considerable protective effects in various diseases. In recent years, several studies have provided preliminary evidence for the protective effects of hydrogen on spinal cord injury (SCI). This paper provides a comprehensive review of the potential molecular biology mechanisms of hydrogen therapy and its application in treating SCI, with an aim to better explore the medical value of hydrogen and provide new avenues for the adjuvant treatment of SCI.Keywords: hydrogen, spinal cord injury, selective antioxidant, anti-inflammatory

Qiaoling Wei,1– 3,* Liangliang Niu,1– 3,* Xianjin Zhou,4 Han Chen,1,2 Rui Jiang1– 3 1Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, People’s Republic of China; 3Ocular Trauma Center, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 4Department of Ophthalmology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rui Jiang; Han Chen, Tel +86-21-64377134, Fax +86-21-6477134, Email 2jiang@163.com; avnus@163.comPurpose: To evaluate the effects of retinal surgery on the ocular surface and corneal subbasal nerve plexus (SNP).Methods: Ninety-eight patients undergoing 23-gauge pars plana vitrectomy for various vitreoretinal disorders were prospectively studied. We collected detailed operative and perioperative data, measuring dry eye syndrome (DED) severity and Ocular Surface Disease Index (OSDI) scores before surgery and at postoperative intervals. In vivo confocal microscopy (IVCM) quantified SNP and dendritic cell (DC) densities.Results: Fifty-three patients were analyzed. Post-surgery, OSDI scores rose from a baseline of 5.5 ± 3.5 to 12.24 ± 6.5 at one month, later reducing to 7.8 ± 4.0 after a year. DED severity increased from 0.6 ± 0.6 initially to 1.6 ± 0.6 at three months, returning to near baseline (0.9 ± 0.6) one year after surgery. DC densities increased notably by the third (58.85 ± 75.6 cells/mm²) and ninth (59.95 ± 86 cells/mm²) postoperative months, especially in patients undergoing combined phacoemulsification, vitrectomy, and C3F8 gas tamponade. SNP parameters, particularly nerve fiber density and length, showed significant declines one month post-surgery, not recovering to baseline levels within a year. Fiber density dropped from 19.06 ± 8.3 fibers/mm² preoperatively to 4.68 ± 4.8 fibers/mm² at one month, partially recovering to 10.64 ± 8.2 fibers/mm² at twelve months. Fiber length decreased from 13.31 ± 3.2 mm/mm² to 6.86 ± 3.4 mm/mm² at one month, later improving to 9.81 ± 4.5 mm/mm² at twelve months, notably in patients with silicone oil (SiO2) tamponade.Conclusion: Retinal surgery, especially when combined with phacoemulsification and C3F8 or SiO2 tamponade, significantly affects ocular surface integrity and SNP density, with these changes lasting up to a year. Expanded studies with more patients and longer follow-up, using finer 25- and 27-gauge vitrectomy tools, are recommended to confirm and extend these findings.Keywords: corneal subbasal nerve plexus, ocular surface, retinal surgical procedures, confocal microscopy, dry eye syndrome after vitrectomy, intraocular surgery

Yinan Cao,1– 3,* Fan Li,1– 3,* Zhenxuan Sun,1– 3 Jin Liu,1– 3 Jie Liu,1– 3 Qi Yang,1– 3 Peng Ge,1– 3 Yalan Luo,1– 3 Hailong Chen1– 3 1Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, People’s Republic of China; 3Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yalan Luo; Hailong Chen, Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Zhongshan Road 222, Dalian, 116011, Liaoning, People’s Republic of China, Tel +86-411-83635963, Fax +86-411-83622844, Email luoyalanxueshu@163.com; chenhailong@dmu.edu.cnPurpose: Explore the therapeutic effects and regulatory mechanism of Qingyi Decoction (QYD) on severe acute pancreatitis (SAP) associated acute lung injury (ALI).Methods: We identified the constituents absorbed into the blood of QYD based on a network pharmacological strategy. The differentially expressed genes from the GEO database were screened to identify the critical targets of QYD treatment of SAP-ALI. The SAP-ALI rat model was constructed.Some methods were used to evaluate the efficacy and mechanism of QYD in treating SAP-ALI. LPS-stimulated pulmonary microvascular endothelial cell injury simulated the SAP-induced pulmonary endothelial injury model. We further observed the therapeutic effect of QYD and CDK5 plasmid transfection on endothelial cell injury.Results: 18 constituents were absorbed into the blood, and 764 targets were identified from QYD, 25 of which were considered core targets for treating SAP-ALI. CDK5 was identified as the most critical gene. The results of differential expression analysis showed that the mRNA expression level of CDK5 in the blood of SAP patients was significantly up-regulated compared with that of healthy people. Animal experiments have demonstrated that QYD can alleviate pancreatic and lung injury inflammatory response and reduce the upregulation of CDK5 in lung tissue. QYD or CDK5 inhibitors could decrease the expression of NFAT5 and GEF-H1, and increase the expression of ACE-tub in SAP rat lung tissue. Cell experiments proved that QYD could inhibit the expression of TNF-α and IL-6 induced by LPS. Immunofluorescence results suggested that QYD could alleviate the cytoskeleton damage of endothelial cells, and the mechanism might be related to the inhibition of CDK5-mediated activation of NFAT5, GEF-H1, and ACE-tub.Conclusion: CDK5 has been identified as a critical target for pulmonary endothelial injury of SAP-ALI. QYD may partially alleviate microtubule disassembly by targeting the CDK5/NFAT5/GEF-H1 signaling pathway, thus relieving SAP-induced pulmonary microvascular endothelial cell injury. Keywords: Qingyi decoction, severe acute pancreatitis, acute lung injury, CDK5, microtubule

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

Wei Liao,1,2,* Jiaxuan Lu,3,* Yuyuan Xu,4,* Chulin Yang,1,5 Hongjie Chen,4 Shaohang Cai,4 Lili Liu,1,6 Shuwei Chen1,5 1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 3Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 5Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 6Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaohang Cai, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China, Email shaohangcai@foxmail.com Shuwei Chen, Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Dongfeng East Road, Guangzhou, 510060, People’s Republic of China, Email chenshuw@sysucc.org.cnBackground: To compare and analyze the presence of CD4+ and CD8 + lymphocyte infiltrates in Oral squamous cell carcinoma (OSCC) tissue versus adjacent tissue and their clinical significance.Methods: We enrolled a total of 152 patients diagnosed with OSCC, all of whom had confirmed diagnoses through pathological reports. Clinical and demographics data were extracted from medical records. Tissue microarrays were constructed and immunohistochemical staining for CD4 and CD8 was performed.Findings: The average number of infiltrating CD4+ T cells in OSCC tumor tissue was 1026.22± 1163.36 cells/mm2, which did not significantly differ from the count in adjacent tissue, which was 1163.36± 1013.23 cells/mm2. However, the number of CD8+ T cell infiltration in tumor tissue was significantly higher than in adjacent tissue (655.25± 705.70 vs 504.56± 659.26 cells/mm2, p = 0.026). We observed that, among patients who consumed alcohol, the CD4+ T cell infiltration in tumor tissue being significantly lower than that in adjacent tissue (P=0.036). Moreover, the CD8+ T cell infiltration in cancer tissue was significantly higher than in adjacent tissue for T1-2 patients (p=0.005). Patients with higher CD8+ T cell in tumor tissue exhibited significantly improved overall survival (p = 0.043). Multivariate analyses revealed that alcohol consumption had a significant impact on the number of CD4+T lymphocytes in tumor tissue (OR = 0.403, P = 0.033) while T stage was the independent factor affecting CD8+ T lymphocyte infiltration in tumor tissue (OR = 0.459, P = 0.031).Interpretation: OSCC patients with a higher number of CD8+ T lymphocyte infiltration in tumor tissue exhibited an improved prognosis.Keywords: microenvironment, OSCC, CD8 T cells, CD4 T cells, prognosis

Shuk-Ching Wong,1 Pui-Hing Chau,2 Hong Chen,3 Simon Yung-Chun So,4 Kelvin Hei-Yeung Chiu,4 Jonathan Hon-Kwan Chen,4 Xin Li,5 Celine Sze-Ling Chui,2,6 Kwok-Yung Yuen,5 Vincent Chi-Chung Cheng1,4 1Infection Control Team, Queen Mary Hospital, Hong Kong West Cluster, Hong Kong Special Administrative Region, People’s Republic of China; 2School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China; 3Centre for Health Protection, Department of Health, Hong Kong Special Administrative Region, People’s Republic of China; 4Department of Microbiology, Queen Mary Hospital, Hong Kong Special Administrative Region, People’s Republic of China; 5School of Clinical Medicine, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China; 6School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of ChinaCorrespondence: Vincent Chi-Chung Cheng, Infection Control Team, Queen Mary Hospital, Hong Kong West Cluster, Hong Kong Special Administrative Region, People’s Republic of China, Tel +852-22552351, Fax +852-23523698, Email vcccheng@hku.hkPurpose: This study describes the emergence of Candida auris in Hong Kong, focusing on the incidence and trends of different Candida species over time. Additionally, the study analyzes the relationship between C. auris and antifungal prescription, as well as the impact of outbreaks caused by C. auris.Patients and Methods: Data were collected from 43 public hospitals across seven healthcare networks (A to G) in Hong Kong, including Candida species culture and antifungal prescription information. Among 150,267 patients with 206,405 hospitalization episodes, 371,653 specimens tested positive for Candida species. Trends in Candida species and antifungal prescription were analyzed before (period 1: 2015 1Q to 2019 1Q) and after (period 2: 2019 2Q to 2023 2Q) the emergence of C. auris in Hong Kong.Results: Candida albicans was the most prevalent species, accounting for 57.1% (212,163/371,653) of isolations, followed by Candida glabrata (13.1%, 48,666), Candida tropicalis (9.2%, 34,261), and Candida parapsilosis (5.3%, 19,688). C. auris represented 2.0% of all Candida species isolations. Comparing period 2 to period 1, the trend of C. albicans remained stable, while C. glabrata, C. tropicalis, and C. parapsilosis demonstrated a slower increasing trend in period 2 than in period 1. Other species, including C. auris, exhibited a 1.1% faster increase in trend during period 2 compared to period 1. Network A, with the highest antifungal prescription, did not experience any outbreaks, while networks F and G had 40 hospital outbreaks due to C. auris in period 2. Throughout the study period, healthcare networks B to G had significantly lower antifungal prescription compared to network A, ranging from 54% to 78% less than that of network A.Conclusion: There is no evidence showing correlation between the emergence of C. auris and antifungal prescription in Hong Kong. Proactive infection control measures should be implemented to prevent nosocomial transmission and outbreak of C. auris.Keywords: epidemiology, outbreak, antifungal prescription, infection control measure

Fan Li,1– 3,* Zhengjian Wang,4,* Yinan Cao,1– 3 Boliang Pei,1– 3 Xinyu Luo,1– 3 Jin Liu,1– 3 Peng Ge,1– 3 Yalan Luo,1– 3 Shurong Ma,1,3 Hailong Chen1– 3 1Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shurong Ma; Hailong Chen, Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Zhongshan Road 222, Dalian, Liaoning, 116011, People’s Republic of China, Tel +86-411-83635963, Fax +86-411-83622844, Email shurongma94@163.com; chenhailong@dmu.edu.cnAbstract: The pathogenesis of severe acute pancreatitis-associated acute lung injury (SAP-ALI), which is the leading cause of mortality among hospitalized patients in the intensive care unit, remains incompletely elucidated. The intestinal mucosal immune barrier is a crucial component of the intestinal epithelial barrier, and its aberrant activation contributes to the induction of sustained pro-inflammatory immune responses, paradoxical intercellular communication, and bacterial translocation. In this review, we firstly provide a comprehensive overview of the composition of the intestinal mucosal immune barrier and its pivotal roles in the pathogenesis of SAP-ALI. Secondly, the mechanisms of its crosstalk with gut microbiota, which is called gut-lung axis, and its effect on SAP-ALI were summarized. Finally, a number of drugs that could enhance the intestinal mucosal immune barrier and exhibit potential anti-SAP-ALI activities were presented, including probiotics, glutamine, enteral nutrition, and traditional Chinese medicine (TCM). The aim is to offer a theoretical framework based on the perspective of the intestinal mucosal immune barrier to protect against SAP-ALI.Keywords: severe acute pancreatitis-associated acute lung injury, intestinal mucosal immune barrier, gut microbiota, gut-lung axis, migration of immune cells

Longjiang Zhou,1,* Haitao Xiang,2,* Susu Liu,3 Honglin Chen,4 Yuanwei Yang,4 Jianyong Zhang,4 Wei Cai4 1Department of Neurology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225012, People’s Republic of China; 2Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou, 215028, People’s Republic of China; 3School of Life Science and Technology, Xidian University and Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, Xi’an, 710126, People’s Republic of China; 4Department of Neurosurgery, Suqian First Hospital, Suqian, 223800, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Cai; Jianyong Zhang, Department of Neurosurgery, Suqian First Hospital, No. 120, Suzhi Road, Sucheng District, Suqian, Jiangsu Province, People’s Republic of China, Tel +86 15162908957 ; +86 15261296169, Fax +86 527 80766363 ; +86 527 80766155, Email doccaiwei@126.com; 935349804@qq.comPurpose: Hypoxia is often associated with glioma chemoresistance, and alleviating hypoxia is also crucial for improving treatment efficacy. However, although there are already some methods that can improve efficacy by alleviating hypoxia, real-time monitoring that can truly achieve hypoxia relief and efficacy feedback still needs to be explored.Methods: AQ4N/Gd@PDA-FA nanoparticles (AGPF NPs) were synthesized using a one-pot method and were characterized. The effects of AGPF NPs on cell viability, cellular uptake, and apoptosis were investigated using the U87 cell line. Moreover, the effectiveness of AGPF NPs in alleviating hypoxia was explored in tumor-bearing mice through photoacoustic imaging. In addition, the diagnosis and treatment effect of AGPF NPs were evaluated by magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) on orthotopic glioma mice respectively.Results: In vitro experiments showed that AGPF NPs had good dispersion, stability, and controlled release. AGPF NPs were internalized by cells through endocytosis, and could significantly reduce the survival rate of U87 cells and increase apoptosis under irradiation. In addition, we monitored blood oxygen saturation at the tumor site in real-time through photoacoustic imaging (PAI), and the results showed that synergistic mild-photothermal therapy/chemotherapy effectively alleviated tumor hypoxia. Finally, in vivo anti-tumor experiments have shown that synergistic therapy can effectively alleviate hypoxia and inhibit the growth of orthotopic gliomas.Conclusion: This work not only provides an effective means for real-time monitoring of the dynamic feedback between tumor hypoxia relief and therapeutic efficacy, but also offers a potential approach for the clinical treatment of gliomas.Keywords: gliomas, hypoxia relief, photothermal therapy, real-time monitoring, photoacoustic imaging

Jing Zhang,1,2 Ke Ma,3 Jun Yan,4 Pingsheng Pan,5 Jiangshan Yin,6 Fuqing Lin,7 Hui Chen,8 Weiwei Zhao,1,2 Menglei Chen,1,2 Zhe Zhang,1,2 Minghui Liu,1,2 Xiaoli Gu,1,2 Xinghe Liao,1,2 Chenyue Zhang,1,2 Wenwu Cheng1,2 1Department of Integrated Therapy, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China; 3Department of Pain Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China; 5Department of Oncology, Fangta Hospital of Traditional Chinese Medicine in Songjiang District, Shanghai, People’s Republic of China; 6Department of Oncology, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, People’s Republic of China; 7Department of Anaesthesiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 8Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People’s Hospital Affiliated to Tongji University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Wenwu Cheng, Email cwwxxm@sina.comPurpose: This study aimed to assess the current status of clinical practice of refractory cancer pain (RCP) among a sample of physicians specializing in cancer pain management in Shanghai.Methods: From 2019 to 2021, a questionnaire survey was conducted among physicians engaged in diagnosis and treatment of cancer pain through the questionnaire WJX network platform in Shanghai, China.Results: A total of 238 responses participated in the survey. This survey reports physicians’ understanding and incidence rate of breakthrough cancer pain (BTCP). The choice of analgesics and satisfaction of analgesic effect were investigated. We also investigated doctors’ knowledge of the diagnostic criteria for RCP and their tendency to choose analgesics. Oral immediate-release morphine and intravenous or subcutaneous morphine injection have been the common treatment approach for transient cancer pain exacerbations. The main barriers to pain management are lack of standardized treatment methods for RCP, lack of knowledge related to RCP, and single drug dosage form. Doctors believe the most necessary measures to improve the current situation of poor cancer pain control include improving medical staff’s understanding and treatment techniques for RCP, updating treatment techniques and methods, and improving the configuration of drug types in medical institutions. Clinicians expect to improve understanding and treatment techniques through systematic training.Conclusion: Despite multiple available analgesic measures, the treatment of RCP remains challenging. Improving the understanding of medical staff towards RCP, improving treatment techniques, and increasing the accessibility of multiple drug types are important ways to improve the satisfaction of cancer pain management in the future.Keywords: refractory cancer pain, breakthrough cancer pain, pain management, opioid drugs

Yanxia He,1,* Zhumei Luo,1,* Haoqing Chen,2,3,* Liqing Ping,2,3 Cheng Huang,2,3 Yan Gao,2,3 Huiqiang Huang2,3 1Department of Oncology, The Third People’s Hospital of Chengdu, Sichuan, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huiqiang Huang; Yan Gao, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China, Email huanghqsysucc@163.com; gaoyan@sysucc.org.cnBackground: Systemic inflammation, immunity, and nutritional status are closely related to patients’ outcomes in several kinds of cancers. This study aimed to establish a new nomogram based on inflammation-immunity-nutrition score (IINS) to predict the prognosis of extranodal natural killer/T-cell lymphoma (ENKTL) patients.Methods: The clinical data of 435 patients with ENTKL were retrospectively reviewed and randomly assigned to training cohort (n=305) and validation cohort (n=131) at a ratio of 7:3. Cox regression analysis was employed to identify independent prognostic factors and develop a nomogram in the training cohort. Harrell’s concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) curve were employed to assess the performance of the nomogram and compare it with traditional prognostic systems (PINK, IPI, KPI). Internal validation was performed using 1000 bootstrap resamples in the validation cohort. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) of patients in different risk groups.Results: In the training cohort, in addition to several classic parameters, IINS was identified as an independent prognostic factor significantly associated with the OS of patients. The nomogram established based on the independent prognostic indicators showed superior survival prediction efficacy, with C-index of 0.733 in the training cohort and 0.759 in the validation cohort compared to the PINK (0.636 and 0.737), IPI (0.81 and 0.707), and KPI (0.693 and 0.639) systems. Furthermore, compared with PINK, IPI, and IPI systems, the nomogram showed relatively superior calibration curves and more powerful prognostic discrimination ability in predicting the OS of patients. DCA curves revealed some advantages in terms of clinical applicability of the nomogram compared to the PINK, IPI, and IPI systems.Conclusion: Compared with traditional prognostic systems, the nomogram showed promising prospects for risk stratification in ENKTL patient prognosis, providing new insights into the personalized treatment.Keywords: inflammation-immunity-nutrition score, extranodal natural killer/T-cell lymphoma, nomogram, prognosis, overall survival

Yan Fang,1,2 Huali Liu,1,2 Yuan Li,1,2 Ji Cheng,1 Xia Wang,1 Bing Shen,3 Hongbo Chen,1,2 Qunhua Wang4 1Department of Obstetrics and Gynaecology, Maternal and Child Health Hospital Affiliated to Anhui Medical University, Hefei, People’s Republic of China; 2The Fifth Clinical College of Anhui Medical University, Hefei, People’s Republic of China; 3School of Basic Medicine, Anhui Medical University, Hefei, People’s Republic of China; 4Department of Obstetrics and Gynaecology, the First Affiliated Hospital of USTC, Hefei, People’s Republic of ChinaCorrespondence: Hongbo Chen, Maternal and Child Health Hospital Affiliated to Anhui Medical University, No. 15 Yimin Street, Luyang District, Hefei City, Anhui Province, People’s Republic of China, Email chenhongbo@ahmu.edu.cn Qunhua Wang, Department of Obstetrics and Gynaecology, the First Affiliated Hospital of USTC, Hefei, People’s Republic of China, Email wqh971234@163.comPurpose: To investigate the risk factors associated with preeclampsia in hyperglycemic pregnancies and develop a predictive model based on routine pregnancy care.Patients and Methods: The retrospective collection of clinical data was performed on 951 pregnant women with hyperglycemia, including those diagnosed with diabetes in pregnancy (DIP) and gestational diabetes mellitus (GDM), who delivered after 34 weeks of gestation at the Maternal and Child Health Hospital Affiliated to Anhui Medical University between January 2017 and December 2019. Observation indicators included liver and kidney function factors testing at 24– 29+6 weeks gestation, maternal age, and basal blood pressure. The indicators were screened univariately, and the “rms” package in R language was applied to explore the factors associated with PE in HIP pregnancy by stepwise regression. Multivariable logistic regression analysis was used to develop the prediction model. Based on the above results, a nomogram was constructed to predict the risk of PE occurrence in pregnant women with HIP. Then, the model was evaluated from three aspects: discrimination, calibration, and clinical utility. The internal validation was performed using the bootstrap procedure.Results: Multivariate logistic regression analysis showed that cystatin C, uric acid, glutamyl aminotransferase, blood urea nitrogen, and basal systolic blood pressure as predictors of PE in pregnancy with HIP. The predictive model yielded an area under curve (AUC) value of 0.8031 (95% CI: 0.7383– 0.8679), with an optimal threshold of 0.0805, at which point the sensitivity was 0.8307 and specificity of 0.6604. Hosmer–Lemeshow test values were P = 0.3736, Brier score value was 0.0461. After 1000 Bootstrap re-samplings for internal validation, the AUC was 0.7886, the Brier score was 0.0478 and the predicted probability of the calibration curve was similar to the actual probability. A nomogram was constructed based on the above to visualize the model.Conclusion: This study developed a model for predicting PE in pregnant women with HIP, achieving high predictive performance of PE risk through the information of routine pregnancy care.Keywords: hyperglycemia in pregnancy, preeclampsia, prediction model, nomogram, internal validation

Chun-Shuang Guan,1,* Jing Yu,2,* Yan-Ni Du,1,* Xin-Gang Zhou,3 Zi-Xin Zhang,1 Hui Chen,1 Yu-Xue Xing,1 Ru-Ming Xie,1 Zhi-Bin Lv1 1Department of Radiology, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Ultrasonography, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ru-Ming Xie; Zhi-Bin Lv, Tel +8613911320739 ; +8613683151127, Email mingrux1@163.com; xiaochun324@126.comPurpose: To retrospectively analyse the different imaging manifestations of acquired immunodeficiency syndrome-associated hepatic Kaposi’s sarcoma (AIDS-HKS) on CT, MRI, and Ultrasound.Patients and Methods: Eight patients were enrolled in the study. Laboratory tests of liver function were performed. The CT, MRI, and Ultrasound manifestations were reviewed by two radiologists and two sonographers, respectively. The distribution and imaging signs of AIDS-HKS were evaluated.Results: AIDS-HKS patients commonly presented multiple lesions, mainly distributed around the portal vein on CT, MRI, and Ultrasound. AIDS-HKS presented as ring enhancement in the arterial phase on contrast-enhanced CT and MRI scanning, and nodules gradually strengthen in the portal venous phase and the delayed phase. AIDS-HKS presented as intrahepatic bile duct dilatation and bile duct wall thickening around the lesion. Five patients (62.5%, 5/8) were followed up. After chemotherapy, the lesions were completely relieved (60.0%), or decreased (40.0%).Conclusion: AIDS-HKS presented as multiple nodular lesions with different imaging features. The combination of different imaging methods was helpful for the imaging diagnosis of AIDS-HKS.Keywords: Kaposi’s sarcoma, liver, diagnostic imaging, magnetic resonance imaging, tomography, spiral computed, ultrasonography

Baojiang Liu,* Song Gao,* Jianhai Guo, Fuxin Kou, Shaoxing Liu, Xin Zhang, Aiwei Feng, Xiaodong Wang, Guang Cao, Hui Chen, Peng Liu, Haifeng Xu, Qinzong Gao, Renjie Yang, Liang Xu, Xu Zhu Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xu Zhu, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Interventional Therapy, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China, Tel + 86-10-8819-6059, Email drzhuxu@163.comPurpose: Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity for hepatocellular carcinoma (HCC). Several studies have compared HAIC and Transarterial chemoembolization (TACE). However, comparisons between TACE plus HAIC and HAIC are rarely reported. Here, we evaluated the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) compared to HAIC in patients with advanced HCC.Patients and Methods: In this retrospective study, we enrolled 167 patients diagnosed with advanced HCC and treated at Peking University Cancer Hospital from May 2018 to May 2022. The cohort comprised 74 patients who received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients who received HAIC-FOLFOX. Over 60% of patients received prior treatments. To avoid selection bias, propensity score matching was applied to the efficacy and safety analyses. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoints include objective response rate (ORR), disease control rate (DCR), and safety.Results: Propensity-matching yielded 48 pairs, and group baselines were almost equal after matching. Median PFS and median OS were both higher in the matched Hepa-HAIC cohort (median PFS: 8.9 vs 5.8 months, p = 0.035; median OS: 22.4 vs 9.5 months, p = 0.027), which was consistent with pre-matching analysis. The ORR in the Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; the DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Grade 3– 4 ALT elevation was more frequent in the Hepa-HAIC group (33.3% vs 8.3%, p = 0.003), while vomiting was more frequent in the HAIC group (29.2% vs 12.5%, p = 0.084).Conclusion: The Hepa-HAIC group is superior to the HAIC group in metrics of PFS, OS, ORR, and DCR, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with a comparable safety profile in advanced HCC.Keywords: transarterial chemoembolization, advanced hepatocellular carcinoma, hepatic arterial infusion chemotherapy, propensity score matching

Fei Shu,* Hong Chen,* Zhihao Zhang, Zhiyue Dun, Weijin Lv, Wangxinyue Sun, Mei Liu Department of Prosthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu Province Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mei Liu, Department of Prosthodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu Province Key Laboratory of Oral Diseases, Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing, People’s Republic of China, Tel +86-25-69593081, Fax +86-25-69593186, Email liumei2017@njmu.edu.cnIntroduction: Poor interfacial bonding between the fibers and resin matrix in fiber-reinforced composites (FRCs) is a significant drawback of the composites. To enhance the mechanical properties of FRC, fibers were modified by depositing SiO2 nanofilms via the atomic layer deposition (ALD) technique. This study aims to evaluate the effect of ALD treatment of the fibers on the mechanical properties of the FRCs.Methods: The quartz fibers were modified by depositing different cycles (50, 100, 200, and 400) of SiO2 nanofilms via the ALD technique and FRCs were proposed from the modified fibers. The morphologies, surface characterizations of nanofilms, mechanical properties, and cytocompatibility of FRCs were systematically investigated. Moreover, the shear bond strength (SBS) of FRCs to human enamel was also evaluated.Results: The SEM and SE results showed that the ALD-deposited SiO2 nanofilms have good conformality and homogeneity. According to the results of FTIR and TGA, SiO2 nanofilms and quartz fiber surfaces had good chemical combinations. Three-point bending tests with FRCs showed that the deposited SiO2 nanofilms effectively improved FRCs’ strength and Group D underwent 100 deposition cycles and had the highest flexural strength before and after aging. Furthermore, the strength of the FRCs demonstrated a crescendo-decrescendo tendency with SiO2 nanofilm thickness increasing. The SBS results also showed that Group D had outstanding performance. Moreover, the results of cytotoxicity experiments such as cck8, LDH and Elisa, etc., showed that the FRCs have good cytocompatibility.Conclusion: Changing the number of ALD reaction cycles affects the mechanical properties of FRCs, which may be related to the stress relaxation and fracture between SiO2 nanofilm layers and the built-up internal stresses in the nanofilms. Eventually, the SiO2 nanofilms could enhance the FRCs’ mechanical properties and performance to enamel by improving the interfacial bonding strength, and have good cytocompatibility. Keywords: atomic layer deposition, SiO2 nanofilms, surface modification, interfacial bonding

Sen Li,1 Shuling Liang,2 Shunyu Xie,1 Haixia Chen,1 Haoying Huang,1 Qixin He,3 Huayan Zhang,4,5 Xiaohui Wang1 1Guangzhou Women and Children’s Medical Center, State Key Laboratory of Respiratory Disease and Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 2Guangdong Provincial Research Center for Child Health, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 3Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People’s Republic of China; 4Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children’s Medical Center, Guangzhou, Guangdong Province, People’s Republic of China; 5Division of Neonatology, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USACorrespondence: Xiaohui Wang; Huayan Zhang, Email xiaohuiwang2021621818@gzhmu.edu.cn; zhangh@chop.eduBackground: Bronchopulmonary dysplasia (BPD) has become a major cause of morbidity and mortality in preterm infants worldwide, yet its pathogenesis and underlying mechanisms remain poorly understood. The present study sought to explore microRNA-mRNA regulatory networks and immune cells involvement in BPD through a combination of bioinformatic analysis and experimental validation.Methods: MicroRNA and mRNA microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed microRNAs (DEMs) were identified in BPD patients compared to control subjects, and their target genes were predicted using miRWalk, miRNet, miRDB, and TargetScan databases. Subsequently, protein-protein interaction (PPI) and functional enrichment analyses were conducted on the target genes. 30 hub genes were screened using the Cytohubba plugin of the Cytoscape software. Additionally, mRNA microarray data was utilized to validate the expression of hub genes and to perform immune infiltration analysis. Finally, real-time PCR (RT-PCR), immunohistochemistry (IHC), and flow cytometry were conducted using a mouse model of BPD to confirm the bioinformatics findings.Results: Two DEMs (miR-15b-5p and miR-20a-5p) targeting genes primarily involved in the regulation of cell cycle phase transition, ubiquitin ligase complex, protein serine/threonine kinase activity, and MAPK signaling pathway were identified. APP and four autophagy-related genes (DLC1, PARP1, NLRC4, and NRG1) were differentially expressed in the mRNA microarray dataset. Analysis of immune infiltration revealed significant differences in levels of neutrophils and naive B cells between BPD patients and control subjects. RT-PCR and IHC confirmed reduced expression of APP in a mouse model of BPD. Although the proportion of total neutrophils did not change appreciably, the activation of neutrophils, marked by loss of CD62L, was significantly increased in BPD mice.Conclusion: Downregulation of APP mediated by miR-15b-5p and miR-20a-5p may be associated with the development of BPD. Additionally, increased CD62L− neutrophil subset might be important for the immune-mediated injury in BPD.Keywords: bronchopulmonary dysplasia, CD62L− neutrophil, immune infiltration analysis, miRNA-mRNA regulatory circuits

Meng Luo,1,2,&ast; Xue Han,1,2,&ast; Huan Li,1,2 Guangyue Zhou,1,2 Haoxuan Chen,1,2 Fang Gao1,2 1Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Gao, Department of Anesthesiology, the Affiliated Hospital of Xuzhou Medical University, No. 99 Huaihai West Road, Xuzhou, Jiangsu, 221002, People’s Republic of China, Tel +86-18052268331, Email gaofangxz@126.comBackground: Remifentanil-induced hyperalgesia (RIH) increases the risk of persistent postoperative pain, making early postoperative analgesic therapy ineffective and affecting postoperative patient satisfaction. This study aimed to verify the effects of gradual withdrawal of remifentanil combined with postoperative pump infusion of remifentanil on postoperative hyperalgesia and pain in patients undergoing laparoscopic hysterectomy.Methods: This trial was a factorial design, double-blind, randomized controlled trial. Patients undergoing laparoscopic hysterectomy were randomly allocated to the control group, postoperative pump infusion of remifentanil group, gradual withdrawal of remifentanil group, or gradual withdrawal plus postoperative pump infusion of remifentanil group (n = 35 each). The primary outcome was postoperative mechanical pain thresholds in the medial forearm. The secondary outcomes included postoperative mechanical pain thresholds around the incision, pain numeric rating scale scores, analgesic utilization, awakening agitation or sedation scores, a 15-item quality of recovery survey, and postoperative complications.Results: Gradual withdrawal of remifentanil significantly increased postoperative pain thresholds versus abrupt discontinuation (P < 0.05), whereas postoperative infusion did not show significant differences compared to the absence of infusion (P > 0.05). The combined gradual withdrawal and postoperative infusion group exhibited the highest thresholds and had the lowest postoperative pain scores and analgesic requirements as well as the highest quality of recovery scores (P < 0.05). No significant differences were observed for agitation scores, sedation scores, or complication rates (P > 0.05).Conclusion: The novel combined gradual withdrawal and postoperative infusion of remifentanil uniquely attenuates postoperative hyperalgesia, pain severity, analgesic necessity, and improves recovery quality after laparoscopic hysterectomy.Keywords: opioid-induced hyperalgesia, remifentanil-induced hyperalgesia, laparoscopic hysterectomy, mechanical pain thresholds, postoperative recovery

Xiaoli Wang,1,&ast; Heng Hu,1,2,&ast; Xinhui Yu,1 Chengcheng Liang,1 Yanquan Han,1 Hongxia Chen,1 Jijun Chu1 1The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, 230031, People’s Republic of China; 2Anhui University of Chinese Medicine, Hefei, Anhui, 230038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongxia Chen; Jijun Chu, Department of Gynaecology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, People’s Republic of China, Email 13305690727@163.com; chujijun8888@163.comEthnopharmacological Relevance: Zishen Yutai pills (ZYP), a traditional Chinese patent medicine, was listed in China in 1981. It is composed of 15 traditional Chinese medicines and has the effects of regulating menstruation, helping pregnancy, and preventing abortion. In clinical practice, it is effective in preventing habitual and threatened miscarriages, and continuing to explore its mechanism of action is very meaningful research.Aim of the Study: To explore the possible mechanism of ZYP promoting angiogenesis at the maternal-fetal interface in recurrent spontaneous abortion (RSA).Materials and Methods: In vitro experiments, placental trophoblast cells (PTCs) were isolated from the placental tissue of RSA mice and divided into six groups: Control group, Model group, ZYP group, miR-187 inhibitor NC group, miR-18 7 inhibitor group, and miR-187 inhibitor+ZYP group. Cell viability and cell cycle were measured using CCK8 and flow cytometry, respectively. The expression levels of miR-187, VEGF, VEGF-R1, and VEGF-R2 were measured using RT-qPCR, WB, and IF staining. Animal experiments first establish an RSA mice model (CBA/J × DBA/2) and then randomly divide the mice into four groups (n=10): normal pregnancy group, RSA model group, ZYP group, and progesterone capsule group. Observed the changes in embryo absorption rate, pathological morphology of decidual tissue, and ultrastructure of vascular endothelial cells in each group of mice. RT-qPCR, WB, and IF staining methods were used to determine the expression of miR-187, VEGF, VEGF-R1, and VEGF-R2.Results: In vitro, ZYP promoted the viability of PTCs and regulated their cell cycle, and ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2 levels. miR-187 inhibitor showed the same effects, and further ZYP intervention enhanced the effects. In vivo, ZYP remarkably reduced embryo resorption rates, and improved the pathological morphology of decidual tissues and ultrastructure of vascular endothelial cells. Moreover, ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2.Conclusion: In summary, ZYP can regulate the expression of VEGF via miR-187, then promote the angiogenesis at the maternal-fetal interface, and playing a therapeutic role in RSA. Keywords: recurrent spontaneous abortion, Zishen Yutai pills, miR-187, vascular endothelial growth factor, VEGF, angiogenesis

Chengying Hong,1 Yihan Xiong,2 Jinquan Xia,3 Wei Huang,4 Andi Xia,1 Shunyao Xu,1 Yuting Chen,1 Zhikun Xu,1 Huaisheng Chen,1 Zhongwei Zhang5 1Department of Critical Care Medicine, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, People’s Republic of China; 2Neurology Department, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, People’s Republic of China; 3Department of Clinical Medical Research Center, The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, People’s Republic of China; 4Department of Clinical Microbiology, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, People’s Republic of China; 5Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaCorrespondence: Huaisheng Chen, Department of Critical Care Medicine, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, People’s Republic of China, Email sunshinic@hotmail.com Zhongwei Zhang, Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China, Email 716461751@qq.comObjective: The objective of this study was to utilize LASSO regression (Least Absolute Shrinkage and Selection Operator Regression) to identify key variables in septic patients and develop a predictive model for intensive care unit (ICU) mortality.Methods: We conducted a cohort consisting of septic patients admitted to the ICU between December 2016 and July 2019. The disease severity and laboratory index were analyzed using LASSO regression. The selected variables were then used to develop a model for predicting ICU mortality. AUCs of ROCs were applied to assess the prediction model, and the accuracy, sensitivity and specificity were calculated. Calibration were also used to assess the actual and predicted values of the predictive model.Results: A total of 1733 septic patients were included, among of whom 382 (22%) died during ICU stay. Ten variables, namely mechanical ventilation (MV) requirement, hemofiltration (HF) requirement, norepinephrine (NE) requirement, septicemia, multiple drug-resistance infection (MDR), thrombocytopenia, hematocrit, red-cell deviation width coefficient of variation (RDW-CV), C-reactive protein (CRP), and antithrombin (AT) III, showed the strongest association with sepsis-related mortality according to LASSO regression. When these variables were combined into a predictive model, the area under the curve (AUC) was found to be 0.801. The AUC of the validation group was 0.791. The specificity of the model was as high as 0.953. Within the probability range of 0.25 to 0.90, the predictive performance of the model surpassed that of individual predictors within the cohort.Conclusion: Our findings suggest that a predictive model incorporating the variables of MV requirement, HF requirement, NE requirement, septicemia, MDR, thrombocytopenia, HCT, RDW-CV, CRP, and AT III exhibiting an 80% likelihood of predicting ICU mortality in sepsis and demonstrates high accuracy.Keywords: sepsis, mortality, LASSO regression, predictive model, ICU

Wei Li,1,&ast; Mingrui Lin,1,&ast; Jiapeng Li,2,&ast; Qihang Ding,2 Xiaoling Chen,3 Huaiyu Chen,1 Zhiqing Shen,1 Xueli Zhu1 1The People’s Hospital of Fujian Traditional Medical University, Fuzhou, Fujian, People’s Republic of China; 2Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 3Department of Infectious Disease, Fujian Medical University Union Hospital, Fuzhou, Fujian, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiqing Shen; Xueli Zhu, Email 1191863753@qq.com; zhuxueli19840205@163.comBackground: Xijiao Dihuang decoction (XJDHT), a traditional Chinese medicine, is widely used to treat patients with sepsis. However, the mechanisms underlying the effects of XJDHT on cardiac dysfunction have yet to be fully elucidated. The present study evaluated the potential utility of XJDHT in protecting against sepsis-induced cardiac dysfunction and myocardial injury.Methods: The mice were randomly divided into 3 groups and administered Lipopolysaccharide (LPS,10 mg/kg) or equivalent saline solution (control) and treated with XJDHT (10 g/kg/day) or saline by gavage for 72 hours. XJDHT was dissolved in 0.9% sodium chloride and administered at 200 μL per mouse. Transthoracic echocardiography, RNA-seq, TUNEL assays and hematoxylin and eosin (H&E) staining of cardiac tissues were performed.Results: Treatment with XJDHT significantly enhanced myocardial function and attenuated pathological change, infiltration of inflammatory cells, levels of TNF-α, IL-1β and expression of TLR4 and NF-κB in mice with sepsis. RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analyses identified 531 differentially expressed genes and multiple enriched signaling pathways including the PI3K/AKT pathway. Further, XJDHT attenuated cardiac apoptosis and decreased Bax protein expression while increasing protein levels of Bcl-2, PI3K, and p-AKT in cardiac tissues of mice with sepsis.Conclusion: In summary, XJDHT improves cardiac function in a murine model of sepsis by attenuating cardiac inflammation and apoptosis via suppressing the TLR4/NF-κB pathway and activating the PI3K/AKT pathway. Keywords: XJDHT, sepsis, inflammation, apoptosis, TLR4/NF-κB, PI3K/AKT pathway

Lingling Dong,1,&ast; Yong Wang,1,&ast; Haipin Chen,1 Zhouyang Li,1 Xuchen Xu,1 Jiesen Zhou,1 Huahao Shen,1,2 Zhihua Chen1 1Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhihua Chen, Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People’s Republic of China, Tel +86-571-8898-1913, Fax +86-571-8778-3729, Email zhihuachen@zju.edu.cnBackground: Macrophage-derived matrix metalloproteinase 12 (MMP12) can cause destruction of lung tissue structure and plays a significant role in the development and progression of chronic obstructive pulmonary disease (COPD). MTOR is a serine/threonine kinase that plays a crucial role in cell growth and metabolism. The activity of MTOR in the lung tissues of COPD patients also shows significant changes. However, it is unclear whether MTOR can regulate the development and progression of COPD by controlling MMP12. This study primarily investigates whether MTOR in macrophages can affect the expression of MMP12 and participate in the progression of COPD.Methods: We tested the changes in MTOR activity in macrophages exposed to cigarette smoke (CS) both in vivo and in vitro. Additionally, we observed the effect of MTOR on the expression of MMP12 in macrophages and on lung tissue inflammation and structural damage in mice, both in vivo and in vitro, using MTOR inhibitors or gene knockout mice. Finally, we combined inhibitor treatment with gene knockout to demonstrate that MTOR primarily mediates the expression of MMP12 through the NF-κB signaling pathway.Results: Exposure to CS can enhance MTOR activity in mouse alveolar macrophages. Inhibiting the activity of MTOR or suppressing its expression leads to increased expression of MMP12. Myeloid-specific knockout of MTOR expression can promote the occurrence of CS-induced pulmonary inflammation and emphysema in mice. Inhibiting the activity of NF-κB can eliminate the effect of MTOR on MMP12.Conclusion: Macrophage MTOR can reduce the expression of MMP12 by inhibiting NF-κB, thereby inhibiting the occurrence of COPD inflammation and destruction of lung tissue structure. Activating the activity of macrophage MTOR may be beneficial for the treatment of COPD.Keywords: matrix metalloproteinase 12, MMP12, pulmonary emphysema, cigarette smoke, CS, mechanistic target of rapamycin, MTOR

Shan Niu,1,&ast; Xiaoxiao Yin,1,&ast; Bing Pan,2 Haotian Chen,1 Chunxiao Dai,3 Chunnan Tong,4 Fang Chen,2 Xiuqin Feng1 1Nursing Department, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Psychiatry, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Clinical Psychology, Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Department of Psychiatry, The Second Hospital of Jinhua, Jinhua, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiuqin FengNursing Department, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang, People’s Republic of China, Email fengxiuqin@zju.edu.cnBackground: Non-suicidal self-injury (NSSI) and depression often co-occur among adolescents with more severe clinical symptoms. This study examined the network structures of NSSI and depressive symptoms in adolescents.Methods: Participants were recruited in the psychiatric outpatient clinics of three tertiary hospitals between April 10 and July 10, 2023. All participants been already found with self-injury behaviors in outpatient when enrolled. NSSI diagnostic criteria and Patient Health Questionnaire-9 (PHQ-9) were utilized to collect NSSI and depressive symptoms separately. We performed a network analysis to visualize the correlation between each symptom and to identify core and bridging symptoms in comorbidities.Results: A total of 248 patients were enrolled in the study, with a mean age of 15.48 (SD = 1.62). Based on the PHQ-9 scores and grades, our results showed that the incidence of depression in adolescents with non-suicidal self-injury behavior was relatively high (N=235, 94.76%), with the majority having severe depression. The network analysis revealed that nodes D-6 “feeling bad, failing or letting yourself or your family down”, D-1 “little interest or pleasure” and D-4 “feeling tired” were the most vital and most central symptoms. The most crucial bridging symptom is the node NSSI-8 “frequent thinking about self-injury”, which connects the NSSI to the depression comorbid network.Conclusion: This study offers a significant symptom-level conceptualization of the association between NSSI and depressive symptoms in a clinical sample of adolescents, which not only enhances our understanding of the comorbid but also identifies potential treatment targets to prevent and treat comorbidity between adolescent NSSI and depression.Keywords: non-suicidal self-injury, depression, comorbidity network, bridge symptoms, network analysis

Han Chen,1,2 Dan Cao,1,2 Ning Han,1,2 Mingming Zhang,1,2 Wei Jiang,1,2 Xin Wang,1,2 Qinmin Zeng,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Hong Tang, Email tanghong6198@wchscu.cnIntroduction: Hepatocellular carcinoma (HCC) is a solid tumor with a rich blood supply, and anti-angiogenesis has important clinical significance. Hepatitis B Virus-Encoded MicroRNA 3 (HBV-miR-3) has recently been reported to be involved in HCC development. In this study, we aim to elucidate the role of HBV-miR-3 in promoting HBV-related HCC angiogenesis through Factor Inhibiting Hypoxia-inducible factor 1 (FIH-1).Results: By analyzing HBV-related HCC tissue samples, we found that high expression of HBV-miR-3 was associated with poor overall survival and HBV-miR-3 expression was significantly correlated with VEGFR2 and FIH-1 expressions. In vitro, HBV-miR-3 agomir repressed FIH-1 expression and promoted HIF-1α/VEGFA signaling activation in HepG2 cells, resulting in increased HUVEC lumen formation in HepG2-HUVEC co-culture model. Conversely, HBV-miR-3 antagomir induced FIH-1 expression and inhibited HIF-1α/VEGFA signaling activation in HepG2.2.15 cells, resulting in decreased HUVEC lumen formation in HepG2.2.15-HUVEC co-culture model. The effect of HBV-miR-3 to HCC angiogenesis was also confirmed by a mouse tumor bearing model. We also confirmed that HBV-miR-3 repressed FIH-1 expression via targeting the 3’-UTR of FIH-1 mRNA by luciferase activity assay.Conclusion: HBV-miR-3 was related to HCC patients’ overall survival and it promoted angiogenesis by repressing FIH-1 expression. HBV-miR-3 may be a new marker for predicting prognosis and a novel target for anti-angiogenic treatment of HBV-related HCC. Keywords: HBV-miR-3, FIH-1, HBV-related HCC, angiogenesis

HongKui Chen,1,2,&ast; Xianwei Xie,2,3,&ast; Huazhen Xiao,1,2,&ast; Wenjia Liang,1,2 Zhi-Jie Lin,1,2 Biting Lin,2,3 Kai-Yang Lin,2,3 Chun Chen,4 Yansong Guo1,2 1Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350000, People’s Republic of China; 2Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases, Fuzhou, Fujian Province, 350000, People’s Republic of China; 3Fujian Heart Failure Center Al liance, Fuzhou, Fujian Province, 350000, People’s Republic of China; 4School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, 350000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yansong Guo; Chun Chen, Email ysguo1234@126.com; chenchun-0428@163.comBackground: As a chronic inflammatory disease, atherosclerosis (AS) and ischemia events are primarily affected by inflammation in AS. PANoptosis has been implicated in many human systemic disorders, including infection, cancer, neurodegeneration, and inflammation. On the other hand, little is understood about PANoptosis’s function in AS.Methods: We used consensus clustering to divide the GSE100927 dataset into two panoptosis-related subgroups. PANoptosis-associated genes were screened by differential analysis and weighted gene co-expression network analysis (WGCNA) and enriched by ClueGO software. Investigating LASSO regression and MCODE to identify AS Diagnostic Markers. Immunoinfiltration analysis and single-cell analysis were used to search for cell types associated with the diagnostic genes. Final validation was performed by polymerase chain reaction (PCR).Results: We classified the GSE100927 dataset into two PANoptosis-related subtypes based on the expression of PANoptosis-related genes (PRGs) using consensus clustering. A total of 36 PANoptosis-associated genes were screened in the differentially expressed genes and WGCNA-related module. 4 hub genes were identified by MCODE and LASSO regression, and 3 AS diagnostic markers (ACP5, CCL3, HMOX1) were screened by external validation set. Immunoinfiltration analysis and single-cell analysis showed that the three diagnostic markers were associated with macrophages, and PCR results demonstrated that ACP5 and HMOX1 could be used as AS diagnostic markers.Conclusion: Our study identified ACP5 and HMOX1 as diagnostic genes for AS that may be associated with PANoptosis. ACP5 and HMOX1 may be involved in the pathogenesis of AS by regulating macrophage PANoptosis.Keywords: atherosclerosis, PANoptosis, macrophage, subtypes

Chenglin Miao,1,&ast; Yali Cui,1– 3,&ast; Yingying Li,1 Qianqian Qi,1 Wenling Shang,1 Huilian Chen,2,3 Yujie Gao,2,3 Ruomei Yuan,2,3 Qichen Long,4 Wenjing Wu,1 Xia Wang,1 Ziyi Yan,1 Yongmei Jiang1,5 1Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Laboratory Medicine, Meishan Women and Children’s Hospital, Alliance Hospital of West China Second University Hospital, Sichuan University, Meishan, Sichuan Province, People’s Republic of China; 3Department of Laboratory Medicine, West China Second University Hospital (Tianfu), Sichuan University/Sichuan Provincial Children’s Hospital, Meishan, Sichuan Province, People’s Republic of China; 4Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 5Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ziyi Yan; Yongmei Jiang, Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China, Tel +86 28 8857050 ; +86 28 85501543, Email yan_z_y2@qq.com; jiangyongmeiwst@163.comPurpose: This study was designed to evaluate the immune protective efficacy of the novel Streptococcus pneumoniae (S. pneumoniae) protein vaccine PiuA-PlyD4 through immunoinformatics prediction and in vitro and in vivo experiments.Methods: In this study, we conducted immunoinformatics prediction and protection analysis on the fusion protein PiuA-PlyD4. The epitope composition of the vaccine was analyzed based on the prediction of B-cell and helper T-cell epitopes. Meanwhile, the molecular docking of PiuA and TLR2/4 was simulated. After immunizing C57BL/6 mice with the prepared vaccine, the biological safety, immunogenicity and conservation were evaluated. By constructing different infection models and from the aspects of adhesion inhibition and cytokines, the protective effect of the fusion protein vaccine PiuA-PlyD4 on S. pneumoniae infection was explored.Results: PiuA-PlyD4 has abundant B-cell and helper T-cell epitopes and shows a high antigenicity score and structural stability. Molecular docking analysis suggested the potential interaction between PiuA and TLR2/4. The specific antibody titer of fusion protein antiserum was as high as (7.81± 2.32) × 105. The protective effect of the immunized mice on nasal and lung colonization was significantly better than that of the control group, and the survival rate against S. pneumoniae infection of serotype 3 reached 50%. Cytokine detection showed that the humoral immune response, Th1, Th2 and Th17 cellular immune pathways were all involved in the process.Conclusion: The study indicates that PiuA-PlyD4, whether the results are predicted by immunoinformatics or experimentally validated in vivo and in vitro, has good immunogenicity and immunoreactivity and can provide effective protection against S. pneumoniae infection. Therefore, it can be considered a promising prophylactic vaccine candidate for S. pneumoniae.Keywords: Streptococcus pneumoniae, fusion protein vaccine, PiuA-PlyD4, immunoinformatics prediction, protective efficacy

Daniel Hsiang-Te Tsai,1,2 J Simon Bell,3 Shahab Abtahi,4 Brenda N Baak,5 Marloes T Bazelier,4 Ruth Brauer,6 Adrienne YL Chan,6– 9 Esther W Chan,9– 12 Haoqian Chen,13 Celine SL Chui,9,14,15 Sharon Cook,16 Stephen Crystal,16 Poonam Gandhi,13 Sirpa Hartikainen,17 Frederick K Ho,18 Shao-Ti Hsu,1 Jenni Ilomäki,3 Ju Hwan Kim,19 Olaf H Klungel,4 Marjaana Koponen,17 Wallis CY Lau,6,8,9 Kui Kai Lau,20,21 Terry YS Lum,22 Hao Luo,22 Kenneth KC Man,6,8,9 Jill P Pell,18 Soko Setoguchi,13,23 Shih-Chieh Shao,1,24 Chin-Yao Shen,1 Ju-Young Shin,19,25,26 Patrick C Souverein,4 Anna-Maija Tolppanen,17 Li Wei,6,9 Ian CK Wong,6,8,9,27 Edward Chia-Cheng Lai1 1School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Centre for Neonatal and Paediatric Infection, St George’s University of London, London, UK; 3Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia; 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; 5PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 6Research Department of Practice and Policy, UCL School of Pharmacy, London, UK; 7Groningen Research Institute of Pharmacy, Unit of Pharmacotherapy, ‐Epidemiology and ‐Economics, University of Groningen, Groningen, the Netherlands; 8Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 9Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong, Special Administrative Region, People’s Republic of China; 10Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 11Department of Pharmacy, the University of Hong Kong-Shenzhen Hospital, Shenzhen, People’s Republic of China; 12The University of Hong Kong Shenzhen Institute of Research and Innovation, Shenzhen, People’s Republic of China; 13Center for Pharmacoepidemiology and Treatment Science (PETS), Institute for Health, Rutgers University, New Brunswick, NJ, USA; 14School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 15School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 16Center for Health Services Research, Rutgers University, New Brunswick, NJ, USA; 17Kuopio Research Centre of Geriatric Care and School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 18School of Health and Wellbeing, University of Glasgow, Glasgow, UK; 19School of Pharmacy, Sungkyunkwan University, Suwon, South Korea; 20Division of Neurology, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 21State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 22Department of Social Work and Social Administration, University of Hong Kong, Hong Kong, Special Administrative Region, People’s Republic of China; 23Department of Medicine, Rutgers Robert Wood Johnson Medical School and Pharmacoepidemiology and Treatments Science, Institute for Health, Rutgers University, New Brunswick, NJ, USA; 24Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 25Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea; 26Department of Biohealth Regulatory Science, Sungkyunkwan University, Seoul, South Korea; 27Aston Pharmacy School, Aston University, Birmingham, UKCorrespondence: Edward Chia-Cheng Lai, School of Pharmacy and Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Email edward_lai@mail.ncku.edu.twPurpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN).Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives.Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK.Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.Keywords: meta-data, data repository, Neurological and Mental Health Global Epidemiology Network, NeuroGEN

Ying Wang,1 Xin Guo,1 Bo Chen,2 Hong Chen,3 Yanling Chen,1 Ling Ma,1 Huan Liu2 1Department of Rheumatology and Immunology, West China Hospital of Sichuan University/West China School of Nursing, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Rheumatology and Immunology, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3West China School of Nursing/West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Hong Chen, West China School of Nursing/West China Hospital, Sichuan University, No. 37, Guoxue Alley, Wuhou District, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86 18980601733, Email 1366109878@qq.comPurpose: Gout is more severe in men, leading to a poor quality of life. Previous studies did not sufficiently pay attention to the quality of life and related factors in gout patients in Southwest China. This study aimed to investigate the quality of life of men with gout in Southwest China and explore the relationship between psychosocial factors and health-related quality of life from the perspective of an information-motivation-behavioral skill model.Patients and Methods: This was a cross-sectional study conducted in the West China Hospital of Sichuan University located in Southwest China. In total, 230 male patients with gout were enrolled. The health-related quality of life of patients was assessed using the gout impact scale. The gout knowledge questionnaire was used to assess patients’ information. The positive psycap questionnaire was used to assess motivation. The gout patients’ self-management assessment scale was used to assess behavioral skills. Multiple linear regression was used to identify the factors associated with the health-related quality of life of patients.Results: The overall mean gout impact scale score was 52.7± 15.3 (maximum possible = 100). Factors associated with the total gout impact scale score were tophi (β=0.138, P=0.050), pain (β=0.255, P< 0.001), and resiliency (β=− 0.282, P< 0.001). In addition, demographic characteristics (educational level, smoking and marital status), clinical characteristics (tophi, pain, number of attacks over half a year, and number of affected joints) and psychosocial behavior variables (resiliency, hope, disease treatment management, diet management) were associated with several dimensions of the gout impact scale.Conclusion: The health-related quality of life of male patients with gout in Southwest China was at a medium level. We found that demographic characteristics, clinical characteristics, and psychosocial factors were associated with health-related quality of life of patients with gout. These findings can be used as a reference to improve health-related quality of life of patients with gout.Keywords: gout impact scale, gout knowledge level, positive psycap, self-management

Hao Chen,1,&ast; Xi Luo,1,&ast; Wei Cai,2,&ast; Shile Wang,3 Jingfeng Xiang,1 Zeming Liu,4 Daoming Zhu1,5 1Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China; 2Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 3Academy of Medical Sciences, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Plastic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 5Department of Electronic Science and Technology, School of Physics and Technology, Wuhan University, Wuhan, 430072, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zeming Liu; Daoming Zhu, Email zemingliutj@163.com; zhudaoming666@smu.edu.cnIntroduction: Photothermal therapy (PTT) has a significant potential for its application in precision tumour therapy. However, PTT-induced hyperthermia may damage healthy tissues and trigger the expression of heat shock proteins (HSPs), thereby compromising the long-term therapeutic efficacy of PTT.Methods: In this study, a biomimetic drug delivery system comprising CuP nanozymes as the inner core and platelet membrane (PM) as the outer shell was successfully developed for administering synergistic chemodynamic therapy and mild PTT. PM is encapsulated on CuP to form this biomimetic nanoparticle (PM-coated CuP nanoparticles, PC). PC possesses peroxidase (POD) activity, can facilitate the conversion of hydrogen peroxide into ·OH, thereby inhibiting the expression of HSPs.Results: Upon exposure to low-power laser irradiation (0.5 W/cm2, 1064 nm), PC can convert near-infrared II laser energy into heat energy, thereby enabling the administration of enhanced mild PTT. In vitro and in vivo experiments have demonstrated that this synergistic approach can induce over 90% tumour eradication with favourable biocompatibility.Discussion: PC exhibits high efficacy and biocompatibility, making it a promising candidate for future applications.Keywords: biomimetic nanoparticles, copper-doped polypyrrole nanoparticles, low-temperature photothermal therapy

Wan Tang,1,2 Hongdou Chen,1,2 Zixin Zhang,1,2 Gang Wu,1,2 Yanquan Lin1– 3 1Pharmacy, Suqian Hospital of Nanjing Drum-Tower Hospital Group, Suqian, People’s Republic of China; 2Pharmacy, Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, People’s Republic of China; 3Pharmacy, Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Hongdou Chen, Email chenhongdou2000@aliyun.comObjective: To analyse the relationship between the adverse drug reactions (ADRs) of essential drugs and visits, based on the recorded annual increase in ADRs associated with essential medicines in China, to provide a reliable theoretical basis for further analysis and optimization of the safety of essential drugs.Methods: The data of adverse reactions of essential drugs in China from 2011 to 2020, time series analysis was conducted, and vector autoregressive (VAR) model was established. The relationship between the number of ADRs and visits was explored empirically through Granger causality test, impulse response function and variance decomposition.Results: There was a long-term cointegration relationship and one-way causality between the number of visits and ADRs caused by essential medicines. In the initial stage, the ADR response to the number of visits increased sharply, but with an increase in the number of lag periods, the impact remained basically stable, even showing a slight decreasing trend.Conclusion: The number of visits impacts ADRs caused by essential medicines, but this impact remains basically stable after reaching a certain level.Keywords: essential medicines, adverse drug reactions, vector autoregressive model, time-series analysis

Meng Xu,1,&ast; Ke Che,1,&ast; Cong Wang,2,&ast; Ya-Ru Chen,1 Meng-Yuan Chen,1 Guang-Lei Zhang,1 Hao Yu,3 Hao-Nan Xu,1 Ya-Bao Li,1 Ping Sheng,1 Hao Chen1 1College of Life and Health Sciences, Anhui Science and Technology University, Fengyang, 233100, People’s Republic of China; 2School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 210094, People’s Republic of China; 3Bozhou University, Bozhou, 236800, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Chen; Ping Sheng, Email chenhao@ahstu.edu.cn; astu100@126.comIntroduction: Cholestasis is a common liver disorder that currently has limited treatment options. Gardenia Iridoid Glucosides (GIG) have been found to possess various physiological activities, such as cholagogic, hypoglycemic, antibacterial, and anti-inflammatory effects. The objective of this study was to investigate the effects of GIG on bile acid enterohepatic circulation and explore the underlying mechanism in cholestatic rats.Methods: In order to identify key pathways associated with cholestasis, we conducted Gene Ontology (GO) Enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. In vivo experiments were then performed on alpha-naphthylisothiocyanate (ANIT)-treated rats to assess the impact of GIG. We measured bile flow and various biomarkers including total bilirubin (TB), total bile acids (TBA), total cholesterol (TC), malondialdehyde (MDA), glutamic-pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), and total superoxide dismutase (T-SOD) in the serum. We also examined the expression levels of bile salt export pump (BSEP), ATP-binding cassette subfamily B member 4 (ABCB4), far-nesoid X receptor (FXR), small heterodimer partner (SHP), cholesterol 7α-hydroxylase (CYP7A1), and sodium taurocholate cotransporting polypeptide (NTCP) in liver tissue. In vitro experiments were conducted on primary hepatocytes to further investigate the mechanism of action of GIG on the expression of SHP, CYP7A1, NTCP, and FXR.Results: Our in vivo experiments demonstrated that GIG significantly increased bile flow and reduced the levels of TB, TBA, TC, MDA, GPT, and GOT, while increasing T-SOD levels in ANIT-treated rats. Addi-tionally, GIG ameliorated liver tissue damage induced by ANIT, upregulated the expression of BSEP and ABCB4, and modulated the protein expression of FXR, SHP, CYP7A1, and NTCP in model rats. In vitro experiments further revealed that GIG inhibited the expression of SHP, CYP7A1, and NTCP by suppressing the expression of FXR.Conclusion: This study provides new insights into the therapeutic potential of GIG for the treatment of cholestasis. GIG demonstrated beneficial effects on bile acid enterohepatic circulation and liver biomarkers in cholestatic rats. The modulation of FXR and its downstream targets may contribute to the mechanism of action of GIG. These findings highlight the potential of GIG as a therapeutic intervention for cholangitis.Keywords: Gardenia Iridoid Glucosides, FXR, SHP, cholestasis

Jiaojiao Dong,&ast; Zhousheng Jin,&ast; Hongfei Chen, Nana Bao, Fangfang Xia&ast; Department of Anesthesiology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fangfang Xia, Department of Anesthesiology, The First Affiliated Hospital, Wenzhou Medical University, Shangcai Village, Nanbaixiang Town, Ouhai District, Wenzhou, Zhejiang Province, 325000, People’s Republic of China, Email Helenxia4271@163.comPurpose: We examined whether the addition of sufentanil to local anesthetics improves the quality of continuous femoral nerve block in patients undergoing total knee arthroplasty (TKA).Patients and Methods: With institutional ethical approval and having obtained written informed consent from each, 35 patients scheduled for elective bilateral TKA with ASA I or II physical status were studied. Bilateral femoral perineural catheters were preoperatively inserted. Both-sided catheters were randomly assigned to receive perineural ropivacaine of 0.2% plus 0.5μg/mL sufentanil deemed as RS group or 0.2% ropivacaine alone deemed as R group at the end of surgery. Visual analogue pain scores (VAS) during activity and at rest of each lower limb were recorded at 6,12,18,24,30,36,42 and 48h after surgery. During the first 48 postoperative hours, the number and reason of patients sleep interruption at night, the number of painful compressions, patient satisfaction and morphine requirements were recorded for each lower limb of patients.Results: Pain scores of RS group on movement were significantly lower than R group, but no difference was noted at rest. When compared to R group, RS group had a lower incidence of sleep interruption at night, fewer painful compressions, higher satisfaction scores and less morphine requirement.Conclusion: The addition of sufentanil to ropivacaine improved analgesia quality of continuous femoral nerve block after arthroplasty. Keywords: continuous femoral nerve block, ultrasound guidance, total knee arthroplasty, analgesia, ropivacaine

Hongfeng Chen,1 Zhen Li,1 Xiaoqi Li,1 Jiongjiong Lu,1 Beibei Chen,1 Qiongchao Wang,1 Guangliang Wu2 1Department of Foot and Ankle Surgery, The Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, 462300, People’s Republic of China; 2Department of Orthopaedics, The Second Affiliated Hospital of Luohe Medical College, Luohe, Henan, 462300, People’s Republic of ChinaCorrespondence: Guangliang Wu, Department of Orthopaedics, The Second Affiliated Hospital of Luohe Medical College, Western Haihe Road, Luohe, Henan, 462300, People’s Republic of China, Email wuguangliang6@sina.comAbstract: Gene therapy has emerged as a promising and innovative approach in cartilage regeneration. Integrating biomaterials into gene therapy offers a unique opportunity to enhance gene delivery efficiency, optimize gene expression dynamics, modulate immune responses, and promote tissue regeneration. Despite the rapid progress in biomaterial-based gene delivery, there remains a deficiency of comprehensive discussions on recent advances and their specific application in cartilage regeneration. Therefore, this review aims to provide a thorough overview of various categories of biomaterials employed in gene delivery, including both viral and non-viral vectors, with discussing their distinct advantages and limitations. Furthermore, the diverse strategies employed in gene therapy are discussed and summarized, such as the utilization of growth factors, anti-inflammatory cytokines, and chondrogenic genes. Additionally, we highlights the significant challenges that hinder biomaterial-based gene delivery in cartilage regeneration, including immune response modulation, gene delivery efficiency, and the sustainability of long-term gene expression. By elucidating the functional properties of biomaterials-based gene therapy and their pivotal roles in cartilage regeneration, this review aims to enhance further advances in the design of sophisticated gene delivery systems for improved cartilage regeneration outcomes.Keywords: cartilage, regeneration, delivery systems, biomaterials, osteoarthritis

Xie Wang,1,&ast; Nan Shao,1,&ast; Xiaoyan Zhang,1,&ast; Hong Chen,1,&ast; Ze Chang,2,&ast; Daojun Xie,3 Juan Zhang3 1The First Clinical Medical College of Anhui University of Chinese Medicine, Hefei, 230038, People’s Republic of China; 2Xiyuan Hospital of China Academy of Traditional Chinese Medicine, Beijing, 100091, People’s Republic of China; 3Department of Neurology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, 230031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Daojun Xie, Department of Neurology, the First Affiliated Hospital of Anhui University of Chinese Medicine, 117 Meishan Road, Hefei, Anhui, People’s Republic of China, Email 482159505@qq.comBackground: Wilson’s disease (WD), an autosomal recessive genetic disease, is characterized by copper metabolism disorder. WD patients may have a series of cognitive deficits in terms of neurological symptoms. Ferroptosis (FPT), a type of programmed cell death, is involved in the pathological progression of various cognitive disorders, and silent information regulator 1 (SIRT1) is considered to be a key factor in FPT. Ferulic acid (FA) is a traditional Chinese medicine monomer, with a remarkable effect in the clinical treatment of cognitive impairment-related disease. However, its intrinsic effect on FPT is still unclear. This study aims to investigate the protective effect of FA on cognitive impairment in animal and cell models of WD, and whether the pharmacological mechanism is related to the SIRT1-mediated FPT signaling pathway.Methods: Copper-loaded WD rats and PC12 cells WD were used as models of cognitive dysfunction in vivo and in vitro, respectively. Morris Water Maze (MWM) was used to evaluate the spatial exploration and memory abilities of rats. HE staining was used to observe neuronal damage in the CA1 region of the rat hippocampus. Immunofluorescence (IF) was used to detect the expression of GPX4 protein. Transmission electron microscopy (TEM) was used to observe the ultrastructure of neurons. The levels of Fe2+, MDA, SOD, GSH, 4HNE, and ROS were detected. Western blot and qRT-PCR were used to detect the protein and mRNA levels of SIRT1, Nrf2, SCL7A11, and GPX4.Results: In the WD copper-loaded model rats, MWM, TEM, and IF results showed that FA could promote the repair of learning and memory function, improve the morphological damage to hippocampal neurons, and maintain mitochondria integrity. In the PC12 cell experiment, the MTT method showed that FA increased the viability of copper-overloaded cell models. Western blot and qRT-PCR results confirmed that FA significantly increased the expression of proteins and mRNA in SIRT1, Nrf2, SCL7A11, and GPX4. In addition, FA reversed the expression of oxidative stress-related indicators, including MDA, SOD, GSH, 4HNE, and ROS.Conclusion: FA alleviates hippocampal neuronal injury by activating SIRT1-mediated FPT, providing a valuable candidate for traditional Chinese medicine monomer for the clinical therapeutics of WD cognitive impairment.Keywords: ferulic acid, Wilson’s disease cognitive impairment, ferroptosis, SIRT1, PC12 cells

Huan He,1 Qichun Cui,1 Hengheng Chen,2,&ast; Xiao Huang,3,&ast; Shuai Wang,3,&ast; Tian Yu,2,&ast; Jinqiu Feng,3 Yun Shao1 1Department of Anesthesiology, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200002, People’s Republic of China; 2Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200002, People’s Republic of China; 3Department of Pediatric Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200002, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yun Shao, Department of Anesthesiology, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, No. 356 East Beijing Road, Shanghai, 200002, People’s Republic of China, Tel/Fax +86 2163295852, Email shaoyun07078@sina.com Jinqiu Feng, Department of Pediatric Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, No 356 East Beijing Road, Shanghai, 200002, People’s Republic of China, Tel/Fax +86 2163601149, Email feng_jinqiu356@fudan.edu.cnPurpose: Sevoflurane is the preferred anesthetic agent for induction and maintenance of ambulatory surgery due to its property of fast onset and recovery. However, it has been recognized as one of the major contributors of emergence delirium. The aim of this study was to evaluate the preventive effect of intranasal dexmedetomidine on the occurrence of emergence delirium in pediatric patients under general anesthesia with sevoflurane.Patients and Methods: Ninety pediatric patients undergoing dental rehabilitation under sevoflurane anesthesia were enrolled in this study. The patients were divided into three groups (n=30 each in the 2 μg/kg dexmedetomidine, 1 μg/kg dexmedetomidine, and control with saline groups). The same volume (0.02mL/kg) of the mixed solution was dropped into the nasal cavity of the children 30 minutes before surgery. We used the Pediatric Anesthesia Emergence Delirium Scale (PAED) to assess the level and incidence of delirium in the post-anesthesia care unit.Results: Compared with the control group, prophylactic use of different dosages of intranasal dexmedetomidine significantly reduces the incidence of ED and severe ED in PACU (P< 0.001). Intranasal administration of 2 μg/kg dexmedetomidine was associated with a better acceptance of mask induction and a better tolerance of separation with parents.Conclusion: Both 2 μg/kg and 1 μg/kg intranasal dexmedetomidine can achieve ED preventive effects in PACU in dental rehabilitation under general anesthesia. A dosage of 2 μg/kg is more effective in preventing severe ED and providing better mask acceptance.Keywords: intranasal dexmedetomidine, emergence delirium, sevoflurane anesthesia, pediatric patients, dental rehabilitation

Zishuai Li,1– 3,&ast; Zihan Zhang,4,&ast; Letian Fang,1– 3,&ast; Jiayi Zhao,1– 3,&ast; Zheyun Niu,4 Hongsen Chen,1– 3 Guangwen Cao1– 3 1Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 2Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 3Department of Epidemiology, Second Military Medical University, Shanghai, 200433, People’s Republic of China; 4Department of Epidemiology, Tongji University School of Medicine Tongji University, Shanghai, 200120, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangwen Cao, Department of Epidemiology, Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, People’s Republic of China, Tel/Fax +86 21-8187-1060, Email gcao@smmu.edu.cnAbstract: Globally, primary liver cancer is the third leading cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 75%– 95%. The tumor microenvironment (TME), composed of the extracellular matrix, helper cells, immune cells, cytokines, chemokines, and growth factors, promotes the immune escape, invasion, and metastasis of HCC. Tumor metastasis and postoperative recurrence are the main threats to the long-term prognosis of HCC. TME-related therapies are increasingly recognized as effective treatments. Molecular-targeted therapy, immunotherapy, and their combined therapy are the main approaches. Immunotherapy, represented by immune checkpoint inhibitors (ICIs), and targeted therapy, highlighted by tyrosine kinase inhibitors (TKIs), have greatly improved the prognosis of HCC. This review focuses on the TME compositions and emerging therapeutic approaches to TME in HCC. Keywords: hepatocellular carcinoma, tumor microenvironment, immunotherapy, targeted therapy

Qi Yang,1– 4 Yalan Luo,1– 3 Peng Ge,1– 3 Bowen Lan,1– 3 Jin Liu,1– 3 Haiyun Wen,1– 3 Yinan Cao,1– 3 Zhenxuan Sun,1– 3 Guixin Zhang,1– 3 Huiming Yuan,5 Lihua Zhang,5 Hailong Chen1– 3 1Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 2Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 3Laboratory of Integrative Medicine, the First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of China; 4Department of Traditional Chinese Medicine, the Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, People’s Republic of China; 5CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic Research and Analysis Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, 116023, People’s Republic of ChinaCorrespondence: Hailong Chen, Email chenhailong@dmu.edu.cnBackground: Numerous preclinical investigations have exhibited the beneficial impact of emodin (EMO) on the management of severe acute pancreatitis (SAP)-associated acute lung injury (ALI). However, the potential of EMO to mitigate organ damage through the modulation of exosome (Exo)-specific miRNA expression profiles remains unclear.Methods: The SAP rat model was established by retrograde injection of 5% sodium taurocholate into the pancreatic bile duct. Rats received intragastric administration of EMO at 2 h and 12 h post-modeling. Plasma and bronchoalveolar lavage fluid (BALF)-derived exosomes were isolated and purified from SAP rats treated with EMO. The therapeutic effects of these Exos in SAP rats were assessed using hematoxylin-eosin staining and measurement of inflammatory factor levels. MicroRNA (miRNA) sequencing was conducted on plasma and BALF-derived Exos, and rescue experiments were performed to investigate the function of NOVEL miR-29a-3p in the treatment of SAP using EMO.Results: EMO exhibits ameliorative effects on pancreatic and lung injury and inflammation in rats with SAP. Plasma/BALF-derived Exos from EMO-treated SAP rats also have therapeutic effects on SAP rats. The miRNA expression profile of plasma and BALF-derived Exos in SAP rats underwent significant changes upon exposure to EMO. In particular, 34 differentially expressed miRNAs (DEmiRNAs) were identified when comparing BALF-SAP+EMO-Exo and BALF-SAP-Exo. 39 DEmiRNAs were identified when comparing plasma-SAP+EMO-Exo to plasma-SAP-Exo. We found that SAP rats treated with Exos derived from BALF exhibited a more potent therapeutic response than those treated with Exos derived from plasma. EMO may rely on NOVEL-rno-miR-29a-3p expression to prevent pulmonary injury in SAP rats.Conclusion: The mechanism of action of EMO is observed to have a significant impact on the miRNA expression profile of Exos derived from plasma and BALF in SAP rats. NOVEL-rno-miR-29a-3p, which is specific to Exos, and is derived from BALF, may play a crucial role in the therapeutic efficacy of EMO. Plain Language Summary: Exosomes extracted from plasma/BALF of EMO-treated SAP rats show a substantial therapeutic impact on SAP-Associated ALI, with BALF-derived exosomes having a higher therapeutic effect than plasma-derived exosomes.EMO dramatically altered the miRNA expression patterns of plasma and BALF-derived exosomes in SAP rats.The lung protective effect of EMO in SAP rats is somewhat reliant on Novel-rno-miR-29a-3p expression.Keywords: severe acute pancreatitis, acute lung injury, emodin, exosome, microRNA

Yunxiang Zhou,1,2,&ast; Xianan Guo,1,2,&ast; Lu Shen,1,2 Kexin Liu,1,2 Qunan Sun,3 Yali Wang,4 Hui Wang,5 Wenyu Fu,6 Yihan Yao,7 Shijie Wu,2 Huihui Chen,1 Jili Qiu,1 Tao Pan,1 Yongchuan Deng1 1Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 2Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, People’s Republic of China; 5Department of Pathology, Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, People’s Republic of China; 6Department of Surgery, Hangzhou Fuyang Hospital of Traditional Chinese Medicine, Hangzhou, People’s Republic of China; 7Institute of Immunology, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongchuan Deng; Tao Pan, Email dyc001@zju.edu.cn; 2311318@zju.edu.cnBackground: Peripheral blood inflammation indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have become research hotspots in the diagnosis, treatment, and prognosis prediction of breast cancer, whereas existing research findings remain controversial.Methods: Data pertaining to 1808 breast cancer patients were collected retrospectively to analyze the predictive value of NLR/PLR/SII for breast cancer clinicopathological characteristics, chemotherapy response, and relapse. 1489, 258, and 53 eligible breast cancer patients entered into the three analyses, respectively. Logistic regression analyses were used to assess the correlation between these indices and poor response to chemotherapy. A predictive scoring model was established to predict chemotherapeutic responses based upon the odds ratio values of significant variables identified in logistic regression analyses.Results: Higher pretherapeutic NLR/PLR/SII values were significantly correlated with higher tumor stage, triple-negative breast cancer, premenopausal status, and younger age. Logistic regression analyses indicated that pretherapeutic high SII (as a continuous variable or with a cut-off value of 586.40) and HER2-negative status were independent predictors of poor response to neoadjuvant chemotherapy. A first-in-class SII-based predictive scoring model well distinguished patients who might not benefit from neoadjuvant chemotherapy, with an area under the curve of 0.751. In HR-positive cancers, SII was more strongly associated with clinicopathological features and chemotherapy response. In addition, a receiver operating characteristic curve analysis indicated that the specificity of follow-up SII in identifying cancer relapse was greater than 98.0% at a cut-off value of 900.Conclusion: As a predictor of breast cancer, especially in the HR-positive subtype, SII may eclipse NLR/PLR. SII-high patients are more likely to have a worse chemotherapy response and a higher risk of recurrence.Keywords: breast cancer, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, chemotherapy response, predictor

Jun Wang,1,&ast; Hongmei Chen,2,&ast; Lin Yang,2 Xiuli Yu,3 Dandan Zhang,3 Qinghua Zhao,1 Mingzhao Xiao4 1Department of Nursing, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Qinggang Senior Care Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingzhao Xiao, Department of Urology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, People’s Republic of China, Tel +8613608399433, Fax +86-23-89012206, Email mingzhaoxiao@cqmu.edu.cnAbstract: This paper aims to describe a randomized controlled trial protocol evaluating the effectiveness, cost, and process of a stress process model-based program in dementia caregiving (DeCare-SPM) for family caregivers. Family caregivers of individuals with dementia will be recruited from memory clinics and community settings and randomly assigned to either DeCare-SPM or usual care. DeCare-SPM comprises three face-to-face sessions (ie, problem-based coping, emotion-based coping, meaning-based coping), and a fourth session (ie, social support) including weekly telephone-based consultation for four weeks and then monthly face-to-face boosters. Outcomes will be measured at baseline (T0), and at one (T1), three (T2), and six months (T3). The primary outcome is positive aspects of caregiving and secondary outcomes are caregiving (ie, sense of competence, caregiver burden, social support, anxiety, depression, and quality of life), dementia-related (ie, care dependency, neuropsychiatric symptoms, and quality of life), and stress-related biomarkers of blood and saliva. In addition, process and economic evaluations will be performed. Mixed-effects models will be used to assess intervention effects. Content analysis will be performed on the qualitative data. This paper described the protocol for comprehensive evaluation of the effectiveness, cost, and process of the theory-driven DeCare-SPM to inform how and why interventions work. It highlights the need to reduce challenges and enhance the positive aspects of dementia care. The DeCare-SPM will provide evidence-based insights into how to support and empower family caregivers in their important roles, thereby, leading to improved dementia care.Keywords: Alzheimer’s disease, stress coping, informal caregivers, community, psychosocial

Lietao Wang,1,&ast; Xin Fu,1,&ast; Min He,1,&ast; Lvyuan Shi,1 Dingyuan Wan,1 Yucong Wang,1 Qin Wu,1 Jing Yang,1 Bayuan Cai,2 Hongtao Xia,3 Hongxu Chen,4 Ge Zhang,5 Xianying Lei,6 Wei Zhang,7 Zhongxue Feng,7 Bo Wang,1 Zhongwei Zhang1 On behalf of Heat Stroke Research Group in Southwestern China1Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Critical Care Medicine, The People’s Hospital of Jiajiang, Leshan, People’s Republic of China; 3Department of Critical Care Medicine, Suining Central Hospital, Suining, People’s Republic of China; 4Department of Critical Care Medicine, The Hospital of Traditional Chinese Medicine of Leshan, Leshan, People’s Republic of China; 5Department of Critical Care Medicine, The First People’s Hospital of Longquanyi District, Chengdu, People’s Republic of China; 6Department of Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 7Department of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bo Wang; Zhongwei Zhang, Department of Critical Care Medicine, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, People’s Republic of China, Tel/Fax +86-28-85422739, Email wchicu@126.com; 716461751@qq.comObjective: The aim of this nationwide multicenter study was to ascertain the risk factors associated with in-hospital mortality in patients with heat stroke admitted to intensive care units (ICUs) and to develop a nomogram for prognostic prediction.Methods: A retrospective analysis was conducted on clinical data collected from ICU patients diagnosed with heat stroke across multiple centers nationwide. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors for in-hospital mortality. Based on the results of the multivariate analysis, a nomogram was constructed to estimate the individualized probability of mortality. Internal validation of the nomogram was performed, and its performance was assessed using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA).Results: A total of 292 ICU patients with heat stroke were included in this study. Three risk factors, namely Cr (creatinine), AST (aspartate aminotransferase), and SBP (systolic blood pressure), were found to be significantly associated with in-hospital mortality. These risk factors were incorporated into the nomogram, which exhibited good discriminative ability (area under the ROC curve of the training and validation cohorts were 0.763 and 0.739, respectively) and calibration. Internal validation and decision curve analysis confirmed the stability and reliability of the nomogram.Conclusion: This nationwide multicenter study identified key risk factors for in-hospital mortality in ICU patients with heat stroke. The developed nomogram provides an individualized prediction of mortality risk and can serve as a valuable tool for clinicians in the assessment and management of ICU patients with heat stroke.Keywords: heat stroke, intensive care unit, in-hospital mortality, risk factors, nomogram

Hui Wang,1,&ast; Xiaonan Zhou,2,&ast; Xingyu Li,1,&ast; Zeng Xu,1,&ast; Qingbing Meng,3 Jianxi Wang,1 Xiaolong Shen,1 Huajiang Chen,1 Wen Yuan,1 Xiaodong Wu1 1Department of Orthopedics, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Anesthesiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Orthopedics, Shanghai Zhongshan Hospital, Fudan University Shanghai School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huajiang Chen; Xiaodong Wu, Email chenhuajspine@163.com; wuxiaodongspine@163.comIntroduction: Low back pain following transforaminal endoscopic lumbar discectomy (TELD) is prevalent (15– 25% incidence). Modifying TELD techniques to avoid excessive disc removal has been suggested to reduce such pain. Facet injury, re-herniation, and disc space collapse might contribute. This retrospective study aimed to explore factors linked to post-TELD low back pain.Methods: A total of 351 patients with L3/4, L4/5, and L5/S1 intervertebral lumbar disc herniations, who underwent TELD at two spine centers, were included. Patients were followed for one year. Low back and leg pain visual analogue scale (VAS) scores, Oswestry Disability Index (ODI), Pfirrmann grade, and disc height were measured at 3 months and 1 year. Correlation analyses examined links between postoperative low back pain VAS scores, age, sex, disc/vertebrae height ratio (D/V H ratio), Pfirrmann grade, cannula position grade, re-herniation grade, high-intensity zone (HIZ), disc calcification, surgical grade, and other factors. Significant variables were identified using partial least square tests, with variable importance in projection (VIP) values quantifying their impact on low back pain.Results: Univariate analysis indicated that surgical grade correlated with long-term postoperative low back pain (P = 0.023), while re-herniation (P = 0.008, P = 0.000), disc height (P = 0.001, P = 0.034), and sex (P = 0.025, P = 0.003) correlated with both short- and long-term postoperative low back pain. Trephine/cannula position is correlated with short-term low back pain (P = 0.036). Worsening low back pain was associated with female sex, improper trephine/cannula position, re-herniation, and post-surgical disc space collapse. Intradiscal irrigation was linked to decreased low back pain.Discussion: This study highlights factors influencing low back pain after TELD. Loss of disc height, extent of re-herniation, quality of trephine/cannula position, and sex were associated with low back pain at both 3 months and 1-year post-TELD. Proper techniques, like minimizing disc height loss and re-herniation, may help mitigate postoperative low back pain.Keywords: spine, endoscopy, radiology, minimally invasive surgical procedure, postoperative low back pain

Yanqing Ye,1,2,&ast; Ze-Lin Yan,3,&ast; Yuanshou Huang,2,&ast; Li Li,3 Shiming Wang,1 Xiaoxing Huang,1 Jingmeng Zhou,1 Liyi Chen,4 Chun-Quan Ou,3 Huaihong Chen1 1Department of Otorhinolaryngology-Head and Neck Surgery, Nan Fang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2Otolaryngology Department, Foshan Nan Hai District People’s Hospital, Foshan, People’s Republic of China; 3State Key Laboratory of Organ Failure Research, Department of Biostatistics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People’s Republic of China; 4Yidu Cloud Technology Ltd, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huaihong Chen, Department of Otorhinolaryngology Head and Neck Surgery, Nan fang Hospital, Southern Medical University, 1838 Guangzhou Avenue, Bai-Yun District, Guangzhou, People’s Republic of China, Email chh19760306@163.com Chun-Quan Ou, Department of Biostatistics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, 1838 Guangzhou Avenue, Bai-Yun District, Guangzhou, People’s Republic of China, Email ouchunquan@hotmail.comPurpose: Obstructive sleep apnea (OSA) is a disease with high morbidity and is associated with adverse health outcomes. Screening potential severe OSA patients will improve the quality of patient management and prognosis, while the accuracy and feasibility of existing screening tools are not so satisfactory. The purpose of this study is to develop and validate a well-feasible clinical predictive model for screening potential severe OSA patients.Patients and Methods: We performed a retrospective cohort study including 1920 adults with overnight polysomnography among which 979 cases were diagnosed with severe OSA. Based on demography, symptoms, and hematological data, a multivariate logistic regression model was constructed and cross-validated and then a nomogram was developed to identify severe OSA. Moreover, we compared the performance of our model with the most commonly used screening tool, Stop-Bang Questionnaire (SBQ), among patients who completed the questionnaires.Results: Severe OSA was associated with male, BMI≥ 28 kg/m2, high blood pressure, choke, sleepiness, apnea, white blood cell count ≥ 9.5× 109/L, hemoglobin ≥ 175g/L, triglycerides ≥ 1.7 mmol/L. The AUC of the final model was 0.76 (95% CI: 0.74– 0.78), with sensitivity and specificity under the optimal threshold selected by maximizing Youden Index of 73% and 66%. Among patients having the information of SBQ, the AUC of our model was statistically significantly greater than that of SBQ (0.78 vs 0.66, P = 0.002).Conclusion: Based on common clinical examination of admission, we develop a novel model and a nomogram for identifying severe OSA from inpatient with suspected OSA, which provides physicians with a visual and easy-to-use tool for screening severe OSA.Plain Language Summary: Question: How to build a more efficient screening model for severe OSA using some common variables for community physicians or non-sleep physicians?Findings: It was found that severe OSA was associated with male, BMI≥ 28 kg/m2, high blood pressure, choke, sleepiness, apnea, white blood cell count ≥ 9.5× 109/L, hemoglobin ≥ 175g/L, and triglycerides ≥ 1.7 mmol/L. The nomogram based on these variables was developed and validated. It seemed that our model outperformed the SBQ.Meaning: A clinically easy-to-use nomogram was provided for the screening of severe OSA in both non-sleep departments and community hospitals.Keywords: severe obstructive sleep apnea, clinical prediction model, nomogram

Zihan Hu,1,&ast; Danjiang Dong,2,&ast; Fei Peng,1,&ast; Xing Zhou,1 Qin Sun,1 Hui Chen,1,3 Wei Chang,1 Qin Gu,2,&ast; Jianfeng Xie,1,&ast; Yi Yang1,&ast; 1Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People’s Republic of China; 2Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China; 3Department of Critical Care Medicine, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianfeng Xie; Qin Gu, Department of Critical Care Medicine, Zhongda Hospital, School of medicine, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China, Tel/Fax +00862583262500, Email xie820405@126.com; guqinicu012323@126.comPurpose: Immune dysfunction plays a pivotal role in sepsis pathogenesis. Previous studies have revealed the crucial role of T cells and human leukocyte antigen-DR (HLA-DR) in sepsis. However, the function of natural killer (NK) cells remains unclear. This study aimed to investigate whether NK cells are associated with sepsis prognosis. In addition, we aimed to explore the interrelation and influence between NK and other immunological features in patients with sepsis.Patients and Methods: This retrospective, observational study included patients with sepsis from two hospitals in mainland China. The clinical characteristics and immune results during the early phase were collected. Patients were classified according to the level of immune cells to analyze the relationship between immunological features and 28-day mortality.Results: A total of 984 patients were included in this study. Non-survivors were older and had lower levels of lymphocytes, monocytes, NK cells, HLA-DR, and T cells. Patients were classified into eight groups according to their levels of NK cells, HLA-DR, and T cells. Only patients with decreased NK and T cell counts showed a significant increase in 28-day mortality. An increase in CD8+ T cells was correlated with the alleviation of 28-day mortality only among patients with high NK cell levels.Conclusion: This study provides novel insights into the association between NK cells and 28-day mortality as well as the interrelation between NK cells and other immune cells in sepsis. The relationship between CD8+ T cells and 28-day mortality in sepsis is dependent on NK cell count.Keywords: sepsis, immune dysfunction, natural killer cell, HLA-DR, T cell

Haoran Chen,1,2,&ast; Zhongyu Han,2,&ast; Yi Wang,1,&ast; Junyan Su,3 Yumeng Lin,4 Xuhua Cheng,1 Wen Liu,1 Jingyu He,5 Yiyue Fan,6 Liuyan Chen,2 Houdong Zuo1 1Department of Orthopaedics, Chengdu Xinhua Hospital, Chengdu, 610000, People’s Republic of China; 2School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, People’s Republic of China; 3Department of Orthopaedics, The First People’s Hospital of Longquanyi District, Chengdu, 610000, People’s Republic of China; 4School of Ophthalmology, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, People’s Republic of China; 5Sichuan Judicial and Police Officers Professional College, Deyang, 618000, People’s Republic of China; 6Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Houdong Zuo, Department of Orthopaedics, Chengdu Xinhua Hospital, Chengdu, 610000, People’s Republic of China, Email xhyyzhd@163.com Liuyan Chen, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, People’s Republic of China, Email Lycheecly@163.comAbstract: Ferroptosis is a new cell fate decision discovered in recent years. Unlike apoptosis, autophagy or pyroptosis, ferroptosis is characterized by iron-dependent lipid peroxidation and mitochondrial morphological changes. Ferroptosis is involved in a variety of physiological and pathological processes. Since its discovery, ferroptosis has been increasingly studied concerning bone-related diseases. In this review, we focus on the latest research progress and prospects, summarize the regulatory mechanisms of ferroptosis, and discuss the role of ferroptosis in the pathogenesis of bone-related diseases, such as osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), and osteosarcoma (OS), as well as its therapeutic potential.Keywords: ferroptosis, cell death, iron accumulation, lipid peroxidation, bone-related diseases

Si Liu,1,2 Xiao-yun Xiong,2 Hua Chen,1 Meng-die Liu,1 Ying Wang,1 Ying Yang,1 Mei-jun Zhang,1 Qin Xiang1 1School of Nursing, Nan Chang University, Nan Chang, Jiang Xi, People’s Republic of China; 2Nursing Department, the Second Affiliated Hospital of Nan Chang University, Nan Chang, Jiang Xi, People’s Republic of ChinaCorrespondence: Xiao-yun Xiong, Nursing Department, the Second Affiliated Hospital of Nan Chang University, Min de Road &num;, Nan Chang, 330006, People’s Republic of China, Tel +86-791-8627-4550, Email 1028970010@qq.comObjective: The purpose of this study was to clarify the concept of transitional care in patients with heart failure.Background: Transitional care is increasingly being applied in patients with heart failure, but the concept of transitional care in heart failure patients is not uniform and confused with other definitions, which limits further research and practice on transitional care for these patients.Design: Rodgers’ evolutionary concept analysis.Methods: A comprehensive literature search was conducted using the PUBMED, EMBASE, EBSCO, Chinese Biological Medicine (CBM), CNKI, and WANFANG databases (up to January 26, 2023). We used Rodgers’ evolutionary concept analysis method to identify related concepts, attributes, antecedents, and consequences of transitional care in patients with heart failure.Results: A total of 33 articles were included. The following attributes belonging to transitional care in patients with heart failure were extracted from the literature: self-care, multidisciplinary collaboration, and information transmission. The antecedents were patients’ health status, the health literacy of patients and caregivers, the role functions of the main implementer and social and medical resources. Consequences were separated into two categories: patient-centered health outcomes (all-cause mortality, health-related quality of life, discharge preparedness, self-care behaviors, satisfaction of patients) and healthcare utilization outcomes (hospital readmission, length of hospital stay, emergency department visits).Conclusion: This study found that transitional care in heart failure patients is a systemic care process during a vulnerable period that improves patient self-management and coordination between hospital resources and social support systems for continuous management to promote smooth patient transitions between different locations. This concept analysis will inform healthcare providers in designing evidence-based interventions and quality improvement strategies to ensure that transition processes lead to desired outcomes. In addition, this study will also be helpful for developing specific assessment tools to identify patients with HF who need transitional care.Keywords: concept analysis, heart failure, transitional care, self care, collaboration

Anqi Wang,1,&ast; Yujia Zhou,2,&ast; Huangying Chen,1 Jiawei Jin,1 Yingqi Mao,3 Shuiliang Tao,4 Tao Qiu5 1First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang, People’s Republic of China; 2Second Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang, People’s Republic of China; 3Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People’s Republic of China; 4Basic Medicine College, Zhejiang Chinese Medical University, Zhejiang, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shuiliang Tao, Basic Medicine College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, People’s Republic of China, Email lanethtao@163.com Tao Qiu, Department of Neurology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, People’s Republic of China, Email qiutao2002002@163.comPurpose: This study aimed to investigate the effect of small-conductance calcium-activated potassium channels (SK channels) on the dopaminergic (DA) neuron pathways in the ventral tegmental area (VTA) during the pathogenesis of post-stroke depression (PSD) and explore the improvement of PSD by inhibiting the SK channels.Patients and Methods: Four groups of Sprague-Dawley rats were randomly divided: Control, PSD, SK channel inhibitor (apamin) and SK channel activator (CyPPA) groups. In both control and CyPPA groups, sham surgery was performed. In the other two groups, middle cerebral arteries were occluded. The behavioral indicators related to depression in different groups were compared. Immunofluorescence was used to measure the activity of DA neurons in the VTA, while qRT-PCR was used to assess the expression of SK channel genes.Results: The results showed that apamin treatment improved behavioral indicators related to depression compared to the PSD group. Furthermore, the qRT-PCR analysis revealed differential expression of the KCNN1 and KCNN3 subgenes of the SK channels in each group. Immunofluorescence analysis revealed an increase in the expression of DA neurons in the VTA of the PSD group, which was subsequently reduced upon apamin intervention.Conclusion: This study suggests that SK channel activation following stroke contributes to depression-related behaviors in PSD rats through increased expression of DA neurons in the VTA. And depression-related behavior is improved in PSD rats by inhibiting the SK channels. The results of this study provide a new understanding of PSD pathogenesis and the possibility of developing new strategies to prevent PSD by targeting SK channels.Keywords: small conductance calcium-activated potassium channel, ventral tegmental area, dopamine, gating modulation, post-stroke depression

Yang Zhang,1,2,&ast; Anqing Lu,2– 4,&ast; Zixuan Zhuang,1,2 Su Zhang,5 Sicheng Liu,5 Haining Chen,1,2 Xuyang Yang,1,2 Ziqiang Wang1,2 1Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 3Department of Central Transportation, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 4West China School of Nursing, Sichuan University, Chengdu, 610041, People’s Republic of China; 5Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-Related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ziqiang Wang; Xuyang Yang, Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China, Email wangziqiang@scu.edu.cn; yangxuyang@wchscu.cnAbstract: Extracellular vesicles (EVs) are small membrane-bound vesicles that are released by cells into the extracellular environment. The role of EVs in tumors has been extensively studied, and they have been shown to play a crucial role in tumor growth, progression, and metastasis. Past research has mainly used 2D-cultured cell line models to investigate the role of EVs in tumors, which poorly simulate the tumor microenvironment. Organoid technology has gradually matured in recent years. Organoids are similar in composition and behavior to physiological cells and have the potential to recapitulate the architecture and function of the original tissue. It has been widely used in organogenesis, drug screening, gene editing, precision medicine and other fields. The integration of EVs and organoids has the potential to revolutionize the field of cancer research and represents a promising avenue for advancing our understanding of cancer biology and the development of novel therapeutic strategies. Here, we aimed to present a comprehensive overview of studies using organoids to study EVs in tumors.Keywords: organoids, extracellular vesicles, tumors, model, review

Hui Han,1 Penggang Lian,2 Haiyuan Chen,3 Bilal Haider Shamsi,4 Yonglin Liu,4 Yongliang Niu5 1Clinical Laboratory, Shenmu Hospital, the Affiliated Shenmu Hospital of Northwest University, Shenmu, 719300, People’s Republic of China; 2Otorhinolaryngologic Department, Shenmu Hospital, the Affiliated Shenmu Hospital of Northwest University, Shenmu, 719300, People’s Republic of China; 3Information Department, Shenmu Hospital, the Affiliated Shenmu Hospital of Northwest University, Shenmu, 719300, People’s Republic of China; 4Department of Science and Education, Shenmu Hospital, the Affiliated Shenmu Hospital of Northwest University, Shenmu, 719300, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Shenmu Hospital, the Affiliated Shenmu Hospital of Northwest University, Shenmu, 719300, People’s Republic of ChinaCorrespondence: Yongliang Niu, Tel/Fax +86-13892234287, Email niuyl7312@126.comBackground: Environmental factors and genetic predisposition can influence the occurrence and development of AR. Toll-like receptor 1 (TLR1) belongs to the TLR receptor family, which plays a fundamental role in the activation of innate immunity. This study aimed to explore the association between TLR1 genetic loci and AR susceptibility in the Han Chinese from northern China.Methods: Genotyping of three SNPs in the TLR1 has proceeded using the Agena MassARRAY platform. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the correlation between candidate SNPs and AR susceptibility. Using FPRP (false-positive report probability analysis) to detect whether the positive results are noteworthy findings. The SNP-SNP interactions were detected by multifactor dimensionality reduction (MDR).Results: TLR1-rs72493538 (Allele “G”: OR=0.77, p = 0.034) and -rs76600635 (Allele “G”: OR=0.75, p = 0.024) were associated with reducing the risk of AR among Han Chinese in northern China. In addition, we found evidence that TLR1-rs72493538 (males, participants with aging > 43 years, or coming from the wind-blown sand region) and -rs76600635 (males, participants with BMI ≤ 24 kg/m2, or coming from the wind-blown sand region) were associated with AR risk in stratified analyses. FPRP showed that all positive results are noteworthy findings. MDR analysis showed that a two-loci genetic model composed of rs72493538 and rs76600635 can be chosen as the best genetic model to predict the risk of AR.Conclusion: TLR1-rs72493538 and -rs76600635 have a close association with reducing the risk of AR.Keywords: allergic rhinitis, TLR1, susceptibility, case-control study

Xuan Zhang,1 Yaqing Lin,2 Huixin Chen,1 Jianhua Hu,1 Hong Zhao,1 Meifang Yang,1 Dongsheng Han3– 5 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Laboratory Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 4Key Laboratory of Clinical in vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, Zhejiang, People’s Republic of China; 5Institute of Laboratory Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Dongsheng Han, Centre of Clinical Laboratory, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel +86-571-87236394, Fax +86-571-87236394, Email hands@zju.edu.cnPurpose: Metagenomic next-generation sequencing (mNGS) has been widely used to diagnose infectious diseases. However, there are few studies on its diagnostic performance in the central nervous system (CNS) cryptococcosis. This study examined the diagnostic efficacy of mNGS in identifying Cryptococcus spp. in cerebrospinal fluid (CSF) samples.Patients and Methods: From March 2021 to March 2023, 290 patients with suspected CNS infection were recruited from the First Affiliated Hospital, School of Medicine, Zhejiang University, and 74 patients were ultimately included in the study. Lastly, 22 patients with CNS cryptococcosis were included. Of these patients, 25 CSF samples were enrolled. The diagnostic performance of conventional assays [including India ink, cryptococcal antigen (CrAg) testing, and culture] and mNGS was evaluated for CNS cryptococcosis.Results: In the 25 samples collected, the coincidence rates of mNGS with India ink, CrAg, and culture were 64.0% (16/25), 80.0% (20/25), and 80.0% (20/25), respectively. Without antifungal drug exposure, the coincidence rates were increased to 66.7% (10/15), 100.0% (15/15), and 93.3% (14/15), respectively. The coincidence rates after antifungal therapy were all decreased to 60.0% (6/10), 50.0% (5/10), and 60.0% (6/10), respectively. Moreover, in the 25 samples, the sensitivity of mNGS reached 80.0%, and of India ink, CrAg testing, and culture were 68.0, 100.0, and 60.0%, respectively. The mNGS showed an excellent positive rate (100.0%) in the 15 samples collected without antifungal drug exposure, which was significantly higher than the antifungal drug-exposed group (n = 10) (50.0%) (P = 0.005). The reads of Cryptococcus spp. before antifungal therapy were significantly higher than after it (median, 25,915 vs 2, P = 0.008).Conclusion: mNGS is an effective tool for diagnosing CNS cryptococcosis using CSF; however, its sensitivity decreases considerably in patients who have been effectively treated with antifungal drugs.Keywords: metagenomic next-generation sequencing, central nervous system cryptococcosis, cerebrospinal fluid, invasive fungal infection

Mengying Yao,1– 3,&ast; Dawei Lian,1– 3,&ast; Meizhu Wu,1– 3 Yuting Zhou,1– 3 Yi Fang,1– 4 Siyu Zhang,1– 3 Wenqiang Zhang,1– 3 Yanyan Yang,1– 4 Renfeng Li,1– 3 Hong Chen,1– 3 Youqin Chen,5 Aling Shen,1– 4 Jun Peng1– 3 1Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 2Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 3Fujian Collaborative Innovation Center for Integrative Medicine in Prevention and Treatment of Major Chronic Cardiovascular Diseases, Fuzhou, Fujian, People’s Republic of China; 4Innovation and Transformation Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of China; 5Department of Pediatrics, Case Western Reserve University School of Medicine, Rainbow Babies and Children’s Hospital, Cleveland, OH, USA&ast;These authors contributed equally to this workCorrespondence: Aling Shen; Jun Peng, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, People’s Republic of China, Tel +86 18050286255 ; +86 15806070011, Email saling86@hotmail.com; pjunlab@hotmail.comPurpose: This study aimed to investigate the molecular mechanisms of isoliensinine, a kind of bibenzyl isoquinoline alkaloid which isolated from a TCM named Lotus Plumule (Nelumbo nucifera Gaertn), in treating renal interstitial fibrosis (RIF) by using RNA sequencing, KEGG analysis and in vivo experimental approaches.Methods: Spontaneous hypertension rats (SHRs) were randomly assigned into five groups, consisting of SHR, SHR+Isoliensinine-L (2.5 mg/kg/day), SHR+Isoliensinine-M (5 mg/kg/day), SHR+Isoliensinine-H (10 mg/kg/day), and SHR+Valsartan (10 mg/kg/day) groups (n = 6 for each group). A control group of Wistar Kyoto rats (n = 6) was also included. Rats were treated intragastrically with isoliensinine, valsartan, or double-distilled water of equal volume for 10 weeks. To examine the therapeutic impact on hypertensive renal injury, fibrosis, and its underlying mechanisms, multiple techniques were employed, including hematoxylin and eosin staining, Masson trichrome staining, RNA sequencing, gene ontology (GO) function and pathway enrichment analysis and immunohistochemistry.Results: Resultantly, the use of isoliensinine at different concentrations or valsartan showed significant improvement in renal pathological injury in SHRs. RNA sequencing and KEGG analysis uncovered 583 differentially expressed transcripts and pathways enriched in collagen formation and ECM–receptor interaction after treatment with isoliensinine. There was also a reduction in the increase of collagen and upregulation of collagen I & III, TGF-β 1, p-Smad2, and p-Smad3 in the renal tissue of SHRs. Thus, isoliensinine ameliorated renal injury and collagen deposition in hypertensive rats, and inhibiting the activation of the TGF-β 1/Smad2/3 pathway might be one of the underlying mechanisms.Conclusion: This study showed that treatment with isoliensinine effectively reduced the renal injury and fibrosis in SHRs. In addition, isoliensinine inhibited the TGF-β 1/Smad2/3 signaling in-vivo. These findings provided strong evidence for the therapeutic benefits of isoliensinine in combating renal injury and fibrosis.Graphical Abstract: Keywords: isoliensinine, RNA sequencing, hypertension, renal injury, TGF-β 1/Smad2/3 pathway, collagen deposition

Yuanli Li,1,&ast; Xiaoyi He,2,&ast; Ling Deng,2 Hai Chen,1 Xi Chen,1 Xuhu Mao,2 Yang Xiang2 1Department of Clinical Laboratory, Sanya People’s Hospital, Sanya, Hainan, People’s Republic of China; 2Department of Clinical Microbiology and Immunology, College of Pharmacy and Laboratory Medicine Science, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Xiang, Email xiangyang@tmmu.edu.cnAbstract: Burkholderia pseudomallei, the causative agent of melioidosis can be responsible for a wide spectrum of clinical manifestations and heterogeneous prognoses, with a high mortality in the acute onset. We report a case of a deep abdominal abscess with sepsis secondary to melioidosis in a young farmer from a non-high-risk population. Emergency medical treatment was administered according to the detection of serum antibodies against Hcp1, the results of which provided etiological evidence of B. pseudomallei infection for the timely and properly antimicrobial therapy in the absence of direct evidence of melioidosis. To our knowledge, this is the first reported case of serodiagnosis of acute exacerbation of melioidosis in China.Keywords: melioidosis abscess, serodiagnosis, Burkholderia pseudomallei, antibody detection, Hcp-1

Yewei Fang,1 Shuan Tao,2 Huimin Chen,2 Yao Xu,3 Luyan Chen,4 Wei Liang1 1Department of Clinical Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China; 2School of Medicine, Jiangsu University, Zhejiang, People’s Republic of China; 3School of Medicine, Ningbo University, Ningbo, People’s Republic of China; 4Department of Blood Transfusion, The First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Wei Liang, Department of Clinical Laboratory, The First Affiliated Hospital of Ningbo University, No. 59. Liuting Road, Haishu District, Zhejiang, 315010, People’s Republic of China, Tel +86 15351883016, Fax +86-51885213100, Email hslwys@163.comPurpose: The objectives of this study are to determine the differences in clonality, virulence gene (VG) content and phylogenetic group between non extended-spectrum beta-lactamase-producing E. coli (non-ESBL-EC) and ESBL-EC isolates from urine.Patients and Methods: This study characterized a total of 100 clinical E. coli isolates consecutively obtained from the inpatients hospitalized in The First Affiliated Hospital of Ningbo University in China by polymerase-chain reaction (PCR).Results: Phylogenetic group B2 was found to be the most prevalent in both ESBL-EC and non-ESBL-EC group. Among 100 clinical isolates, the count of acquired virulence genes in group B2 was found to be significantly higher than that in group A, B1, and D (p < 0.001). Additionally, the presence of content within virulence genes (the total number of virulence genes detected per isolate) in B2 of non-ESBL-EC and ESBL-EC showed a significant difference (p< 0.001). ST131 was detected exclusively in ESBL-EC, while ST95 and ST73 were the main sequence types in non-ESBL-EC.Conclusion: Our study demonstrated the different distribution of MLST, phylogenetic group in ESBL-EC and non-ESBL-EC group. The inverse association between beta-lactamase resistance and VG content performed in this study should get a lot more attention. At the same time, we should also be wary of the appearance of non-ESBL-EC isolates of group B2 harboring more virulence genes which will lead to high pathogenicity.Keywords: E. coli, clonal structure, ST73, ST95, ST131, ST1193, virulence genes