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Aijia Wang,1 Kai Qin,2 Simin Ma3 1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, People’s Republic of China; 2Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Department of Nosocomial Infection Management, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Kai Qin, Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email gczxqk@163.com Simin Ma, Department of Nosocomial Infection Management, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email masimimsm@126.comBackground: Using antimicrobials wisely is crucial for effective treatment and reducing antimicrobial resistance (AMR). As ocular infections can lead to serious consequences and ophthalmic surgery has a great impact on patients, the application of antimicrobials in ophthalmology needs to be managed in a standardized manner.Methods: A multidisciplinary team (MDT) on antimicrobial stewardship was set up by adopting comprehensive management measures and a continuous improvement model with all-staff training and empowerment, information-assisted medical prescription control, and transparent supervision.Results: After intervention, the antibiotics use density, antibiotics utilization rate and antibiotics prophylactic utilization rate for type I incision operation among inpatients decreased from 30.02%, 49.64% and 58.04% in 2018 to 8.78% (decrease by 70.77%), 18.31% (p < 0.001) and 8.93% (p < 0.001) in 2022, respectively; the microbiological submission rate related to antibiotics utilization, etiological submission rate before antibiotic therapy and before combined use of key antibiotics rose from 13.44%, 17.39% and 50.00% to 27.33% (p < 0.001), 51.3% (p < 0.001) and 100.00% (increase by 100%), respectively; the incidence of nosocomial infection and surgical site infection for type I incision operation both reduced to zero, while the use of hand hygiene products markedly increased. For pathogen detection, a total of 489 pathogens were isolated from 2018 to 2022, of which 69.30% were Gram-positive bacteria, 26.02% were Gram-negative bacteria, and 4.68% were fungi. Ocular secretion was the main detection site (89.31%). Antibiotic resistance analysis results indicated that Staphylococci maintained complete sensitivity to linezolid, vancomycin, and teicoplanin. Streptococcus pneumoniae maintained complete sensitivity to vancomycin, benzathine, levofloxacin, and moxifloxacin, with resistance to penicillin G and ceftriaxone down to zero.Conclusion: Multidisciplinary team and information-assisted transparent supervision have displayed obvious effects in promoting the standardized application of antimicrobials in ophthalmology, via distinctly improving indicators relevant to antimicrobial application and nosocomial infection. Our work may provide guidance for improving the medical quality and curbing the AMR.Keywords: antimicrobial stewardship, nosocomial infection, transparent supervision, multidisciplinary team, ophthalmology

Shumeng Ma, Ning Jia College of Education, Hebei Normal University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Ning Jia, College of Education, Hebei Normal University, Shijiazhuang, 050024, People’s Republic of China, Email jianing@hebtu.edu.cnBackground: In China, as educational reforms progress, the characteristics of teachers’ work have undergone significant changes, resulting in extremely high levels of stress that can trigger anxiety and depression. Anxiety and depression often co-occur, with two mainstream theories explaining this co-existence: the tripartite model and the diathesis-stress model. However, systematic research focusing on this population is relatively scarce, and the applicability of these models has not been thoroughly tested. This study aims to use network analysis methods to examine the interactions between symptoms and analyze the co-existence of anxiety and depression, thereby expanding the research on teachers.Methods: Data were provided by the Science Database of People Mental Health, which includes 1670 teachers with a mean age of 30.01. The Self-Rating Anxiety Scale and Self-Rating Depression Scale were used to estimate the network structures of anxiety and depression, respectively. Shared symptoms between depression and anxiety were identified using network analysis and clique percolation methods. Bayesian Networks was used to estimate causal relationships between symptoms. Data were analyzed using R packages. Network structure was constructed with the qgraph package, node centrality and bridge symptoms were evaluated using the networktools package, and network stability was measured via the bootnet package. The Clique Percolation method was implemented with the CliqurPercolation package, and Bayesian network modeling was performed via the Bnlearn package.Results: Dizziness and Easy Fatigability & Weakness were central symptoms in the network. Bridging strength results showed that, the important bridging symptoms included Tachycardia, Depressed Affect, Fatigue, Crying Spell, Easy Fatigability & Weakness, Nightmares, Face Flushing, and Sweating were the strong bridging symptoms. Additionally, Sleep Disturbance played a key mediating role. Depressed Affect and Dissatisfaction were activation symptoms for anxiety-depression co-existence.Conclusion: Using network analysis, this study elucidated core, bridging, and shared symptoms, as well as potential causal pathways between anxiety and depression. Specifically, somatic symptoms are crucial in maintaining and developing the anxiety-depression network among teachers. Sleep disturbance serves as the sole gateway for mild symptoms to develop into other communities. The Bayesian network identified two key activating symptoms within the teacher anxiety-depression network, validating the applicability of the tripartite model among teachers.Keywords: network analysis, teachers, depression, anxiety, co-existence

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

Jie Jin,1 Jie Lu,1 Xinyang Su,2 Yinhuan Xiong,3 Shasha Ma,4 Yang Kong,5 Hongmei Xu1 1School of Nursing, Binzhou Medical University, Binzhou, People’s Republic of China; 2Department of Spine Surgery, Binzhou Medical University Hospital, Binzhou, People’s Republic of China; 3Department of Nursing, Binzhou People’s Hospital, Binzhou, People’s Republic of China; 4Department of Neurosurgery, Binzhou Medical University Hospital, Binzhou, People’s Republic of China; 5School of Health Management, Binzhou Medical University, Yantai, People’s Republic of ChinaCorrespondence: Hongmei Xu, School of Nursing, Binzhou Medical University, No. 525 Huanghe 3rd Road, Binzhou, 256600, People’s Republic of China, Tel +86-13754689536, Email hmx58@163.com Yang Kong, School of Health Management, Binzhou Medical University, No. 346 Guanhai Road, Yantai, 264003, People’s Republic of China, Tel +86-13773576163, Email kongyang@bzmc.edu.cnPurpose: The purpose of this study was to establish and validate machine learning-based models for predicting the risk of venous thromboembolism (VTE) in intensive care unit (ICU) patients.Patients and Methods: The clinical data of 1494 ICU patients who underwent Doppler ultrasonography or venography between December 2020 and March 2023 were extracted from three tertiary hospitals. The Boruta algorithm was used to screen the essential variables associated with VTE. Five machine learning algorithms were employed: Random Forest (RF), eXtreme Gradient Boosting (XGBoost), Support Vector Machine (SVM), Gradient Boosting Decision Tree (GBDT), and Logistic Regression (LR). Hyperparameter optimization was conducted on the predictive model of the training dataset. The performance in the validation dataset was measured using indicators, including the area under curve (AUC) of the receiver operating characteristic (ROC) curve, specificity, and F1 score. Finally, the optimal model was interpreted using the SHapley Additive exPlanation (SHAP) package.Results: The incidence of VTE among the ICU patients in this study was 26.04%. We screened 19 crucial features for the risk prediction model development. Among the five models, the RF model performed best, with an AUC of 0.788 (95% CI: 0.738– 0.838), an accuracy of 0.759 (95% CI: 0.709– 0.809), a sensitivity of 0.633, and a Brier score of 0.166.Conclusion: A machine learning-based model for prediction of VTE in ICU patients were successfully developed, which could assist clinical medical staff in identifying high-risk populations for VTE in the early stages so that prevention measures can be implemented to reduce the burden on the ICU patients.Keywords: venous thromboembolism, machine learning, algorithm, prediction model, intensive care unit

Boye Zhang,1,2 Jianliang Man,3,4 Lingyun Guo,1 Xiaoxia Ru,1 Chengwu Zhang,1,2 Wen Liu,1,2,5 Lihong Li,1,2,5 Sufang Ma,1,2 Lixia Guo,2,4 Haojiang Wang,1,2 Bin Wang,1,2 Haipeng Diao,1,5 Renchao Che,6,7 Lili Yan1,2,5 1School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 2Shanxi Province Brain Degenerative Diseases Precision Diagnosis and Treatment Engineering Research Center, Shanxi Medical University, Jinzhong, 030606, People’s Republic of China; 3Academy of Medical Sciences, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 4College of Pharmacy, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 5Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, People’s Republic of China; 6Laboratory of Advanced Materials, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Academy for Engineering &Technology, Fudan University, Shanghai, 200438, People’s Republic of China; 7Zhejiang Laboratory, Hangzhou, 311100, People’s Republic of ChinaCorrespondence: Lili Yan; Renchao Che, Email yanlili@sxmu.edu.cn; rcche@fudan.edu.cnBackground: Challenges such as poor drug selectivity, non-target reactivity, and the development of drug resistance continue to pose significant obstacles in the clinical application of cancer therapeutic drugs. To overcome the limitations of drug resistance in chemotherapy, a viable treatment strategy involves designing multifunctional nano-platforms that exploit the unique physicochemical properties of tumor microenvironment (TME).Methods: Herein, layer-by-layer nanoparticles with polyporous CuS as delivery vehicles, loaded with a sonosensitizer (tetra-(4-aminophenyl) porphyrin, TAPP) and sequentially functionalized with pH‐responsive CaCO3, targeting group hyaluronic acid (HA) were designed and synthesized for synergistic treatment involving chemodynamic therapy (CDT), sonodynamic therapy (SDT), photothermal therapy (PTT), and calcium overload. Upon cleavage in an acidic environment, CaCO3 nanoparticles released TAPP and Ca2+, with TAPP generating 1O2 under ultrasound trigger. Exposed CuS produced highly cytotoxic ·OH in response to H2O2 and also exhibited a strong PTT effect.Results: CuS@TAPP-CaCO3/HA (CTCH) delivered an enhanced ability to release more Ca2+ under acidic conditions with a pH value of 6.5, which in situ causes damage to HeLa mitochondria. In vitro and in vivo experiments both demonstrated that mitochondrial dysfunction greatly amplified the damage caused by reactive oxygen species (ROS) to tumor, which strongly confirms the synergistic effect between calcium overload and reactive oxygen therapy.Conclusion: Collectively, the development of CTCH presents a novel therapeutic strategy for tumor treatment by effectively responding to the acidic TME, thus holding significant clinical implications.Keywords: mitochondria damage, calcium overload, reactive oxygen oncotherapy, pH-responsive, synergistic treatment

Shixin Ma,1,2 Fei Li,2 Lunqing Wang2 1Graduate School, Dalian Medical University, Dalian, Liaoning, 116000, People’s Republic of China; 2Department of Thoracic Surgery, Qingdao Municipal Hospital, Qingdao, Shandong, 266071, People’s Republic of ChinaCorrespondence: Lunqing Wang, Department of Thoracic Surgery, Qingdao Municipal Hospital, No. 5 Donghai Middle Road, Qingdao, People’s Republic of China, Tel +86 532 87077952, Email wanglunqing1973@163.comPurpose: The purpose of this study was to investigate the predictive value of Pan-Immune-Inflammation Value (PIV) combined with the PILE score for immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and to construct a nomogram prediction model to provide reference for clinical work.Patients and Methods: Patients with advanced NSCLC who received ICIs treatment in Qingdao Municipal Hospital from January 2019 to December 2021 were selected as the study subjects. The chi-square test, Kaplan-Meier survival analysis, and Cox proportional risk regression analysis were used to evaluate the prognosis. The results were visualized by a nomogram, and the performance of the model was judged by indicators such as the area under the subject operating characteristic curve (AUC) and C-index. The patients were divided into high- and low-risk groups by PILE score, and the prognosis of patients in different risk groups was evaluated.Results: Multivariate Cox regression analysis showed that immune-related adverse events (irAEs) were prognostic factors for overall survival (OS) improvement, and ECOG PS score ≥ 2, bone metastases before treatment, and high PIV expression were independent risk factors for OS. The C index of OS predicted by the nomogram model is 0.750 (95% CI: 0.677– 0.823), and the Calibration and ROC curves show that the model has good prediction performance. Compared with the low-risk group, patients in the high-risk group of PILE were associated with a higher inflammatory state and poorer physical condition, which often resulted in a poorer prognosis.Conclusion: PIV can be used as a prognostic indicator for patients with advanced NSCLC treated with ICIs, and a nomogram prediction model can be constructed to evaluate the survival prediction of patients, thus contributing to better clinical decision-making and prognosis assessment.Keywords: non-small cell lung cancer, immune checkpoint inhibitors, pan-immune-inflammation value, prognosis, nomogram

David Singer,1 Philippe Thompson-Leduc,2 Siyu Ma,1,3 Deepshekhar Gupta,4 Wendy Y Cheng,5 Selvam R Sendhil,6 Manasvi Sundar,6 Ella Hagopian,5 Nikita Stempniewicz,1 Mei Sheng Duh,5 Sara Poston1 1GSK, US Health Economics and Outcomes Research, Philadelphia, PA, USA; 2Analysis Group, Inc., Health Economics and Outcomes Research, Montreal, QC, Canada; 3Tufts Medical Center, Boston, MA, USA; 4Analysis Group, Inc., Health Economics and Outcomes Research, Menlo Park, CA, USA; 5Analysis Group, Inc., Health Economics and Outcomes Research, Boston, MA, USA; 6Analysis Group, Inc., Health Economics and Outcomes Research, Los Angeles, CA, USACorrespondence: Nikita Stempniewicz, GSK, US Health Economics and Outcomes Research, FMC Tower Suite 1700, 2929 Walnut Street, Philadelphia, PA, 19104, USA, Tel +1 203 803 9909, Email nikita.x.stempniewicz@gsk.comPurpose: Patients with psoriasis (PsO) and psoriatic arthritis (PsA) are at increased risk of herpes zoster (HZ), but healthcare resource use (HRU) and costs relating to HZ in adults with PsA are unknown. We aimed to estimate the incidence of HZ among adults with PsA vs without psoriatic disease and the additional HRU and costs among patients with PsA with vs without HZ.Patients and Methods: This retrospective, longitudinal, cohort study estimated HZ incidence in PsA+ vs PsO–/PsA– cohorts and HRU and medical/pharmacy costs among PsA+/HZ+ vs PsA+/HZ– cohorts comprised of adults from Optum’s de-identified Clinformatics Data Mart Database during 2015– 2020. For the HRU/cost analyses, index was the date of first HZ diagnosis (PsA+/HZ+ cohort) or was randomly assigned (PsA+/HZ– cohort). Generalized linear models were used for adjusted comparisons between cohorts.Results: HZ incidence was higher in the PsA+ (n = 57,126) vs PsO–/PsA– (n = 23,837,237) cohort (14.85 vs 7.67 per 1000 person-years; adjusted incidence rate ratio [aIRR]: 1.23; 95% confidence interval [CI]: 1.16– 1.30). Numbers of outpatient visits, emergency department visits, and inpatient admissions were significantly higher in the PsA+/HZ+ (n = 1045) vs PsA+/HZ– (n = 36,091) cohorts during the first month after HZ diagnosis (outpatient: aIRR: 1.74; 95% CI: 1.63– 1.86; emergency department: 3.14; 95% CI: 2.46– 4.02; inpatient: aIRR: 2.61; 95% CI: 1.89– 3.61). Mean all-cause per-patient costs were significantly higher in the PsA+/HZ+ vs PsA+/HZ– cohorts during the first month after index (&dollar;6493 vs &dollar;4521; adjusted cost difference: &dollar;2012; 95% CI: &dollar;1204–&dollar;3007). HRU and costs were numerically higher in the PsA+/HZ+ cohort during the first 3 and 12 months.Conclusion: These findings, which provide evidence on the increased incidence and HRU and economic burden associated with HZ among adults with PsA, could be used to inform clinical practice and decision-making.Plain Language Summary: Why was the study done?Psoriatic arthritis affects the joints of around 20% of patients with the skin condition, psoriasis.Patients with psoriatic arthritis are at increased risk of shingles, which can cause a painful skin rash and complications.This study aimed to provide information on how many patients with psoriatic arthritis get shingles and the healthcare use and costs of caring for patients with psoriatic arthritis and shingles.What did the researchers do and find?Using data from a large US health plan database, we estimated that for every 1000 patients with psoriatic arthritis observed for 1 year, 15 will develop shingles.Patients with psoriatic arthritis were 23% more likely to develop shingles than people without psoriatic disease.Patients with psoriatic arthritis and shingles had 2– 3 times as many healthcare visits in the month after a shingles diagnosis as patients with psoriatic arthritis but no shingles.This resulted in an average additional cost of approximately &dollar;2000 per patient.What do these results mean?Psoriatic arthritis increases the risk of shingles.The costs associated with shingles in patients with psoriatic arthritis are substantial.Measures to prevent shingles in this population could be beneficial. Keywords: claims database, costs, healthcare resource use, incidence, psoriatic arthritis, United States

Ruiwei Guo,1,2 Jin Wu,1,2 Yanmin Zheng,1,2 Xiaona Lin,1,2 Zelin Zhuang,1,2 Jingjing Yin,1,2 Zhirong Lin,1 Lei Xie,1,2 Shuhua Ma1,2 1Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Laboratory of Medical Molecular Imaging, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of ChinaCorrespondence: Shuhua Ma; Lei Xie, Email shuhua6633@163.com; 13lxie1@stu.edu.cnBackground: Inflammatory Bowel Disease (IBD) patients may experience cognitive impairments in Visuospatial Working Memory (VSWM), significantly impacting their quality of life. However, the mechanisms underlying these impairments remain poorly understood.Methods: We studied functional MRI and graph theory analysis to investigate changes in functional connectivity networks during the Mental Rotation Task (MRT) in IBD patients. Twenty IBD patients (13 males, 7 females; mean age = 34.95 ± 13.80 years; mean disease duration = 2.43 ± 2.37 years) participated in the study. Exclusion criteria encompassed recent use of analgesics, 5-Aminosalicylate, corticosteroids, or immunosuppressants within the past three months. Additionally, we recruited 20 age-, gender-, and education-matched healthy controls for comparison.Results: Compared to a control group, IBD patients exhibited significantly longer reaction times and reduced accuracy during the MRT. Our analysis revealed abnormalities in multiple nodal attributes within the functional connectivity network, particularly in regions such as the bilateral orbitofrontal cortex, right supplementary motor area, bilateral parahippocampal gyrus, and bilateral anterior temporal lobe. We observed that the nodal efficiency in the left temporal pole is negatively correlated with Red Blood Cell Distribution Width (RDW) and positively correlated with response time of MRT.Conclusion: Our findings revealed notable abnormalities in multiple node attributes among IBD patients during MRT, providing evidence of cognitive impairments in VSWM in IBD patients. This study found RDW maybe can serve as a clinical indicator for predicting early VSWM impairment in patients with IBD.Keywords: inflammatory bowel disease, graph theory, visuospatial working memory, cognitive impairment, mental rotation task

Fan Li,1– 3,&ast; Zhengjian Wang,4,&ast; 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&ast;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

Shen Ma,1,&ast; Ran Hao,2,&ast; Yi-Wei Lu,1 Hui-Po Wang,1 Jie Hu,2,3 Yi-Xin Qi1 1Department of Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050035, People’s Republic of China; 2Institutes of Health Research, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China; 3Department of Science and Technology, Hebei Medical University, Shijiazhuang, Hebei, 050017, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi-Xin Qi; Jie Hu, Tel +86-13932153600 ; +86-311-86266321, Email qiyixin@hebmu.edu.cn; Hujie@hebmu.edu.cnBackground: Distant metastasis remains the leading cause of death among patients with breast cancer (BRCA). The process of cancer metastasis involves multiple mechanisms, including compromised immune system. However, not all genes involved in immune function have been comprehensively identified.Methods: Firstly 1623 BRCA samples, including transcriptome sequencing and clinical information, were acquired from Gene Expression Omnibus (GSE102818, GSE45255, GSE86166) and The Cancer Genome Atlas-BRCA (TCGA-BRCA) dataset. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed using the GSE102818 dataset to identify the most relevant module to the metastasis of BRCA. Besides, ConsensusClusterPlus was applied to divide TCGA-BRCA patients into two subgroups (G1 and G2). In the meantime, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct a metastasis-related immune genes (MRIGs)_score to predict the metastasis and progression of cancer. Importantly, the expression of vital genes was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC).Results: The expression pattern of 76 MRIGs screened by WGCNA divided TCGA-BRCA patients into two subgroups (G1 and G2), and the prognosis of G1 group was worse. Also, G1 exhibited a higher mRNA expression level based on stemness index score and Tumor Immune Dysfunction and Exclusion score. In addition, higher MRIGs_score represented the higher probability of progression in BRCA patients. It was worth mentioning that the patients in the G1 group had a high MRIGs_score than those in the G2 group. Importantly, the results of RT-qPCR and IHC demonstrated that fasciculation and elongation protein zeta 1 (FEZ1) and insulin-like growth factor 2 receptor (IGF2R) were risk factors, while interleukin (IL)-1 receptor antagonist (IL1RN) was a protective factor.Conclusion: Our study revealed a prognostic model composed of eight immune related genes that could predict the metastasis and progression of BRCA. Higher score represented higher metastasis probability. Besides, the consistency of key genes in BRCA tissue and bioinformatics analysis results from mRNA and protein levels was verified.Keywords: breast cancer, metastasis, immune genes, weighted gene co-expression network analysis, prognostic mode

Shengshan Ma,1,2,&ast; Suyang Zheng,1,&ast; Dong Li,3 Wenhao Hu,4 Liming Wang1 1Department of Orthopedic Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Sports Medicine, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, Jiangsu, People’s Republic of China; 3Department of Trauma Center, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu, People’s Republic of China; 4Department of Orthopedic Surgery, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liming Wang, Department of Orthopedic Surgery, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu, People’s Republic of China, Tel +86-25-5227-1000, Fax +86-25-5226-9924, Email wlmnjsy@163.comPurpose: This study aims to explore a novel scaffold for osteotendinous junction regeneration and to preliminarily verify its osteogenic and tenogenic abilities in vitro.Methods: A polycaprolactone (PCL) scaffold with aligned and orthogonal fibers was created using melt electrowriting (MEW) and fused deposition modeling (FDM). The scaffold was coated with Type I collagen, and hydroxyapatite was carefully added to separate the regions intended for bone and tendon regeneration, before being rolled into a cylindrical shape. Human adipose-derived stem cells (hADSCs) were seeded to evaluate viability and differentiation. Scaffold characterization was performed with Scanning Electron Microscope (SEM). Osteogenesis was assessed by alkaline phosphatase (ALP) and Alizarin red staining, while immunostaining and transcription-quantitative polymerase chain reaction (RT-qPCR) evaluated osteogenic and tendogenic markers.Results: Scaffolds were developed in four variations: aligned (A), collagen-coated aligned (A+C), orthogonal (O), and mineral-coated orthogonal (O+M). SEM analysis confirmed surface morphology and energy-dispersive X-ray spectroscopy (EDS) verified mineral coating on O+M types. Hydrophilicity and mechanical properties were optimized in modified scaffolds, with A+C showing increased tensile strength and O+M improved in compression. hADSCs demonstrated good viability and morphology across scaffolds, withO+M scaffolds showing higher cell proliferation and osteogenic potential, and A and A+C scaffolds supporting tenogenic differentiation.Conclusion: This study confirms the potential of a novel PCL scaffold with distinct regions for osteogenic and tenogenic differentiation, supporting the regeneration of osteotendinous junctions in vitro.Keywords: tendon-bone healing, biomimetic, electrospun scaffold, near-field direct writing, tissue engineering

Xingping Zhou,1,&ast; Jinjin Luo,1,&ast; Xi Liang,1,2 Peng Li,1 Keke Ren,1 Dongyan Shi,1,2 Jiaojiao Xin,1,2 Jing Jiang,1,2 Jiaxian Chen,1 Lulu He,1 Hui Yang,1 Shiwen Ma,1 Bingqi Li,1 Jun Li1,2 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, 310003, People’s Republic of China; 2Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun Li, State 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, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel/Fax +86-571-87236425, Email lijun2009@zju.edu.cnBackground and Aim: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF.Methods: The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA).Results: TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥ 8.4 ng/mL.Conclusion: This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.Keywords: thrombomodulin, HBV-ACLF, biomarker, organ failure

Chenghui Tan,1,&ast; Huan Song,2,3,&ast; Shanshan Ma,3,4 Xinyu Liu,3,5 Yuan Zhao6 1Department of Psychology, Renmin University of China, Beijing, People’s Republic of China; 2School of Educational Science, Neijiang Normal University, Neijiang, People’s Republic of China; 3School of Education, Soochow University, Suzhou, People’s Republic of China; 4School of Marxism, Nanjing Forestry University, Nanjing, People’s Republic of China; 5Department of Psychology, Wuhan University, Wuhan, People’s Republic of China; 6Police Officer Academy, Shandong University of Political Science and Law, Jinan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuan Zhao, Police Officer Academy, Shandong University of Political Science and Law, Jinan, People’s Republic of China, Email sdjnzhaoyuan@163.comBackground: The existence of aggressive behavior in autism spectrum disorders (ASD) raises questions about whether cognitive and emotional factors in social information processing play a role between autistic traits (ATs) and aggressive behavior in the general population, especially in the context of Chinese culture. Moreover, given a possible gender difference in these variables, the study aimed to examine the effect of ATs on aggressive behavior, and the potential mediating role of hostile attribution bias and alexithymia on this association, as well as gender difference.Methods: 850 Chinese college students participated in the assessment, including their ATs, hostile attribution bias, alexithymia, and aggressive behavior. Pearson correlation, mediation effects analyses, and multiple-group comparison were conducted.Results: The results indicated that ATs indirectly predicted increased aggressive behavior through attribution bias and alexithymia. Gender difference in mediating effects was revealed: ATs indirectly predicted increased aggressive behavior through the serial mediating effect only in males.Conclusion: Hostile attribution bias and alexithymia completely mediated the association between ATs and aggressive behavior, which contained the separate mediating effects of (a) hostile attribution bias and (b) alexithymia and the serial mediating effect of (c) hostile attribution bias and alexithymia. Gender differences in mediating effects were found only in the serial mediating effect, which was significant in males but not in females. The findings revealed the internal mechanism of ATs affecting aggressive behavior and gender difference, which have implications for the intervention of aggressive behavior of individuals with autism and those with high levels of ATs.Keywords: autistic traits, aggressive behavior, hostile attribution bias, alexithymia, serial mediating effect, gender difference

Jiashu Zhu,1 Ye Li,1 Rui Wang,1 Jinfang Zhang,2 Can Liu,1 Hongyu Li,1 Deguang Yang,1 Shuqin Ma,2 Suzhen Guan1 1School of Public Health, Ningxia Medical University, Yinchuan City, Ningxia, People’s Republic of China; 2Obstetric Clinic, General Hospital of Ningxia Medical University, Yinchuan City, Ningxia, People’s Republic of ChinaCorrespondence: Suzhen Guan, School of Public Health, Ningxia Medical University, Yinchuan City, Ningxia, 750004, People’s Republic of China, Tel +86 13389511821, Email guansz_nx2017@sina.com Shuqin Ma, General Hospital of Ningxia Medical University, Yinchuan City, Ningxia, 750004, People’s Republic of China, Tel +86 13895493649, Email 3117957376@qq.comObjective: To examine the relationship between pregnancy-related anxiety, family functions, and sleep quality, and to determine whether family functions mediate the relationship between pregnancy-related anxiety and sleep quality.Methods: A cross-sectional survey was conducted on pregnant women between April to August in 2022 in the obstetrics outpatient clinic of a tertiary care hospital in the Ningxia Hui Autonomous Region of China. A total of 1014 pregnant women aged 18 years and older were surveyed. They completed questionnaires, including: general demographic characteristics, the Pregnancy-related anxiety scale (PAQ), the Family Adaptation, Partnership, Growth, Affection, and Resolve (APGAR), and the Pittsburgh Sleep Quality Index Questionnaire (PSQI). Model 4 in PROCESS was used to analyze the relationships among pregnancy-related anxiety, family functions, and sleep quality, with family functions as a mediator.Results: Among the 1014 pregnant women, the pregnancy-related anxiety scale score was (21.84 ± 5.64). The total score of the family functions scale was (8.10± 2.26), and the overall sleep quality scale score was (7.89± 2.99). When participants were grouped according to different socio-demographic characteristics, the study showed that all variables differed from anxiety, family functions or sleep quality, except for age, pre-pregnancy BMI and whether or not they had a first birth, which was not associated with anxiety, family functions, or sleep quality (P< 0.05). The pregnancy-related anxiety was positively associated with sleep quality (P< 0.01), while family functions were negatively associated with sleep quality (P< 0.01). In addition, family functions mediate the relationship between pregnancy-related anxiety and sleep quality during pregnancy, on the first and second trimesters, intermediation rate is 9.31% (P< 0.05), and on the third trimesters, intermediation rate is 21.38% (P< 0.05).Conclusion: Pregnancy- related anxiety is a risk factor for sleep quality, however, family functions are protective factors for sleep quality. Family functions play an intermediary role in sleep quality caused by pregnancy-related anxiety, especially on the third trimesters. This finding may provide a scientific basis for developing intervention strategies to improve the sleep quality of pregnant women.Keywords: pregnancy-related anxiety, family functions, sleep quality, mediation effect

Xia Su,1,2 Shuli Ma,3 Xiaoxi Yang,4 Can Zhang,1 Weiwei Chen5 1Hepatobiliary and Pancreatic Center, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China; 2School of Nursing & Public Health, Yangzhou University, Yangzhou, Jiangsu, People’s Republic of China; 3Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 4School of Health and Wellness, Panzhihua University, Panzhihua, Sichuan, People’s Republic of China; 5Medical College of Yangzhou University, Yangzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Weiwei Chen, Tel +86 18051062900, Email cww1984@126.comBackground: The incidence and recurrence rate of acute pancreatitis (AP) continues to increase worldwide. The risk of AP attack and recurrence is closely related to the patient’s health literacy. Previous studies have shown that AP patients had low levels of health literacy. Understanding patients’ experience in AP’s diagnosis and treatment process and their health literacy needs might significantly improve their health status.Objective: This study aims to understand the experience of acute pancreatitis (AP) patients in the diagnostic and treatment process and explore their health literacy needs at various phases of this process.Methods: This study utilized a qualitative approach based on Timing It Right theory. A purposive sampling strategy was employed to select 31 participants diagnosed with AP at various phases of the diagnosis and treatment process. These patients were selected from the Pancreatitis Treatment Centers of two tertiary hospitals in Eastern China. Subsequently, semi-structured in-depth interviews were conducted with the selected participants. The qualitative data was analyzed using the Colaizzi’s method.Results: The themes of AP patients’ experiences and health literacy needs at various phases of the diagnosis and treatment process were presented as follows. 1. Diagnosis phase: inability to obtain disease information, psychological support seeking, and change unhealthy lifestyle; 2. Hospitalization phase: disease treatment information needs and medical professionals’ healthcare. 3. Discharge Preparation phase: fear of recurrence, individualized healthy lifestyle instruction. 4. Home Recovery phase: self-management, continuous healthcare needs, and family support.Conclusion: AP patients’ HL needs and health-related problems vary during the diagnosis and treatment process. Medical professionals should comprehend AP patients’ changing needs and individual differences, provide continuous healthcare, and involve families in patient management. These factors support patients’ long-term self-management and preserve their overall health.Keywords: acute pancreatitis, Timing It Right, health literacy need, qualitative study

Gengyao Hu,1,&ast; Yuanhang Pan,1,&ast; Na Yuan,1,&ast; Zhixian Yang,2 Xiuyu Shi,3 Sha Ma,4 Shan Li,4 Xiaohua Hou,5 Fei Liu,5 Dongmei Li,6 Junxiang Bao,7 Yonghong Liu1 1Department of Neurology, Xijing Hospital, Fourth Military Medical University (Air Force Medical University), Xi’an, People’s Republic of China; 2Department of Pediatrics, Peking University First Hospital, Beijing, People’s Republic of China; 3Department of Pediatrics, Chinese People’s Liberation Army General Hospital, Beijing, People’s Republic of China; 4Department of Neurology, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China; 5Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 6Department of Dentistry for Special Services, Fourth Military Medical University (Air Force Medical University), Xi’an, People’s Republic of China; 7Department of Aerospace Hygiene, Fourth Military Medical University (Air Force Medical University), Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yonghong Liu, Email liuyhong@fmmu.edu.cnBackground: Sleep-related facial mandibular myoclonus (SRFMM) remains rare in clinical practice. The aim of this study was to provide a comprehensive understanding of the electroclinical manner, therapeutic regimen, and prognosis of SRFMM.Methods: Twenty-three patients who were diagnosed with SRFMM by clinical manifestation, video-electroencephalography (EEG) and electromyography over bilateral masseter and temporalis muscles were enrolled. Clinical and electrophysiological evaluation as well as follow-up information were recorded and analyzed.Results: The cohort involved 4 infants and 19 adults with a mean onset age of 43.5 years for SRFMM, among whom 19 were male. Twenty-one patients complained of tongue injuries and disturbed night-time sleep. SRFMM in 4 patients were ascribed to oral aripiprazole, brainstem ischemia and brain trauma. In 62 SRFMM episodes, 93.5% occurred in NREM sleep and 6.5% in REM sleep, and all events were associated with EEG arousals. In 13 patients with or without clonazepam, the motor events gradually disappeared, and the rest turned to be sporadic.Conclusion: SRFMM is a characteristic parasomnia manifested by tongue biting and accompanying facial mandibular myoclonus, leading to disrupted sleep. Besides adults, infants can also experience SRFMM with spontaneous remission. Most patients respond well to clonazepam, eventually with favorable prognosis.Keywords: sleep-related facial mandibular myoclonus, tongue biting, movement disorder, SRFMM

Jinxin Ma,1,&ast; Peng Yu,1,&ast; Shang Ma,1,&ast; Jinjin Li,1 Zhen Wang,1 Kunpeng Hu,1 Xinzhe Su,1 Bei Zhang,1 Shao Cheng,1– 3 Shangzeng Wang1– 3 1School of Osteopathy, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 2Department of Arthropathy, Henan Province Hospital of Chinese Medicine (The Second Affiliated Hospital of Henan University of Chinese Medicine), Zhengzhou, People’s Republic of China; 3School of Osteopathy, Henan Province Engineering Research Center of Basic and Clinical Research of Bone and Joint Repair in Chinese Medicine, Zhengzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shao Cheng; Shangzeng Wang, 156 Jinshui East Road, Zhengzhou, Henan, People’s Republic of China, Tel +86 15093141825 ; +86 13838527504, Fax +0371-86667366, Email chengshao4476@163.com; wangsz74@163.comPurpose: Osteoarthritis (OA) is the most common joint disease worldwide and is the primary cause of disability and chronic pain in older adults.Ferroptosis is a type of programmed cell death characterized by aberrant iron metabolism and reactive oxygen species accumulation; however, its role in OA is not known.Methods: To identify ferroptosis markers co-expressed in articular cartilage and synovium samples from patients with OA, in silico analysis was performed.Signature genes were analyzed and the results were evaluated using a ROC curve prediction model.The biological function, correlation between Signature genes, immune cell infiltration, and ceRNA network analyses were performed. Signature genes and ferroptosis phenotypes were verified through in vivo animal experiments and clinical samples. The expression levels of non-coding RNAs in samples from patients with OA were determined using qRT-PCR. ceRNA network analysis results were confirmed using dual-luciferase assays.Results: JUN, ATF3, and CDKN1A were identified as OA- and ferroptosis-associated signature genes. GSEA analysis demonstrated an enrichment of these genes in immune and inflammatory responses, and amino acid metabolism. The CIBERSORT algorithm showed a negative correlation between T cells and these signature genes in the cartilage, and a positive correlation in the synovium. Moreover, RP5-894D12.5 and FAM95B1 regulated the expression of JUN, ATF3, and CDKN1A by competitively binding to miR-1972, miR-665, and miR-181a-2-3p. In vivo, GPX4 was downregulated in both OA cartilage and synovium; however, GPX4 and GSH were downregulated, while ferrous ions were upregulated in patient OA cartilage and synovium samples, indicating that ferroptosis was involved in the pathogenesis of OA. Furthermore, JUN, ATF3, and CDKN1A expression was downregulated in both mouse and human OA synovial and cartilage tissues. qRT-PCR demonstrated that miR-1972, RP5-894D12.5, and FAM95B1 were differentially expressed in OA tissues. Targeted interactions between miR-1972 and JUN, and a ceRNA regulatory mechanism between RP5-894D12.5, miR-1972, and JUN were confirmed by dual-luciferase assays.Conclusion: This study identified JUN, ATF3, and CDKN1A as possible diagnostic biomarkers and therapeutic targets for joint synovitis and OA. Furthermore, our finding indicated that RP5-894D12.5/miR-1972/JUN was a potential ceRNA regulatory axis in OA, providing an insight into the connection between ferroptosis and OA.Keywords: osteoarthritis, ferroptosis, synovitis, bioinformatics, JUN, ATF3, CDKN1A, GPX4

Yinzheng Li,1 Shulin Ma,1 Zheng Wang,1 Mengxia Shi,1 Rui Zeng,1– 4,&ast; Ying Yao1,5,&ast; 1Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, People’s Republic of China; 3NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, People’s Republic of China; 4Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, People’s Republic of China; 5Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Yao; Rui Zeng, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China, Tel +86 13720379867 ; +86 15002726366, Email yaoyingkk@126.com; zengrui@tjh.tjmu.edu.cnPurpose: The distal nephron of kidney plays a pivotal role in advancing acute kidney injury (AKI). Understanding the role of distal nephrons in AKI and identifying markers of injured distal nephrons are critical to comprehending the mechanism of renal injury and identifying novel therapeutic targets.Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data from mice with AKI induced by ischemia-reperfusion (IR), unilateral ureteral obstruction (UUO), cisplatin (CP), sodium oxalate (SO) and lipopolysaccharide (LPS). Additionally, we analyzed renal transcriptomics samples for AKI. Subsequently, we validated the effectiveness of targeting the biomarker Gclc in vitro and in vivo through metabolomics and immunofluorescence.Results: The LOH-Inj and DCT-Inj subtypes were identified through scRNA-seq. Compared to normal distal nephrons, the injured distal nephrons exhibited higher levels of ferroptosis, pro-inflammation, and fibrosis. The expression of ferroptosis-related gene Gclc were high in various AKI models. Furthermore, Gclc was exclusively expressed in the distal nephron and upregulated in the injury subtype. To confirm our findings, we suppressed GCLC expression in the kidneys, resulting to aggravated IR-induced AKI. Inhibition of Gclc promoted damage to primarily renal tubular epithelial cells by promoting inflammatory infiltration, inhibiting glutathione metabolism and exacerbating oxidative stress.Conclusion: Our research findings suggest that Gclc is a potential marker for injured distal nephron.Keywords: Gclc, distal nephron, acute kidney injury, single-cell sequencing

Changyou Luo,1,&ast; Ruiqing Zhang,2,&ast; Ji Liu,1,&ast; Xingyue He,1 Shengzhou Li,1 Chuanjiang Ran,1 Songbo Ma,3 Yan Shen1 1Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 211100, People’s Republic of China; 2Children’s Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, 225300, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Shen; Songbo Ma, Email shenyan@cpu.edu.cn; masongbo1978@163.comPurpose: Rapid detection and diagnosis of diseases facilitate timely and effective treatment of cardiovascular diseases (CVD). The establishment of a one-step rapid detection method provides a new method for the initial screening and disease risk assessment of patients with cardiovascular diseases in primary medical units.Methods: Hollow gold nanoparticles (HGNPs) were synthesized using a cobalt template method followed by use as signal amplification probes for ultra-sensitive quantitative detection of serum C-reactive protein (CRP). To induce the localized surface plasmon resonance (LSPR) and improve protein labeling efficiency, we developed a sensitive detection mode by coating polyvinylpyrrolidone (PVP-K30) on the HGNPs, resulting in a significant improvement in detection performance.Results: Compared to traditional colloidal GNP-based LFTA, PVP-coated HGNPs exhibit a lower visual detection limit of 1 ng/mL, which a 25-fold decrement compare to using GNPs as the antibody-labeled probe, and the detection limit could be reduced to 0.14 ng/mL under the quantitative instrument.Conclusion: The one-step method based on HGNP immunochromatographic strips modified with PVP established in this study can be used for the detection of CRP and hs-CRP in biological samples. The performance of the immunochromatographic technique designed in this study was evaluated from the perspective of synthetic markers, and the application conditions of this strip were screened, verifying its high specificity, indicating that it has high sensitivity and strong detection limit compared to colloidal gold. The sensitivity of the hollow gold immunochromatographic test strip in this article has been increased by about 25 times, providing a new method for rapid detection of CVD in clinical diagnosis.Keywords: C-reactive protein, lateral flow immunoassay, hollow gold nanoparticles, in vitro diagnostics, polyvinylpyrrolidone

Qiao Yang,1,&ast; Ying He,2,&ast; Yi Zhou,3 Qinzhu Jia,3 Nan Dai,4 Siyuan Ma,5 Xiu Yang,3 Xi Zhang,6 Jianguo Sun3 1Department of Ultrasound, The 941st Hospital of the PLA Joint Logistic Support Force, Xining, 810007, People’s Republic of China; 2Department of Psychiatry, Xinqiao Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China; 3Department of Oncology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China; 4Department of Oncology, Daping Hospital, Army Medical University, Chongqing, 400042, People’s Republic of China; 5Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University, Chongqing, 400038, People’s Republic of China; 6Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianguo Sun; Xi Zhang, Xinqiao Hospital, Army Medical University, 83 Xinqiao Zhengjie Road, Shapingba District, Chongqing, 400037, People’s Republic of China, Tel +86-23-68774490, Fax +86-23-68774631, Email sunjg09@aliyun.com; zhangxxi@sina.comBackground: This study aimed to investigate the risk factors for persistent viral shedding in cancer patients after Omicron infection.Methods: Patients with asymptomatic or mild Omicron infection (≥ 18 years) who were treated in a makeshift hospital in Shanghai were enrolled from 9 Apr to 11 May, 2022. Deidentified information of all patients were collected retrospectively. Logistic regression model was used to identify risk factors associated with prolonged duration of viral shedding (defined as the time from the day of first positive SARS-CoV-2 RNA test to the first day of two consecutive negative SARS-CoV-2 RNA tests).Results: A total of 1442 Omicron-infected patients were enrolled, including 129 cancer patients and 1313 non-cancer patients. The baseline clinical characteristics of cancer and non-cancer patients were balanced by propensity score matching (1:4). Compared with non-cancer patients, a higher odds ratio ([OR] 1.84, 95% CI 1.24– 2.76, P = 0.003) of lasting viral shedding for ≥ 7 days was found in cancer patients. Further subgroup analyses found that cancer patients were at higher risk for prolonged viral shedding in a subgroup of patients without hypertension (OR 1.89), diabetes (OR 1.80), or other chronic disease (OR 2.13), unvaccinated (OR 1.97), and asymptomatic (OR 2.36). In addition, 29 patients with active cancer and 19 patients with inactive cancer were identified. The median duration of viral shedding in the active cancer group was longer than that in the inactive cancer group (10 vs 6 days, P = 0.002). The risk of persistent viral shedding ≥ 7 days was also increased in the active cancer group (OR 5.33, 95% CI 1.49– 21.51, P = 0.013).Conclusion: Cancer disease is an independent risk factor for prolonged viral shedding in Omicron infected patients, especially in patients with active cancer.Keywords: omicron, cancer, persistent viral shedding, SARS-CoV-2

Yurun Liu,1,&ast; Shengnan Yu,2,&ast; Sha Ma,2 Juan Yu,2 Dachen Zuo,2 Weiqing Zhao,2 Juan Wang,2 Jing Wang2 1Department of Rheumatology and Immunology, The Affiliated Hospital of Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, People’s Republic of China; 2Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Wang, Department of Rheumatology and Immunology, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China, Email wjing1981@163.comBackground: An overlap of systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibodies- (ANCA-) associated vasculitis (AAV) is extremely uncommon and no clear definition has been proposed. The SLE/AAV overlap syndrome mainly affects kidney, blood count, nervous system and lung. However, few previous cases reported nasal septal and palatal perforation in this disorder.Case Presentation: We presented a case of a 16-year-old female with a 6-month history of SLE, developed perforation of the nasal septum and palate. She was diagnosed with SLE due to facial malar rash, oral ulcer, increased erythrocyte sedimentation rate (ESR), low complement levels, and positive anti-Smith antibody. Approximately 6 months later, she had a perforation of the nasal septum and palate with positive anti-proteinase 3 antibody (anti-PR3-ANCA). A nasal endoscopic biopsy revealed an inflammatory polyp with chronic suppurative inflammation and inflammatory granulomatous hyperplasia. In this case, the clinical, biological, radiological, and histological findings substantiated the diagnosis of AAV. Infections, drug abuse, malignancies, IgG4-related disease (IgG4-RD) and trauma were excluded. So we diagnosed her with SLE/AAV overlap syndrome.Conclusion: When a patient’s symptoms cannot be explained by one disease, we need to consider the overlapping of two diseases, especially in patients with autoimmune diseases.Keywords: perforation of palate, systemic lupus erythematosus, ANCA-associated vasculitis, SLE/AAV overlap syndrome

Jian Yang,1,&ast; Xuanhao Zhang,1,2,&ast; Guanyu Wang,1,2 Shixing Ma,1,2 Yejia Yu,1 Chengcheng Liao,1 Zhuo Wang,1,2 Cheng Liang,1 Maojiao Li,1,2 Weidong Tian,1,2 Li Liao1,2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Liao; Weidong Tian, State Key Laboratory of Oral Disease, West China School of Stomatology, Sichuan University, No. 14, 3Rd Section of Ren Min Nan Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86-28-85503499 ; +86-28-85501256, Email lliao@scu.edu.cn; drtwd@sina.comBackground: Diabetic chronic wounds present a formidable challenge in clinical management, lacking effective treatment options. Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for tissue repair and regeneration. However, transplanted MSCs often undergo rapid apoptosis, giving rise to heterogeneous extracellular vesicles (EVs), including apoptotic bodies (apoBDs) and apoptotic small extracellular vesicles (apoSEVs). The potential stimulatory role of these EVs in diabetic wound healing remains unknown.Methods: In this study, we investigated the effects of apoSEVs derived from adipose-derived mesenchymal/stromal cells (ADSCs) on the recovery of diabetic wounds by modulating the function of versatile target cells. First, we characterized the apoSEVs and apoBDs derived from apoptotic ADSCs. Subsequently, we evaluated the effects of apoSEVs and apoBDs on macrophages, endothelial cells, and fibroblasts, three essential cell types in wound healing, under high-glucose conditions. Furthermore, we developed a gelatin methacryloyl (GelMA) hydrogel for the sustained release of apoSEVs and investigated its therapeutic effects on wound healing in type 2 diabetic mice in vivo.Results: apoSEVs facilitated the polarization of M1 phenotype macrophages to M2 phenotype, promoted proliferation, migration, and tube formation of endothelial cells, and enhanced fibroblast proliferation and migration. However, apoBDs failed to improve the function of endothelial cells and fibroblasts. In vivo, the apoSEVs-loaded GelMA effectively promoted wound healing by facilitating collagen fiber deposition, angiogenesis, and immune regulation.Conclusion: Our study elucidates the beneficial effects of apoSEVs on wound recovery in diabetes and introduces a novel strategy for diabetic wound treatment based on apoSEVs. Keywords: apoptotic small extracellular vesicles, wound healing, diabetes, stem cells, GelMA

Ling Zhou,1,&ast; Yu Gan,1,&ast; Yanjun Wu,1 Dongdong Xue,1 Jianhong Hu,1 Yilan Zhang,2 Yang Liu,3 Siyuan Ma,1 Junyi Zhou,1 Gaoxing Luo,1 Daizhi Peng,1 Wei Qian1 1Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 2Department of Oral and Maxillofacial Head and Neck Surgery, Army Medical Center of PLA/Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, 400042, People’s Republic of China; 3Department of Urology, Urology Institute of PLA, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Daizhi Peng; Wei Qian, Email dzpengpub@126.com; weiqian87@126.comIntroduction: Indocyanine green (ICG) fluorescence imaging has been used in the resection surgery and sentinel lymph node biopsy of many tumors. The aim of the present study is to verify the feasibility and effectiveness of ICG fluorescence imaging used for guiding the biopsy and resection of skin squamous cell carcinoma (SSCC).Methods: Sixty patients were enrolled, including 18 patients of suspected SSCC and 42 patients of diagnosed SSCC on admission. The ICG fluorescence imaging-guided skin biopsy was performed preoperatively in the 18 cases of suspected SSCC. Fifty-three patients underwent ICG fluorescence imaging-guided radical excision.Results: The results showed that 138 skin tissue samples in 60 patients with preoperative or intraoperative ICG fluorescence imaging-guide biopsy were collected. For a total number of 138 biopsies, 122 specimens were squamous cell carcinoma, and the accuracy rate was 88.4%, which was significantly higher than that of the group without preoperative ICG fluorescence imaging (41/62, 66.1%, P < 0.05). Fifty-three patients underwent surgery guided with ICG fluorescence imaging. Residual fluorescent signals in 24 patients were intraoperatively found and the excision was then expanded until the signals disappeared. Follow-up to November 2022, 12 patients died, of which 5 cases died from the tumor recurrence, and the others died due to advanced ages or other reasons. The recurrence rate was 9.4%, which was not significantly different from that of the group received routine radical resection (4/35, 11.4%, P > 0.05). Moreover, sentinel lymph nodes were successfully detected under ICG fluorescence imaging in the 4 patients with suspected lymph node metastases, and the location of lymph nodes can be precisely identified.Conclusion: ICG fluorescence imaging technique can guide the pathology biopsy to improve the accuracy of pathological examination, and help to identify the boundaries of tumor tissues and sentinel lymph nodes to resect tumor radically during operation.Keywords: indocyanine green, ICG, near-infrared fluorescence imaging, skin squamous cell carcinoma, biopsy, radical resection

Suyang Zheng,1,&ast; Dong Li,1,2,&ast; Qingbai Liu,1,3 Cheng Tang,1 Wenhao Hu,1,4 Shengshan Ma,1,5 Yan Xu,1,6,7 Yong Ma,8 Yang Guo,8 Bo Wei,1 Chuanlin Du,9 Liming Wang1,6,7 1Department of Orthopedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Trauma Center, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou, Jiangsu Province, People’s Republic of China; 3Department of Orthopedics, Lianshui People’s Hospital of Kangda College Affiliated to Nanjing Medical University, Huai’an, Jiangsu Province, People’s Republic of China; 4Department of Orthopedics, The Affiliated Huai’an No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu Province, People’s Republic of China; 5Department of Sports Medicine, The First People’s Hospital of Lianyungang, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang, Jiangsu Province, People’s Republic of China; 6Key Laboratory of Additive Manufacturing Technology, Institute of Digital Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 7Cartilage Regeneration Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 8Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, People’s Republic of China; 9Department of Orthopedics, Ganyu District People’s Hospital of Lianyungang, Lianyungang, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Liming Wang; Chuanlin Du, Tel +86-25-5227-1000 ; +86-518-8621-2626, Fax +86-25-5226-9924 ; +86-518-8622-5984, Email wlmnjsy@outlook.com; chuanlindu@foxmail.comPurpose: This study aims to investigate the impact of enhancing subchondral bone repair on the efficacy of articular cartilage restoration, thereby achieving improved osteochondral regeneration outcomes.Methods: In this study, we modified the surface of nano-hydroxyapatite (n-HAp) through alkylation reactions to prepare n-HApMA. Characterization techniques, including X-ray diffraction, infrared spectroscopy scanning, thermogravimetric analysis, particle size analysis, and electron microscopy, were employed to analyze n-HApMA. Bioinks were prepared using n-HApMA, high porosity GelMA hydrogel, and adipose tissue derived stromal cells (ADSCs). The rheological properties of the bioinks during photocuring were investigated using a rheometer. Based on these bioinks, a biphasic scaffold was constructed. The viability of cells within the scaffold was observed using live-dead cell staining, while the internal morphology was examined using scanning electron microscopy. The stiffness of the scaffold was evaluated through compression testing. Scaffolds were implanted into the osteochondral defects of New Zealand rabbit knees, and microCT was utilized to observe the subchondral bone repair. Hematoxylin and eosin (H&E) staining, Masson’s trichrome staining, and Safranin O/Fast Green staining were performed to assess the regeneration of subchondral bone and cartilage. Furthermore, immunohistochemical staining was employed to detect the expression of osteogenic and chondrogenic-related molecules.Results: Scaffold characterization revealed that surface modification enables the uniform distribution of n-HApMA within the GelMA matrix. The incorporation of 5% n-HApMA notably enhanced the elastic modulus and stiffness of the 6% high-porosity GelMA in comparison to n-HAp. Moreover, in-vivo study showed that the homogeneous dispersion of n-HApMA on the GelMA matrix facilitated the osteogenic differentiation of adipose-derived stem cells (ADSCs) and promoted osteochondral tissue regeneration.Conclusion: These findings suggest potential applications of the n-HApMA/GelMA composite in the field of tissue engineering and regenerative medicine.Graphical Abstract: Keywords: subchondral bone, surface modification, bio-ink, scaffold, hydrogel

Hui Feng,1 Shanhu Qiu,2 Xiang Hong,3 Shaolei Ma,4 Zhenghua Hou,5 Kongbo Zhu,6 Ming Guo,1 Changsong Wang,1 Yingzi Huang7 1Department of Traditional Chinese Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 2Department of General Practice, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 3Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, People’s Republic of China; 4Department of Emergency and Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 5Department of Psychosomatics & Psychiatry, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 6Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 7Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of ChinaCorrespondence: Yingzi Huang, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China, Email yz_huang@126.com Changsong Wang, Department of Traditional Chinese Medicine, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China, Email kingidoc@163.comPurpose: Traditional Chinese Medicine (TCM) constitution and disease occurrence, development, and prognosis are interrelated. This study aimed to investigate the association between TCM constitution and the time to negative nucleic acid test results in patients with coronavirus disease 2019 (COVID-19) infected with the SARS-CoV-2 Omicron variant.Patients and Methods: We identified COVID-19 patients (≥ 18 years) infected with the SARS-CoV-2 Omicron variant and collected clinical data, including clinical symptoms, time to negative nucleic acid test results, and TCM constitution. Linear and logistic regression analyses explored the relationship between TCM constitution and the time to negative nucleic acid test results in patients with the COVID-19 Omicron variant.Results: We included 486 patients with COVID-19, with a mean age of 40.2 years; 321 (66.0%) men and 165 (34.0%) women. Balanced constitution accounted for 43.8%, and unbalanced constitution accounted for 56.2%. Chi-square test showed that different TCM constitutions had significant differences in the influence of clinical symptoms of COVID-19 patients (P < 0.01). After controlling for various factors, multiple linear regression analysis revealed that an unbalanced constitution was significantly positively correlated with time to negative nucleic acid test results (P < 0.05). After controlling for various factors, logistic regression analysis revealed that an unbalanced constitution was closely related to the 7-day nucleic acid test conversion rate (odds ratio (OR): 0.53, 95% confidence interval (CI): 0.36– 0.80, P < 0.05). After dividing the unbalanced constitution into deficiency constitution and non-deficiency constitution, the non-deficiency constitution was closely associated with the 7-day nucleic acid test conversion rate (OR = 0.45, 95% CI: 0.28– 0.74, P < 0.05). Further analysis revealed that damp-heat constitution in the non-deficiency constitution was associated with the 7-day nucleic acid test conversion rate (OR = 0.33, 95% CI: 0.18– 0.60, P < 0.05).Conclusion: In patients with COVID-19, an unbalanced constitution is associated with a longer time to negative nucleic acid test results and lower 7-day nucleic acid test conversion rates.Keywords: traditional Chinese medicine constitution, COVID-19, SARS-CoV-2 omicron variant, time to negative nucleic acid test, seven-day conversion rate to negative

Shaolei Ma,&ast; Haofei Wang,&ast; Kongbo Zhu, Hui Chen, Jianfeng Xie, Yingzi Huang Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, Nanjing, 210009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yingzi Huang, Jiangsu 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, Tel +86-025-83262553, Email yz_huang@126.comPurpose: This study aimed to determine the clinical profile connected to the nucleic acid conversion time of COVID-19 patients harboring the SARS-CoV-2 Omicron variant at the hospitals at the Fangcang shelter.Methods: We reported 39,584 COVID-19 patients who were hospitalized in Shanghai, China, between April 5 and May 5, 2022, and who had contracted the Omicron strain of SARS-CoV-2. Demographic data, medical and vaccination history, clinical symptoms, and NCT were reported for the patient.Results: The median age of the patients with COVID-19 included in this study was 45 (interquartile range [IQR]: 33– 54), and 64.2% of them were male. The two most prevalent comorbidities among the patients were hypertension and diabetes. Additionally, we discovered that the percentage of unimmunized patients was negligible (13.2%). We found that male sex, age under 60, and other comorbidities including hypertension and diabetes are significant risk factors for extending NCT when we analyzed the risk variables for NCT. We discovered that vaccination with two or more doses can significantly reduce NCT. The analysis of the young (18– 59 years) and older (60 years) populations produced the same outcomes.Conclusion: Our findings confirm that a full COVID-19 vaccine series or booster doses are highly recommended to significantly reduce NCT. In order to reduce NCT, it is also advised that elderly people who have no clear contraindications take vaccination shots.Keywords: COVID-19, nucleic acid conversion time, Fangcang shelter hospitals, vaccination

Lei Guo,1,&ast; Xiangzhao Xu,2,&ast; Rui Qin,1 Yongqiang Shi,1 Wei Xue,3 Ling He,3 Shuqin Ma,3 Yi Chen1 1Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China; 2Department of Anesthesiology, The People’s Hospital of Nanchuan, Chongqing, People’s Republic of China; 3Department of Obstetrics, General Hospital of Ningxia Medical University, Yinchuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Chen, Department of Anesthesiology and Perioperative Medicine, General Hospital of Ningxia Medical University, 804S Shengli Street, Yinchuan, Ningxia, 750004, People’s Republic of China, Tel +86-951-6743252, Email czzyxgp@163.comBackground: Norepinephrine and phenylephrine are widely used for obstetric anesthesia. Our central objective was to determine the ED (effective dose) 90 and potency ratio of prophylactic norepinephrine and phenylephrine boluses for preventing postspinal anesthesia hypotension during cesarean section.Methods: Patients scheduled for elective cesarean section (n = 80) were randomly allocated to receive prophylactic norepinephrine (NE) or phenylephrine (PE) boluses immediately after induction of spinal anesthesia. An initial dose of NE (3 μg) and PE (37.5 μg) was given to the first patient, and an up-and-down sequential allocation method was used to determine the next dose level according to the responses (the effectiveness for preventing postspinal anesthesia hypotension [defined as SBP < 80% of baseline value]). Primary outcomes were ED90 and the potency ratio of prophylactic norepinephrine and phenylephrine boluses. Secondary outcomes were the incidence of postspinal anesthesia hypotension, severe postspinal anesthesia hypotension, nausea, vomiting, bradycardia, hypertension, umbilical artery blood gas values, and Apgar scores.Results: The ED90 values for prophylactic norepinephrine and phenylephrine boluses were 8.0 μg (95% CI 7.1– 11.0 μg) and 90.9 μg (95% CI 82.0– 123.9 μg), respectively. The estimated relative potency ratio was 11.4:1. The incidence of bradycardia was lower in the NE group (2.5% vs 20%, P = 0.034). Other outcomes were comparable between the two groups.Conclusion: An 8-μg prophylactic bolus of norepinephrine and a 90-μg prophylactic bolus of phenylephrine can effectively prevent postspinal anesthesia hypotension in patients during cesarean section.Keywords: cesarean section, norepinephrine, phenylephrine, postspinal anesthesia hypotension

Shenglan Ma,1– 3,&ast; Peijun Ju,4,&ast; Qingrong Xia,1– 3 Zhongde Pan,5 Jianliang Gao,1– 3 Loufeng Zhang,1– 3 Hua Gao,1– 3 Junwei Yan,1– 3 Jie Zhang,1– 3 Keming Wang,1– 3 Chao Li,1– 3 Wen Xie,1– 3,&ast; Cuizhen Zhu1– 3,&ast; 1Affiliated Psychological Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of China; 2Clinical Center for Psychiatry and Mental Health, Hefei Fourth People’s Hospital, Hefei, 230022, People’s Republic of China; 3Anhui Mental Health Center, Hefei, People’s Republic of China; 4Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Traditional Chinese Medicine for Mental Health, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory of Forensic Medicine, Academy of Forensic Science, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Xie; Cuizhen Zhu, Affiliated Psychological Hospital of Anhui Medical University, No. 316 Huangshan Road, Shushan District, Hefei, Anhui, People’s Republic of China, Tel +86 13339102285 ; +86 13705535258, Fax +86 055163616000, Email xiewen0808@sina.com; zhucuizhen88@126.comPurpose: The study aims to clarify the negative psychological state and resilience impairments of schizophrenia (SCZ) with metabolic syndrome (MetS) while evaluating their potential as risk factors.Patients and Methods: We recruited 143 individuals and divided them into three groups. Participants were evaluated using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HAMD)-24, Hamilton Anxiety Rating Scale (HAMA)-14, Automatic Thoughts Questionnaire (ATQ), Stigma of Mental Illness scale and Connor–Davidson Resilience Scale (CD-RISC). Serum biochemical parameters were measured by automatic biochemistry analyzer.Results: The score of ATQ was highest in the MetS group (F = 14.5, p < 0.001), and the total score of CD-RISC, subscale tenacity score and subscale strength score of CD-RISC were lowest in the MetS group (F = 8.54, p < 0.001; F = 5.79, p = 0.004; F = 10.9, p < 0.001). A stepwise regression analysis demonstrated that a negative correlation was observed among the ATQ with employment status, high-density lipoprotein (HDL-C), and CD-RISC (β=− 0.190, t=− 2.297, p = 0.023; β=− 0.278, t=− 3.437, p = 0.001; β=− 0.238, t=− 2.904, p = 0.004). A positive correlation was observed among the ATQ with waist, TG, WBC, and stigma (β=0.271, t = 3.340, p = 0.001; β=0.283, t = 3.509, p = 0.001; β=0.231, t = 2.815, p = 0.006; β=0.251, t=− 2.504, p = 0.014). The area under the receiver-operating characteristic curve analysis showed that among all independent predictors of ATQ, the TG, waist, HDL-C, CD-RISC, and stigma presented excellent specificity at 0.918, 0.852, 0.759, 0.633, and 0.605, respectively.Conclusion: Results suggested that the non-MetS and MetS groups had grievous sense of stigma, particularly, high degree of ATQ and resilience impairment was shown by the MetS group. The TG, waist, HDL-C of metabolic parameters, CD-RISC, and stigma presented excellent specificity to predict ATQ, and the waist showed excellent specificity to predict low resilience level.Keywords: years of education, negative symptoms, waist circumstance

Yiran Chen,1,2,&ast; Xiaoling Wu,3,&ast; Xi Chen,1,2 Deliang Guo,1,2 Weijie Ma,1,2 Yonghua Guo,1,2 Kequan Xu,1,2 Shuxian Ma,1,2 Yufeng Yuan,1,2,4 Qian Zhu1,2 1Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, People’s Republic of China; 2Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan, Hubei, 430071, People’s Republic of China; 3Department of Liver Surgery, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 4TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yufeng Yuan; Qian Zhu, Email yuanyf1971@whu.edu.cn; zhuqian@whu.edu.cnIntroduction: Hepatocellular carcinoma (HCC) was the sixth most prevalent cancer worldwide. Long non-coding RNA TGFB2-OT1 has been proven to mediate inflammation and autophagy in vascular endothelial cells. However, its function in HCC is still unknown.Methods: We analyzed the relationship between TGFB2-OT1 expression and the clinicopathological features of 202 HCC patients. RT-qPCR was used to analyze the TGFB2-OT1 expression in HCC cell lines and tissues. In vitro and in vivo assays were conducted to verify the effect of TGFB2-OT1 on the phenotype of HCC. RNA pull-down assays were applied to reveal the proteins binding to the TGFB2-OT1. Western-blot assays were conducted to analyze the protein expression in HCC cell lines.Results: TGFB2-OT1 was found to be highly expressed in HCC samples and hepatoma cells. TGFB2-OT1 expression was significantly associated with age (P = 0.001), cirrhosis (P = 0.003), tumor size (P < 0.001), tumor encapsulation (P = 0.029), tumor protruding from the liver surface (P = 0.040), and alpha fetoprotein (AFP, P < 0.001) levels. TGFB2-OT1 promoted proliferation, migration, invasion, and angiogenesis in HCC cells, both in vitro and in vivo. TGFB2-OT1 binds to β-catenin and competitively impaired the binding of β-catenin to GSK3β, thus suppressing the phosphorylation of β-catenin at Ser33, Ser37, and Thr41.Conclusion: TGFB2-OT1 is overexpressed in HCC and predicts the poor prognosis of HCC patients. TGFB2-OT1 impedes the phosphorylation of β-catenin and acts as an alternative activator of the Wnt/β-catenin pathway to promote the progression and angiogenesis of HCC.Keywords: TGFB2-OT1, HCC, β-catenin, angiogenesis, phosphorylation

Kongbo Zhu,1 Shaolei Ma,2 Hui Chen,3 Jianfeng Xie,3 Dan Huang,1 Cuiping Fu,4 Genshan Ma,1 Yingzi Huang3 1Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 2Department of Emergency and Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 3Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China; 4Department of Respiratory Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of ChinaCorrespondence: Yingzi Huang, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, People’s Republic of China, Email yz_huang@126.comBackground: The pathogenicity of Omicron is different from that of the previous strains. The value of hematological indicators in patients at high risk of Omicron infection remains unclear. We need rapid, inexpensive and widely available biomarkers to guide the early detection of people at risk of pneumonia and to provide early intervention. We aimed to assess the value of hematological indicators as risk factors for pneumonia in symptomatic COVID-19 patients infected with the SARS-CoV-2 Omicron variant.Patients and Methods: The study enrolled 144 symptomatic COVID-19 patients with Omicron infection. We collected available clinical details, including laboratory tests and CT examinations. Univariate and multivariate logistic analyses and receiver operating characteristic (ROC) curve analyses were used to assess the value of laboratory markers in predicting the development of pneumonia.Results: Among the 144 patients, 50 (34.7%) had pneumonia. The ROC analysis revealed that the areas under the ROC curve (AUC) for leukocytes, lymphocytes, neutrophils, and fibrinogen were 0.603 (95% confidence interval (CI): 0.501– 0.704, P=0.043), 0.615 (95% CI: 0.517– 0.712, P=0.024), 0.632 (95% CI: 0.534– 0.730, P=0.009) and 0.635 (95% CI: 0.539– 0.730, P=0.008), respectively. The AUC for neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), fibrinogen to lymphocyte ratio (FLR), and fibrinogen to D-dimer ratio (FDR) were 0.670 (95% CI: 0.580– 0.760, P=0.001), 0.632 (95% CI: 0.535– 0.728, P=0.009), 0.669 (95% CI: 0.575– 0.763, P=0.001) and 0.615 (95% CI: 0.510– 0.721, P=0.023), respectively. Univariate analysis showed that elevated levels of NLR (odds ratio (OR): 1.219, 95% CI: 1.046– 1.421, P=0.011), FLR (OR: 1.170, 95% CI: 1.014– 1.349, P=0.031) and FDR (OR: 1.131, 95% CI: 1.039– 1.231, P=0.005) were significantly correlated with the presence of pneumonia. Multivariate analysis indicated elevated NLR (OR: 1.248, 95% CI: 1.068– 1.459, P=0.005) and FDR (OR: 1.160, 95% CI: 1.054– 1.276, P=0.002) levels were associated with the existence of pneumonia. The AUC for the combination of NLR and FDR was 0.701 (95% CI: 0.606– 0.796, P< 0.001, sensitivity 56.0%, specificity 83.0%).Conclusion: NLR and FDR can predict the presence of pneumonia in symptomatic COVID-19 patients infected with the SARS-CoV-2 Omicron variant.Keywords: COVID-19, Omicron, pneumonia, neutrophil to lymphocyte ratio, fibrinogen, D-dimer

Yajuan Fu,1,2 Lingbo Xu,1– 3 Hui Zhang,1– 3 Ning Ding,1– 3 Juan Zhang,1– 3 Shengchao Ma,1– 3 Anning Yang,1– 3 Yinjv Hao,1– 3 Yujing Gao,1,2 Yideng Jiang1– 3 1National Health Commission Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, People’s Republic of China; 2Ningxia Key Laboratory of Vascular Injury and Repair Research, Ningxia Medical University, Yinchuan, People’s Republic of China; 3School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, People’s Republic of ChinaCorrespondence: Yujing Gao; Yideng Jiang, Email gaoyujing2004@126.com; jydeng@nxmu.edu.cnBackground: Atherosclerosis and type 2 diabetes mellitus contribute to a large part of cardiovascular events, but the underlying mechanism remains unclear. In this study, we focused on identifying the linking genes of the diagnostic biomarkers and effective therapeutic targets associated with these two diseases.Methods: The transcriptomic datasets of atherosclerosis and type 2 diabetes mellitus were obtained from the GEO database. Differentially expressed genes analysis was performed by R studio software, and differential analysis including functional enrichment, therapeutic small molecular agents prediction, and protein–protein interaction analysis were applied to the common shared differentially expressed genes. Hub genes were identified and further validated using an independent dataset and clinical samples. Furthermore, we measured the expression correlations, immune cell infiltration, and diagnostic capability of the three key genes.Results: We screened out 28 up-regulated and six down-regulated common shared differentially expressed genes. Functional enrichment analysis showed that cytokines and immune activation were involved in the development of these two diseases. Six small molecules with the highest absolute enrichment value were identified. Three critical genes (CD4, PLEK, and THY1) were further validated both in validation sets and clinical samples. The gene correlation analysis showed that CD4 was strongly positively correlated with PLEK, and ROC curves confirmed the good discriminatory capacity of CD4 and PLEK in two diseases.We have established the co-expression network between atherosclerosis lesions progressions and type 2 diabetes mellitus, and identified CD4 and PLEK as key genes in the two diseases, which may facilitate both development of diagnosis and therapeutic strategies.Keywords: small molecular agents, immune infiltration, atherosclerosis, diabetes mellitus, inflammation

Siyuan Ma,1,&ast; Yali Gong,1,&ast; Xiaoqiang Luo,1,&ast; Yuan Peng,2 Cheng Zhang,1 Xiaorong Zhang,1 Xiaohong Hu,1 Peng Tang,3 Zhiqiang Yuan,1 Gaoxing Luo,1 Haisheng Li1 1State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 2Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Clinical Laboratory, the Second Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haisheng Li, Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Street, Shapingba District, Chongqing, 400038, People’s Republic of China, Tel +86-023-68765952, Email lee58427@163.comBackground: Elizabethkingia meningoseptica infections have gradually emerged as life-threatening nosocomial infections worldwide, accompanied by increasing incidence, multidrug resistance and poor outcomes. However, the epidemiology and clinical features of E. meningoseptica infection are still limited in mainland China.Methods: Patients with E. meningoseptica infections from 2011 to 2019 in southwestern China were retrospectively analyzed. The clinical features, infection patterns and outcomes were extracted from medical records and analyzed. A comprehensive systematic review was performed in accordance with PRISMA guidelines from conception to August 23, 2021.Results: Ninety-two patients were ultimately included, with the prevalence rapidly rising from 0 in 2011 to 0.19 per 1000 inpatients in 2019. A total of 93.48% of E. meningoseptica isolates were multidrug resistant, including 100% resistance to carbapenem. Furthermore, 75% of E. meningoseptica infections were concomitant with other pathogens. The mortality of our cohort was 36.96%, with risk factors for mechanical ventilation (OR=9.51, P=0.004), male sex (OR=0.27, P=0.031) and more concomitant pathogens. After propensity score matching, central venous catheters, exposure to carbapenem and antifungal drugs, and underlying tumors were associated with E. meningoseptica infection. Sixteen articles were also summarized, with reported mortality rates ranging from 11.0% to 66.6%. Blood and respiratory tract were the common sources. Piperacillin/tazobactam, trimethoprim/sulfamethoxazole, fluoroquinolone and minocycline were the most sensitive antibiotics. Inappropriate antibiotic treatment was the most commonly reported risk factor for mortality.Conclusion: Nosocomial infection with E. meningoseptica has become an emerging problem with high mortality in southwestern China. Inappropriate antibiotic treatment and central venous catheters are risk factors for infection and death and should receive adequate attention.Keywords: meningoseptica, nosocomial infection, epidemiology, risk factor, multidrug resistance, infection control

Jie Pan,1 Qiuyan Li,1 Yan Sun,1 Yingying Gu,1 Yijie Ding,1 Nengzhi Pang,1 Yujia Zhou,1 Lei Pei,1 Mengqi Gao,1 Sixi Ma,1 Ying Xiao,1 Feilong Wu,1 De Hu,1 Yu-Ming Chen,2 Lili Yang1 1Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaCorrespondence: Lili Yang, Department of Nutrition, School of Public Health, Sun Yat-sen University, No. 74, Zhongshan Road 2, Yuexiu District, Guangzhou, Guangdong, 510080, People’s Republic of China, Tel +86-20-87330625, Email yangll7@mail.sysu.edu.cnPurpose: A panel of international experts proposed a new definition of fatty liver in 2020, namely metabolic dysfunction-associated fatty liver disease (MAFLD). As an adipokine, adipsin is closely related to metabolic-related diseases. In this study, we aimed to evaluate the relationship among MAFLD, serum adipsin, and metabolic risk abnormalities.Methods: Our study was a cross-sectional study based on the first follow-up of the Guangzhou Nutrition and Health Study (GNHS). A total of 908 patients with hepatic steatosis were involved in our study. Detailed data of patients were collected based upon questionnaire information, physical examination, and blood biochemical test.Results: Among the 908 patients, 789 patients were diagnosed with MAFLD. The levels of serum adipsin in the MAFLD group and non-MAFLD group were (3543.00 (3187.94– 3972.50) ng/mL) and (3095.33 (2778.71– 3354.77) ng/mL) (P < 0.001), respectively. After adjusting for potential confounders, adipsin levels were found to be associated with MAFLD. The OR was 3.46 (95% CI: 1.57– 7.64) for adipsin when comparing subjects in the highest tertile with those in the lowest tertile. With the increase in the number of metabolic risk abnormalities, both the levels of serum adipsin and the proportion of moderate to severe fatty liver increased (all p-trend < 0.001).Conclusion: Increased serum adipsin correlates with MAFLD. Both adipsin levels as well as fatty liver severity increase with higher numbers of metabolic risk abnormalities.Keywords: metabolic dysfunction-associated fatty liver disease, adipsin, metabolic risk abnormalities, hepatic steatosis

Qingjuan Zuo,1,2 Guorui Zhang,1,3 Lili He,2 Sai Ma,4 Huijuan Ma,5 Jianlong Zhai,6 Zhongli Wang,7 Tingting Zhang,2 Yan Wang,2 Yifang Guo1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3Department of Cardiology, the Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, People’s Republic of China; 4Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 5Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 6Department of Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 7Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Yifang Guo, Department of Geriatric Cardiology, Hebei General Hospital, No. 348, Heping West Road, Xinhua District, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-15100189182, Email guoyifang@hotmail.comPurpose: To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism.Methods: Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR.Results: Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1β, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPβ were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS.Conclusion: Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.Keywords: canagliflozin, hepatic steatosis, atherosclerosis, RNA-seq, dyslipidemia, inflammatory response, autophagy

Shi Chen,1,&ast; Xugui Song,2,&ast; Hongfei Shi,3 Jing Li,4 Shengqi Ma,4 Linan Chen,4 Ying Lu,4 Conglin Hong,4 Hanyun Zhu,4 Hongyan Sun,3 Mingzhi Zhang5 1Department of Nursing, School of Nursing, Suzhou Vocational Health College, Suzhou, People’s Republic of China; 2Shishan Community Health Service Center, Suzhou, People’s Republic of China; 3Center for Disease Prevention and Control of Tianning District, Changzhou, People’s Republic of China; 4Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, People’s Republic of China; 5Department of Biostatistics, School of Public Health, Medical College of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mingzhi Zhang, Department of Biostatistics, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou, People’s Republic of China, 215123, Tel +86 512 6588 0079, Fax +86 512 6588 0052, Email zhangmingzhi@suda.edu.cn Hongyan Sun, Center for Disease Prevention and Control of Tianning District, Changzhou, People’s Republic of China, Email 1106925654@qq.comBackground: Poor sleep quality is becoming very common in a developed society and relates to many health disorders. However, the association between sleep quality and hypertension has not been well studied in Chinese adults.Methods: Blood pressure was measured and sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) for 5167 participants (mean aged 51± 15 years, 41.5% males) in the Tianning Cohort. A logistic regression model was constructed to examine the association between sleep quality, as well as its components, and hypertension, adjusting for age, sex, education level, current smoking, current drinking, physical activity, obesity, glucose, and blood lipids.Results: After multivariate adjustment, a higher score Of the PSQI was significantly associated with an increased risk of prevalent hypertension (OR=1.03, P=0.018). Compared to participants with normal sleep (the PSQI score < 5), those with a poor sleep quality (the PSQI score ≥ 5) had a 17% increased risk of prevalent hypertension (OR=1.17, P=0.042). Three of the seven components of sleep quality, such as subjective sleep quality (OR=1.17, P=0.001), sleep latency (OR=1.11, P=0.010), and sleep disturbances (OR=1.19, P=0.004), were also significantly associated with prevalent hypertension.Conclusion: Poor sleep quality is increasingly prevalent in developed societies and may be related to an increased risk of hypertension in Chinese adults. The underlying causality is waiting to be studied.Keywords: sleep quality, hypertension, Pittsburgh Sleep Quality Index

Qingqing Li,1,&ast; Tong Su,2,&ast; Xu Zhang,3,&ast; Yanfeng Pan,1,&ast; Shengli Ma,4 Lu Zhang,4 Xianqiang Zhang,1 Xiaojuan Gao1 1Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 2Department of Medical, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou city, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Surgery, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou city, People’s Republic of China; 4Department of Infectious Diseases, The People’s Hospital of Yongcheng, Yongcheng city, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanfeng Pan, Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Jinshui District, Zhengzhou city, 450000, People’s Republic of China, Tel +8613938448759, Email panfirstfeng@163.comPurpose: To observe the efficacy and safety of anlotinib as a first-line treatment for patients with advanced hepatocellular carcinoma (aHCC) in a real-word environment, explore the optimal treatment regimen for patients with aHCC using anlotinib as a first-line treatment.Patients and Methods: Data from 62 patients with aHCC who received anlotinib single-drug first-line therapy between February 2019 and November 2021. Patients received anlotinib monotherapy, which may be interrupted or discontinued or changed in the event of unacceptable or severe adverse events (AEs) or failure to inhibit tumor progression. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate(ORR), disease control rate (DCR), overall survival (OS), and safety.Results: Among the 62 patients, in the best overall response assessment, there were 12 with complete response (CR; 19.4%), 17 with partial response (PR; 27.4%), 25 with stable disease (SD; 40.3%), and 8 with progressive disease (PD; 14.5%). The ORR and DCR were 46.8% and 87.1%, respectively. Among the 11 patients who received tyrosine kinase inhibitors (TKIs) combined with programmed death 1 (PD-1) inhibitors after disease progression, three (27.3%) had CR, one (9.1%) had PR, three (27.3%) had SD, and four (36.4%) had PD. Therefore, the ORR and DCR were 36.4% and 63.6%, respectively. The median PFS for anlotinib monotherapy was 7.37 months (95% confidence interval [CI]: 5.88– 8.86) and the median OS did not reach. AEs occurred in 95.2% of patients during anlotinib monotherapy, with the most common being thrombocytopenia (51.6%). The incidence of grade ≥ 3 AEs was 38.7%.Conclusion: Anlotinib is effective and well-tolerated as a first-line treatment for patients with aHCC. Treatment with TKIs and PD-1 inhibitors after disease progression has also shown preliminary efficacy and safety; therefore, sequential therapy with anlotinib-TKIs and PD-1 inhibitors may be an effective treatment for patients with aHCC.Keywords: hepatocellular carcinoma, anlotinib, sequential therapy, real world

Dongrui Liang,1,&ast; Shengnan Ma,1,&ast; Xiaodong Li2 12nd Department of Ophthalmology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China; 2Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding, Hebei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaodong Li, Department of Nephrology, Baoding No. 1 Central Hospital of Hebei Medical University, Baoding Great Wall North Street No 320, Baoding, Hebei, 071000, People’s Republic of China, Tel +8618617789590, Email lxd_765@sina.com

Frédérique St-Pierre,1 Shuo Ma1,2 1Department of Medicine, Division of Hematology/Oncology and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA; 2Department of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USACorrespondence: Shuo Ma, Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Tel +1 312-695-0990, Email shuo-ma@northwestern.eduAbstract: The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has changed significantly since the development of oral Bruton’s tyrosine kinase (BTK) inhibitors. While chemoimmunotherapy was previously the standard of care for first-line treatment, BTK inhibitors have proven to be a highly effective and safe therapeutic option for CLL/SLL, and now constitute one of the preferred first-line options. Ibrutinib, the first approved covalent BTK inhibitor in CLL/SLL, has the most long-term data supporting its efficacy in CLL/SLL treatment although is associated with increased risk of cardiovascular and hemorrhage adverse events due to off-target kinase inhibition. The second-generation covalent BTK inhibitors, including acalabrutinib and zanubrutinib, are more selective to BTK with less off-target effects. Resistance to covalent BTK inhibitors may emerge over time due to mutations in BTK and downstream kinases. Novel non-covalent BTK inhibitors currently being studied are showing promising activities to overcome such resistance. In this review, we discuss the role of BTK inhibitors in treatment of CLL/SLL, review the data that led to approval of BTK inhibitors in CLL/SLL, outline the toxicity profile of each approved BTK inhibitor and management, and give practical guidance on how to select the most appropriate agent for treatment.Keywords: Bruton’s tyrosine kinase inhibitor, chronic lymphocytic leukemia/small lymphocytic lymphoma, ibrutinib, acalabrutinib, zanubrutinib

Huiting Zhou,1,&ast; Xiaying Lu,2,3,&ast; Jie Huang,1,&ast; Patrick Jordan,2 Shurong Ma,1 Lingqi Xu,1 Fangjie Hu,1 Huan Gui,1 He Zhao,1 Zhenjiang Bai,1 H Paul Redmond,2 Jiang Huai Wang,2 Jian Wang1 1Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland; 3Department of Physiology, Gannan Medical University, Ganzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jian Wang, Institute of Pediatric Research, Children’s Hospital of Soochow University, Suzhou, People’s Republic of China, Email wj196312@vip.163.com Jiang Huai Wang, Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland, Email jh.wang@ucc.ieBackground: Neonates are susceptible to a wide range of microbial infection and at a high risk to develop severe sepsis and septic shock. Emerged evidence has shown that induction of trained immunity triggers a much stronger inflammatory response in adult monocytes/macrophages, thereby conferring protection against microbial infection.Methods: This study was carried out to examine whether trained immunity is inducible and exerts its protection against microbial sepsis in neonates.Results: Induction of trained immunity by Bacillus Calmette-Guerin (BCG) plus bacterial lipoprotein (BLP) protected neonatal mice against cecal slurry peritonitis-induced polymicrobial sepsis, and this protection is associated with elevated circulating inflammatory cytokines, increased neutrophil recruitment, and accelerated bacterial clearance. In vitro stimulation of neonatal murine macrophages with BCG+BLP augmented both inflammatory response and antimicrobial activity. Notably, BCG+BLP stimulation resulted in epigenetic remodeling characterized by histone modifications with enhanced H3K4me3, H3K27Ac, and suppressed H3K9me3 at the promoters of the targeted inflammatory and antimicrobial genes. Critically, BCG+BLP stimulation led to a shift in cellular metabolism with increased glycolysis, which is the prerequisite for subsequent BCG+BLP-triggered epigenetic reprogramming and augmented inflammatory response and antimicrobial capacity.Conclusion: These results illustrate that BCG+BLP induces trained immunity in neonates, thereby protecting against microbial infection by boosting both inflammatory and antimicrobial responses.Keywords: trained immunity, inflammatory response, antimicrobial activity, epigenetic reprogramming, intracellular metabolic rewiring, neonatal sepsis

Yujuan Mao,1 Yumeng Chen,2 Chang Liu,2 Xingyue He,2 Yi Zheng,1 Xiaolan Chen,1 Ying Wang,1 Wei Chen,1 Yanling Wu,1 Yan Shen,2 Haifeng Yang,1 Songbo Ma3 1Jiangsu Animal Husbandry and Veterinary College, Taizhou, Jiangsu, 225300, People’s Republic of China; 2State Key Laboratory of Natural Medicines, Center for Research Development and Evaluation of Pharmaceutical Excipients and Generic Drugs, Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China; 3Department of Oral and Maxillofacial Surgery, Taizhou People’s Hospital, Taizhou, Jiangsu, 225300, People’s Republic of ChinaCorrespondence: Haifeng Yang, Email yhf8142@sina.com; Songbo Ma, Email masongbo1978@163.comIntroduction: Cefquinome sulfate (CS) is the first fourth-generation antibiotic for animals, which has a wide antibacterial spectrum, strong antibacterial activity and low drug resistance. However, it is accompanied by problems of poor therapeutic efficacy. In this context, the use of nanosuspensions have been found to be an attractive strategy. The main objective of this work is to develop a new oily nanosuspension to improve bioavailability and stability of CS formulations.Methods: After screening the formulations, cefquinome sulfate oily nanosuspension (CS-NSP) was prepared by mortar grinding, using propylene glycol dicaprolate/dicaprate (Labrafac™ PG) as oil medium and caprylocaproyl polyoxyl-8 glycerides (Labrasol®) as stabilizer. The properties of CS-NSP were investigated by testing its physicochemical characteristics, stability, in vitro release, hemolysis, and muscle irritation. The in vivo pharmacokinetics of CS-NSP was studied using rats.Results: Results show that CS-NSP presents suitable stability, physicochemical properties and safety. Moreover, a rapid release and high bioavailability of CS-NSP have also been verified in the study. Pharmacokinetic experiments in vivo showed that the bioavailability of CS-NSP was about 1.6 times that of commercial cefquinome sulfate injection (CS-INJ, Chuangdao®) (p< 0.01). These advantages of CS-NSP were carried out by small particle size and low viscosity, being associated with the use of Labrafac PG and stabilizer Labrasol.Conclusion: The results proved that the new preparation is safe and effective and is expected to become a promising veterinary nanodelivery system.Keywords: cefquinome sulfate, oily nanosuspension, Labrafac PG, labrasol, pharmacokinetics

Jiangshan He,1 Yuxue Wang,1 Li Zhang,2 Chunjun Li,3 Xin Qi,3 Jianxiong Wang,4 Pei Guo,1 Shuo Chen,5 Yujie Niu,6,7 Feng Liu,5 Rong Zhang,6,7 Qiang Li,5 Shitao Ma,6,7 Mianzhi Zhang,8,9 Chenglin Hong,10 Minying Zhang1 1School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Tianjin First Central Hospital, Tianjin, People’s Republic of China; 3Tianjin Union Medical Center, Tianjin, People’s Republic of China; 4Graduate School of Tianjin Medical University, Tianjin, People’s Republic of China; 5Beijing Physical Examination Center, Beijing, People’s Republic of China; 6Hebei Key Laboratory of Environment and Human Health, Shijiazhuang, People’s Republic of China; 7Department of Occupational Health and Environmental Health, Hebei Medical University, Shijiazhuang, People’s Republic of China; 8Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 9Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, People’s Republic of China; 10Department of Social Welfare, School of Public Affairs, University of California, Los Angeles, CA, USACorrespondence: Minying Zhang, School of Medicine, Nankai University, 94 Weijin Road, Nankai District, Tianjin, 300071, People’s Republic of China, Tel +86-13752516700, Fax +86-22-23502554, Email zhangminying@nankai.edu.cnPurpose: We hypothesize the association between sleep duration and cardiovascular disease (CVD) risk varies with age category; however, evidence for the relationship between sleep duration and CVD risk among young and middle-aged adults remains scarce. This research aims to assess the association between night sleep duration and cardiovascular risk by sex among young and middle-aged Chinese adults.Patients and Methods: We used the baseline data of a cohort of adults for physical examination by stratified cluster sampling. The Framingham risk score and the Pittsburgh Sleep Quality Index were used to measure CVD risk and sleep duration, respectively. Demographic characteristics, lifestyle factors, height, weight, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C) were collected. We performed multiple logistic regressions to examine the association between night sleep duration and the predicted cardiovascular risk.Results: We included 27,547 participants aged 18– 64 years free of CVD, cerebral stroke, and not taking lipid-lowering agents. Overall, 12.7%, and 20.4% were at medium and high predicted CVD risk, respectively; 11.9% and 12.3% reported short and long sleep, respectively. Short sleep was independently associated with 23% (95% CI: 1.08– 1.40) increased odds of medium-to-high CVD risk and 26% (95% CI: 1.11– 1.45) increased odds of high CVD risk among females. Whereas long sleep was independently associated with 17% (95% CI: 0.71– 0.98) decreased odds of medium-to-high CVD risk among males.Conclusion: Among young and middle-aged adults, long sleep was associated with decreased odds of CVD risk in males, whereas short sleep was associated with increased odds of cardiovascular risk in females.Keywords: predicted 10-year CVD risk, sleep duration, Framingham risk score, young and middle-aged population

Conglin Hong,1,&ast; Qiu Zhang,2,&ast; Yan Chen,3,&ast; Ying Lu,1 Linan Chen,1 Yan He,1 Jing Li,1 Shengqi Ma,1 Jun Jiang,4 Xiaolong Zhang,4 Jianwei Hu,5 Yi Ding,6 Mingzhi Zhang,1 Hao Peng1,7 1Department of Epidemiology, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China; 2Department of Chronic Disease, Gusu Center for Disease Prevention and Control, Suzhou, People’s Republic of China; 3Department of Nephrology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, People’s Republic of China; 4Department of Tuberculosis Control, Suzhou Center for Disease Control and Prevention, Suzhou, People’s Republic of China; 5Department of Central Office, Maternal and Child Health Bureau of Kunshan, Suzhou, People’s Republic of China; 6Department of Preventive Medicine, College of Clinical Medicine, Suzhou Vocational Health College, Suzhou, People’s Republic of China; 7Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Peng; Mingzhi Zhang, Department of Epidemiology, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park District, Suzhou, 215123, People’s Republic of China, Tel +86 512 6588 0078; 86 512 6588 0079, Email penghao@suda.edu.cn; zhangmingzhi@suda.edu.cnObjective: Although elevated uric acid is associated with obesity and considered a predictor of hypertension, the causal linkage between the three metabolic conditions is not very clear. We aim to examine whether elevated uric acid mediates the effects of obesity on hypertension development.Methods: A total of 1984 participants (mean aged 53 years, 62.10% female) with repeated measurements of obesity, blood pressure, and uric acid 4 years apart in the Gusu cohort were included. We first applied cross-lagged panel analysis and bidirectional association analysis to delineate the temporal association between obesity and hyperuricemia. Then, a causal mediation model was constructed to further examine the causal role of hyperuricemia in the linkage between obesity and hypertension. Age, sex, education, cigarette smoking, alcohol consumption, fasting blood glucose, and lipids were adjusted.Results: The cross-lagged panel analysis demonstrated that the relationship from baseline obesity to follow-up hyperuricemia was stronger than that from baseline hyperuricemia to follow-up obesity (β: 0.09 vs 0.06, P< 0.01 for BMI, β: 0.13 vs 0.07, P< 0.01 for WC). Bidirectional association analysis found that baseline obesity predicted the risk of incident hyperuricemia (OR = 1.09, P< 0.01 for BMI, OR = 1.05, P< 0.01 for WC), but the other directional association was not statistically significant (all P> 0.05). The causal mediation analysis found that hyperuricemia partially mediated the association of baseline BMI (mediate proportion: 3.09%, 95% CI: 0.97%∼ 6.00% for SBP, 3.74%, 95% CI: 1.55%∼ 7.00% for DBP) and baseline WC (mediate proportion: 5.56%, 95% CI: 2.01%∼ 11.00% for SBP, 5.81%, 95% CI: 2.59%∼ 10.00% for DBP) with follow-up blood pressures.Conclusion: Obesity preceded hyperuricemia and the latter partially mediated the relationship between obesity and hypertension, independent of behavioral and other metabolic factors.Keywords: bidirectional association analysis, causal mediation analysis, cross-lagged panel analysis, blood pressures, temporal relationship, uric acid, obesity

Shijiao Ma,1 Chenchen Gu,1 Junjie Xu,1 Jinxin He,2 Shuli Li,1 Haolan Zheng,1 Bo Pang,1 Ying Wen,1 Qiaojun Fang,3 Weiquan Liu,1 Jiesheng Tian1 1State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, 100193, People’s Republic of China; 2College of Veterinary Medicine, Shanxi Agriculture University, Taigu, Shanxi, 030801, People’s Republic of China; 3CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, People’s Republic of ChinaCorrespondence: Weiquan Liu; Jiesheng Tian, Tel/Fax +8610-62732676 ; +8610-62731440, Email weiquan8@cau.edu.cn; tianhome@cau.edu.cnPurpose: Nanoparticles (NPs) decorated with functional ligands are promising candidates for cancer diagnosis and treatment. However, numerous studies have shown that chemically coupled targeting moieties on NPs lose their targeting capability in the biological milieu because they are shielded or covered by a “protein corona”. Herein, we construct a functional magnetosome that recognizes and targets cancer cells even in the presence of protein corona.Methods: Magnetosomes (BMPs) were extracted from magnetotactic bacteria, M. gryphiswaldense (MSR-1), and decorated with trastuzumab (TZ) via affibody (RA) and glutaraldehyde (GA). The engineered BMPs are referred to as BMP-RA-TZ and BMP-GA-TZ. Their capacities to combine HER2 were detected by ELISA, the quantity of plasma corona proteins was analyzed using LC-MS. The efficiencies of targeting SK-BR-3 were demonstrated by confocal laser scanning microscopy and flow cytometry.Results: Both engineered BMPs contain up to ∼ 0.2 mg TZ per mg of BMP, while the quantity of HER2 binding to BMP-RA-TZ is three times higher than that binding to BMP-GA-TZ. After incubation with normal human plasma or IgG-supplemented plasma, GA-TZ-containing BMPs have larger hydrated radii and more surface proteins in comparison with RA-TZ-containing BMPs. The TZ-containing BMPs all can be targeted to and internalized in the HER2-overexpressing breast cancer cell line SK-BR-3; however, their targeting efficiencies vary considerably: 50– 75% for RA-TZ-containing BMPs and 9– 19% for GA-TZ-containing BMPs. BMPs were incubated with plasma (100%) and cancer cells to simulate human in vivo environment. In this milieu, BMP-RA-TZ uptake efficiency of SK-BR-3 reaches nearly 80% (slightly lower than for direct interaction with BMP-RA-TZ), whereas the BMP-GA-TZ uptake efficiency is < 17%.Conclusion: Application of the RA scaffold promotes and orients the arrangement of targeting ligands and reduces the shielding effect of corona proteins. This strategy improves the targeting capability and drug delivery of NP in a simulated in vivo milieu.Keywords: affibody, protein corona, magnetosomes, human epidermal growth factor receptor 2, HER2

Huijing Tan,1 Lijie Zuo,1,2 Shutao Ma,1 Dingyuan Wang,3 Rui Li,1,2 Yiqi Yang,1,2 Weili Liu,1,2 Yihebali Chi1 1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China; 2Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China; 3Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of ChinaCorrespondence: Yihebali ChiDepartment of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 South Panjiayuan Lane, Chaoyang District, Beijing, 100021, People’s Republic of ChinaTel +8613911075626Email yihebalichi@hotmail.comBackground: Leiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS.Methods: This was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020.Results: We examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths.Conclusion: EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.Keywords: epirubicin, temozolomide, advanced leiomyosarcoma, chemotherapy

Xiudong Guan,1,2,&ast; Yangyang Wang,1,2,&ast; Yueqian Sun,2,3 Chuanbao Zhang,1,2 Shunchang Ma,2,4 Dainan Zhang,1,2 Deling Li,1,2 Wang Jia1,2,4 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, People’s Republic of China; 3Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Beijing Neurosurgical Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wang JiaDepartment of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No. 119 South 4th Ring West Road, Fengtai District, Beijing, 100070, People’s Republic of ChinaTel +86 18810671839Fax +86-10-67051377Email jwttyy@126.comPurpose: CTLA4, the immune checkpoint, has been widely reported to contribute to immune evasion in anti-tumor activity. The inhibitors of CTLA4 provide a novel strategy to improve the outcome of peripheral cancer, but their clinical effects are limited in glioblastoma (GBM), thus the comprehensive role of CTLA4 needs to be addressed.Patients and Methods: A total of 471 GBM cases were enrolled in this study from 5 cohorts. In our works, the Cancer Genome Atlas (TCGA) cohort was divided into the training set, and the Chinese Glioma Genome Atlas (CGGA), REMBRANDT, and GSE84465 cohorts were divided into validation sets. Tissues from our cohort were collected for histopathologic validation. Then, the role of CTLA4 in the TME of GBM was comprehensively investigated.Results: Significant differences exist in immunological characteristics between the low and high CTLA4 expression groups. Mutation analysis found different genomic patterns associated with CTLA4 expression. Next, network analysis found the module named c1-1562 including CTLA4 correlated with over survival (OS) in GBM. We also developed a predictive model to calculate the risk score for every GBM case and the risk score was independently related to OS. Furthermore, the expression of CTLA4 was positively related to the infiltration level and function of macrophage in GBM TME based on seven independent algorithms, single-cell RNA-seq data and immunohistochemistry.Conclusion: These findings implicate that CTLA4 could serve as a novel target for prognosis and therapy in GBM patients. CTLA4-mediated immune suppression may be attributed to the infiltration of macrophages in the tumor microenvironment.Keywords: glioblastoma, tumor microenvironment, CTLA4, macrophage, multi‐omics

Yuehui Jia,1,&ast; Shuli Ma,1,&ast; Lianjie Bai,2 Qiong Xiao,3 Yu Wu,3 Ying Gao,4 Yunfeng Han,1 Zhiping Xie,1 Xiaowei Tang,5 Jie Ge1 1School of Public Health, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 2The Second Affiliated Hospital, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 3School of Nursing, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 4School of Mental Health, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 5Sanitary Analysis Center, Scientific Research Office, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jie GeSchool of Public Health, Qiqihar Medical University, 333 Bukui Street, Jianhua District, Qiqihar, 161000, People’s Republic of ChinaTel +86452-2663409Fax +86452-2663755Email gejieqiao@126.comPurpose: This study aimed to assess the knowledge, attitude and practice (KAP) towards COVID-19 of Chinese college students during the COVID-19 outbreak and identify the determinants considerably associated with KAP.Methods: An online cross-sectional questionnaire survey was conducted in February 2020 in China to recruit participants on the Wen-Juan-Xing online platform. A self-made questionnaire was used to assess the KAP towards COVID-19.Results: The average scores of COVID-19-related KAP among college students were 32.16 ± 4.09, 16.84 ± 3.18 and 15.36 ± 1.83, respectively. The average correct response rate of COVID-19-related knowledge was 84.62%. 94.59% of the respondents believed China could control and conquer the pandemic; 98.92% of the respondents wore a mask when they went out. The multiple linear regression showed that the female students had higher scores of COVID-19-related knowledge than male students (β = 0.79, P = 0.01), and the students from 985 or 211 universities (β = − 2.22, P < 0.01) were significantly associated with higher knowledge scores. Furthermore, a significantly positive correlation was found between the scores of COVID-19-related KAP among students.Conclusion: The college students had a good KAP towards the COVID-19 pandemic. The present study was able to access the COVID-19-related KAP among college students during the pandemic and identify their weaknesses in pandemic prevention. Consequently, the results of this study provide theoretical basis for implementing precision health education among college students and reference for campuses to conduct scientific prevention and control during a pandemic. Results also provide beneficial experience to curb similar major public health emergencies in the future.Keywords: COVID-19, knowledge, attitude, practice, college students

Sijia Ma,1 Mingming Zhao,1 Jiao Fan,1 Meiying Chang,1 Zhiyu Pan,1 Ziyan Zhang,1 Shunxuan Xue,1 Qi Li,2 Yu Zhang1 1Department of Nephrology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Department of Clinical Laboratory, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Yu Zhang Email zhangyu8225@126.comIntroduction: Renal clear cell carcinoma (ccRCC) is a common tumor of the urinary system, most of which are primary malignant tumors with high metastatic rate and remaining incurable. Ferroptosis is a newly discovered form of iron-dependent programmed cell necrosis in recent years, which is inextricably linked to the occurrence and development of tumors progression. Due to the complexity of the interaction between genes in ccRCC, the research on the pathogenesis of ccRCC is still not remarkably accurate. Therefore, whether ferroptosis-related genes (FRGs) can play a role in predicting prognosis in ccRCC needs to be discussed.Methods: We entered the Cancer Genome Mapping Project (TCGA) database and downloaded the relevant genes and clinical research data of ccRCC patients. Lasso Cox regression was used to construct a multi-gene prognostic model in the TCGA cohort. R language software was used for drawing pictures related to our study.Results: Most of the genes involved in ferroptosis (86.2%) existing differences between the tumor and normal tissues in the TCGA public gene database. In terms of univariate Cox regression analysis, 20 differentially expressed genes (DEGs) were associated with prognosis and survival (P< 0.05). A prognostic model of 12 FRGs was constructed, and patients were segmented into two different groups depending on how risky they are. Considering overall survival, the high-risk group is dramatically lower than the low-risk group (P< 0.001). In multivariate Cox regression analysis, risk scores and stage turned out be an independent prognostic factor (P< 0.001). GO and KEGG analysis and ssGSEA analysis of DEGs revealed that these genes were related to immune-related pathways (P< 0.05).Conclusion: This study established and identified the changes in FRGs expression and prognostic factors of ccRCC, which can be helpful for prognosis evaluation and clinical treatment of this disease.Keywords: renal clear cell carcinoma, ferroptosis, TCGA database, the prognosis

Kai Guo,1 Lijuan Qiu,1 Yufen Xu,2 Xiaoqiong Gu,2 Linyuan Zhang,3 Kun Lin,3 Xiaohuan Wang,1 Shanshan Song,1 Yu Liu,1 Zijian Niu,1 Shuxuan Ma1 1Department of Transfusion Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China; 3Department of Clinical Lab, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of ChinaCorrespondence: Shuxuan MaDepartment of Transfusion Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health No. 56 Nan Lishi Road, Xi Cheng District, Beijing, 100045, People’s Republic of ChinaTel +86 10 59616422Email masxfwyy@sina.comBackground: Kawasaki disease (KD) is a multisystem vasculitis in infants and young children and involved in the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activation. Genetic factors may increase the risk of KD. To assess the association between rs7248320 in long noncoding RNA (lncRNA) AC008392.1 located in the upstream region of CARD8 and the risk of KD, a case–control study was conducted in the Han Chinese population.Methods: This study genotyped the polymorphism rs7248320 in the lncRNA AC008392.1 gene using the TaqMan real-time polymerase chain reaction assay. The genetic contribution of rs7248320 was evaluated using odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. The association between rs7248320 and KD susceptibility was analyzed by performing a hospital-based case–control study including 559 KD patients and 1055 non-KD controls.Results: In this study, a significant relationship between rs7248320 and KD risk was observed in the genotype/allele frequency distribution. The rs7248320 polymorphism was associated with a significantly decreased risk of KD after adjustment for age and sex (AG vs AA: adjusted OR = 0.80, 95% CI: 0.64– 0.99, P = 0.0421; GG vs AA: adjusted OR = 0.71, 95% CI: 0.51– 1.00, P = 0.0492; AG/GG vs AA: adjusted OR = 0.78, 95% CI: 0.63– 0.96, P = 0.0186). Moreover, the rs7248320 G allele also exhibited a decreased risk for KD (adjusted OR = 0.83, 95% CI: 0.72– 0.97, P = 0.0193) compared with the A allele. In the stratification analysis, compared to the rs7248320 AA genotype, AG/GG genotypes were more protective for males (OR = 0.71, 95% CI: 0.55– 0.93, P = 0.0122).Conclusion: This study suggests for the first time that the lncRNA AC008392.1 rs7248320 polymorphism may be involved in KD susceptibility in the Han Chinese population.Keywords: Kawasaki disease, rs7248320, AC008392.1, CARD8, lncRNA, single-nucleotide polymorphism

Jian Yang,1,2 Xin Gao,1,2 Xiaotao Xing,1,2 Haisen Huang,1,2 Qi Tang,1,3 Shixing Ma,1,2 Xun Xu,1,2 Cheng Liang,1,2 Maojiao Li,1,2 Li Liao,1,2 Weidong Tian1,2 1State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of China; 3West China School of Public Health & West China Fourth Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Li Liao; Weidong TianState Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Engineering Research Center of Oral Translational Medicine, Ministry of Education & National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People’s Republic of ChinaTel/ Fax +86-28-85503499Email lliao@scu.edu.cn; drtwd@sina.comPurpose: Extracellular vesicles (EVs) are membrane-encapsulated nanoparticles that function as carriers and play a role in intercellular communication. There are a large number of EVs in the blood and serve as an indicator of pathophysiological conditions. Studies on the basics and application of EVs are hampered by the limitations of current protocols to isolate EVs from blood. However, current isolation methods are difficult to achieve a balance between yield and purity.Methods: Firstly, we use Sepharose-4B to build a self-made size exclusion chromatography (SEC) column and perform separation and characteristics. Then, we use the SEC column to systematically compare the efficiency with the most common EV isolation methods: Ultracentrifugation (UC) and total exosomes isolation commercial kit (TEI). The EVs isolated through different methods were characterized the yield and size of EVs, analyzed their protein profiles, the morphology and purity were observed under the transmission electron microscope. To further improve the quality and purity, we combined SEC and UC methods and established a two-steps method to isolated EVs from serum.Results: Self-made SEC column can well separate EVs from complex serum protein, and EVs enriched in the 8– 13 fractions with good morphology and yield. By systematically compare SEC with the commonly used UC and TEI kit, SEC is outstanding in all aspects and balances both isolation purity and yield. However, using the SEC method alone still has certain limitations and residual impurities. The SEC+UC combined method can cleverly solve the shortcomings of SEC and optimize the quality and purity of EVs from serum, which is much better than using one method alone.Conclusion: Our study presents the combination of size-exclusion chromatography and ultracentrifugation as a feasible and time-saving method to isolate high-quality and purity extracellular vesicles from serum.Keywords: extracellular vesicles, size-exclusion chromatography, ultracentrifugation, total exosomes isolation, combination methods

Shengqi Ma,1,&ast; Lei Wu,2,&ast; Qing Yu,3,&ast; Donghui Chen,2 Chunsong Geng,3 Hao Peng,1 Lugang Yu,2 Mingzhi Zhang1 1Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Department of Maternal and Child Health, Suzhou Industrial Park Centers for Disease Control and Prevention, Suzhou, Jiangsu, People’s Republic of China; 3Department of Gynecology and Obstetrics, Suzhou Kowloon Hospital, Suzhou, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lugang YuDepartment of Maternal and Child Health, Suzhou Industrial Park Centers for Disease Control and Prevention, 200 Suhong West Road, Industrial Park, Suzhou, 215123, People’s Republic of ChinaTel +86 512 6761 4200Fax +86 512 6761 4233Email YLG@sipcdc.comMingzhi ZhangDepartment of Biostatistics, School of Public Health, Medical College of Soochow University, 199 Renai Road, Industrial Park, Suzhou, 215123, People’s Republic of ChinaTel +86 512 6588 0079Fax +86 512 6588 0052Email zhangmingzhi@suda.edu.cnBackground: High blood pressure during pregnancy has been suggested to be associated with adverse birth outcomes (ABO), but it is unclear how different blood pressure changes and the extent of the effect. Therefore, we aimed to investigate the association between blood pressure trajectories (systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP)) of pregnant women and ABO in a real-world study.Material and Methods: Leveraging 28,679 pregnant women and their fetuses from a register-based cohort from January 1, 2010, to December 31, 2019. Blood pressure trajectories were estimated by package “traj” in R software using real-world blood pressure data of routine antenatal care examinations. Logistic regression models were applied to examine the association between trajectories of different blood pressure components (SBP, DBP, MAP, and PP) during pregnancy and the risk of ABO.Results: Trajectories of all blood pressure components were identically labeled as low-stable, moderate-increasing, moderate-decreasing and high-stable. After adjusting for confounding factors, compared with pregnant women with the low-stable pattern, pregnant women with a high-stable or moderate-increasing pattern had a significantly increased risk of developing adverse birth outcomes. Pregnant women with a moderate-decreasing pattern had no significant increased risk of ABO but had a lower risk of adverse birth outcomes than those with a moderate-increasing pattern. The trajectories crossed at 17– 20 weeks of gestation for all blood pressure components.Conclusion: Our study results indicated that reduction and maintenance of blood pressure to a low level of less than 110 mmHg for SBP and 65 mmHg for DBP after 20 weeks of gestation would benefit prevention of adverse birth outcomes, regardless of the level of blood pressure at early pregnancy.Keywords: blood pressure, trajectory, pregnancy, adverse birth outcomes, real-world study