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Bin Cao,1,2,&ast; Kun Li,1,2,&ast; Jing Ke,1,2 Dong Zhao1,2 1Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China; 2Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Ke; Dong Zhao, Email kejing@ccmu.edu.cn; zhaodong@ccmu.edu.cnObjective: This study aimed to investigate the potential association between long-term variations in remnant cholesterol (RC) levels and the development of diabetic foot ulcers (DFU) in participants with type 2 diabetes (T2D).Methods: This was a retrospective cohort study. Variation in RC was assessed by the following metrics: mean, standard deviation (SD), coefficient of variation (CV) and trajectories pattern of RC. To identify RC trajectories, we employed the latent class mixture model. The primary endpoint was the development of DFU, and the time-to-event data were analyzed using Cox regression.Results: A total of 1874 patients with T2D were included, with a median follow-up duration of 4.7 years. Among them, 129 individuals (6.9%) developed DFU. The proportion of DFU was significantly higher in the U-shaped group compared to the median group (P for trend < 0.001). Upon adjustment for confounding variables, the U-shaped trajectory correlated with a higher risk of DFU, demonstrating a hazard ratio (HR) of 2.57 (95% CI, 1.54– 4.27). Subgroup analysis showed the U-shaped trajectory had a higher DFU risk regardless of gender (HR=2.40 and 2.81, respectively), glycemic control (HR=1.89 and 7.41, respectively), smoking (HR=2.36 and 2.93, respectively), or hypertension (HR=2.30 and 2.97, respectively). No association was found between mean, SD and CV of RC and DFU.Conclusion: A U-shape trajectory of RC was independently associated with an elevated risk of DFU among patients with T2D.Keywords: diabetic foot ulcer, remnant cholesterol, trajectories, type 2 diabetes

Qiming Gan,1,&ast; Quanzhen Liu,1,2,&ast; Yanjuan Wu,1,&ast; Xiaofeng Zhu,1,2 Jingcun Wang,1 Xiaofen Su,1 Dongxing Zhao,1 Nuofu Zhang,1 Kang Wu1 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Disease, Department of Sleep Medicine Center, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510160, People’s Republic of China; 2Nanshan School, Guangzhou Medical University, Guangzhou, Guangdong, 511436, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Kang Wu; Nuofu Zhang, Department of Pulmonary and Critical Care Medicine, Sleep Medicine Center, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, No. 28 Qiaozhong Mid Road, Guangzhou, Guangdong, 510160, People’s Republic of China, Email d102_wk@126.com; nfzhanggird@163.comPurpose: Obstructive sleep apnea (OSA) had been associated with asthma in observational studies, but the effect of OSA on the onset of asthma in childhood or adulthood remains unclear, and the causal inferences have not been confirmed. This study aims to investigate the potential causal association between OSA with asthma, including different age-of-onset subtypes, providing reliable basis for the clinical treatment of OSA and asthma.Patients and Methods: Causality between OSA and asthma was assessed using a two-sample bi-directional Mendelian randomization (MR) analysis. OSA data were obtained from the FinnGen consortium R9, while asthma and its subtypes (adult-onset asthma, child-onset asthma, and moderate-to-severe asthma) were sourced from the IEU OpenGWAS project. The inverse-variance weighted (IVW) method was chosen as the primary analysis and was complemented by various sensitivity analyses. The MR-PRESSO outlier test was employed to systematically identify and remove outlier variants, mitigating heterogeneity and potential effects of horizontal pleiotropy.Results: The MR analyses provided evidence of genetically predicted OSA having a promoting effect on child-onset asthma (OR,1.49; 95% CI, 1.05– 2.11; P=0.025) and moderate-to-severe asthma (OR,1.03; 95% CI, 1.00– 1.06; P=0.046). However, no causal association between OSA with asthma and adult-onset asthma was observed.Conclusion: Our study revealed a causal association between OSA and child asthma, but not in adults. Moderate-to-severe asthma may have a potential promoting effect on OSA. These findings underscore the importance of age-specific considerations in managing asthma and suggests the need for personalized approaches in clinical practice.Keywords: asthma, obstructive sleep apnea, Mendelian randomization, genetic

Weiwei Guan,1,2 Congyue Zhang,1 Tongguo Miao,1 Chen Dong,1 Lu Li,1 Xiwei Yuan,1 Dandan Zhao,1 Rong Ai,1 Xiaoxiao Zhang,1 Mengjiao Sun,1 Haiyan Kang,2,&ast; Yuemin Nan1,&ast; 1Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital & Hebei International Joint Research Center for Liver Cancer Molecular Diagnosis, Hebei International Science and Technology Cooperation Base, Shijiazhuang, Hebei Province, 050051, People’s Republic of China; 2Department of Liver Disease, The Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei, 050023, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Hebei Medical University Third Hospital & Hebei International Joint Research Center for Liver Cancer Molecular Diagnosis, Hebei International Science and Technology Cooperation Base, No. 139, Ziqiang Road, Shijiazhuang, Hebei Province, 050051, People’s Republic of China, Tel +86 18533112266, Email nanyuemin@163.com Haiyan Kang, Department of Liver Disease, The Fifth Hospital of Shijiazhuang, Hebei Medical University, No. 42, Tanan Road, Shijiazhuang, Hebei Province, 050023, People’s Republic of China, Tel +86 13315952782, Email kanghaiyan1976@126.comPurpose: Long noncoding RNAs (lncRNAs) might be closely associated with hepatocellular carcinoma (HCC) progression and could serve as diagnostic and prognostic markers. This study aimed to investigate lncRNA-based diagnostic biomarkers for hepatitis B virus (HBV)-associated HCC.Materials and Methods: High‐throughput transcriptome sequencing was conducted on the liver tissues of 15 patients with HBV-associated liver diseases (5 with chronic hepatitis B [CHB], 5 with liver cirrhosis [LC], and 5 with HCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze lncRNA expressions. Potential diagnostic performance for HBV-associated HCC screening was evaluated.Results: Through trend analysis and functional analysis, we found that 8 lncRNAs were gradually upregulated and 1 lncRNA was progressively downregulated by regulation of target mRNAs and downstream HCC-associated signaling pathways. The validation of dysregulated lncRNAs in peripheral blood mononuclear cells (PBMCs) and HCC tissues by qRT-PCR revealed that ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were significantly increased in HCC compared with CHB and cirrhosis. Moreover, differentially expressed lncRNAs were aberrantly elevated in Huh7, Hep3B, HepG2, and HepG2.215 cells compared with LX2 cells. Furthermore, ADAMTSL4-AS1, SOCS2-AS1, and AC067931 were identified as novel biomarkers for HBV-associated HCC. For distinguishing HCC from CHB, ADAMTSL4-AS1, AC067931, and SOCS2-AS1 combined with alpha-fetoprotein (AFP) had an area under the curve (AUC) of 0.945 (sensitivity, 83.9%; specificity, 89.8%). Similarly, for distinguishing HCC from LC, this combination had an AUC of 0.871 (sensitivity, 91.1%; specificity, 68.2%). Furthermore, this combination showed the highest diagnostic ability to distinguish HCC from CHB and LC (AUC, 0.905; sensitivity, 91.1%; specificity, 75.3%). In particular, this combination identified AFP-negative (AFP < 20 ng/mL) (AUC = 0.814), small (AUC = 0.909), and early stage (AUC = 0.863) tumors.Conclusion: ADAMTSL4-AS1, SOCS2-AS1, and AC067931 combined with AFP in PBMCs may serve as a noninvasive diagnostic biomarker for HBV-associated HCC, especially AFP-negative, small, and early stage HCC.Keywords: ADAMTSL4-AS1, AC067931, SOCS2-AS1, HBV-associated HCC, diagnostic biomarkers

Jiachen Yu,1,&ast; Yingchun Zhang,1,&ast; Rong Ran,2,&ast; Zixiao Kong,3 Duoyi Zhao,1 Wei Zhao,1 Yingxin Yang,4 Lianbo Gao,5 Zhiyu Zhang1 1Department of Orthopedics, the Fourth Affiliated Hospital of China Medical University, China Medical University, Shen Yang, 110032, People’s Republic of China; 2Department of Anesthesia, the Fourth Affiliated Hospital of China Medical University, China Medical University, Shen Yang, 110032, People’s Republic of China; 3China Medical University, Shen Yang, 110032, People’s Republic of China; 4General Hospital of Northern Theater Command, China Medical University, Shen Yang, 110032, People’s Republic of China; 5Department of Neurology, the Fourth Affiliated Hospital of China Medical University, China Medical University, Shen Yang, 110032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhiyu Zhang; Lianbo Gao, The Fourth Affiliated Hospital of China Medical University, No. 4 Chongshan Road, Huanggu District, Shenyang, Liaoning, People’s Republic of China, Email zyzhang@cmu.edu.cn; lbgao@cmu.edu.cnAbstract: The development of therapeutic drugs and methods has been greatly facilitated by the emergence of tumor models. However, due to their inherent complexity, establishing a model that can fully replicate the tumor tissue situation remains extremely challenging. With the development of tissue engineering, the advancement of bioprinting technology has facilitated the upgrading of tumor models. This article focuses on the latest advancements in bioprinting, specifically highlighting the construction of 3D tumor models, and underscores the integration of these two technologies. Furthermore, it discusses the challenges and future directions of related techniques, while also emphasizing the effective recreation of the tumor microenvironment through the emergence of 3D tumor models that resemble in vitro organs, thereby accelerating the development of new anticancer therapies.Keywords: bioprinting, bioink, organoids, tumor spheroids, tumor chips

Changxiu Ma,1 Ying Zhang,1 Tingchao Tian,2 Ling Zheng,1 Jing Ye,1 Hui Liu,1 Dahai Zhao1 1Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Anhui Medical University, Hefei, 230601, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Huoqiu First People’s Hospital, Huoqiu, 237400, People’s Republic of ChinaCorrespondence: Dahai Zhao, Second Affiliated Hospital, Anhui Medical University, 678 Furong Road, Hefei, Anhui Province, 230601, People’s Republic of China, Tel +86-13721027959, Email zhaodahai@ahmu.edu.cnPurpose: To explore the role of the mean apnea–hypopnea duration (MAD) and apnea–hypopnea duration per hour (HAD) in hypoxemia and evaluate whether they can effectively predict the occurrence of hypoxemia among adults with OSA.Patients and Methods: A total of 144 participants underwent basic information gathering and polysomnography (PSG). Logistic regression models were conducted to evaluate the best index in terms of hypoxemia. To construct the prediction model for hypoxemia, we randomly divided the participants into the training set (70%) and the validation set (30%).Results: The participants with hypoxemia tend to have higher levels of obesity, diabetes, AHI, MAD, and HAD compared with non-hypoxemia. The most relevant indicator of blood oxygen concentration is HAD (r = 0.73) among HAD, MAD, and apnea–hypopnea index (AHI). The fitness of HAD on hypoxemia showed the best. In the stage of establishing the prediction model, the area under the curve (AUC) values of both the training set and the validation set are 0.95. The increased HAD would elevate the risk of hypoxemia [odds ratio (OR): 1.30, 95% confidence interval (CI): 1.13– 1.49].Conclusion: The potential role of HAD in predicting hypoxemia underscores the significance of leveraging comprehensive measures of respiratory disturbances during sleep to enhance the clinical management and prognostication of individuals with sleep-related breathing disorders.Keywords: mean apnea–hypopnea duration, obstructive sleep apnea, apnea–hypopnea duration per hour, polysomnography, apnea–hypopnea index

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

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

Xiu-Li Xiao,1,&ast; Qian-Xue Yang,2,&ast; Hui-Zhong Niu,1 Li-Jing Li,1 Jian-Lei Geng,1 Dan Zhao,1 Hui Ren,1 Pan-Pan Yang1 1Department of General Surgery I, Hebei Children’s Hospital, Shijiazhaung, 050000, People’s Republic of China; 2Department of Operating Room, Hebei Children’s Hospital, Shijiazhaung, 050000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiu-Li Xiao, Department of General Surgery I, Hebei Children’s Hospital, No. 133 Jianhuanan Street, Shijiazhuang, Yuhua District, 050000, People’s Republic of China, Tel +86 0311 8591 1321, Email xxlwwvt7@email.cnPurpose: This study aimed to investigate the maintenance effect of two puncture methods using non-coring needles in children with totally implantable venous access device (TIVAD).Methods: The 110 children who received TIVAD implantation for short bowel syndrome and solid tumors in our department from 2021.12 to 2022.12 were selected as the study subjects. Blinded method was used and divided into experimental group and control group according to random number table The experimental group underwent painless surround puncture method to place the needles and compound lidocaine ointment for topical anesthesia, while the control group underwent traditional puncture method to complete this operation. The effects of the two puncture methods on pain, catheter seal fluid volume, and catheter occlusion rate were evaluated using the Facial Pain Scale Revised, Behavioral Assessment Scale, and in vitro digital subtraction angiography test.Results: In the control group, the degree of puncture pain was mild in 5 patients, moderate in 19 patients, and severe in 28 patients; the amount of catheter sealing solution was 9.32 ± 1.32 mL, and the catheter occlusion rate was 25.00%. In the experimental group, the degree of puncture pain was mild in 16 patients, moderate in 22 patients, and severe in 16 patients; the amount of sealing solution was 7.66 ± 1.08 mL, and the blocking rate was 9.26%. The total pain score in the experimental group was lower than that in the control group (5.23± 6.17 VS 7.89± 2.38). The difference between the two groups had statistical significance (P < 0.05).Conclusion: The use of the painless surround puncture method can effectively reduce the pain experienced by children during puncture, decrease the volume of catheter sealing fluid, reduce the rate of catheter blockage, provide a valuable basis for enhancing the maintenance effect of TIVAD in clinical practice for children.Keywords: catheter blockage rate, catheter sealing fluid volume, pain, puncture method, totally implantable venous access device

Zhongyin Zhou,1,&ast; Feiyan Ma,2,&ast; Jianxiang Zhu,1 Jialing Wang,1 Jing Zhang,3 Dongsheng Zhao4 1Department of Echocardiography, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, Nantong, 226000, People’s Republic of China; 2Department of Ultrasound, the People’s Hospital of Rugao, Nantong, 226000, People’s Republic of China; 3Department of Electroencephalogram, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, Nantong, 226000, People’s Republic of China; 4Department of Cardiology, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, Nantong, 226000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Zhao, Department of Cardiology, Affiliated Hospital 2 of Nantong University, First People’s Hospital of Nantong City, No. 666 Shengli Road, Nantong, 226006, People’s Republic of China, Tel +86 13814710785, Email dongshengzhaoss@126.comObjective: Left ventricular (LV) mechanical dyssynchrony (LVMD) is fundamental to the progression of heart failure and ventricular remodeling. The status of LVMD in different patterns of bundle branch blocks (BBB) is unclear. In this study, we analyzed the relationship between LVMD and left ventricular systolic dysfunction using real-time three-dimensional echocardiography (RT-3DE).Methods: RT-3DE and conventional two-dimensional echocardiography were performed on 68 patients with left bundle branch block (LBBB group), 106 patients with right bundle branch block (RBBB group), and 103 patients without BBB (Normal group). The RT-3DE data sets provided time-volume analysis for global and segmental LV volumes. The LV systolic dyssynchrony index (LVSDI) was calculated using the standard deviation (SD) and maximal difference (Dif) of time to minimum segmental volume (tmsv) for LV segments adjusted by the R-R interval. LVMD was considered if the LVSDI (Tmsv-16-SD) was greater than or equal to 5%.Results: LVSDI is negatively and significantly correlated with left ventricular ejection fraction (LVEF), but not with BBB or QRS duration. The proportion of LVMD in the LBBB, RBBB, and Normal group was 30.88%, 28.30%, and 25.24%, respectively, and there was no significant difference.Conclusion: In dilated cardiomyopathy, LVMD is more closely related to LVEF reduction than QRS morphology and duration.Keywords: bundle branch block, dilated cardiomyopathy, mechanical dyssynchrony

Miaomiao Li,1,2 Xiaoyu Wang,1,2 Fang Wang,3 Fengqi Wang,1,2 Dehua Zhao,4 Shiguo Liu1,2 1Department of Medical Genetic, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Prenatal Diagnosis Center, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Endocrinology Department, the Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 4Neonatal Screening Center, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Dehua Zhao, The Third Affiliated Hospital of Zhengzhou University, Neonatal Screening Center, Zhengzhou, Henan, 450052, People’s Republic of China, Email zhaodehua369@163.com Shiguo Liu, The Affiliated Hospital of Qingdao University, Department of Medical Genetic, Prenatal Diagnosis Center, Qingdao, Shandong, 266003, People’s Republic of China, Email liushiguo@qdu.edu.cnBackground and Objective: Congenital hypothyroidism (CH) is indeed a prevalent neonatal endocrine disorder, affecting approximately 1 in 2000– 3000 newborns worldwide, and 1 in 2400 newborns in China. Despite its high incidence, the genetic causes of CH, particularly those related to thyroid dysgenesis (TD), are still not well understood. However, previous studies have suggested that JAG1 may be a potential susceptibility gene for congenital thyroid defects. To explore the association between JAG1 and CH, we screened JAG1 variants in a large cohort of 813 CH patients.Methods: We performed genetic analysis of JAG1 using next-generation sequencing in 813 CH cases. The pathogenicity of the variants was assessed by bioinformatics softwares, protein sequence conservation analysis, and hydrophobic analysis. Further genetic analysis was conducted targeting 20 CH-related genes in these 25 JAG1 variant carriers.Results: We identified 10 pathogenic missense mutations (p.V45L, p.V272I, p.P552L, p.G610E, p.G852D, p.A891T, p.E1030K, p.R1060W, p.A1131T, p.P1174L) carried by 25 patients, the mutation rate of JAG1 in CH was 3.08%. Among these 25 patients, 16 with 1 variant, 6 with 2 variants, and the other 3 with 3 variants. Our findings indicated that JAG1 variants confer genetic susceptibility to both TD and DH, but with different inheritance models. JAG1 variants lead to TD mainly through monogenic model, while for DH cases, both monogenic mechanisms and oligogenic mechanisms play a pivotal role. Oligogenicity may contribute to the disease severity of DH.Conclusion: JAG1 is a shared genetic factor in TD and DH, with a detection rate of 3.08% in Chinese individuals with CH. A comparison between the oligogenic and monogenic groups suggests a gene dosage effect in CH. Patients with the same JAG1 mutation exhibit diverse clinical phenotypes, indicating complex mechanisms underlying phenotypic heterogeneity.Keywords: congenital hypothyroidism, JAG1, pathogenic variant, inheritance model, phenotypic heterogeneity

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

Jun Cheng,&ast; Jinjin Pan,&ast; Dongmei Zhao, Xuejiao Ma, Qiulin Sun, Jiabin Li Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiabin Li, Tel/Fax +86-551-62922281, Email lijiabin@163.comAbstract: The global prevalence of hepatitis C virus (HCV) infection is approximately 3%, with a post-infection chronicity rate of up to 50%– 85%. HCV reactivation can occur when anti-HCV positive individuals receive antineoplastic therapy. In this study, we report a case of an anti-HCV positive patient with negative HCV RNA after 12 weeks of direct antiviral therapy. Two months later, sorafenib was used to treat hepatocellular carcinoma, and HCV reactivation occurred after 8 months of the treatment. HCV RNA was negative after 12 weeks of antiviral treatment with Sofosbuvir-velpatasvir. We also discussed the mechanism of HCV reactivation caused by sorafenib and the antiviral treatment regimen after HCV reactivation with the relevant literature.Keywords: hepatocellular carcinoma, sorafenib, HCV-RNA, anti-HCV therapy, reactivation

Xiaotian Ji,1 Shuhui Wu,1 Dan Zhao,1 Qi Bai,1 Yun Wang,1 Ke Gong,2 Huie Zheng,1 Mingfang Zhu1 1Department of Dermatology, the Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, People’s Republic of China; 2Department of Traditional Chinese Medicine, Cangzhou Central Hospital, Cangzhou, People’s Republic of ChinaCorrespondence: Mingfang Zhu, Department of Dermatology, the Second Affiliated Hospital of Hunan University of Chinese Medicine, 233 Cai E North Road, Kaifu District, Changsha, People’s Republic of China, Tel +86-13907317358, Fax +86-731-84917727, Email 320492@hnucm.edu.cnBackground: The association between acne and gut microbiota has garnered considerable attention; nevertheless, given the substantial diversity within gut microbiota, the precise cause-and-effect relationship linking specific microbial species to acne remains elusive. To address this gap in knowledge, our study utilized Mendelian randomization analysis to elucidate a potential causal link between gut microbiota composition and acne development while also investigating underlying mechanisms involving microbial factors associated with metabolic disorders.Materials and Methods: The independent single nucleotide polymorphisms (SNPs) closely associated with 196 gut microbiota samples (N=18340) were selected as variable tools. The relationship between gut microbiota and acne (N=212438) was analyzed using the Twosample package in R4.3.1, employing various methods including inverse variance weighting (IVW), weighted median, MR-Egger, Simple-mode, and Weighted-mode. To ensure the stability of the estimates, a series of sensitivity analyses were conducted, such as Cochran’s Q-test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Additionally, the impact of each instrumental variable was calculated.Results: In the Mendelian randomization analysis, we identified twelve microbial taxa potentially associated with acne: family.Bacteroidaceae, family.Clostridiaceae1, genus.Allisonella, genus.Bacteroides, genus.Butyricimonas, genus.Clostridiumsensustricto1, and genus.Coprococcus3. These seven bacterial groups were found to be potential risk factors for acne. Conversely, family.Lactobacillaceae and genus.Ruminococcustorquesgroup along with genus.CandidatusSoleaferrea, genus.Fusicatenibacter, family.Lactobacillaceae, and genus.Lactobacillus exhibited a protective effect against acne. Furthermore, our investigation revealed that some of these microbial taxa have been implicated in metabolic diseases through previous studies. Importantly though, no causal relationship was observed in the reverse Mendelian randomization analysis.Keywords: acne, gut microbiota, Mendelian randomization, metabolic disease

Lin Xu,&ast; Dongxu Zhao,&ast; Pengcheng Tian,&ast; Jiaan Ding,&ast; Zhengyu Jiang, Guanyin Ni, Zhongheng Hou, Caifang Ni Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Caifang Ni, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China, Email szncf@suda.edu.cn Zhongheng Hou, Department of Interventional Radiology, Huzhou Central Hospital, Huzhou, People’s Republic of China, Email 1453713285@qq.comPurpose: We aimed to develop a prognostic nomogram utilizing preoperative serum prealbumin levels to predict the overall survival (OS) in patients undergoing transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC).Patients and Methods: A total of 768 individuals with unresectable HCC who underwent TACE at three medical facilities in Suzhou between January 2007 December 2018 were included. The patient cohort was assigned to a training set (n = 461) and a validation set (n = 307). Cox regression analysis identified independent prognostic factors, which were then used to construct a prognostic nomogram. Internal validation was performed in the testing group, and its effectiveness and capability were evaluated with reference to the concordance index (C-index), area under the curve (AUC), calibration curve, and decision curve analysis (DCA).Results: Independent risk factors identified through Cox regression analyses included the BCLC stage, cirrhosis, invasion, tumor number, preoperative serum PALB, performance status (PS), and tumor size. The nomogram demonstrated a C-index of 0.734 (95% confidence interval (CI): 0.710– 0.758) in the training set and 0.717 (95% CI: 0.678– 0.756) in the validation set, indicating strong discriminatory ability. The nomogram also demonstrated favorable discriminatory performance with AUC values of 0.873, 0.820, and 0.833 for 1-, 2-, and 3-year OS, respectively, in the training set, and 0.854, 0.765, and 0.724 in the validation set. The AUC value of the nomogram (0.843) was significantly higher than that of the four conventional staging systems. Moreover, calibration graphs confirmed a strong concordance between the predicted and observed results. Furthermore, DCA underscored the significant clinical utility of the nomogram. Additionally, the low-risk group exhibited considerably superior rates of survival compared to the high-risk group.Conclusion: The developed nomogram demonstrated excellent prognostic capability, which served as a valuable tool for personalized clinical decision-making for patients with HCC.Keywords: hepatocellular carcinoma, nomogram, prealbumin, overall survival, prognosis

Xuan Zhong,1,&ast; Nongping Feng,2,&ast; Binfa Ouyang,1 Dan Zhao,1 Lin Lei,3 Ji Peng,3 Xiaolin Peng1 1Department of Oncology, Injury and Nutrition, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong Province, People’s Republic of China; 2Department of Non-Communicable Disease Prevention and Control, Shenzhen Longgang Center for Chronic Disease Control, Shenzhen, Guangdong Province, People’s Republic of China; 3Department of Cancer Prevention and Control, Shenzhen Center for Chronic Disease Control, Shenzhen, Guangdong Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaolin Peng, Department of Oncology, Injury and Nutrition, Shenzhen Nanshan Center for Chronic Disease Control, No. 7, Huaming Road, Nanshan District, Shenzhen, Guangdong Province, People’s Republic of China, Tel +86-0755-26640203, Email 25731738@qq.comAim: The rising incidence and death rate of colorectal cancer (CRC) have posed a severe danger to the lives and health of residents. Individuals at high risk of CRC are drawing growing attention as the majority of the population impacted by CRC. Hence, it is imperative to examine the detection rates and modifiable factors affecting the populations at high risk for CRC in Shenzhen.Methods: The multi-stage stratified cluster sampling method was used to select residents aged 45– 74 years old from September 2020 to December 2021. The community-based CRC screening was attended by a total of 30,921 residents from urban and suburb regions. The association between modifiable risk factors and the detection rate of high-risk groups was analyzed using multinomial logistic regression with the inverse probability treatment weighting (IPTW) based on the propensity score.Results: The cross-sectional analysis included 24,613 people after excluding 6308 people who had missing or invalid fecal occult blood test (FOBT) results. The detection rate for high-risk groups during CRC screening was 28.50%. Higher rate of high-risk groups was detected among those who were male, aged 60 or above, college or above, other marital status, and living in urban (P < 0.05). Demographic characteristics after IPTW showed a weak correlation coefficient with the detection rate of CRC high-risk both in high-risk and general-risk groups (SMD < 0.1), suggesting a balanced group of participants. The results of logistic regression with IPTW indicated that smoking, drinking, obesity, lack of exercise, vegetable or fruit eating infrequently, red meat, processed meat, cereal food and their clustering status were more inclined to be risk indicators of CRC (P < 0.05).Conclusion: The detection rate for high-risk CRC groups was comparatively high in Shenzhen. The distribution characteristics of lifestyle and dietary risk factors of high-risk groups should be given consideration when adopting individualized intervention measures and comprehensive prevention and control strategies.Keywords: modifiable risk factors, colorectal cancer, high-risk group, propensity score method

Yan Fu,1,&ast; Hongji Pu,2,&ast; Qun Huang,2,&ast; Peng Qiu,2 Deyin Zhao,3 Yong Cheng1 1Department of Nursing, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Vascular Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Second Ward of General Surgery, Suzhou Hospital of Anhui Medical University (Suzhou Municipal Hospital of Anhui Province), Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Cheng; Deyin Zhao, Email cy7107@163.com; 9168722@qq.comIntroduction: Critical limb ischemia (CLI) is a severe condition characterized by inadequate blood flow to the lower extremities, often leading to tissue damage and amputation. CLI is characterized by microcirculatory dysfunction, muscle tissue necrosis, and inflammation. Patients may suffer from the traumatic pain and the increase of plantar pressure, and foot care for patients with CLI has become the “last mile” to improve their life quality. Traditional shoe insoles often lack individual customization, failing to address the unique anatomical needs and hemodynamic characteristics of patients. The study aims to investigate the effects of this innovative intervention on improving the clinical outcomes, and quality of life in CLI patients.Methods and Analysis: This Critical Limb Ischemia Hemodynamic Insole Study is a randomized controlled study performed to explore the effect of a 3D printing insole on foot care of CLI patients. This study recruitment began on November 1, 2021. Patients with CLI confirmed by clinical symptoms and imaging were recruited as the research objects. Participants will be randomly assigned to either the experimental group, which will receive 3D-printed insoles customized based on their hemodynamics, or the control group, which will receive traditionally manufactured insoles. Both groups were followed up for up to 24 months after surgery, including claudication distance, claudication time, pain score, rehospitalization, etc.Trial Registration Number: ChiCTR2100051857.Keywords: 3D printing, insole, hemodynamics, critical limb ischemia

Jiangnan Wu,1,&ast; Chao Zhang,2,&ast; Feng He,3,&ast; Yuan Wang,4 Liangnan Zeng,5 Wei Liu,6 Di Zhao,7 Jingkun Mao,1 Fei Gao8 1Department of Artificial Intelligence, Tianjin University of Technology, Tianjin, People’s Republic of China; 2Sixth Department of Oncology, Hebei General Hospital, Shijiazhuang, People’s Republic of China; 3The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 4Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan, People’s Republic of China; 5Department of Nursing, Chengdu Fifth People’s Hospital, The Fifth People’s Hospital Affiliated to Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 6Hebei Psychological Counselor Association, Shijiazhuang, People’s Republic of China; 7Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 8Hebei General Hospital, Shijiazhuang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Di Zhao; Fei Gao, Tel +86-13363833833 ; +86-13933173693, Email 179381749@qq.com; 27909361@qq.comBackground: The intention to leave among intensive care unit (ICU) healthcare professionals in China has become a concerning issue. Therefore, understanding the factors influencing the intention to leave and implementing appropriate measures have become urgent needs for maintaining a stable healthcare workforce.Objective: This study aims to investigate the current status of intention to leave among ICU healthcare professionals in China, explore the relevant factors affecting this intention, and provide targeted recommendations to reduce the intention to leave among healthcare professionals.Methods: A cross-sectional survey was conducted, involving ICU healthcare professionals from 3-A hospitals of the 34 provinces in China. The survey encompassed 22 indicators, including demographic information (marital status, children, income), work-related factors (weekly working hours, night shift frequency, hospital environment), and psychological assessment (using Symptom Checklist-90 (SCL-90)). The data from a sample population of 3653 individuals were analyzed using the extreme gradient boosting (XGBoost) method to predict intention to leave.Results: The survey results revealed that 62.09% (2268 individuals) of the surveyed ICU healthcare professionals expressed an intention to leave. The XGBoost model achieved a predictive accuracy of 75.38% and an Area Under the Curve (AUC) of 0.77.Conclusion: Satisfaction with income was found to be the strongest predictor of intention to leave among ICU healthcare professionals. Additionally, factors such as years of experience, night shift frequency, and pride in hospital work were found to play significant roles in influencing the intention to leave.Keywords: ICU healthcare professionals, intention to leave, cross-sectional survey, extreme gradient boosting, XGBoost

Shuyun Zhang,1,&ast; Lijuan Wu,1,&ast; Xue Li,1 Li Yang,1 Sujuan Shen,1 Hong Shen,1 Dan Zhao,2 Lin Qi2,3 1Center of Reproductive Medicine, The Second Affiliated Hospital of Soochow University, Su Zhou, People’s Republic of China; 2Precision Medicine Center, The Second Affiliated Hospital of Soochow University, Su Zhou, People’s Republic of China; 3State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, 215000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Qi, Precision Medicine Center, The Second Affiliated Hospital of Soochow University, Su Zhou, People’s Republic of China, Tel +86-13962187070, Email drhuan@126.comPurpose: Karyotype analysis of villus chromosomes in spontaneous abortion by high-throughput ligation-dependent probe amplification (HLPA) was performed to explore relationship between spontaneous abortion and chromosomal abnormalities in spontaneous abortion tissues.Patients and Methods: The karyotypes of chromosomes of villus tissues from 516 patients with spontaneous abortion who were admitted to our hospital between 2014 and 2019 were analyzed. The data were grouped by the age (ie, ≤ 29, 30– 35, and ≥ 36 years old) in which embryonic chromosomal abnormality rate, and abnormal distribution of chromosome number in abortion tissue of 294 patients.Results: The examination of 516 samples of spontaneous abortion tissues showed that the chromosomes of 294 samples were abnormal, and the abnormality rate was 60.97%. Among 294 samples with chromosomal abnormalities, 136 (89.47%) samples had numerical chromosomal abnormalities, 15 (9.87%) samples had structural chromosomal abnormalities, and 1 (0.07%) sample had uniparental disomy. A total of 308 couples voluntarily underwent peripheral blood chromosome analysis. The results showed that 56 couples had abnormality in one or both spouses, and rate of embryonic chromosomal abnormality in these 26 cases with chromosomal abnormalities was 100%.Conclusion: Numerical and structural chromosomal abnormalities are among the important causes of embryonic arrest, while the increase in age could also be a high-risk factor for embryonic chromosomal abnormality. Therefore, examination of the karyotypes of embryo chorionic villus may help understand the reasons of embryonic arrest, which could provide important guidance for more genetic counseling for patients with early spontaneous abortion, as well as improving the preconception preparation.Keywords: spontaneous abortion, villus tissue, HLPA test, chromosomal abnormality

Yiqi Lin,&ast; Li Sang,&ast; Jiahe Wang, Yating Chen, Jianxiong Lai, Xiaofeng Zhu, Yuhan Yang, Zhuofan Zhang, Yinghua Liu, Shenyu Wen, Nuofu Zhang, Dongxing Zhao State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510160, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongxing Zhao; Nuofu Zhang, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510160, People’s Republic of China, Email rieast@msn.com; nfzhanggird@163.comBackground: Differences in lung function for Chronic Obstructive Pulmonary Disease (COPD) cause bias in the findings when identifying frequent exacerbator phenotype-related causes. The aim of this study was to determine whether computed tomographic (CT) biomarkers and circulating inflammatory biomarkers were associated with the COPD frequent exacerbator phenotype after eliminating the differences in lung function between a frequent exacerbator (FE) group and a non-frequent exacerbator (NFE) group.Methods: A total of 212 patients with stable COPD were divided into a FE group (n=106) and a NFE group (n=106) according to their exacerbation history. These patients were assessed by spirometry, quantitative CT measurements and blood sample measurements during their stable phase. Univariate and multivariate logistic regression were used to assess the association between airway thickening or serum cytokines and the COPD frequent exacerbator phenotype. Receiver operating characteristic (ROC) curves were calculated for Pi10, WA%, IL-1β and IL-4 to identify frequent exacerbators.Results: Compared with NFE group, FE group had a greater inner perimeter wall thickness of a 10 mm diameter bronchiole (Pi10), a greater airway wall area percentage (WA%) and higher concentrations of IL-1β and IL-4 (p< 0.001). After adjusting for sex, age, BMI, FEV1%pred and smoking pack-years, Pi10, WA%, IL-β and IL-4 were independently associated with a frequent exacerbator phenotype (p< 0.001). Additionally, there was an increase in the odds ratio of the frequent exacerbator phenotype with increasing Pi10, WA%, IL-4, and IL-1β (p for trend < 0.001). The ROC curve demonstrated that IL-1β had a significantly larger calculated area under the curve (p < 0.05) than Pi10, WA% and IL-4.Conclusion: Pi10, WA%, IL-4, and IL-1β were independently associated with the frequent exacerbator phenotype among patients with stable COPD, suggesting that chronic airway and systemic inflammation contribute to the frequent exacerbator phenotype.Trial Registration: This trial was registered in Chinese Clinical Trial Registry (https://www.chictr.org.cn). Its registration number is ChiCTR2000038700, and date of registration is September 29, 2020.Keywords: COPD, frequent exacerbator phenotype, airway thickening, inflammation

Xia Lei,1,&ast; Hongdan Xu,2,&ast; Yan Wang,3 Hainan Gao,4 Deping Zhao,4 Jinfeng Zhang,4 Ziyue Zhu,4 Kun Zuo,4 Ying Liu,3 Xiaoliang Li,3,5 Ning Zhang4 1Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, 214071, People’s Republic of China; 2Department of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi, 214000, People’s Republic of China; 3Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, 571199, People’s Republic of China; 4College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China; 5Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Cardiovascular Diseases Institute of the First Affiliated Hospital, Hainan Medical University, Haikou, 571199, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ning Zhang, College of Pharmacy, Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin, Heilongjiang Province, 150040, People’s Republic of China, Email zhangning0454@163.com Xiaoliang Li, College of Pharmacy, Hainan Medical University, No. 3 Xueyuan Road, Longhua District, Haikou City, Hainan Province, 571199, People’s Republic of China, Email lixiaoliang-1984@163.comPurpose: To elucidate the potential mechanisms of QFY for the treatment of Alzheimer’s Disease (AD), and explore the effective substances of QFY.Materials and Methods: UPLC-LTQ-Orbitrap-MS was used to identify the chemical constituents of the serum samples and the cerebrospinal fluid samples of rats after QFY administration. Network pharmacology was used to predict potential targets and pathways of QFY against AD. The AD mice model was established by subcutaneous injection of D-gal for 8 consecutive weeks. New object recognition (NOR) and Morris water maze test (MWM) were used to evaluate the learning and memory abilities of mice. Moreover, the levels of TNF-α, IL-1β, and IL-18 in the brain hippocampus of mice were determined by ELISA. The expression of Bax, Bcl-2, Caspase-1, PSD95, SYP, ICAM-1 and MCP-1 proteins in the hippocampus was detected by Western blotting. Furthermore, qRT-PCR was used to detect the gene expressions of PSD95, SYP, M1 and M2 polarization markers of microglia, including iNOS, CD16, ARG-1, and IL-10 in the hippocampus.Results: A total of 51 prototype compounds were detected in rat serum and 15 prototype components were identified in rat cerebrospinal fluid. Behavioral experiments revealed that QFY significantly increased the recognition index, decreased the escape latency, increased the platform crossing times and increased the residence time in the target quadrant. QFY also could alleviate the ultrastructural pathological changes in the hippocampus of AD mice. Meanwhile, QFY treatment suppressed the expression of inflammatory factors, such as TNF-α, IL-1β, and IL-18. QFY improved the synaptic plasticity of the hippocampus in D-gal model mice by significantly increasing the expression of proteins and mRNAs of PSD95 and SYP.Conclusion: QFY could effectively improve the learning and memory impairment of D-gal-induced AD mice by inhibiting the excessive activation of microglia, enhancing the expression of M2 microglia, inhibiting the increase of inflammatory factors, cell adhesion factors and chemokines, anti-apoptosis, and improving synaptic plasticity.Graphical Abstract: Keywords: Qi-Fu-Yin, Alzheimer’s disease, D-galactose, microglia phenotype, neuroinflammation

Jiaojiao Xue,1 Ziwei Zhang,1 Yuting Sun,2 Di Jin,3 Liming Guo,1 Xiangyan Li,4 Daqing Zhao,4 Xiaochun Feng,5 Wenxiu Qi,4 Haoyu Zhu5 1College of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 2Department of Endocrinology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 3Department of Nephrology, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 4Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, People’s Republic of China; 5Department of Nephropathy and Rheumatology in Children, Children’s Medical Center, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People’s Republic of ChinaCorrespondence: Wenxiu Qi, Northeast Asia Research Institute of Traditional Chinese Medicine, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Biomacromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin, 130117, People’s Republic of China, Tel +86-431-860177630, Email qiwenxiu0517@163.com Haoyu Zhu, Department of Nephropathy and Rheumatology in Children, Children’s Medical Center, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, 130021, People’s Republic of China, Tel +86-431-81953813, Email doctorzhuhaoyu163@163.comAbstract: Endothelial cells (ECs) are widely distributed inside the vascular network, forming a vital barrier between the bloodstream and the walls of blood vessels. These versatile cells serve myriad functions, including the regulation of vascular tension and the management of hemostasis and thrombosis. Inflammation constitutes a cascade of biological responses incited by biological, chemical, or physical stimuli. While inflammation is inherently a protective mechanism, dysregulated inflammation can precipitate a host of vascular pathologies. ECs play a critical role in the genesis and progression of vascular inflammation, which has been implicated in the etiology of numerous vascular disorders, such as atherosclerosis, cardiovascular diseases, respiratory diseases, diabetes mellitus, and sepsis. Upon activation, ECs secrete potent inflammatory mediators that elicit both innate and adaptive immune reactions, culminating in inflammation. To date, no comprehensive and nuanced account of the research progress concerning ECs and inflammation in vascular-related maladies exists. Consequently, this review endeavors to synthesize the contributions of ECs to inflammatory processes, delineate the molecular signaling pathways involved in regulation, and categorize and consolidate the various models and treatment strategies for vascular-related diseases. It is our aspiration that this review furnishes cogent experimental evidence supporting the established link between endothelial inflammation and vascular-related pathologies, offers a theoretical foundation for clinical investigations, and imparts valuable insights for the development of therapeutic agents targeting these diseases.Keywords: endothelial cells, endothelial inflammation, vascular-related diseases, atherosclerosis, diabetes mellitus, cardiovascular diseases

Kun Li,1,2,&ast; Bin Cao,1,2,&ast; Jing Ke,1,2 Longyan Yang,1,2 Dong Zhao1,2 1Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China; 2Beijing Key Laboratory of Diabetes Research and Care, Beijing, 101149, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Zhao; Longyan Yang, Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 101149, People’s Republic of China, Tel +86-10-69543901, Email zhaodong@ccmu.edu.cn; lingbeiyangstudent@163.comBackground: Diabetic vascular complications are the leading cause of crippling and death of diabetic patients and seriously affect patients’ quality of life. It is essential to control the risk factors contributing to vascular complications in patients with Type 2 diabetes (T2DM). This study aimed to examine the association between hyper-triglyceridemic waist phenotype (HWP) and the risk of vascular complication index of diabetes in T2DM patients.Methods: The participants with type 2 diabetes mellitus in this study registered at the National Metabolic Management Center (MMC) of Beijing Luhe Hospital from June 2017 to June 2021. Data were collected by trained personnel according to the protocol. The questionnaire containing information on demographic characteristics and lifestyle factors (including alcohol drinking and cigarette smoking et al) was administered by trained interviewers. Logistic regression analysis assessing the associations between the hyper-triglyceridemic waist phenotype and vascular complication index of diabetes. In addition, the subgroup analysis was performed by age, sex, HbA1c, hypertension or not, and education level.Results: After data cleaning, a total of 3221 participants with T2DM were enrolled. The median (IQR) duration of diabetes was 47.00 (3.00, 125.00) months. Compared to the participants in the Normal triglycerides level and Normal waist circumference group (NTNW), those in the Elevated triglycerides level and Enlarged waist circumference group (HTGW) have a higher risk of CKD-related vascular complications; the OR of decreased estimated glomerular filtration rate (GFR) and elevated urinary albumin creatinine ratio (UACR) were 2.21 (95% CI:1.32– 3.82) and 2.18 (95% CI:1.69– 2.81), respectively. Moreover, compared to the participants in the NTNW group, the ORs of the decreased ankle-brachial index (ABI) and elevated Brachial-ankle pulse wave velocity (baPWV) were 2.24 (95% CI:1.38– 3.80) and 1.63 (95% CI:1.28– 2.06) in the HTGW group.Conclusion: In summary, there was an association between hyper-triglyceridemic waist phenotype and diabetic vascular complications in the Chinese population.Keywords: hyper-triglyceridemic waist phenotype, type 2 diabetes mellitus, vascular complication

Lu Li,1,&ast; Rong Ai,1,&ast; Xiwei Yuan,1 Shiming Dong,1 Dandan Zhao,1 Xiaoye Sun,2 Tongguo Miao,1 Weiwei Guan,1 Peilin Guo,1 Songhao Yu,1 Yuemin Nan1 1Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University & Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, 050051, People’s Republic of China; 2Department of Organ Transplant Center, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86 311-66781227, Fax +86 311-87023626, Email nanyuemin@163.comPurpose: As the major subtype of liver cancer, hepatocellular carcinoma (HCC) suffers from high mortality and is prone to recurrence. Long non-coding RNAs (lncRNAs) are well characterized to be pivotal players contributing to HCC pathogenesis and progression. Therefore, this study intended to probe the biological functions of LINC00886 in hepatocarcinogenesis.Patients and Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to analysis of LINC00886, microRNA-409-3p (miR-409-3p), microRNA-214-5p (miR-214-5p), RAB10 and E2F2 expression. Subcellular localization of LINC00886 was identified through a fluorescent in situ hybridization (FISH) kit and a subcellular assay. Additionally, proliferated cells were determined with EdU as well as cell counting kit-8 (CCK-8) assays. Scratch and Transwell assays were applied to detect migratory and invasive cells. Apoptotic cells were measured via TUNEL staining assay. Furthermore, targeted binding between LINC00886 and miR-409-3p or miR-214-5p was validated utilizing dual-luciferase reporter assays. RAB10, E2F2 and NF-κB signaling-associated protein levels were evaluated utilizing Western blot.Results: LINC00886, RAB10 and E2F2 levels were aberrantly increased, with the abnormal expressed decline of miR-409-3p and miR-214-5p, in HCC tissues, cells and peripheral blood mononuclear cells (PBMCs). Silencing LINC00886 attenuated the proliferative, migratory, invasive, and anti-apoptotic potential of HCC cells, while LINC00886 overexpression proceeded in the contrary direction. Mechanistically, miR-409-3p and miR-214-5p were validated as binding targets for LINC00886 and inverted the biological functions of LINC00886 during HCC progression. Furthermore, the LINC00886-miR-409-3p/miR-214-5p axis could regulate RAB10 and E2F2 expression via mediating NF-κB pathway activation in hepatocarcinogenesis.Conclusion: Our findings indicated that LINC00886 facilitated HCC progression via absorbing miR-409-3p or miR-214-5p to upregulate RAB10 and E2F2 through activation of NF-κB pathway, offering a promising novel target for HCC therapy.Graphical Abstract: Keywords: LINC00886, miR-409-3p, miR-214-5p, hepatocellular carcinoma, NF-κB signaling