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Jing Ye,1,2,* Ping Li,1,2,* Pengcheng Liu,1,2 Wenjing Pei,1,2 Ruowen Wang,1,2 Hui Liu,1,2 Changxiu Ma,1,2 Dahai Zhao1,2 1Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of China; 2Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dahai Zhao, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Anhui Medical University, 678 Furong Road, Hefei, Anhui Province, 230601, People’s Republic of China, Email zhaodahai@ahmu.edu.cnBackground: Anxiety and depression are two of the most common comorbidities of COPD, which can directly lead to the number of acute exacerbations and hospitalizations of COPD patients and reduce their quality of life. At present, there are many studies on anxiety and depression in stable COPD, but few studies on anxiety and depression in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients.Objective: We aim to explore the changes of serum metabolomics in AECOPD complicated with anxiety and depression and to provide some clues for further understanding its pathogenesis.Methods: This is an observational high-throughput experimental study based on retrospective data extraction. Twenty-one AECOPD with anxiety and depressive patients and 17 healthy controls (HCs) were retrospectively enrolled in the Second Affiliated Hospital of Anhui Medical University. Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) for anxiety and depression were used to assess the patients with AECOPD. Untargeted metabolomics analysis was carried out to investigate different molecules in the serum of all participants. General information of all participants, baseline data and clinical measurement data of AECOPD patients were collected. Statistical analysis and bioinformatics analysis were performed to reveal different metabolites and perturbed metabolic pathways.Results: A total of 724 metabolites in positive ionization mode and 555 metabolites in negative ionization mode were different in AECOPD patients with anxiety and depression. The 1,279 serum metabolites could be divided into 77 categories. Based on multivariate and univariate analysis, 74 metabolites were detected in positive ionization mode, and 60 metabolites were detected in negative ionization as differential metabolites. The 134 metabolites were enriched in 18 pathways, including biosynthesis of unsaturated fatty acids, aldosterone synthesis and secretion, protein digestion and absorption, ovarian steroidogenesis, long−term depression, retrograde endocannabinoid signaling, and so on.Conclusion: This work highlights the key metabolites and metabolic pathways disturbed in AECOPD patients with anxiety and depression. These findings support the use of metabolomics to understand the pathogenic mechanisms involved in AECOPD patients with anxiety and depression.Keywords: metabolomics, AECOPD, anxiety, depression, exacerbation

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

Danya Zhao,1 Danping Qin,2 Liming Yin,3 Qiang Yang4 1The First School of Clinical Medicine of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Institute of Hematology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4Department of Gastroenterology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, People’s Republic of ChinaCorrespondence: Danping Qin, Email qindp19841@sina.comBackground: Ulcerative colitis is a recurrent autoimmune disease. At present, the pathogenesis of UC is not completely clear. Hence, the etiology and underlying molecular mechanism need to be further investigated.Methods: Three sets of microarray datasets were included from the Gene Expression Omnibus database. The differentially expressed genes in two sets of datasets were analyzed using the R software, and the core genes of UC were screened using machine learning. The sensitivity and specificity of the core genes were evaluated with the receiver operating characteristic curve in another microarray dataset. Subsequently, the CIBERSORT tool was used to analyze the relationship between UC and its core genes and immune cell infiltration. To verify the relationship between UC and core genes and the relationship between core genes and immune cell infiltration in vivo.Results: A total of 36 DEGs were identified. AQP8, HMGCS2, and VNN1 were determined to be the core genes of UC. These genes had high sensitivity and specificity in receiver operating characteristic curve analysis. According to the analysis of immune cell infiltration, neutrophils, monocytes, and macrophages were positively correlated with UC. AQP8, HMGCS2, and VNN1 were also correlated with immune cell infiltration to varying degrees. In vivo experiments verified that the expressions of neutrophils, monocytes, and macrophages increased in the UC colon. Furthermore, the expressions of AQP8 and HMGCS2 decreased, whereas that of VNN1 increased. Azathioprine treatment improved all the indicators to different degrees.Conclusion: AQP8, HMGCS2, and VNN1 are the core genes of UC and exhibit different degrees of correlation with immune cells. These genes are expected to become new therapeutic targets for UC. Moreover, the occurrence and development of UC are influenced by immune cell infiltration.Keywords: ulcerative colitis, bioinformatics analysis, core genes, immune cells

Yuncheng Zhu,1– 3,&ast; Zhiguo Wu,4,&ast; Dongmei Zhao,5 Xiaohui Wu,2 Ruoqiao He,6 Zuowei Wang,1,3 Daihui Peng,2 Yiru Fang2,7– 9 1Division of Mood Disorders, Shanghai Hongkou Mental Health Center, Shanghai, People’s Republic of China; 2Clinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China; 3Clinical Research Center for Mental Health, School of Medicine, Shanghai University, Shanghai, People’s Republic of China; 4Clinical Research Center in Mental Health, Shanghai Yangpu District Mental Health Center, Shanghai University of Medicine & Health Sciences, Shanghai, People’s Republic of China; 5Division of Psychiatry, Shanghai Changning Mental Health Center, Shanghai, People’s Republic of China; 6New York University, New York, NY, USA; 7Department of Psychiatry & Affective Disorders Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 8CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, People’s Republic of China; 9Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yiru Fang, Email yirufang@aliyun.comObjective: This survey aims to explore the current medical treatment of major depressive disorder (MDD) in China and match its degree with Canadian Network for Mood and Anxiety Treatments (CANMAT).Methods: A total of 3275 patients were recruited from 16 mental health centers and 16 general hospitals in China. Descriptive statistics presented the total number and percentage of drugs, as well as all kinds of treatments.Results: Selective serotonin reuptake inhibitors (SSRIs) accounted for the largest proportion (57.2%), followed by serotonin-noradrenaline reuptake inhibitors (SNRIs) (22.8%) and mirtazapine (7.0%) in the first therapy, while that of SNRIs (53.9%) followed by SSRIs (39.2%) and mirtazapine (9.8%) in the follow-up therapy. An average of 1.85 medications was administered to each MDD patient.Conclusion: SSRIs were the first choice in the first therapy, while the proportion of those drugs decreased during the follow-up therapy and were replaced by SNRIs. Plenty of combined pharmacotherapies were directly selected as the first trial of patients, which was inconsistent with guideline recommendations.Keywords: major depressive disorder, Chinese, guideline, antidepressants

Donghao Wang,1,&ast; Yingying Ren,2,&ast; Riken Chen,1,&ast; Xiangxia Zeng,1,&ast; Qiming Gan,1,&ast; Zhiyang Zhuang,1 Xiaofen Su,1 Kang Wu,1 Sun Zhang,1 Yongkang Tang,1 Shiwei Li,1 Haojie Zhang,1,3 Yanyan Zhou,1 Nuofu Zhang,1 Dongxing Zhao1 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; 2Medical Records and Statistics Room, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3The Clinical Medicine Department, Henan University, Zhengzhou, 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, 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 +86-13650901411 ; +86-13600460056, Email rieast@msn.com; nfzhanggird@163.comObjective: Obstructive sleep apnea (OSA) is a common sleep-disordered breathing disease. We aimed to establish an improved screening questionnaire without physical examinations for OSA named the CNCQ-OSA (Chinese community questionnaire for OSA).Methods: A total of 2585 participants who visited sleep medicine center and underwent overnight polysomnography were grouped into two independent cohorts: derivation (n = 2180) and validation (n = 405). The CNCQ-OSA was designed according to the baseline of patients in derivation cohort. We comprehensively analyzed the data to evaluate the predictive value of the CNCQ-OSA, compared to the GOAL questionnaire, STOP-Bang questionnaire (SBQ) and NoSAS questionnaire.Results: The CNCQ-OSA included seven variables: loud snoring, BMI ≥ 25 kg/m2, male gender, apnea, sleepiness, hypertension and age ≥ 30, with a total score ranging from 7 to 16.7 points (≥ 13.5 points indicating high risk of OSA, ≥ 14.5 points indicating extremely high risk). In the derivation and validation cohorts, the areas under the curve of the CNCQ-OSA were 0.761 and 0.767, respectively. In the validation cohort, the sensitivity and specificity of a CNCQ-OSA score ≥ 13.5 points for the apnea–hypopnea index (AHI) ≥ 5/h were 0.821 and 0.559, respectively (Youden index, 0.380), and the score ≥ 14.5 points were 0.494 and 0.887, respectively (Youden index, 0.375). The CNCQ-OSA had a better predictive value for AHI ≥ 5/h, AHI > 15/h and AHI > 30/h, with the highest Youden index, compared to the other questionnaires.Conclusion: The CNCQ-OSA can effectively identify the risk of OSA, which is appropriate for self-screening at home without physical examinations.Keywords: obstructive sleep apnea, screening, GOAL, STOP-Bang, NoSAS

Renming Li,1,&ast; Xiaomin Zhao,1,&ast; Pengcheng Liu,1 Dandan Wang,1 Chen Chen,1 Yu Wang,1 Ningning Zhang,1 Bing Shen,2 Dahai Zhao1 1Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, People’s Republic of China; 2School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dahai Zhao, Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, People’s Republic of China, Tel +86-551-63869656, Email zhaodahai@ahmu.edu.cn Bing Shen, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, People’s Republic of China, Tel +86-551-65161132, Fax +86-551-65161126, Email shenbing@ahmu.edu.cnPurpose: As a common respiratory disease, chronic obstructive pulmonary disease (COPD) has a high morbidity and mortality. Current clinical therapies are not ideal and do not improve lung function or long-term life quality. It is very important to find new potential pathogenic mechanisms, biomarkers, and targets with therapeutic value in COPD.Methods: Serum samples collected from acute exacerbation and stable COPD and healthy participants were analyzed using label-free liquid chromatography tandem mass spectrometry to identify the differentially expressed proteins (DEPs) between two groups. Bioinformatics analyses were performed to determine the biological processes associated with those DEPs. Key proteins were validated by enzyme linked immunosorbent assay (ELISA).Results: In total, 661 proteins were detected in serum from patients with COPD and healthy participants. Compared with healthy participants, patients with acute exacerbation of COPD had 45 DEPs, 13 were upregulated and 32 were downregulated; and patients with stable COPD had 79 DEPs, 18 were upregulated and 61 were downregulated. Gene Ontology functional annotation results indicated that the DEPs identified in patients with COPD were associated with the terms cellular anatomical entity, binding, and cellular process. Kyoto Encyclopedia of Genes and Genomes functional annotation analysis and the Clusters of Orthologous Genes database analysis indicated that the functions of these DEPs were primarily in signal transduction mechanisms and amino acid transport and metabolism. The ELISA results for three key proteins of IGFBP2, LRG1 and TAGLN were consistent with the LC-MS/MS results and the area under the receiver operating characteristic of the combined index was 0.893 (95% CI: 0.813, 0.974).Conclusion: Our findings suggested pathogenic mechanisms underlying COPD stages and indicated three key proteins that may warrant further study as potential biomarkers for early diagnosis or prognosis of COPD or as therapeutic targets.Keywords: chronic obstructive pulmonary disease, respiration, proteomics, differentially expressed proteins, bioinformatics, LC-MC/MS

Dehua Zhao, Xiaoqing Long, Jisheng Wang Department of Clinical Pharmacy, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, People’s Republic of ChinaCorrespondence: Dehua Zhao; Jisheng Wang, Email zhaoyaoshi0566@163.com; wangjishengyaoshi@163.comAbstract: Poly (ADP-ribose) polymerase (PARP) inhibitors are small-molecule inhibitors of PARP enzymes (including PARP1, PARP2, and PARP3) that exhibit activity against tumor cells with defects in DNA repair. In recent years, five PARP inhibitors, olaparib, niraparib, rucaparib, talazoparib and veliparib, have been developed for the treatment of solid tumors, particularly in patients with breast-related cancer antigen (BRCA) 1/2 mutations, or those without a functional homologous recombination repair pathway. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. The five PARP inhibitors are eliminated primarily via the liver and kidneys, hepatic or renal impairment may significantly affect their pharmacokinetics (PK). Therefore, it is important to know the effects of hepatic or renal impairment on the PK and safety of PARP inhibitors. In this review, we characterize and summarize the effects of hepatic and renal function on the PK of PARP inhibitors and provide specific recommendations for clinicians when prescribing PARP inhibitors in patients with hepatic or renal impairment.Keywords: PARP inhibitors, cancer, hepatic impairment, renal impairment, PK

Changjuan Li,1,2 Min Wang,3 Junwei Wei,2 Wenjuan Zhang,2 Haitao Liu,2 Dongqiang Zhao1 1Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People’s Republic of China; 2Department of Gastroenterology, The First Hospital of Handan City, Handan, Hebei Province, People’s Republic of China; 3Department of Anorectal Surgery, The First Hospital of Handan City, Handan, Hebei Province, People’s Republic of ChinaCorrespondence: Dongqiang Zhao, Department of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, He ping West Road, Xinhua District, Shijiazhuang, Hebei, People’s Republic of China, Email hbzdq1998@163.comBackground: Effective prognostic assessment and appropriate drug selection are important for the clinical management of pancreatic cancer (PaC). Here, we aimed to establish a pyroptosis-associated genes (PRGs) signature to predict the prognostic outcomes of PaC and guide clinical drug therapy.Methods: We identified the differentially expressed PRGs between pancreatic adenocarcinoma (n = 178) and control pancreas samples (n = 171) obtained from different databases, and performed Lasso and Cox regression analysis to create a prognosis signature. Kaplan–Meier (K-M) survival curves and time-dependent receiver operating characteristics were further constructed to assess the utility of the risk model. The International Cancer Genome Consortium (ICGC) PACA-AU cohort (n = 95) was used as a validation dataset to examine the validity of this prognostic model. The correlations of risk score (RS) with clinical features, immune cell infiltration, tumor mutation burden and half-maximal inhibitory concentrations (IC50) of chemotherapeutic drugs were analyzed, and the expression levels of PRGs in cell lines were detected.Results: A prognostic signature was constructed, which consisted of 4 PRGs (AIM2, IL18, GSMDC and PLCG1). K-M analysis demonstrated a remarkable difference in overall survival (OS) time between low-risk (LR) and high-risk (HR) groups (P < 0.001). The RS contributed to the progression of PaC, and could be a significant independent factor for prognostic prediction. The validation of the ICGC cohort confirmed the effectiveness of the proposed signature. The patients with a HR score in the TCGA cohort had higher tumor mutation burden and more sensitivity to paclitaxel, gemcitabine, 5-fluorouracil and cisplatin than those with a LR score. The differential expression levels of signature genes were verified in vitro.Conclusion: The PRGs signature can be applied for predicting the prognosis of PaC, and may provide useful information for selection of therapeutic drugs.Keywords: pancreatic cancer, pyroptosis-related genes, TCGA, prognosis, bioinformatics analysis, tumor mutation burden

Dandan Zhao,1,2 Xiaoxiao Zhang,1,2 Yuhui Tang,1,2 Peilin Guo,1,2 Rong Ai,1,2 Mengmeng Hou,1,2 Yiqi Wang,1,2 Xiwei Yuan,1,2 Luyao Cui,1,2 Yuguo Zhang,1,2 Suxian Zhao,1,2 Wencong Li,1,2 Yang Wang,1,2 Xiaoye Sun,1,2 Lingdi Liu,1,2 Shiming Dong,1,2 Lu Li,1,2 Wen Zhao,1,2 Yuemin Nan1,2 1Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China; 2Hebei Provincial Key Laboratory of Liver Fibrosis in Chronic Liver Diseases, Shijiazhuang, Hebei, People’s Republic of ChinaCorrespondence: Yuemin Nan, Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, No. 139 Ziqiang Road, Shijiazhuang, Hebei Province, 050051, People’s Republic of China, Tel +86 311-66781227, Fax +86 311-66781289, Email nanyuemin@163.comPurpose: The aim of this study was to identify and validate novel biomarkers for distinguishing among hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), liver fibrosis/liver cirrhosis (LF/LC) and chronic hepatitis B (CHB).Patients and Methods: Transcriptomic sequencing was conducted on the liver tissues of 5 patients with HCC, 5 patients with LF/LC, 5 patients with CHB, and 4 healthy controls. The expression levels of selected mRNAs and proteins were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical (IHC) staining, and were verified in validation set (n=200) and testing set (n=400) via enzyme-linked immunosorbent assay (ELISA).Results: A total of 9 hub mRNAs were identified by short time-series expression miner and weighted gene co-expression network analysis. Of note, the results of qRT-PCR and IHC staining demonstrated that SHC adaptor protein 1 (SHC1), SLAM family member 8 (SLAMF8), and interleukin-32 (IL-32) exhibited gradually increasing trends in the four groups. Subsequent ELISA tests on the validation cohort indicated that the plasma levels of SHC1, SLAMF8 and IL-32 also gradually increased. Furthermore, a diagnostic model APFSSI (age, PLT, ferritin, SHC1, SLAMF8 and IL-32) was established to distinguish among CHB, LF/LC and HCC. The performance of APFSSI model for discriminating CHB from healthy subjects (AUC=0.966) was much greater compared to SHC1 (AUC=0.900), SLAMF8 (AUC=0.744) and IL-32 (AUC=0.821). When distinguishing LF/LC from CHB, APFSSI was the most outstanding diagnostic parameter (AUC=0.924), which was superior to SHC1, SLAMF8 and IL-32 (AUC=0.812, 0.684 and 0.741, respectively). Likewise, APFSSI model with the greatest AUC value displayed an excellent performance for differentiating between HCC and LF/LC than other variables (SHC1, SLAMF8 and IL-32) via ROC analysis. Finally, the results in the test set were consistent with those in the validation set.Conclusion: SHC1, SLAMF8 and IL-32 can differentiate among patients with HCC, LF/LC, CHB and healthy controls. More importantly, the APFSSI model greatly improves the diagnostic accuracy of HBV-associated liver diseases.Keywords: HBV-associated liver diseases, transcriptome sequencing technology, SHC adaptor protein 1, SLAM family member 8, interleukin-32

Yuxian Yang,&ast; Shuting Li,&ast; Yuechao Xu, Jing Ke, Dong Zhao Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing, 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.cnPurpose: Obesity is an important risk factor for nonalcoholic fatty liver disease (NAFLD). Perirenal fat and paranephric fat were seldom studied in NAFLD. We aimed to explore the relationship between perirenal fat thickness (PrFT) and paranephric fat thickness (PnFT) and NAFLD in patients with type 2 diabetes mellitus (T2DM).Patients and Methods: A total of 493 diabetic patients including 231 NAFLD patients were enrolled in our study from September 2019 to December 2020. Patients with NAFLD were categorized into three subgroups according to the severity and fibrosis risk of NAFLD. Anthropometric indices and clinical characteristics were collected from clinical records. PrFT and PnFT were measured via ultrasound. Multivariate logistic regression analysis was used to assess the association between PrFT, PnFT and presence, severity and advanced fibrosis risk of NAFLD.Results: Compared with non-NAFLD patients, those with NAFLD had significantly higher PrFT and PnFT. The PrFT and PnFT were independently associated with presence of NAFLD and the PrFT was independently associated with the advanced fibrosis risk of NAFLD after adjusting confounding factors.Conclusion: The PrFT was independently associated with the presence and advanced fibrosis risk of NAFLD in patients with T2DM.Keywords: nonalcoholic fatty liver disease, perirenal fat thickness, paranephric fat thickness, type 2 diabetes mellitus

Qi Han,1 Feifan Meng,1 Ming Chen,1 Xiangjun Lu,1 Deyuan Zhao,1 Dongze Wu,1 Tingting Wang,2 Rujie Qin1 1Department of Orthopedics, The First People’s Hospital of Lianyungang Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu, People’s Republic of China; 2Department of Dermatology, The First People’s Hospital of Lianyungang Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu, People’s Republic of ChinaCorrespondence: Rujie Qin, Department of Orthopedics, The First People’s Hospital of Lianyungang Affiliated to Xuzhou Medical University, No. 6 East Zhenhua Road, Haizhou, Lianyungang, Jiangsu, 222061, People’s Republic of China, Email gkdrqlyg@sina.comObjective: To evaluate the early clinical effect of percutaneous endoscopic transforaminal lumbar interbody fusion (PE-TLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) surgery in the treatment of middle-aged and elderly patients with single-level lumbar disc herniation accompanied by lumbar instability.Methods: From January 2019 to June 2020, a total of 82 consecutive patients were categorised into PE-TLIF group and MIS-TLIF group based on different surgical methods. The visual analog scale (VAS), Oswestry disability index (ODI), Japanese Orthopaedic Association (JOA) score, perioperative objective serological index, operation time, intraoperative blood loss, time to back to work or normal life, and Modified MacNab score were used as the evaluation indexes. The differences between the two groups were analyzed and the clinical effects were compared.Results: The VAS back pain of PE-TLIF group was decreased compared to that of MIS-TLIF group in the postoperative 1 week and 1 month. The operative time in PE-TLIF group was obviously longer than that in MIS-TLIF group. The hospital stay was significantly shorter in PE-TLIF group than that in MIS-TLIF group. More intraoperative blood loss and postoperative drainage were recorded in MIS-TLIF group. Compared with MIS-TLIF, PE-TLIF surgery was associated with a shorter time to ambulation after surgery and a shorter time to back to work or normal life. Significant statistical differences were observed in IL-6, CRP, and CK on postoperative 3 days between the two groups.Conclusion: For middle-aged and elderly patients, PE-TLIF and MIS-TLIF surgery both have obvious clinical efficacy and safety. However, with less intraoperative blood loss, shorter recovery time and less injury to the patients, people undergoing PE-TLIF surgery can return to work or normal life faster. It is speculated that PE-TLIF has a higher incidence of complications and recurrence rate than that MIS-TLIF. PE-TLIF may be a better choice for middle-aged and elderly patients with single-level lumbar disc herniation.Keywords: lumbar disc herniation, minimally invasive surgery, percutaneous endoscopic transforaminal lumbar interbody fusion, minimally invasive transforaminal lumbar interbody fusion, middle-aged and elderly

Yanan Li, Yan Zhang, Wei Wang, Chong Wei, Danqing Zhao, Wei Zhang Department of Hematology, Peking Union Medical College Hospital, Beijing, People’s Republic of ChinaCorrespondence: Wei Zhang, Email vv1223@vip.sina.comObjects: To systematically evaluate the baseline characteristics, tumour microenvironment indicators such as the lymphocyte/monocyte ratio (LMR) and treatment response (POD24) as prognostic predictors of follicular lymphoma (FL) among Chinese patients.Methods: We retrospectively analysed 112 FL patients from 2000 to 2017, whose pathology grading included 1– 3a. Absolute lymphocyte and monocyte counts were determined by cell blood counting. The Kaplan–Meier method was used to analyse the influence of prognostic predictors on progression-free survival (PFS) and overall survival (OS). Multivariate analysis was conducted using the Cox proportional risk model.Results: The long-term survival of Chinese FL patients (median PFS, 74.8 months) was slightly better than that of patients in foreign countries. Among several prognostic models, the Follicular Lymphoma International Prognostic Index (FLIPI) score had a significant effect on both PFS and OS, while there were no independent prognostic predictors. Patients with LMR ≤ 3.6, ALC ≤ 0.6&ast;109/L and AMC > 0.6&ast;109/L had worse OS, among which LMR was an independent indicator of OS. The POD24 subgroup had a higher frequency of high-risk patients according to FLIPI and FLIPI2 scores (63.0% vs 35.1%, P = 0.013 and 18.5% vs 3.9%, P = 0.003) and had an markedly shorter OS (P < 0.0001).Conclusion: This study is a systematic prognostic evaluation based on Chinese clinical data. We found a new factor, the LMR, that could independently predict prognosis compared with FLIPI or FLIPI2.Keywords: follicular lymphoma, prognosis, clinical characteristics, lymphocyte/monocyte ratio, immunology

Diming Zhao,1 Yilin Liu,2 Shanghao Chen,1 Zhenqiang Xu,3,4 Xiaomei Yang,5 Hechen Shen,1 Shijie Zhang,1 Yi Li,1 Haizhou Zhang,3,4 Chengwei Zou,3,4 Xiaochun Ma3,4 1Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 3Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 4Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People’s Republic of China; 5Department of Anesthesiology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, People’s Republic of ChinaCorrespondence: Xiaochun Ma, Tel +8615169196737, Email mxcmxc2008@163.comBackground: Blood urea nitrogen to albumin ratio (BAR) has been implicated in predicting outcomes of various inflammatory-related diseases. However, the predictive value of BAR in long-term mortality in patients with acute myocardial infarction (AMI) has not yet been evaluated.Methods: In this retrospective cohort study, the patients were recruited from the Medical Information Mart for Intensive Care III (MIMIC III) database and categorized into two groups by a cutoff value of BAR. Kaplan–Meier (K-M) analysis and Cox proportional hazard model were performed to determine the predictive value of BAR in long-term mortality following AMI. In order to adjust the baseline differences, a 1:1 propensity score matching (PSM) was carried out and the results were further validated.Results: A total of 1827 eligible patients were enrolled. The optimal cutoff value of BAR for four-year mortality was 7.83 mg/g. Patients in the high BAR group tended to have a longer intensive care unit (ICU) stay and a higher rate of one-, two-, three- and four-year mortality (all p< 0.001) compared with those in the low BAR group. K-M curves indicated a significant difference in four-year survival (p< 0.001) between low and high BAR groups. The Cox proportional hazards model showed that higher BAR (> 7.83) was independently associated with increased four-year mortality in the entire cohort, with a hazard ratio (HR) of 1.478 [95% CI (1.254– 1.740), p< 0.001]. After PSM, the baseline characteristics of 312 pairs of patients in the high and low BAR groups were well balanced, and similar results were observed in K-M curve (p=0.003).Conclusion: A higher BAR (> 7.83) was associated with four-year mortality in patients with AMI. As an easily available biomarker, BAR can predict the long-term mortality in AMI patients independently.Keywords: acute myocardial infarction, blood urea nitrogen, albumin, long-term mortality, MIMIC III database

Qingen Da,1,2,&ast; Mingming Ren,2,&ast; Lei Huang,2 Jianhua Qu,1 Qiuhua Yang,3 Jiean Xu,4 Qian Ma,4 Xiaoxiao Mao,4 Yongfeng Cai,4 Dingwei Zhao,4 Junhua Luo,5 Zilong Yan,1 Lu Sun,2 Kunfu Ouyang,2 Xiaowei Zhang,6 Zhen Han,2 Jikui Liu,1 Tao Wang2 1Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, People’s Republic of China; 2Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, People’s Republic of China; 3Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; 4Shenzhen Graduate School, Peking University, Shenzhen, People’s Republic of China; 5Department of Urological Surgery, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China; 6School of Basic Medical Sciences, Peking University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jikui Liu, Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, People’s Republic of China, Email liu8929@126.com Tao Wang, Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, People’s Republic of China, Email szwangtao@126.comObjective: We aimed to explore the prognostic patterns of ferroptosis-related genes in papillary renal cell carcinoma (PRCC) and investigate the relationship between ferroptosis-related genes and PRCC tumor immune microenvironment.Methods: We obtained the mRNA expression and corresponding clinical data of PRCC from the public tumor cancer genome atlas database (TCGA). The PRCC patients were randomly divided into two cohort, training cohort and verification cohort, respectively. Univariate Cox regression, LASSO Cox regression, multivariate Cox regression analysis were utilized to construct ferroptosis signature for PRCC patients. And then, risk prognostic model was established and verified. The correlation of ferroptosis-related signature with survival and immune microenvironment was systematically analyzed.Results: A 4-genes ferroptosis signature (CDKN1A, MIOX, PSAT1, and RRM2) was constructed. Multivariate Cox regression assay indicates that the risk score of ferroptosis signature was an independent prognostic indicator (HR=1.391, p< 0.001). The survival curve shows that the high-risk group has a poorer prognosis than the low-risk group (p< 0.001). The risk prognostic model was established based on prognostic factors of clinical-stage, hemoglobin, and risk score. The time-dependent receiver operating characteristic curve (ROC) analysis proves the predictive capacity of the ferroptosis signature, the 3 years area under the curve (AUC) is 0.890, and the 5 years AUC is 0.733. Further analysis suggested that cell cycle, pentose phosphate pathway, P53 signaling pathway were significantly enriched in the high-risk group. The significantly different fractions of dendritic cells resting, macrophage cells, and T cells follicular helper were observed in risk groups.Conclusion: This study implicates a ferroptosis signature which has a good predict capacity of the prognosis in PRCC patients. Ferroptosis-related genes may have a key role in the process of anti-tumor and serve as therapeutic targets for PRCC.Keywords: papillary renal cell carcinoma, ferroptosis, gene signature, prognosis model, tumor immune microenvironment

Yuzhi Zhang,1,2 Hao Fu,1,2 Yongtao Zhang,1,2 Dongdong Wang,1,2 Dan Zhao,1– 3 Jiachan Zhang,1– 3 Meng Li,1,2 Changtao Wang1– 3 1Beijing Key Lab of Plant Resource Research and Development, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, People’s Republic of China; 2Institute of Cosmetic Regulatory Science, Beijing Technology and Business University, Beijing, People’s Republic of China; 3Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing, People’s Republic of ChinaCorrespondence: Meng Li; Changtao Wang, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China, Tel +86 10-68984917, Fax +86 10-68984917, Email limeng@btbu.edu.cn; wangct@th.btbu.edu.cnObjective: To evaluate the efficacy of the dandelion fermentation broth in repairing UVB-induced skin inflammation.Methods: Detection of active ingredients in dandelion fermentation broth and water extract. The antioxidant capacity of dandelion fermentation broth was investigated by in vitro antioxidant experiments. The influence of the broth on the content of inflammatory factors interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-1β (IL-1β), and tumor necrosis factor (TNF-α), in human immortalized epidermal cells (HaCaT) is discussed on the basis of a UVB-induced HaCaT damage model. The effects of the broth on the contents of skin barrier-related proteins kallikrein-7 (KLK-7), filaggrin (FLG) and aquaporin (AQP3) in the UVB-induced damage and repair of the HaCaT mechanism are also comprehensively discussed. The effect of DF on the activation of MAPK pathway proteins was detected by PCR. A chicken embryo chorioallantoic membrane test is used to explore the safety of the dandelion fermentation broth.Results: The results show that the dandelion fermentation broth is rich inTotal sugar, with good free radical scavenging ability and antioxidant effects; it can regulate the MAPK pathway, reduce the expression of inflammatory factors, adjust the skin barrier factors and good safety.Conclusion: Dandelion fermentation broth exhibits repairing effect on UVB-induced skin inflammation.Keywords: dandelion fermentation broth, ultraviolet radiation B, human immortalized epidermal cells, inflammation repair, medicine, daily chemical raw materials

Dan Zhao,1,2 Rui Zhang,1,2 Xuemei Liu,1,2 Xiaoyun Li,1,2 Mengyu Xu,1,2 Xianju Huang,1,2 Xincai Xiao1,2 1School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, People’s Republic of China; 2National Demonstration Center for Experimental Ethnopharmacology Education (South-Central University for Nationalities), Wuhan, 430065, People’s Republic of ChinaCorrespondence: Dan Zhao, Tel +1 806 208 4690, Email wqzhdpai@163.comIntroduction: Pathogenic bacteria, especially the ones with highly organized, systematic aggregating bacteria biofilm, would cause great harm to human health. The development of highly efficient antibacterial and antibiofilm functional fluorescent nanomaterial would be of great significance.Methods: This paper reports the preparation of a series of antibacterial functional carbon dots (CDs) with chitosan (CS) and its derivatives as raw materials through one-step route, and the impact of various experiment parameters upon the optical properties and the antibacterial abilities have been explored, including the structures of the raw materials, excipients, and solvents.Results: The CDs prepared by quaternary ammonium salt of chitosan (QCS) and ethylenediamine (EDA) exhibit multiple antibacterial effects through membrane breaking, DNA and protein destroying, and the production of singlet oxygen. The CDs showed excellent broad-spectrum inhibitory activity against a variety of bacteria (Gram-positive and negative bacteria), in particular, to the biofilm of Staphylococcus aureus with minimum inhibitory concentration at 10 μg/mL, showing great potential in killing bacteria and biofilms. The biocompatibility experiments proved that QCS-EDA-CDs are non-toxic to human normal hepatocytes and have low haemolytic effect. Furthermore, the prepared QCS-EDA-CDs have been successfully used in bacterial and biofilm imaging thanks to their excellent optical properties.Conclusion: This paper explored the preparation and application of functional CDs, which can be used as the visual probe and therapeutic agents in the treatment of infections caused by bacteria and biofilm.Graphical Abstract: Keywords: carbon dots, antibacterial activity, bacterial imaging, anti-biofilm, antibacterial mechanism

Xing-Qi Yin,&ast; Ya-Xin An,&ast; Cai-Guo Yu, Jing Ke, Dong Zhao, Ke Yu Center for Endocrine Metabolism and Immune Diseases, Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke YuCenter for Endocrine Metabolism and Immune Diseases, Luhe Hospital, Capital Medical University, No. 82, Xinhua South Road, Tongzhou District, Beijing, People’s Republic of China, Tel +86 13811657618, Email yuke@ccmu.edu.cnPurpose: To examine the association of short-chain fatty acids (SCFAs), gut microbiota and obesity in individual twins and to control for genetic and shared environmental effects by studying monozygotic intrapair differences.Patients and Methods: The study recruited 20 pairs of monozygotic twins. Body composition measurements were performed by using the multi-frequency bioelectrical impedance technique. SCFAs were extracted from feces and quantified by gas chromatography-mass spectrometer. Gut microbiota was evaluated by 16S rRNA gene sequencing.Results: Fecal SCFAs were negatively correlated with adiposity parameters including body mass index, visceral adipose tissue and waist circumference (all P < 0.05). Metastat analysis showed that the top 5 relatively abundant bacterial taxa of viscerally obese and non-obese groups were Bacteroides, Collinsella, Eubacterium rectale group, Lachnoclostridium, and Tyzzerella. Participants with visceral obesity had lower abundance of Bacteroides and Collinsella compared to non-obese patients (P < 0.05). Among them, the abundance of Collinsella was positively correlated with acetic acid concentrations (r = 0.63, P = 0.011). There were no significant intrapair differences in each SCFA concentrations between the twins in our study (P > 0.05).Conclusion: Low fecal concentrations of SCFAs were associated with visceral obesity, and the gut microbiota might be involved in the underlying mechanism.Keywords: twins, short-chain fatty acids, gut microbiota, obesity, visceral fat

Danni Zhao,1 Jonggyu Baek,1 Anne L Hume,2,3 Emily A McPhillips,1 Kate L Lapane1 1Department of Population and Quantitative Health Sciences, UMass Chan Medical School, Worcester, MA, USA; 2Department of Family Medicine, Alpert Medical School, Brown University, Memorial Hospital of Rhode Island, Providence, RI, USA; 3Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, RI, USACorrespondence: Kate L Lapane, Department of Population and Quantitative Health Sciences, UMass Chan Medical School, Worcester, MA, USA, Email kate.lapane@umassmed.eduBackground: Gabapentinoids have been prescribed off-label for almost all types of pain. The geographic variation in the use of gabapentinoids as analgesics remains unknown.Objective: To describe the geographic variation in gabapentinoids, opioids and concurrent use of both for pain by US state and metropolitan statistical area (MSA).Methods: We conducted a cross-sectional study on December 1, 2018, among commercially insured adults aged 18– 64 years without epilepsy or opioid use disorders using IBM® MarketScan® Research Databases. We described the geographic variation in the analgesic regimens (gabapentinoids, opioids and concurrent use of both) by state and MSA, and assessed factors associated with the geographic variation using multilevel logistic regression.Results: We included 9,314,197 beneficiaries; 1.4% had gabapentinoids, 1.5% had opioids and 0.3% had concurrent use of both. The majority of gabapentinoid use lacked an FDA-approved indication. Use of the analgesic regimens varied across states (gabapentinoids (median (interquartile range)): 1.4% (1.2– 1.7%); opioids: 1.5% (1.2– 1.9%); both: 0.3% (0.2– 0.4%)) and MSAs (gabapentinoids: 1.6% (1.3– 2.0%); opioids: 1.8% (1.3– 2.3%); both: 0.3% (0.2– 0.5%)). Demographics explained the largest proportion of the between-state and between-MSA variation. The pattern of the geographic variation in gabapentinoids was similar to that of opioids across states and MSAs.Conclusion: Gabapentinoids were as commonly used as opioids for pain in a commercially insured population (mostly off-label). The geographic variation in gabapentinoids was similar to that of opioids, which suggests that gabapentinoids may be widely used as alternatives or adjuvants to opioids across the US.Keywords: gabapentinoids, opioids, pain, geographic variation

Jiachan Zhang,1 Changtao Wang,1 Quan An,2 Qianghua Quan,2 Meng Li,2 Dan Zhao1 1Beijing Key Lab of Plant Resource Research and Development, College of chemistry and materials engineering, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 2Yunnan Baiyao Group Co., Ltd., Kunming, 650000, People’s Republic of ChinaCorrespondence: Changtao Wang, Beijing Key Lab of Plant Resource Research and Development, College of chemistry and materials engineering, Beijing Technology and Business University, Fucheng Road, Beijing, 100048, People’s Republic of China, Tel +8610-68984917, Email wangct@th.btbu.edu.cn Quan An, Yunnan Baiyao Group Co., Ltd., Kunming, 650000, People’s Republic of China, Email 59304376@qq.comBackground: Pathogenesis and persistence of many skin diseases are related to Staphylococcus aureus (S. aureus) colonization. S. aureus infection can cause varying degrees of changes in cell gene expression, resulting in complex changes in cell phenotype and finally changes in cell life activities.Materials and Methods: The transcriptomes of healthy and Staphylococcus aureus (S. aureus)-infected murine skin tissues were analyzed. We identified 638 differentially expressed genes (DEGs) in the infected tissues compared to the control samples, of which 324 were upregulated and 314 were downregulated, following the criteria of P < 0.01 and |log2FC| > 3. The DEGs were functionally annotated by Gene Ontology (GO), KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and the protein–protein interaction (PPI) network analyses.Results: The upregulated DEGs were mainly enriched in GO terms, such as response to stimulus, immune system process and signal transduction, as well as in the complement and coagulation cascade pathway. Thus, S. aureus infection likely activates these pathways to limit the influx of neutrophils and prevent skin damage. Four clusters were identified in the PPI network, and the major hubs were mainly related to cell cycle and proliferation, and mostly downregulated. The expression levels of Nox4, Mmrn1, Mcm5, Msx1 and Fgf5 mRNAs were validated by qRT-PCR and found to be consistent with the RNA-Seq data, confirming a strong correlation between the two approaches.Conclusion: The identified genes and pathways are potential drug targets for treating skin inflammation caused by S. aureus and should be investigated further.Keywords: Staphylococcus aureus, inflammation, gene expression profile, transcriptome

Chunyuan Zheng, Jingjing Meng, Xueling Xiao, Ying Xie, Di Zhao, Honghong Wang Xiangya Nursing School, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Honghong WangXiangya Nursing School, Central South University, 172 Tongzipo Road, Changsha, Hunan, People’s Republic of ChinaTel +86-731-82650270Fax +86-731-88710136Email honghong_wang@hotmail.comPurpose: People living with HIV (PLWHIV) are susceptible to non-communicable diseases (NCDs) because of aging and infections. This means that the number of non-HIV medications increases, along with issues of polypharmacy and medication-related burden. The purpose of this study was to identify the current situation of polypharmacy and medication-related burden among PLWHIV aged 50 and above, as well as the relation between medication-related burden and antiretroviral therapy (ART) adherence.Patients and Methods: A cross-sectional study was conducted with 185 participants recruited from two HIV clinics in Yuelu District Center for Disease Control (CDC) and Changsha First Hospital in Hunan, China. Participants filled questionnaires about comorbidities, polypharmacy, medication-related burden, ART adherence and sociodemographic characteristics.Results: Among the participants, 40% were receiving polypharmacy, and PLWHIV, who were female (β = 5.946; 95% CI = 1.354, 10.541), had a lower monthly income (β = − 4.777; 95% CI = − 6.923, − 2.632), and took more drugs (β = 2.200; 95% CI = 1.167, 3.233) were more likely to report a higher level of medication-related burden. The score of ART adherence was negatively associated with medication-related burden (rs = − 0.250 p = 0.001).Conclusion: The findings suggest that more attention should be paid to the issues of polypharmacy and targeted interventions should be developed to reduce medication-related burden among older PLWHIV.Keywords: AIDS, aging, comorbidity, potential drug–drug interaction, medication burden, medication adherence

Qiuting Mo, 1, 2 Hao Fu, 1, 2 Dan Zhao, 1– 3 Jiachan Zhang, 1– 3 Changtao Wang, 1– 3 Dongdong Wang, 1, 2 Meng Li 1, 2 1Beijing Key Laboratory of Plant Resource Research and Development, College of Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, People’s Republic of China; 2Institute of Cosmetic Regulatory Science, Beijing Technology and Business University, Beijing, People’s Republic of China; 3Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University, Beijing, People’s Republic of ChinaCorrespondence: Dongdong Wang; Meng Li Tel/Fax +86-010-68984917Email Wdd@btbu.edu.cn; limeng@btbu.edu.cnPurpose: Damage caused by oxidative stress leads to the premature aging of cells. Mogrosides, the main active components of Siraitia grosvenorii, have strong antioxidant activity; however, it is unclear whether mogroside V (MV) exerts these effects in skin cells. This was investigated in the present study by evaluating the protective effects of MV against oxidative damage induced by hydrogen peroxide (H 2O 2) in skin fibroblasts.Methods: Mouse skin fibroblasts (MSFs) were treated with H 2O 2 and cell viability, total antioxidant capacity, reactive oxygen species (ROS) production, malondialdehyde (MDA) content, and antioxidant enzyme activity were assessed.Results: Treatment with MV reduced the ROS level and MDA content in MSFs treated with H 2O 2. This was accompanied by increased superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities.Conclusion: MV reduces H 2O 2-induced oxidative stress and enhances endogenous antioxidant activity in skin fibroblasts. Thus, MV can potentially be used as an ingredient in anti-aging cosmetic products.Keywords: Siraitia grosvenorii, mogroside V, oxidative stress, antioxidant

Jiliang Feng,1 Ruidong Zhu,2 Yu Yin,3 Shanshan Wang,1 Lei Zhou,4 Fudong Lv,1 Dawei Zhao5 1Clinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 2General Surgical Center, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, People’s Republic of China; 3Department of Pathology, Anhui Medical University, Hefei, 230032, People’s Republic of China; 4Department of Pathology, First Affiliated Hospital of Bengbu Medical College/Bengbu Medical College, Bengbu, 233004, People’s Republic of China; 5Department of Medical Imaging, Capital Medical University, Beijing, 100069, People’s Republic of ChinaCorrespondence: Jiliang FengClinical-Pathology Center, Beijing You-An Hospital, Capital Medical University, No. 8, Xitoutiao, Youanmenwai Street, FengTai District, Beijing, 100069, People’s Republic of ChinaTel +86-10-83997342Fax +86-10-83997343Email jiliangfeng@ccmu.edu.cnAbstract: The primary epithelial tumors of the liver (PETL) are composed of a series of heterogeneous tumors. Although the classification of PETLs has been updated several times by the World Health Organization, the cellular origins of some tumors in this family remain to be precisely depicted. In addition, certain tumors in different categories have similar histology, molecular phenotypes and biological characteristics, suggesting that they may have the same cellular origin. In this work, a narrative review method was adopted to review the relevant papers. By comparing the expression profiles of biomarkers of liver epithelium at different lineages and stages of differentiation, the cells-of-origin of some major members of the PETL family were reassessed. We propose that 1) hepatic adenomas, hepatocellular carcinomas (HCCs) and pure fetal hepatoblastomas (HBs) share the same spectrum in their cellular origin including the hepatocytic-committed progenitors (HCP) and their differentiated descendants. 2) Bile duct adenomas, peribiliary cysts and intrahepatic cholangiocellular carcinomas (ICCs) can share the same spectrum in their cellular origin including the cholangiocytic-committed progenitors (CCP) and their differentiated descendants. 3) The cells-of-origin of embryonal HBs include liver stem cells (LSCs), hepatoblasts, and transitional cells between them. Embryonal HB with small cell element, small cell undifferentiated HB and small cell neuroendocrine carcinoma of the liver can have the same or similar cells-of-origin from LSC. Embryonal HB lacking the small cell component of the LSC phenotype and presenting both hepatocytic and bile duct/ductule components may originate from actual hepatoblasts/hepatic progenitor cells (HPCs) as the combined HCC-ICC does. 4) Teratoid hepatoblastoma and mixed epithelial/mesenchymal HBs can be derived from the LSCs or even less committed extrahepatic pluripotent stem cell. 5) Many members of the PETLs family, including those derived from LSCs, hepatoblasts/HPCs, early HCPs and CCPs, have neuroendocrine potentiality. Except for those primary hepatic neuroendocrine tumor (PHNET) exhibit hepatocytic and/or cholangiocytic phenotypes, other PHNETs subtype may be derived from the descendants of LSC that differentiate towards the upper digestive tract, pancreas or other lineages.Keywords: HCC, tumor-initiating cell, hepatic progenitor, neuroendocrine tumors, hepatoblastoma

Diming Zhao,1 Yilin Liu,2 Zhenqiang Xu,3,4 Hechen Shen,1 Shanghao Chen,1 Shijie Zhang,1 Yi Li,1 Haizhou Zhang,3,4 Chengwei Zou,3,4 Xiaochun Ma3,4 1Department of Cardiovascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Ophthalmology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 3Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 4Department of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Xiaochun MaDepartment of Cardiovascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Jinan, 250021, People’s Republic of ChinaTel +8615169196737Email mxcmxc2008@163.comBackground: Hypoplastic left heart syndrome (HLHS) is one of the most complex congenital cardiac malformations, and the molecular mechanism of heart failure (HF) in HLHS is still elusive.Methods: Integrative bioinformatics analysis was performed to unravel the underlying genes and mechanisms involved in HF in HLHS. Microarray dataset GSE23959 was screened out for the differentially expressed genes (DEGs), after which the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were carried out using the Metascape. The protein–protein interaction (PPI) network was generated, and the modules and hub genes were identified with the Cytoscape-plugin. And the integrated network of transcription factor (TF)-DEGs and miRNA-DEGs was constructed, respectively.Results: A total of 210 DEGs were identified, including 135 up-regulated and 75 down-regulated genes. The functional enrichment analysis of DEGs pointed towards the mitochondrial-related biological processes, cellular components, molecular functions and signaling pathways. A PPI network was constructed including 155 nodes as well as 363 edges. And 15 hub genes, such as NDUFB6, UQCRQ, SDHD, ATP5H, were identified based on three topological analysis methods and mitochondrial components and functions were the most relevant. Furthermore, by integrating network interaction construction, 23 TFs (NFKB1, RELA, HIF1A, VHL, GATA1, PPAR-γ, etc.) as well as several miRNAs (hsa-miR-155-5p, hsa-miR-191-5p, hsa-mir-124-3p, hsa-miR-1-3p, etc.) were detected and indicated the possible involvement of NF-κB signaling pathways in mitochondrial dysfunction in HLHS.Conclusion: The present study applied the integrative bioinformatics analysis and revealed the mitochondrial-related key genes, regulatory pathways, TFs and miRNAs underlying the HF in HLHS, which improved the understanding of disease mechanisms and the development of novel therapeutic targets.Keywords: hypoplastic left heart syndrome, differential expression genes, transcription factors, microRNAs, regulatory networks, integrative bioinformatics analysis

Changjuan Li,1,2 Jianwei Mi,1 Fulai Gao,1 Xinying Zhu,1 Miao Su,1 Xiaoli Xie,1 Dongqiang Zhao1 1Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei Province, People’s Republic of China; 2Department of Gastroenterology, The First Hospital of Handan City, Handan, 056002, Hebei Province, People’s Republic of ChinaCorrespondence: Dongqiang ZhaoDepartment of Gastroenterology, The Second Hospital of Hebei Medical University, No. 215, He ping West Road, Xinhua District, Shijiazhuang, Hebei Province, 050000, People’s Republic of ChinaTel +86 0311 66636179Email hbzdq1998@163.comPurpose: We aimed to compare the histological and/or cytological diagnostic outcomes of EUS-FNA using 19G and 22G needles for solid pancreatic lesions and to evaluate the feasibility and safety of 19G needle.Patients and Methods: Data from patients with solid pancreatic lesions, who underwent EUS-FNA, were retrospectively retrieved from a single tertiary center from June 2017 to January 2021. The sensitivity, specificity, and accuracy of diagnosis, sample adequacy, number and time of punctures, and adverse events, were compared between the 19G and 22G groups. Univariate and multivariate logistic regression analyses were used to identify optimal factors for a correct histological diagnosis.Results: A total of 186 patients (19G group, n = 90; 22G group, n = 96) were analyzed in the study. The higher sensitivity and accuracy were observed in 19G group than those in the 22G group both in histological evaluation (89.3% vs 76%, p = 0.031; 91.1% vs 79.2%, p = 0.023; respectively) and in the combined histological and cytological evaluations (93.3% vs 81.3%, p = 0.027; 94.4% vs 84.3%, p = 0.027, respectively). However, there were no significant differences in specificity, positive predictive value (PPV), and negative predictive value (NPV). The number of needle passes and the puncture time were significantly lower in the 19G group than that in the 22G group (1.66 ± 0.07 vs 2.25 ± 0.08, p < 0.001; 125.4 ± 4.93s vs 169.0 ± 5.6s p < 0.001; respectively). Only 2 cases were failed in the 19G group and no serious complications occurred. Univariate and multivariate logistic analyses suggested that CA199 levels and needle types are related to the accuracy of the EUS-FNA histological diagnosis.Conclusion: EUS-FNA using a 19G needle is effective and safe for solid pancreatic lesions. Compared with the 22G needle, EUS-FNA with a 19G needle can obtain a better histological diagnostic accuracy of solid pancreatic lesions, and with fewer needle passes and in a shorter time.Keywords: sensitivity, specificity, diagnostic accuracy, histology, cytology

Xiuqin Shi,1,2 Wenjing Cheng,1,3,4 Qian Wang,1 Jiachan Zhang,1,3,4 Changtao Wang,1,3,4 Meng Li,1,3,4 Dan Zhao,1,3,4 Dongdong Wang,1,3,4 Quan An2 1Chemistry and Materials Engineering, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 2Yunnan Baiyao Group Co., Ltd, Kunming, 650000, People’s Republic of China; 3Beijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing, 100048, People’s Republic of China; 4Institute of Cosmetic Regulatory Science, Beijing Technology and Business University, Beijing, 100048, People’s Republic of ChinaCorrespondence: Jiachan Zhang; Changtao WangCollege of Chemistry and Materials Engineering, Beijing Technology and Business University, 11 Fucheng Road, Haidian District, Beijing, 100048, People’s Republic of ChinaTel +86-13426258535; +86-18910839617Email xiaochan8787@163.com; wangct@th.btbu.edu.cnBackground: Ganoderma lucidum (G. lucidum) is one of China’s traditional medicinal materials. G. lucidum polysaccharide has a wide range of promising pharmacological applications. However, there are many kinds of G. lucidum and they contain different kinds of polysaccharides. The biological mechanism through which Ganoderma lucidum polysaccharides (GLP) is able to protect human skin fibroblasts (HSFs) from H2O2-induced oxidative damage is still unclear.Methods: Six polysaccharides were obtained from G. lucidum to evaluate their free radical scavenging ability (DPPH free radical, ABTS free radical, hydroxyl-free radical, superoxide anion-free radical) in vitro, and their protective and reparative effects on oxidative damage induced by H2O2 in human skin fibroblasts. One polysaccharide was selected to detect oxidative damage markers and gene expression in the Keap1-Nrf2/ARE signaling pathway in HSFs.Results: All six polysaccharides showed the ability to scavenge free radicals and enhance the tolerance of human skin fibroblasts to H2O2 damage. Among them, GLP1 was selected and separated into two components (GLP1I and GLP1II). The results showed that GLP1, GLP1I and GLPII could significantly reduce the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). The protective effect of GLP1II was stronger than that of positive control vitamin C. In addition, GLP1, GLP1I and GLP1II could significantly increase the levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). And GLP1I works best in both ways. Meanwhile, Nrf2, a key regulator of keAP1-NRF2/ARE signaling pathway, was activated, while Keap1, a negative regulator, was inhibited, thus promoting the expression of downstream antioxidant enzyme genes (GSTs, GCLs, Nqo1, and Ho-1).Conclusion: The results showed that GLP could protect human skin fibroblasts from oxidative damage caused by H2O2 peroxide by enhancing enzyme activity and activating Keap1-Nrf2/ARE signaling pathway. GLP will act as a natural antioxidant to protect the skin from oxidative stress damage.Keywords: Ganoderma lucidum, polysaccharide, oxidative stress, Keap1-Nrf2/ARE signaling pathway

Donglu Zhao, Qi Xing, Hang Song, Yan Zhao, Guiying Guo No. 4 Ward of Hematology Department, Institute of Hematology and Oncology, Harbin First Hospital, Harbin 150010, Heilongjiang Province, People’s Republic of ChinaCorrespondence: Donglu ZhaoNo. 4 Ward of Hematology Department, Institute of Hematology and Oncology, Harbin First Hospital, No. 149 Diduan Street, Daoli District, Harbin 150010, Heilongjiang Province, People’s Republic of ChinaTel +86-13936254716Email zhaodonglu123@163.comBackground: Long noncoding RNA LINC00265 or miR-4500 is involved in the pathogenesis of many cancers. However, their functions in acute lymphoblastic leukemia (ALL) remain unknown. In this study, we investigated how LINC00265 and miR-4500 regulate the malignant characteristics of ALL.Methods: Real-time PCR was used in examining the expression of LINC00265 in ALL cell lines and blood of patients with ALL. Cell proliferation, cell migration, and xenograft tumor assays were performed to verify the function of LINC00265 subjected to overexpressing and silencing experiments. The ceRNA mechanism with LINC00265/miR-4500/STAT3 was investigated through luciferase and RNA pull-down assays. Finally, the function of the LINC00265/miR-4500/STAT3 axis subjected to overexpressing and silencing assays was determined through cell proliferation, cell migration, and xenograft tumor assays.Results: LINC00265 was highly expressed in ALL cell lines and blood of patients with ALL and facilitated the proliferation, migration, invasion, and growth of xenograft tumors of ALL cells. The silencing of LINC00265 expression with LINC00265 siRNA significantly inhibited the malignancy of the ALL cells. RNA pull-down and luciferase assays demonstrated that LINC00265 competitively targeted miR-4500 and enhanced STAT3 expression. Furthermore, miR-4500 inhibitors or overexpressed LINC00265 up-regulated STAT3 expression, and miR-4500 mimics or STAT3 shRNAs eliminated the LINC00265-induced malignancy of the ALL cells.Conclusion: Mechanistically, LncRNA LINC00265 can competitively interact with miR-4500 and thereby up-regulates STAT3 signaling and enhances the malignancy of tumors.Keywords: acute lymphoblastic leukemia, LINC00265, miR-4500, cell proliferation

Jia Liang,1 Ying Jia,1 Haijing Yan,1 Qingyu Shen,1 Weihua Bian,2 Dongmei Zhao,3 Yong Xu,1 Yongjun Jin,4 Meizi Yang1 1Department of Pharmacology, Binzhou Medical University, Yantai, People’s Republic of China; 2Department of Cell Biology, Binzhou Medical University, Yantai, People’s Republic of China; 3Department of Anatomy, Binzhou Medical University, Yantai, People’s Republic of China; 4Department of Endocrinology, Binzhou Medical University, Yantai, People’s Republic of ChinaCorrespondence: Meizi Yang; Yongjun JinDepartment of Pharmacology, Binzhou Medical University, Yantai, 264003, People’s Republic of ChinaTel +86 535 691 9507Fax +86 535 691 3163Email meizyang@126.com; endojin@126.comPurpose: To investigate resistance to diet-induced obesity (DIO) and monosodium glutamate (MSG)-induced obesity as well as the underlying mechanisms.Methods: Newborn mice were used to construct DIO and MSG-induced obesity models. Obesity indices, such as body weight, body length, Lee index, body temperature, food intake, fat weight, and leptin level, were examined. Mice that did not exhibit obesity were defined as the obesity-resistant group. The morphological changes of white adipose tissue were observed by hematoxylin and eosin staining, and expression levels of PR domain containing 16 (Prdm16) and uncoupling protein-1 (Ucp-1) in white adipose tissue were measured by Western blot.Results: Obesity-resistant mice fed a high-fat diet showed resistance beginning at week 5 along with lower weights and lengths than those in the obesity group from weeks 5 to 12. MSG-induced obesity-resistant mice showed features consistent with resistance to obesity from week 1 along with higher body lengths relative to the obesity group; however, the weight difference was not significant until week 10, when body weights decreased significantly in obesity-resistant mice. The Lee index was lower in obesity-resistant mice than in the obesity group and the normal group, further suggesting obesity resistance. Additionally, obesity-resistant mice showed higher levels of leptin, whereas obese mice induced by a high-fat diet showed leptin resistance. Furthermore, Prdm16 and Ucp-1 levels were both downregulated in the obesity group and upregulated in obesity-resistant mice, showing that white fat browning was highest in obesity-resistant mice.Conclusion: The phenotypes of mice with DIO and MSG-induced obesity differed. Obesity resistance might be related to Prdm16 and Ucp-1-mediated white adipocyte browning.Keywords: obesity resistance, brown adipose tissue, Ucp-1, adipocyte browning

Dongxing Zhao,1,2 Asghar Abbasi,1 Richard Casaburi,1 Alessandra Adami,3 Nicholas B Tiller,1 Wei Yuan,1,4 Christopher Yee,5 Nicholas G Jendzjowsky,1 David M MacDonald,6,7 Ken M Kunisaki,6,7 William W Stringer,1 Janos Porszasz,1 Barry J Make,8 Russell P Bowler,8 Harry B Rossiter1 On behalf of the COPDGene Investigators1Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA; 2State 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, 510120, People’s Republic of China; 3Department of Kinesiology, University of Rhode Island, Kingston, RI, USA; 4Respiratory Medicine Department, Beijing Friendship Hospital Affiliated of Capital Medical University, Beijing, 100050, People’s Republic of China; 5MemorialCare Long Beach Medical Center, Long Beach, CA, USA; 6Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN, USA; 7Minneapolis VA Health Care System, Minneapolis, MN, USA; 8National Jewish Health, Denver, CO, USACorrespondence: Harry B Rossiter Email hrossiter@ucla.eduBackground: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?.Study Design and Methods: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations.Results: HRR after 6MWT (bt/min) was categorized in quintiles: ≤ 5 (23.0% of participants), 6– 10 (20.7%), 11– 15 (18.9%), 16– 22 (18.5%) and ≥ 23 (18.9%). Compared to HRR≤ 5, HRR≥ 11 was associated with (p< 0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤ 10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58– 0.66) for identifying FEV1< 30%pred. HRR≥ 11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤ 10 bt/min was associated with (p< 0.001): ≥ 2 exacerbations in the previous year (OR=1.76[1.33– 2.34]); CAT≥ 10 (OR=1.42[1.18– 1.71]); mMRC≥ 2 (OR=1.42[1.19– 1.69]); GOLD 4 (OR=1.98[1.44– 2.73]) and GOLD D (OR=1.51[1.18– 1.95]). HRR≤ 10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07– 3.12], P=0.027).Conclusion: HRR≤ 10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤ 10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.Keywords: autonomic dysfunction, chest computed tomography, COPD exacerbation, exercise, spirometry