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Huifang Niu,1,2,* Minfeng Zhou,1,* Xiaoyun Xu,2 Xiaojuan Xu1 1Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Key Laboratory of Environment Correlative Dietology (Ministry of Education), Hubei Key Laboratory of Fruit Vegetable Processing Quality Control (Huazhong Agricultural University), School of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyun Xu; Xiaojuan Xu, Email xuxiaoyun@mail.hzau.edu.cn; xu_xiaojuan2009@163.comAbstract: Postmenopausal osteoporosis (PMOP) is a major health problem affecting millions of women worldwide. PMOP patients are often accompanied by abnormal accumulation of bone marrow adipose tissue (BMAT). BMAT is a critical regulator of bone homeostasis, and an increasing BMAT volume is negatively associated with bone mass reduction or fracture. BMAT regulates bone metabolism via adipokines, cytokines and the immune system, but the specific mechanisms are largely unknown. This review emphasizes the impact of estrogen deficiency on bone homeostasis and BMAT expansion, and the mechanism by which BMAT regulates PMOP, providing a promising strategy for targeting BMAT in preventing and treating PMOP.Keywords: postmenopausal osteoporosis, bone marrow adipose tissue, bone metabolism, immune system, cytokines

Song Wang,1,&ast; Xiang Zhang,1,&ast; Bo Qu,2,&ast; Kunhai Yang,1 Yongrong Hu,1 Hao Liu,2 Juntao Hong,2 Hao Niu,3 Hongsheng Yang2 1School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China; 2Department of Orthopaedics, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China; 3Computer Science of Sichuan University, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Niu, Computer Science of Sichuan University, Chengdu, Sichuan, People’s Republic of China, Email 13438368112@139.com Hongsheng Yang, Department of Orthopaedics, First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China, Email hongsheng228@163.comPurpose: This study aims to develop a novel MRI-based paravertebral muscle quality (PVMQ) score for assessing muscle quality and to investigate its correlation with the degree of fat infiltration (DFF) and the vertebral bone quality (VBQ) score of paravertebral muscles. Additionally, the study compares the effectiveness of the PVMQ score and the VBQ score in assessing muscle quality and bone quality.Methods: PVMQ scores were derived from the ratio of paravertebral muscle signal intensity (SI) to L3 cerebrospinal fluid SI on T2-weighted MRI. Image J software assessed paravertebral muscle cross-sectional area (CSA) and DFF. Spearman rank correlation analyses explored associations between PVMQ, VBQ scores, DFF, and T-scores in both genders. Receiver operating characteristic (ROC) curves compared PVMQ and VBQ scores’ effectiveness in distinguishing osteopenia/osteoporosis and high paraspinal muscle DFF.Results: In this study of 144 patients (94 females), PVMQ scores were significantly higher in osteoporosis and osteopenia groups compared to normals, with variations observed between genders (P < 0.05). PVMQ showed stronger positive correlation with VBQ scores and DFF in females than males (0.584 vs 0.445, 0.579 vs 0.528; P < 0.01). ROC analysis favored PVMQ over VBQ for low muscle mass in both genders (AUC = 0.767 vs 0.718, 0.793 vs 0.718). VBQ was better for bone mass in males (0.737/0.865 vs 0.691/0.858), whereas PVMQ excelled for females (0.808/0.764 vs 0.721/0.718).Conclusion: The novel PVMQ score provides a reliable assessment of paravertebral muscle quality and shows a strong correlation with VBQ scores and DFF, particularly in females. It outperforms VBQ scores in evaluating muscle mass and offers valuable insights for assessing bone mass in females. These findings underscore the potential of the PVMQ score as a dual-purpose tool for evaluating both muscle and bone health, informing future research and clinical practice.Keywords: muscle quality, osteoporosis, magnetic resonance imaging, dual-energy X-ray absorptiometry, vertebral bone quality score, osteosarcopenia

Yaqing Liu,1,2 Sixian Du,1 Jianbo Cao,1 Haoran Niu,1 Feng Jiang,1 Liwen Gong1 1School of Medicine and Health Management, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 2Huazhong University of Science and Technology’s Double First-Class Discipline Platform in Humanities (Research Center for Hospital High-Quality Development), Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Sixian Du, School of Medicine and Health Management, Huazhong University of Science and Technology, 5th Floor, No. 13 Hangkong Road, Qiaokou District, Wuhan, Hubei, 430030, People’s Republic of China, Tel +8618271878646, Email dusixian16@163.comBackground: Diagnosis-related group (DRG) payment policies are increasingly recognized as crucial instruments for addressing health care overprovision and escalating health care costs. The synthetic control method (SCM) has emerged as a robust tool for evaluating the efficacy of health policies worldwide.Methods: This study focused on Panzhihua city in Sichuan Province, a pilot city for DRG payment reform implementation, serving as the treatment group. In contrast, 20 nonpilot cities within the province were utilized as potential control units. A counterfactual control group was constructed to evaluate the changes in average inpatient stay duration and health care organization costs following the DRG payment reform initiated in 2018.Results: Focusing on Panzhihua, Sichuan Province, the analysis reveals that following the reform in March 2018, the average length of hospital stay in Panzhihua decreased by 1.35 days during 2019– 2021. Additionally, the average cost per hospitalization dropped by 855.48 RMB, the average cost of medication per hospitalization decreased by 68.51 RMB, and the average cost of diagnostic and therapeutic procedures per hospitalization declined by 136.37 RMB. While global evidence backs DRGs for efficiency and cost reduction, challenges persist in addressing emerging issues like new conditions.Conclusion: Since its introduction in 2018, the DRG payment reform in Sichuan Province has effectively reduced both the duration of hospital stays and the operational costs of health care facilities. However, potential drawbacks include compromised service quality and an elevated risk of patient readmission, indicating a need for further refinement in the implementation of DRG payment reforms in China.Keywords: synthetic control method, health policy evaluation, diagnosis-related grouping, DRG, average hospitalization days, average hospital costs, China

Xiaochun Zhou,1– 3,&ast; Kaiying He,1,3,&ast; Jing Zhao,1,3 Guohua Wei,3 Qicai You,1,3 Hongxuan Du,1,3 Wenjiao Gu,1,2 Haiyu Niu,1,4 Qiaoying Jin,1,5 Jianqin Wang,3 Futian Tang1,2 1The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 2Department of Cardiovascular Disease, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 3Department of Nephrology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 4Department of Tumor, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 5Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, Gansu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Futian Tang, Department of Cardiovascular Disease, The Second Hospital & Clinical Medical School, Lanzhou University, No. 82, Cuiyingmen, Lanzhou, Gansu, People’s Republic of China, Tel +8613321330515, Email Tangfutian2023@126.comPurpose: To investigate the therapeutic effect and underlying mechanism of a traditional Chinese medicine (TCM) mixture consisting of Astragalus, rhubarb, and saffron in a mouse model of diabetic kidney disease (DKD).Methods: Forty-eight db/db mice received no TCM (DKD model), low-dose TCM, medium-dose TCM, or high-dose TCM, and an additional 12 db/m mice received no TCM (normal control). Intragastric TCM or saline (controls) was administered daily for 24 weeks. Blood glucose, body weight, serum creatinine (SCr), blood urea nitrogen (BUN), blood lipids, and urinary microalbumin were measured every four weeks, and the urinary albumin excretion rate (UAER) was calculated. After 24 weeks, kidney tissues were collected for transcriptome sequencing, and the main functions of these genes were determined via functional enrichment analysis.Results: Compared with the DKD model group, the medium-dose and high-dose TCM groups had significantly decreased levels of SCr, BUN, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and UAER (all p< 0.05). We identified 42 genes that potentially functioned in this therapeutic response, and the greatest effect on gene expression was in the high-dose TCM group. We also performed functional enrichment analysis to explore the potential mechanisms of action of these different genes.Conclusion: A high-dose of the Astragalus-rhubarb-saffron TCM provided the best prevention of DKD. Analysis of the kidney transcriptome suggested that this TCM mixture may prevent DKD by altering immune responses and oxygen delivery by hemoglobin.Keywords: diabetic kidney disease (DKD), mixture of astragalus, rhubarb, saffron, transcriptome sequencing, db/db mice

Nengwen Wu,&ast; Xiaoqing Shen,&ast; Jianwei Li, Miaolian Chen, Guishen Wu, Haiming Niu, Hongkai Liang, Ting Yang Department of Critical Care Medicine, Zhongshan People’s Hospital, Zhongshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongkai Liang; Ting Yang, Department of Critical Care Medicine, Zhongshan People’s Hospital, Zhongshan, 528400, People’s Republic of China, Email 1019978382@qq.com; 53103334@qq.comAbstract: Septic cardiomyopathy (SCM) is often associated with bacterial infections but also occurs with infections with viruses such as influenza and spirochetes, including syphilis. However, there has been no systematic investigation into whether Aspergillus infections can cause septic cardiomyopathy. We report on such a case for the first time in a patient without immunodeficiency. Therefore, clinicians should be concerned with septic cardiomyopathy caused by some atypical or rare pathogens when admitting such patients.Keywords: septic cardiomyopathy, aspergillus, extracorporeal membrane oxygenation, metagenomic next-generation sequencing

Yuping Ding,1,2 Guiqiang Wang,3,4 Quanjun Deng,1,2 Mei Yang,1,2 Jinghua Li,5 Zuoyu Wang,1,2 Haiyan Niu,1,2 Shihai Xia1,2 1Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, 300162, People’s Republic of China; 2Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, Tianjin, 300162, People’s Republic of China; 3Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, People’s Republic of China; 4Department of Infectious Diseases, Peking University International Hospital, Beijing, People’s Republic of China; 5Department of Endocrinology and Hematology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, 300162, People’s Republic of ChinaCorrespondence: Shihai Xia, Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, 220, Chenglin Road, Dongli, Tianjin, 300162, People’s Republic of China, Email xshhcx@sina.comBackground: Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are closely related conditions.Aim: This study investigated a group of individuals with NAFLD to evaluate if liver fibrosis, identified by FibroScan, correlated with T2DM.Methods: 154 NAFLD patients obtained FibroScan, liver ultrasonography (US), and a thorough assessment of clinical implications and chemical biomarkers.Results: In comparison to the NAFLD without T2DM group, the hemoglobin A1c(HBA1c)(mmol/mol%), homeostasis model of assessment for insulin resistance index (HOMA-IR), gamma-glutamyl transferase (GGT), fibrosis indices, and liver stiffness measurement (LSM) values were all considerably higher in the NAFLD with T2DM group. Patients with NAFLD and T2DM had considerably lower serum uric acid(SUA) levels than those with NAFLD alone.Those with severe fibrosis (79.3%, 23/29) in the NAFLD group showed a greater frequency of T2DM than those with mild fibrosis (45.6%, 21/46) or no fibrosis (27.85%, 22/79) (P=0.000). LSM value and elements of the metabolic syndrome (MetS) were independent risk factors for incident T2DM among NAFLD patients (OR=1.466, 95% CI [1.139-1.888], P=0.003; and OR=0.273, 95% CI [0.081-0.916], P=0.036).Conclusion: FibroScan can identify significant fibrosis, which is independently linked to a higher prevalence of T2DM. As a result, it is crucial to make use of this technology to predict T2DM in NAFLD patients.Keywords: liver stiffness measurement, NAFLD, T2DM, risk factors, early warning

Yuping Ding,1,2 Quanjun Deng,1,2 Mei Yang,1,2 Haiyan Niu,1,2 Zuoyu Wang,1,2 Shihai Xia1,2 1Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force, Tianjin, 300162, People’s Republic of China; 2Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, Tianjin, 300162, People’s Republic of ChinaCorrespondence: Shihai Xia, Department of Gastroenterology and Hepatology, Characteristic Medical Center of the Chinese People’s Armed Police Force; Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis & Treatment, 220, Chenglin Road, Dongli, Tianjin, 300162, People’s Republic of China, Email xshhcx@sina.comAbstract: Obesity,and metabolic dysfunction-associated fatty liver disease (MAFLD) have reached epidemic proportions globally. Obesity and MAFLD frequently coexist and act synergistically to increase the risk of adverse clinical outcomes (both hepatic and extrahepatic). Type 2 diabetes mellitus (T2DM) is the most important risk factor for rapid progression of steatohepatitis and advanced fibrosis. Conversely, the later stages of MAFLD are associated with an increased risk of T2DM incident. According to the proposed criteria, MAFLD is diagnosed in patients with liver steatosis and in at least one in three: overweight or obese, T2DM, or signs of metabolic dysregulation if they are of normal weight. However, the clinical classification and correlation between obesity and MAFLD is more complex than expected. In addition, treatment for obesity and MAFLD are associated with a reduced risk of T2DM, suggesting that liver-based treatments could reduce the risk of developing T2DM. This review describes the clinical classification of obesity and MAFLD, discusses the clinical features of various types of obesity and MAFLD, emphasizes the role of visceral obesity and insulin resistance (IR) in the development of MAFLD,and summarizes the existing treatments for obesity and MAFLD that reduce the risk of developing T2DM.Keywords: obesity, metabolic dysfunction-associated fatty liver disease, phenotypes, type 2 diabetes mellitus, treatment, weight loss

Lu Han,1,2,&ast; Yaping Zhang,2– 4,&ast; Li Li,2,&ast; Qun Zhang,2 Zhihao Liu,2,3 Haiqing Niu,1,2 Jing Hu,2 Zhou Ding,2 Xiao Shi,2 Xiaoping Qian1,2 1Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China; 3Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, People’s Republic of China; 4Department of Pathology, The First People’s Hospital of Yangzhou, Yangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoping Qian, Department of Oncology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-13951743162, Fax +86-25-68182342, Email xiaopingqian@nju.edu.cnPurpose: Exploring the expression and prognosis of mismatch repair proteins and PD-L1 in colorectal cancer.Patients and Methods: A total of 272 patients with surgically resected CRC were enrolled in the study from January 2018 to May 2022 at Nanjing Drum Tower Hospital (The Affiliated Hospital of Nanjing University Medical School). Surgically resected samples were collected from patients along with general, clinicopathological, and imaging data for each patient. Immunohistochemistry (IHC) was used to detect expression of MSH2, MSH6, MLH1, and PMS2 proteins in tumor tissue. X-squared (X2) testing was performed to investigate the correlation between expression of MMR proteins and PD-L1 in CRC tumor tissues and clinicopathological characteristics. Correlation analysis was also used to compare the deletion of four MMR proteins in CRC tumor tissues. A survival curve and Log rank test were used to investigate the relationship between the expression of MMR proteins and PD-L1 with regard to CRC patient prognosis and survival.Results: MMR protein expression deletion was correlated with tumor location, the degree of tissue differentiation, and TNM stage (P< 0.05). PD-L1 expression was correlated with TNM stage (P

Yu Yu,&ast; Ligang Ding,&ast; Yu Deng,&ast; Hao Huang, Sijing Cheng, Chi Cai, Min Gu, Xuhua Chen, Xiaohui Ning, Hongxia Niu, Wei Hua Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Hua, Cardiac Arrhythmia Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China, Email drhuaweifw@sina.comBackground: The joint association of atrial fibrillation (AF) and statin therapy with adverse outcomes in heart failure (HF) patients with cardiac resynchronization therapy (CRT) has not been fully investigated so far. The purpose of this study was to explore the independent and joint association of AF and statin therapy with adverse outcomes.Methods: Study patients were divided into four groups according to AF status and statin use: Non-AF/Statin, Non-AF/Non-Statin, AF/Statin, and AF/Non-Statin. Multivariate Cox proportional hazards regression models were used to evaluate the independent and joint association of AF and statin therapy with poor prognosis.Results: Among 685 CRT patients, there were 180 deaths (26.5%) and 198 HF hospitalization (29.6%) during the 14 years of follow-up. AF was associated with a 46% increased risk of all-cause mortality (HR, 1.46; 95% CI, 1.03– 2.07) and a 59% increased risk of HF hospitalization (HR, 1.59; 95% CI, 1.16– 2.20) than those without AF. However, statin therapy failed to improve the prognosis. In the joint analysis, compared with the Non-AF/Statin group, the AF/Non-Statin group suffered a higher risk of all-cause mortality (HR, 1.75; 95% CI, 1.04– 2.93) and HF hospitalization (HR, 1.76; 95% CI, 1.08– 2.86). Furthermore, adding AF to the traditional risk factor model significantly improved the predictive value for death (C-statistic from 0.654 to 0.691) and HF (C-statistic from 0.613 to 0.675).Conclusion: AF was associated with poor prognosis, and statin use failed to improve the prognosis. Further analysis showed that statin therapy is ineffective in improving prognosis and fails to attenuate the adverse effects of AF.Graphical Abstract: Keywords: atrial fibrillation, cardiac resynchronization therapy, joint association, prognosis, statin therapy

Qin Zhao,1,&ast; Jing Shi,1,&ast; Siyuan Chen,1 Doudou Hao,1 Sha Wan,1 Haomeng Niu,2 Yongqun Zhang1 1Biobank, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region (Hospital.C.T.), Chengdu, Sichuan Povince, People’s Republic of China; 2Medical School, Tibet University, Lhasa, Tibet Autonomous Region, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongqun Zhang, Biobank, Hospital of Chengdu Office of People’s Government of Tibetan Autonomous Region (Hospital.C.T.), No. 20 Ximianqiao Road, Chengdu, Sichuan Povince, 610041, People’s Republic of China, Tel +86-28-85593218, Fax +86 28-85558071, Email yongqun_zhang@163.comPurpose: The purpose of this study was to investigate the regulatory effect of salidroside on the intestinal flora of mice with type 2 diabetes (T2DM) and its protective effect in the body.Patients and Methods: We acclimated 8-week-old mice for 7 days, divided them into 4 groups, and continued dosing for 8 weeks. We recorded weekly blood glucose levels and body weight for each mouse. After the completion of the feeding cycle, the 16S rRNA of the intestinal flora in the mice was sequenced, and the insulin and C-peptide levels in each group of mice were measured. Four samples were taken from each group for liver and kidney section staining.Results: Our results showed that gut microbiota diversity and function were significantly different between the diabetic mice and healthy mice and that insulin levels, body weight, and blood glucose levels could significantly influence gut microbiota changes at the genus level. The gut microbiota diversity and function of db/db mice were also altered after salidroside administration. Salidroside could attenuate inflammatory damage, lipid accumulation and inflammatory changes in the diabetic liver, as well as diabetic kidney damage. Candidatus arthromitus and Odoribacter are important species of the microbiota during diabetes and may serve as potential therapeutic targets.Conclusion: Our investigation of the associated pathological conditions and fecal microbiota in db/db mice provides new insights into the pathogenesis of T2DM and provides implications for the diagnosis and treatment of T2DM.Keywords: salidroside, db/db mice, T2DM, intestinal microbiota

Anbing Zhang,1,&ast; Xiuqiong Xia,1,&ast; Xiaoling Yuan,1 Yuxia Liu,2 Haiming Niu,2 Yinying Zhang,1 Jianping Liang1 1Department of Respiratory and Critical Care Medicine, Zhongshan People’s Hospital, Zhongshan, People’s Republic of China; 2Department of Intensive Care Unit, Zhongshan People’s Hospital, Zhongshan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianping Liang, Department of Respiratory and Critical Care Medicine, Zhongshan People’s Hospital, No. 2, Sunwen East Road, Zhongshan, 528400, People’s Republic of China, Tel +86-1587-602-6693, Fax +86-760-8988-0256, Email ljpzhongshan@163.comPurpose: To explore the clinical characteristics, diagnosis, and treatment of severe Chlamydia psittaci pneumonia complicated by rhabdomyolysis and to improve the success rate of treatment.Patients and Methods: The clinical characteristics, diagnosis, treatment, and outcomes of four patients with severe C. psittaci pneumonia complicated by rhabdomyolysis diagnosed by metagenomic next-generation sequencing (mNGS) in our hospital were analyzed retrospectively.Results: All four patients were male, aged 46– 64 years, and all had a history of bird contact. All patients had fever, fatigue, tea-colored urine, myalgia, and two patients were unable to walk. C. psittaci DNA was found by mNGS of the bronchoalveolar lavage fluid of all four patients. Their creatine kinase was > 1000 U/L, and myoglobin, C-reactive protein, procalcitonin, and brain natriuretic peptide were significantly increased. The McMahon score of three patients was > 6 points, of whom one patient suffered from acute kidney injury; he was treated with continuous renal replacement therapy and eventually died. After diagnosis, three patients were treated with doxycycline and quinolones and were discharged after recovery.Conclusion: Psittacosis complicated by rhabdomyolysis is characterized by fever, fatigue, myalgia, and tea-colored urine, with significant increases in creatine kinase and myoglobin. The McMahon score should be applied early to assess the risk of acute kidney injury, and renal replacement therapy and renal protection therapy should be initiated in the early stage. Among severely ill patients, early use of empirical antibiotics, including quinolones, may improve the prognosis.Keywords: Chlamydia psittaci, severe pneumonia, rhabdomyolysis, metagenomic next-generation sequencing

© 2018. The American Astronomical Society. All rights reserved. The Kepler-9 system harbors three known transiting planets. The system holds significant interest for several reasons. First, the outer two planets exhibit a period ratio that is close to a 2:1 orbital commensurability, with attendant dynamical consequences. Second, both planets lie in the planetary mass "desert" that is generally associated with the rapid gas agglomeration phase of the core accretion process. Third, there exist attractive prospects for accurately measuring both the sky-projected stellar spin-orbit angles as well as the mutual orbital inclination between the planets in the system. Following the original Kepler detection announcement in 2010, the initially reported orbital ephemerides for Kepler-9 b and c have degraded significantly, due to the limited time base-line of observations on which the discovery of the system rested. Here, we report new ground-based photometric observations and extensive dynamical modeling of the system. These efforts allow us to photometrically recover the transit of Kepler-9 b and thereby greatly improve the predictions for upcoming transit mid-times. Accurate ephemerides of this system are important in order to confidently schedule follow-up observations of this system, for both in-transit Doppler measurements as well as for atmospheric transmission spectra taken during transit.

Hua Niu,1 Yinghua Zhou2 1Department of Ultrasound Medicine, Xidian Group Hospital, Xi’an, 710077, People’s Republic of China; 2Department of Ultrasound Medicine, Xi’an Gaoxin Hospital, Xi’an, 710075, People’s Republic of ChinaCorrespondence: Yinghua ZhouDepartment of Ultrasound Medicine, Xi’an Gaoxin Hospital, No. 16, Unity South Road, Xi’an, 710075, Shaanxi, People’s Republic of ChinaTel +86 18991925530Email mswg@tom.comBackground: The aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio has been demonstrated to be associated with insulin resistance and metabolic syndrome. However, few studies have directly explored the association between the AST/ALT ratio and the incidence of type 2 diabetes mellitus (T2DM). As such, the present study aimed to investigate the relationship between the AST/ALT ratio and incident T2DM during follow-up in a population-based cohort.Methods: This retrospective cohort analysis included 15,464 Japanese males and females without DM at baseline between 2004 and 2015. The association between AST/ALT ratio and T2DM was retrospectively examined using the Cox proportional hazard model after adjusting for multiple potential confounders.Results: After follow-up, 373 (2.41%) patients developed T2DM. A nonlinear relationship between the AST/ALT ratio and T2DM was observed after adjusting for potential confounders. The risk for developing T2DM decreased with AST/ALT ratio up to a threshold of 0.93 (adjusted hazard ratio [HR] 0.14 [95% confidence interval (CI) = 0.02– 0.90; P = 0.0385]). An AST/ALT ratio > 0.93 was not associated with the risk for developing T2DM (adjusted HR = 0.67, 95% CI = 0.17– 2.65; P = 0.5718).Conclusion: The AST/ALT ratio was associated with a lower incidence of T2DM in a nonlinear pattern. The threshold AST/ALT ratio for developing T2DM was 0.93. AST/ALT levels were inversely correlated with the occurrence of T2DM when AST/ALT ratio ≤ 0.93.Keywords: AST, ALT, diabetes mellitus, follow-up, nonlinear association

Panghua Ding,1,&ast; Jiajing Liu,2,&ast; Qiuyi Li,2 Qiongqiong Lu,3 Junxiang Li,3 Rui Shi,3 Lei Shi,2 Tangyou Mao,3 Dongyu Ge,4 HaiJun Niu,5 Guiying Peng,2 Zhibin Wang3 1Department of Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 2Department of Immunology and Microbiology, School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 3Department of Gastroenterology, Dong Fang Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Experimental Teaching Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Anhui Joyfar Pharmaceutical Research Institute Co. Ltd, Hefei, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guiying Peng; Zhibin Wang Email penggy@bucm.edu.cn; wangsanger@126.comBackground: Hudi enteric-coated capsule (HDC) is a Chinese medicine prescribed to treat ulcerative colitis (UC). However, its anti-inflammatory active ingredients and mechanisms remain unknown. This study aimed to investigate the active components of HDC and explore its potential mechanisms against UC by integrating network pharmacology and experimental verification.Methods: A DSS-induced colitis murine model was established to validate the efficacy of HDC by detecting disease activity index (DAI) and histopathological changes. Network pharmacological analysis was performed to identify the active compounds and core targets of HDC for the treatment of UC. The main compounds in HDC were identified by high-performance liquid chromatography. The relative expressions of HDC’s core targets were also determined in vivo. Finally, molecular docking was applied to model the interaction between HDC and target proteins.Results: In an in vivo experiment, HDC, especially the middle-dose HDC, effectively reduced clinical symptoms of UC, including weight loss, bloody stool, and colon shortening. Besides, the severity of colitis was considerably suppressed by HDC as evidenced by reduced DAI scores. A total of 118 active compounds and 69 candidate targets from HDC closely related to UC progression were identified via network pharmacology. Enrichment analysis revealed that the key targets of HDC correlated with the expressions of PTGS2, TNF-α, IL-6, and IL-1β. Meanwhile, these cytokines were enriched in various biological processes through the IL-17/JAK2/STAT3 signaling pathway. The middle-dose HDC contributed more to ameliorating DSS-induced colitis through this signaling pathway than other dosages. Nine components binding to JAK2, STAT3, IL-17 and IL-6 were identified by molecular docking, confirming again the inhibition effects of HDC on the IL-17/JAK2/STAT3 signaling pathway.Conclusion: The HDC treatment, particularly the middle-dose, exerted an anti-UC effect in a multi-component, multi-target, and multi-mechanism manner, especially inhibiting the IL-17/JAK2/STAT3 signaling pathway to downregulate the secretion of proinflammatory cytokines.Keywords: Hudi enteric-coated capsule, ulcerative colitis, network pharmacology, IL-17/JAK2/STAT3 pathway

Lingyan You,1– 3 Hongtao Niu,1,2 Ke Huang,1,2 Fen Dong,1,2,4 Ting Yang,1,2 Chen Wang1,2,5 1Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 3Department of Pulmonary and Critical Care Medicine, Quanzhou First Hospital Affiliated Fujian Medical University, Quanzhou, Fujian, People’s Republic of China; 4Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 5Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Ting YangDepartment of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No. 2, East Yinghua Road, Chaoyang District, Beijing, 100029, People’s Republic of ChinaEmail zryyyangting@163.comChen WangChinese Academy of Medical Sciences and Peking Union Medical College, 9 Dongdan 3rd Alley, Dong Dan, Dongcheng, Beijing, 100730, People’s Republic of ChinaEmail cyh-birm@263.netPurpose: To identify clinical features and outcomes associated with pulmonary heart disease among patients with chronic obstructive pulmonary disease exacerbation (COPD), which may help reduce economic burden accrued over hospital stay and shorten length of stay (LOS).Patients and Methods: Totally, 4386 patients with acute exacerbation of COPD (AECOPD) classified into pulmonary heart disease (PHD) group and non-pulmonary heart disease group, were included from the ACURE registry, a prospective multicenter patient registry study. Clinical features and outcomes were compared between groups.Results: PHD patients had a more severe profile, including having higher scores of COPD assessment test and modified British Medical Research Council, worse lung function, more patients hospitalized more than once in the past year due to acute exacerbation of COPD, and more comorbidities. Furthermore, drug cost was higher and length of stay was longer in AECOPD patients with PHD.Conclusion: AECOPD patients with PHD had a more severe profile and worse clinical outcomes, including higher drug cost and longer LOS. PHD is an independent risk factor of drug cost and LOS. Complicated with PHD in COPD/AECOPD patients with PHD means heavier disease burden and worse prognosis. It merits further study to focus on PHD management in COPD/AECOPD patients.Keywords: chronic obstructive pulmonary disease, exacerbation, pulmonary heart disease, cost, length of stay

Lu-feng Shi,1 Qian Zhang,1 Xiao-ying Shou,2 Huan-jiang Niu1 1Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, People’s Republic of China; 2Department of Nursing, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, Zhejiang, People’s Republic of ChinaCorrespondence: Huan-jiang NiuDepartment of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 368 Xiasha Road, Hangzhou, Zhejiang, 310016, People’s Republic of ChinaTel +86 13606618811Email 3203022@zju.edu.cnObjective: This study aimed to reveal the potential function of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and emphasized its importance in brain low-grade glioma (LGG).Methods: We firstly explored the differential expression of MTHFD2 mRNA in LGG and normal tissues, followed by correlation analysis of MTHFD2 mRNA expression with patient’s clinical characteristics. MTHFD2 protein expression in LGG and subcellular location were also evaluated. Then, survival analysis was performed to reveal the influence of MTHFD2 expression on the overall survival of patients, and Cox regression analysis was applied to predict the prognostic factor for overall survival of LGG. Finally, we performed functional analysis to reveal potential MTHFD2-associated pathways involved in LGG.Results: We found that MTHFD2 was highly expressed in LGG patients (P< 0.05), and MTHFD2 expression was related to patient’s age and IDH mutation status (all P< 0.05). MTHFD2 protein was mainly localized to the mitochondria. Survival analysis showed that high expression of MTHFD2 desirably improved the prognosis of LGG patients (P< 0.001), especially for those patients with age ≥ 45 years (P< 0.05). But independent prognostic role of MTHFD2 in LGG was not observed. Pathway enrichment analysis indicated that MTHFD2 high expression significantly and positively participated in the pathway of one carbon pool by folate (all P< 0.05).Conclusion: High expression of MTHFD2 was observed in LGG, which was favorable for the overall survival of LGG patients. Our results assumed that MTHFD2 high expression might play a pivotal role in LGG through positively regulating pathway of one carbon pool by folate.Keywords: MTHFD2, low-grade glioma, high expression, prognosis

Iron-based waterworks sludge was activated using 0.5-3 mol/L H2SO4 acid to obtain the acid-activated iron-based waterworks sludge (AAIBWS). The sludge treated with 1 mol/L H2SO4 acid was best for phosphorus adsorption and used to carry out batch phosphorus adsorption experiments. The influencing factors including solution pH, contact time and reaction temperature were investigated. The results indicated that the acid environment was favourable for P adsorption. The phosphorus adsorption increased with the rising reaction time and temperature. The pseudo-second-order equation was best to describe the adsorption process among the three kinetic models. The Langmuir isotherm provided a better fit of the data than the Freundlich model. Thermodynamic parameters showed that the phosphorus adsorption on AAIBWS-1 had a spontaneous and endothermic nature.

Changcong Wang,1 Yangming Qu,1 Huikun Niu,1 Yingan Pan,1 Yinghua He,2 Jianwei Liu,2 Nan Yao,1 Han Wang,1 Yinpei Guo,1 Yang Pan,2,3 Bo Li1 1Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin, 130021, People’s Republic of China; 2Jilin Provincial Center for Disease Control and Prevention, Changchun, Jilin, 130062, People’s Republic of China; 3Department of Occupational and Environmental Health, School of Public Health, Jilin University, Changchun, 130021, People’s Republic of ChinaCorrespondence: Bo LiDepartment of Epidemiology and Biostatistics, Jilin University School of Public Health, 1163 Xinmin Street, Changchun, Jilin, 130021, People’s Republic of ChinaTel/Fax +86 43185619451Email li_bo@jlu.edu.cnYang PanJilin Provincial Center for Disease Control and Prevention, Changchun, Jilin, 130062, People’s Republic of ChinaTel +86 18844504063Email 18844504063@163.comPurpose: Respiratory disease is a major and increasingly global epidemic that has a great impact on humans, especially children. The purpose of this study was to identify environmental risk factors for respiratory diseases and pulmonary function in children.Patients and Methods: A population-based, cross-sectional survey of respiratory diseases and environmental risk factors was conducted in Jilin Province, China. Complete questionnaire information was available for 2419 children, while adequate pulmonary function data were available for a subgroup of 627 children.Results: Our study found that environmental risk factors for respiratory health in children were mainly concentrated indoors. After adjusting for demographic factors, insecticide exposure and passive smoking were risk factors for respiratory disease and industrial pollutant sources, insecticide exposure and the use of a fume exhauster may be independent risk factors for recurrent respiratory infections. The main fuel for cooking in the winter and passive smoking were the main influencing factors of pulmonary function indicators.Conclusion: The primary risk factors differ in different respiratory diseases. Passive smoking remains a critical adverse factor for respiratory illness and pulmonary function in children, and it is important to reduce children’s exposure to passive smoking to increase pulmonary health. Insecticide exposure may be a neglected environmental risk factor, and further investigations are still needed to explore the relationship and mechanisms between insecticide exposure and children’s respiratory health.Keywords: respiratory diseases, lung function, environmental risk factors

Jingyu Yang, Heng Niu, Xin Chen Department of Breast Thyroid Surgery, The First People’s Hospital of Yunnan Province, Kunming, 650032, People’s Republic of ChinaCorrespondence: Jingyu YangDepartment of Breast Thyroid Surgery, The First People’s Hospital of Yunnan Province, No. 157 Jinbi Road, Kunming, 650032, People’s Republic of ChinaEmail yjy19730719@163.comBackground: Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer with a high mortality rate. Recently, long non-coding RNAs (lncRNAs) are confirmed to modulate the progression of assorted cancers, including TNBC. However, the functions of lncRNA HNF1 homeobox A antisense RNA 1 (HNF1A-AS1) in TNBC are still unclear.Aim: We aimed to investigate the function and mechanism of HNF1A-AS1 in TNBC.Methods: The expression of genes in TNBC cells was tested by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. In vitro loss-of-function assays and in vivo xenograft experiments were conducted for evaluating the impact of HNF1A-AS1 on TNBC progression. RNA pull-down, luciferase reporter and RNA immunoprecipitation (RIP) assays were utilized for assessing the correlations between molecules.Results: We discovered that HNF1A-AS1 was highly expressed in TNBC tissues and cells. Knockdown of HNF1A-AS1 restrained cell proliferation but accelerated cell apoptosis. Besides, GATA-binding protein 1 (GATA1) activated HNF1A-AS1 transcription in TNBC. MicroRNA-32-5p (miR-32-5p) was slowly expressed in TNBC cells and sponged by HNF1A-AS1, and its overexpression hinders TNBC cell growth. Ring finger protein 38 (RNF38) was verified as the target of miR-32-5p, and HNF1A-AS1 was a competing endogenous RNA (ceRNA) of RNF38 through sponging miR-32-5p. Rescue experiments indicated that upregulation of RNF38 reversed the inhibited impacts of silencing HNF1A-AS1 on TNBC cell growth.Conclusion: GATA1-activated HNF1A-AS1 facilitated TNBC progression via miR-32-5p/RNF38 axis. The findings may provide new roads for developing targeted therapies of TNBC.Keywords: HNF1A-AS1, miR-32-5p, RNF38, triple-negative breast cancer

Chen Liang,1 Xihua Mao,1 Hongtao Niu,2– 4 Ke Huang,2– 4 Fen Dong,2– 5 Yahong Chen,6 Kewu Huang,7,8 Qingyuan Zhan,2– 4 Yin Huang,1 Yaowen Zhang,1 Ting Yang,2– 4 Chen Wang2– 4,9 1Chinese Alliance for Respiratory Diseases in Primary Care, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 4Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, People’s Republic of China; 5Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 6Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 7Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Beijing, People’s Republic of China; 8Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China; 9Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Ting YangDepartment of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, No. 2, East Yinghua Road, Chaoyang District, Beijing, 100029, People’s Republic of ChinaEmail zryyyangting@163.comChen WangChinese Academy of Medical Sciences and Peking Union Medical College, 9 Dongdan 3rd Alley, Dong Dan, Dongcheng, Beijing, 100730, People’s Republic of ChinaEmail cyh-birm@263.netPurpose: The study aimed to give a comprehensive overview of characteristics and evaluate in-hospital clinical outcomes among hospitalized acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients in China using data from the AECOPD inpatient registry (ACURE).Patients and Methods: The ACURE is an ongoing, national, multicenter, observational registry. Participants enrolled during phase I stage (1st September 2017 to 25th February 2020) of ACURE with confirmed AECOPD diagnoses were studied. Descriptive analyses were conducted to describe features and occurrences of in-hospital clinical outcomes of AECOPD inpatients in real-world China.Results: A total of 5334 AECOPD inpatients from 163 sites in 28 provinces or province-level municipalities were included. Among all participants, 78.8% were males and the median age was 69.0 [interquartile range (IQR): 63.0– 76.0] years. The proportions of current and former smokers were 23.6% and 44.2%, respectively. The median age at COPD diagnosis was 64.0 (IQR: 57.0– 71.0) years and 88.7% participants demonstrated at least one comorbidity. During stable period, only 56.9% subjects received pharmacological therapies and the influenza vaccination rate was 2.9%. During hospitalization, 99.5% subjects received pharmacological treatments and antibiotics were prescribed to 90.9% participants. The all-cause in-hospital mortality was 0.1% and no significant difference was found across hospital categories.Conclusion: Clinical features of Chinese AECOPD inpatients were different from those of other populations. In real-world China, the clinical management during stable period was unsatisfied, whereas therapy during hospitalization was effective regarding in-hospital clinical outcomes regardless of hospital category.Keywords: registries, demography, therapeutics, disease management, hospital mortality, public health

Ming Zhao,1,* Mingxin Zhang,2,* Yonghua Wang,2 Xuecheng Yang,2 Xue Teng,2 Guangdi Chu,2,3 Xinsheng Wang,2 Haitao Niu2 1Department of Urology, Qingdao 8th People’s Hospital, Qingdao, People’s Republic of China; 2Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 3Department of Clinical Medicine, Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haitao Niu; Xinsheng Wang Email niuht0532@126.com; Wangxs0532@163.comObjective: This study investigated the prognostic value of the preoperative albumin alkaline phosphatase ratio (AAPR) in patients with muscle-invasive bladder cancer after radical cystectomy.Materials and Methods: We performed a retrospective, single-center cohort study among patients with muscle-invasive bladder cancer who underwent radical cystectomy and urinary diversion at the Department of Urology Surgery of the Affiliated Hospital of Qingdao University from 2007 to 2015. Cox proportional hazards regression was used to evaluate the relationship between preoperative AAPR and outcomes which include OS and CSS and RFS. Survival analysis was conducted using the Kaplan–Meier method and the log rank test.Results: In total, 174 patients were followed up for 1– 125 months, with a median follow-up of 30 months, 93 survived and 81 patients died. The median serum AAPR level in all patients was 0.62 (range: 0.12– 1.67). In multivariate analysis, the preoperative AAPR showed to be associated with overall survival (OS: HR 0.22,95% CI 0.06 to 0.82, P=0.024), cancer-specific survival (CSS: HR 0.12,95% CI 0.02 to 0.63, P=0.013) and recurrence-free survival (RFS: HR 0.15,95% CI 0.03 to 0.82, P=0.029) after adjustment for potential confounders. Kaplan–Meier analysis showed that patients with low AAPR tertiles had shorter OS, CSS and RFS than patients with high AAPR tertiles (OS: P< 0.001, CSS: P< 0.001, RFS: P< 0.001). The relationship between AARP and OS, CSS and RFS was linear.Conclusion: Preoperative AAPR may be a potentially valuable prognostic marker in patients who underwent radical cystectomy for muscle-invasive bladder cancer.Keywords: albumin-to-alkaline phosphatase ratio, AAPR, muscle-invasive bladder cancer, radical cystectomy, prognosis

Zeliang Wei,1,2 Haibo Wang,3 Guang Xin,1 Zhi Zeng,1 Shiyi Li,1 Yue Ming,1 Xiaoyu Zhang,1 Zhihua Xing,1 Li Li,2 Youping Li,1 Boli Zhang,1,4 Junhua Zhang,4 Hai Niu,1,5 Wen Huang1 1Laboratory of Ethnopharmacology, West China Medical School, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Dermatology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Textile Institute, College of Light Industry, Textile and Food Engineering, Sichuan University, Chengdu, People’s Republic of China; 4Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 5College of Mathematics, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Wen Huang; Hai Niu Email huangwen@scu.edu.cn; niuhai@scu.edu.cnBackground: The metastasis, one of the biggest barriers in cancer therapy, is the leading cause of tumor deterioration and recurrence. The anti.-metastasis has been considered as a feasible strategy for clinical cancer management. It is well known that diosgenin could inhibit tumor metastasis and doxorubicin (DOX) could induce tumor apoptosis. However, their efficient delivery remains challenging.Purpose: To address these issues, a novel pH-sensitive polymer-prodrug based on diosgenin nanoparticles (NPs) platform was developed to enhance the efficiency of DOX delivery (DOX/NPs) for synergistic therapy of cutaneous melanoma, the most lethal form of skin cancer with high malignancy, early metastasis and high mortality.Methods and Results: The inhibitory effect of DOX/NPs on tumor proliferation and migration was superior to that of NPs or free DOX. What is more, DOX/NPs could combine mitochondria-associated metastasis and apoptosis with unique internalization pathway of carrier to fight tumors. In addition, biodistribution experiments proved that DOX/NPs could efficiently accumulate in tumor sites through enhancing permeation and retention (EPR) effect compared with free DOX. Importantly, the data from in vivo experiment revealed that DOX/NPs without heart toxicity significantly inhibited tumor metastasis by exerting synergistic therapeutic effect, and reduced tumor volume and weight by inducing apoptosis.Conclusion: The nanocarrier DOX/NPs with satisfying pharmaceutical characteristics based on the establishment of two different functional agents is a promising strategy for synergistically enhancing effects of cancer therapy.Keywords: anti-metastasis, antitumor, self-assembly, codelivery, doxorubicin

Cunbo Jia,1,* Chunyu Zhang,1,* Fang Fang,1,* Ke Huang,2 Fen Dong,3 Xiaoying Gu,3 Hongtao Niu,2 Shan Li,4 Chen Wang,2,5 Ting Yang2 1Department of Health Reform and Development, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, People’s Republic of China; 3Data Platform, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 4School of Management, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 5Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this paperCorrespondence: Ting YangDepartment of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Science, Chaoyang District, Beijing 100029, People’s Republic of ChinaTel +8610-84205907Email dryangting@qq.comBackground: Chronic obstructive pulmonary disease (COPD) is prevalent and poses a heavy burden worldwide. However, patients know little about COPD, and primary health care providers have poor therapy capability in China. Enjoying Breathing Program aims to establish a new comprehensive COPD patient management system, including early detection, standardized therapy, and follow-up in China. The goal of the study is to 1) describe the intervention for physicians and patients and 2) to assess the effectiveness of this program.Methods: It is the first nationwide trial involving all levels of health care institutions from primary health care institutions to tertiary hospitals. It includes a series of structured but individualized intervention for both health care providers and COPD patients. Primary health care providers from pilot hospitals will take both online and face-to-face courses, including the procedure of COPD patients’ management and prevention, diagnosis and treatment. Once the patients are diagnosed with COPD, they will undertake standard therapy and self-management education program, perform rehabilitation exercises, and be followed up by primary health care providers every 3 months. The primary outcome will be exacerbation-related hospital/emergency admission and the change of patients’ awareness and primary health care providers’ knowledge of COPD within 36 months. Secondary outcome will include the change of pulmonary function test, structured COPD patients’ management, two-way referral, and standardized therapy.Conclusion: A comprehensive COPD patient management model to promote the standardized therapy will be established; this will improve COPD patients’ awareness and health quality.Trial Registration Number: This study has been registered at www.ClinicalTrials.gov (registration identifier: NCT04318912).Keywords: protocol, national prospective trial, COPD management

Ruirui Duan,1– 4 Hongtao Niu,2– 4 Tao Yu,2– 5 Han Cui,2– 4,6 Ting Yang,1– 5 Ke Hao,7 Chen Wang1– 4,6 1Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3National Clinical Research Center for Respiratory Diseases, Beijing, People’s Republic of China; 4Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 6Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 7Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: Chen WangPeking University China-Japan Friendship School of Clinical Medicine, No. 2, East Yinghua Road, Chaoyang District, Beijing 100029, People’s Republic of ChinaTel/ Fax +86-01-8420 6276Email cyh-birm@263.netPurpose: Circular RNAs (circRNAs) regulate other RNA transcripts by competing for shared microRNAs, which play roles in the pathogenesis of many diseases, including chronic obstructive pulmonary disease (COPD). However, the role of circRNAs in COPD remains unknown. This study aimed to investigate the expression profile and the role of circRNAs in COPD.Patients and Methods: Twenty-one COPD patients and twenty-one normal controls were recruited. Total RNAs were collected from peripheral blood mononuclear cells (PBMCs) of each participant. CircRNAs and protein-coding mRNAs were profiled by microarray and systematically compared between patients with COPD and control subjects. The top differentially expressed circRNAs and mRNAs were validated by quantitative real-time PCR (RT-qPCR). Functional analysis identified pathways relevant to the pathogenesis of COPD. Next, the circRNA target pathway network, the circRNA-miRNA-mRNA network (ceRNA network) and functional ceRNA regulatory modules were constructed.Results: In total, 2132 circRNAs and 2734 protein-coding mRNAs were differentially expressed (|fold change| > 1.5 and P-value < 0.05) in COPD patients. Six out of nine selected RNAs were confirmed by RT-qPCR validation. Our functional analysis suggested that immune imbalances and inflammatory responses play roles in the pathogenesis of COPD. The ceRNA network highlighted the differentially expressed circRNAs and their related miRNAs and mRNAs in COPD. In the circRNA target pathway network and functional ceRNA regulatory modules, hsa_circRNA_0008672 appeared in the top three KEGG pathways (NOD-like receptor signaling pathway, natural killer cell mediated cytotoxicity and Th17 cell differentiation) and may act as the miRNA sponge regulating the hsa_circRNA_0008672/miR-1265/MAPK1 axis.Conclusion: Our findings demonstrate critical roles of the circRNAs in COPD molecular etiology. The data support a plausible mechanism that circRNAs may be involved in the development of COPD by affecting the immune balance. Moreover, the hsa_circRNA_0008672/miR-1265/MAPK1 axis may contribute to the pathogenesis of COPD, warranting further investigation.Keywords: circular RNA, competing endogenous RNAs, chronic obstructive pulmonary disease, expression profile, co-expression network

Yanfeng Xu,1,* Haiying Niu,1,* Tongping Hu,2 Lixia Zhang,2 Shanna Su,1 Huijie He,1 Huimin Wang,1 Dong Zhang1 1Department of Pulmonary Medicine, The First Affiliated Hospital of Baotou Medical College, Baotou, People’s Republic of China; 2Department of Clinical Laboratory, The First Affiliated Hospital of Baotou Medical College, Baotou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dong ZhangDepartment of Pulmonary Medicine, The First Affiliated Hospital of Baotou Medical College, Baotou, People’s Republic of ChinaEmail zhangdonggh@163.comBackground: Bacterial resistance to antibiotics has become a major public health concern. This study aimed to determine the resistance mechanisms to carbapenem in clinical isolates of Pseudomonas aeruginosa.Methods: A total of 62 clinical isolates of carbapenem-resistant P. aeruginosa (CRPA) were collected from 2015 to 2017. Imipenem (IPM)–EDTA disk synergy test was used to screen strains that produced metallo-β-lactamase. In addition, the genes for outer membrane protein OprD2, metallo-β-lactamase and mexR gene were amplified and sequenced. Expression of mexA was detected by real-time PCR.Results: Disk synergy test showed that 51.6% (32/62) of the strains were positive for metallo-β-lactamase. PCR showed that 84.4% of the strains were SIM-positive (27/32), 15.6% of the strains were IMP-positive (5/32), and 12.5% of the strains were VIM-positive (4/32). SPM-positive and GIM-positive strains were not detected. In addition, 5 of the 62 strains had small deletions and/or point mutations in OprD2. Three strains had a high expression of mexA, while eight strains were positive for the regulatory gene mexR with no mutations detected by DNA sequencing.Conclusion: Expression of metallo-β-lactamase is the main resistance mechanism of P. aeruginosa to carbapenem. Mutations in OprD2 and/or the overexpression of efflux pump MexAB-OprM may contribute to P. aeruginosa resistance to carbapenem.Keywords: Pseudomonas aeruginosa, carbapenem, metallo-β-lactamase, outer membrane protein OprD2, efflux pump MexAB-OprM

Mingyang Wang,1 Xuesi Hua,2 Hongmei Niu,1 Zhengyu Sun,1 Li Zhang,1 Yali Li,1 Lan Zhang,1 Lin Li1 1Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, Beijing, People’s Republic of China; 2University of Michigan, Ann Arbor, MI, USACorrespondence: Lin Li; Lan ZhangDepartment of Pharmacy, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, People’s Republic of ChinaTel +86-10-83198886; +86-10-83199443Fax +86-10-63042809Email linlixw@126.com; lanizhg@126.comBackground: Ischemic stroke often induces profound white matter lesions, resulting in poor neurological outcomes and impaired post-stroke recovery. The present study aimed to investigate the effects of cornel iridoid glycoside (CIG), a major active component extracted from Cornus officinalis, on the white matter injury induced by ischemic stroke and further investigate its neuroprotective mechanisms.Methods: Adult male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) surgery for 2 h, followed by reperfusion. Rats were intragastrically administered CIG (60 mg/kg and 120 mg/kg) beginning 6 h afters reperfusion, once daily for seven days. A series of behavioral tests (modified neurological severity scores test, object recognition test, adhesive removal test, and beam walking test) were performed to evaluate the neurological functioning in MCAO rats. Histology of the white matter was studied using luxol fast blue staining and transmission electron microscopy. Immunohistochemical staining was performed to assess myelin loss, oligodendrocyte maturation, and glial activation. Activation of the brain-derived neurotrophic factor (BDNF)/neuregulin-1 (NRG1) pathway was evaluated by Western blotting.Results: CIG treatment remarkably decreased the neurological deficit score, accelerated the recovery of somatosensory and motor functions, and ameliorated the memory deficit in MCAO rats. Furthermore, CIG alleviated white matter lesions and demyelination, increased myelin basic protein expression and the number of mature oligodendrocytes, and decreased the number of activated microglia and astrocytes in the corpus callosum of MCAO rats. In addition, Western blot analysis indicated that CIG increased the expression of BDNF/p-TrkB, NRG1/ErbB4 proteins, which further elevated PI3K p110α/p-Akt/p-mTOR signaling in the corpus callosum of MCAO rats.Conclusion: We demonstrated that CIG protects against white matter lesions induced by cerebral ischemia partially by decreasing the number of activated microglia and astrocytes, increasing BDNF level, and activating NRG1/ErbB4 and its downstream PI3K/Akt/mTOR pathways in the white matter. CIG might be used as a potential neuroprotective agent for the treatment of ischemic stroke.Keywords: cornel iridoid glycoside, white matter lesion, cerebral ischemia, brain-derived neurotrophic factor, neuregulin-1 pathway

Xiaolong Liu,1,* Haiyan Cui,2,* Hongling Niu,1 Liping Wang,3 Xiangzhi Li,1 Jingbo Sun,1 Qingzhu Wei,4 Jianghui Dong,3 Lixin Liu,1 Cory J Xian3 1Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, People’s Republic of China; 2Department of Internal Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, People’s Republic of China; 3School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia; 4Department of Pathology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lixin LiuDepartment of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 Zhongshan Avenue West, Tianhe District, Guangzhou, Guangdong 510630, People’s Republic of ChinaTel/fax +862062784437Email dr.lixin.liu@hotmail.com Cory J XianSchool of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, GPO Box 2471, Adelaide, SA 5001, AustraliaTel +618 8302 1944Fax +618 8302 1087Email cory.xian@unisa.edu.auBackground: Inflammation is implicated in both hepatic cirrhosis development and hepatocellular carcinogenesis, and treatment with long-acting glucocorticoid dexamethasone prevented liver carcinogenesis in mice. However, it is unclear whether glucocorticoids have anti-inflammatory effect on hepatocellular carcinoma (HCC) and if short-acting glucocorticoids (with fewer adverse effects) inhibit paraneoplastic inflammation and HCC progression.Methods: To investigate whether different types of anti-inflammatory agents attenuate HCC progression, the current study compared effects of treatments with hydrocortisone (a short-acting glucocorticoid) or aspirin on HCC progression. HCC was induced in diethylnitrosamine-treated rats which were randomly divided into 4 groups (n=8), respectively receiving orally once daily vehicle, glucuronolactone, glucuronolactone+hydrocortisone, and glucuronolactone+aspirin. Diethylnitrosamine (DEN) was given to rats in drinking water (100mg/L) to induce HCC. At weeks 12 and 16 post-induction, effects were compared on HCC nodule formation, microvessel density, and macrophage infiltration, and levels of paraneoplastic protein expression of tumor necrosis factor (TNF)-α, p38 mitogen-activated protein kinase (p38), phosphorylated p38 (p-p38), nuclear factor (NF)-κB, interleukin (IL)-10, hepatocyte growth factor (HGF), transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF).Results: Compared to the model and glucuronolactone alone groups, HCC nodule number and microvessel density in the glucuronolactone+hydrocortisone group were significantly lower at week 12. At week 12 but not week 16, significantly lower levels of macrophages, TNF-α, p-p38, NF-κB, IL-10, HGF, TGF-β1 and VEGF were observed in the paraneoplastic tissue of the glucuronolactone+hydrocortisone group when compared with the control and glucuronolactone groups.Conclusion: The results suggest that hydrocortisone treatment reduces macrophage polarization, expression of inflammatory and anti-inflammatory cytokines, and angiogenesis in paraneoplastic tissue, and attenuates early HCC progression. Although hydrocortisone did not have attenuation effect on advanced solid tumor, the current study shows the potential benefits and supports potential clinical use of hydrocortisone in attenuating early progression of HCC, which is through suppressing paraneoplastic inflammation and angiogenesis.Keywords: hepatocellular carcinoma, inflammation, macrophage, angiogenesis, steroid, aspirin