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Baokun Liu,1,2,&ast; Lujun Shen,3,4,&ast; Wen Liu,5 Zhiyong Zhang,1,2 Jieqiong Lei,1,2 Zhengguo Li,1,2 Qinquan Tan,6 Hengfei Huang,7 Xingdong Wang,1,2 Weijun Fan3,4 1Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center Gansu Hospital, Lanzhou, 730050, People’s Republic of China; 2Department of Minimally Invasive Interventional Therapy, Gansu Provincial Cancer Hospital, Lanzhou, 730050, People’s Republic of China; 3Department of Minimally Invasive Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 4State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 5Department of Radiotherapy, Lanzhou University Second Hospital, Lanzhou, 730030,People’s Republic of China; 6Department of Oncology, Dongguan People’s Hospital, Dongguan, 523000, People’s Republic of China; 7Department of General Surgery, Chongzuo People’s Hospital, Chongzuo, 523000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xingdong Wang; Weijun Fan, Email wxd101027@163.com; fanwj@sysucc.org.cnPurpose: The majority of new diagnoses of hepatocellular carcinoma (HCC) still pertain to unresectable cases. Currently, the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein-1 (PD-1) inhibitors has become the mainstream treatment. According to multiple clinical guidelines, it is strongly advised to consider local therapy as the primary treatment choice for uHCC. This research was conducted to examine the safety and effectiveness of combining hepatic arterial infusion chemotherapy (HAIC) with TKIs and PD-1 inhibitors for the treatment of uHCC.Methods: Between 2015 and 2020, 208 HCC patients received HAIC alone or HAIC in combination with TKIs and PD-1 inhibitors. The overall survival(OS), and progression-free survival(PFS) and the best treatment response were compared between the two treatment groups. Propensity score matching (PSM)was used to minimize confounding bias.Results: Among the enrolled patients, 116 patients (55.8%) received combination therapy, while 92 patients (44.2%) received HAIC alone. The baseline characteristics were similar between the two groups. After PSM, 82 pairs of well-matched liver cancer patients were selected; the overall response rate in the combination group trended better than that in the HAIC alone group. The hazard ratios (HRs) for OS and PFS of the combination approach compared to the HAIC-alone approach were 0.47 (95% CI, 0.322– 0.687; p< 0.001) and 0.58 (95% CI, 0.397– 0.848; p=0.005), respectively.Conclusion: For uHCC patients, combination therapy can provide better OS and PFS compared to HAIC alone.Keywords: hepatocellular carcinoma, TKIs, PD-1, HAIC, combination therapy

Qiang Tan, Ming Chen, Hongmei Yang, Yao Guo, Xiaoyi Zou Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of ChinaCorrespondence: Qiang Tan, Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of China, Email qhdtanqiang@aliyun.comBackground: Subclinical hypothyroidism (SH) increases the risk of cardiovascular events, however the influence of SH on prognosis of ejection fraction preserved heart failure (HFpEF) is not fully understood.Methods: In this prospective observational study, patients with HFpEF were divided into euthyroidism group (n = 413) and SH group (n = 79). Patients were followed up for at least 30 months to examine the association between SH and cardiovascular events in patients with HFpEF. The primary end point was composite cardiovascular events (cardiovascular death and re-hospitalization). The patients underwent flow-mediated dilation (FMD) measurement by ultrasound in order to value endothelial function.Results: The rate of composite cardiovascular events was higher in SH group than in euthyroidism group (54.49% and 26.36%, respectively; p < 0.001). The higher risk of cardiovascular events in SH group was primarily due to a higher risk of re-hospitalization compared to euthyroidism group (45.56% and 20.58%, respectively; p < 0.001). The rate of cardiovascular death was higher in SH group than in euthyroidism group (13.92% and 5.81%, respectively; p = 0.017). Cox proportional hazards regression showed that SH (hazard ratios [HR] 1.921, 95% confidence interval [CI] 1.139– 3.240), level of TSH (HR 1.025, 95% CI 1.010– 1.054), age (HR 1.017, 95% CI 1.002– 1.034), LVEF (HR 0.975, 95% CI 0.953– 0.996), atrial fibrillation (HR 1.581, 95% CI 1.083– 2.307), eGFR (HR 0.987, 95% CI 0.978– 0.997), and NYHA cardiac function (HR 2.342, 95% CI 1.649– 3.326) were independent predictors of cardiovascular events in patients with HFpEF (all P < 0.05).Conclusion: Subclinical hypothyroidism was associated with increased cardiovascular events and death in patients with HFpEF.Keywords: subclinical hypothyroidism, ejection fraction preserved heart failure, endothelial function, flow-mediated dilation, cardiovascular events

Runmin Zhang, Muzhe Li, Huiyun Li, Xun Ran, Fengtian Jin, Qingshan Tan, Zhiwei Chen Department of Orthopaedics, The First Affiliated Hospital of University of South China, Hengyang, People’s Republic of ChinaCorrespondence: Zhiwei Chen, Department of Orthopaedics, The First Affiliated Hospital of University of South China, 69| Chuanshan Road, Hengyang, Hunan, People’s Republic of China, Tel +86-13973409923, Email CZW9915@sina.comAbstract: Inflammation is a common feature of many inflammatory diseases and tumors, and plays a decisive role in their development. Exosomes are extracellular vesicles unleashed by assorted types of cells, and it is widely known that exosomes of different immune cell sources play different functions. Exosome production has recently been reported for immune cells comprising macrophages, T cells, B cells, and dendritic cells (DCs). Immune cell-derived exosomes are involved in a variety of inflammatory responses.Herein, we summarize and review the role of macrophages, T cells, B cells, and dendritic cells (DC) in inflammatory diseases, with a focus on the role of immune cell-derived exosomes in osteoarthritis, rheumatoid arthritis, and the inflammatory tumor microenvironment (TME).These findings are expected to be important for developing new treatments for inflammatory diseases and ameliorating tumor-related inflammation. Keywords: inflammatory diseases, immune cell-derived exosomes, osteoarthritis, rheumatoid arthritis, inflammatory tumor microenvironment

Xiaojiao Xu,1,2 Yuheng Shan,3 Yuying Cen,2,4 Jiahua Zhao,2,4 Xiaosa Yang,2,4 Rui Liu,1,2 Qingche Tan,2 Yubao Ma,2 Mianwang He,2 Jiatang Zhang,1,2,4 Fei Yang,2 Shengyuan Yu2 1School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China; 2Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China; 3Department of Neurology, Characteristic Medical Centre of People’s Armed Police Force, Tianjin, 300162, People’s Republic of China; 4Medical School of Chinese PLA, Beijing, 100853, People’s Republic of ChinaCorrespondence: Jiatang Zhang; Fei Yang, Department of Neurology, The First Medical Centre, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, 100853, People’s Republic of China, Tel +86 13601380322 ; Tel +86 13910973120, Email zjt1128@aliyun.com; yangfeiyanbian@163.comPurpose: Listeria monocytogenes infections are rare in the central nervous system (CNS) and frequently difficult-to-diagnose. Our goal is to assess CNS listeriosis patients’ clinical characteristics, diagnosis, treatment, and prognosis.Patients and Methods: Patients with CNS listeriosis admitted to the Department of neurology, the first medical center of the Chinese PLA general hospital, were enrolled in this study from March 2018 to August 2022.Results: This study analyzed eight adults, including five males and three females. The average age of onset was (50.25 ± 11.52) years. The clinical manifestations included fever, headache, altered mental status, vomiting, seizures, neck rigidity, hemiplegia and cranial nerve palsies. Cerebrospinal fluid (CSF) tests revealed intracranial hypertension, elevated cell count and protein concentration, and decreased glucose levels. The positive rates of blood and CSF culture were 40% and 28.57%, respectively. All patients underwent CSF metagenomic next-generation sequencing (mNGS), with a 100% positive rate and the specific read number 12– 20394. Magnetic resonance imaging (MRI) exhibited leptomeningitis, meningoencephalitis, and brain abscess, and no specific changes were discovered in two patients. All patients received antibiotic treatment, seven were cured, and one died.Conclusion: Monitoring the proportion of monocytes in blood and mNGS results of CSF can play a crucial role in diagnosing pathogens. Early and sufficient application of two to three sensitive antibiotics with a BBB permeability of 20– 30% for at least 2– 3 months can significantly improve CNS listeriosis prognosis.Keywords: Listeria monocytogenes, central nervous system, CNS, clinical characteristics, treatment, metagenomic next-generation sequencing, mNGS

Zhongyu Li,1 Xiangmin Yuan,2 Xin Liu,2 Yuping Yang,2 Li Huang,2 Qiuhong Tan,2 Cuilin Li2 1Department of Blood Transfusion, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, People’s Republic of China; 2Department of Pharmacy, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, People’s Republic of ChinaCorrespondence: Cuilin Li, Email licuilincindy@163.comBackground: Solute carrier family 22 member 3 (SLC22A3) gene had been reported to be associated with the efficacy of metformin in type 2 diabetes mellitus (T2DM). However, few studies reported the relationship between SLC22A3 polymorphism and T2DM. The aim of this study was to investigate the association of SLC22A3 polymorphism and susceptibility to T2DM in Chinese population.Methods: We identified SLC22A3 rs555754, rs3123636, rs3088442 genotypes of 450 T2DM patients and 220 healthy controls from the Chinese population. The association between SNPs of SLC22A3 and susceptibility of T2DM was evaluated.Results: The clinical characteristics were significantly different between T2DM patients and healthy controls. The polymorphisms of SLC22A3 rs555754 and rs3123636 were obviously associated with the susceptibility of T2DM which was adjusted for age, sex and BMI, while rs3088442 did not. And there was haplotype association of SLC22A3 rs3088442-rs3123636 with T2DM susceptibility.Conclusion: SLC22A3 rs555754 and rs3123636 polymorphisms were associated with the susceptibility to T2DM in Chinese Han population. Large sample size studies would be required to verify this association.Keywords: type 2 diabetes mellitus, SLC22A3 gene, polymorphism, T2DM

Xiaoyi Zou, Ming Chen, Limin Sun, Qiang Tan Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of ChinaCorrespondence: Qiang Tan, Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, No. 258 of Wenhua Road, Qinhuangdao, Hebei Province, 066000, People’s Republic of China, Email qhdtanqiang@aliyun.comBackground and Objectives: Hyperinsulinemia impaired cardiovascular system and endothelial function in the population. The purpose of this study was to explore the relationship between hyperinsulinemia and coronary collateral circulation in patients with chronic total coronary occlusion.Methods: Patients with stable angina and at least one total coronary occlusion were enrolled in this study. Collateral grade was determined according to Rentrop’s classification. Patients were divided into a good coronary collateral circulation (CCC) group (grade 2 or 3 collateral vessels, n = 223) and a poor CCC group (grade 0 or 1 collateral vessels, n = 115). Fasting insulin level (FINS) and fasting glucose level (FBS) were measured. Endothelial function evaluated by flow-mediated dilation (FMD).Results: Serum FINS level was significantly increased in the poor CCC group (P < 0.01). Patients in the poor CCC group had higher levels of FBS, HbA1C, and homeostasis model assessment for insulin resistance (HOMA-IR) than patients in the good CCC group. The poor CCC group also had lower levels of FMD, lower LVEF and higher syntax scores than the good CCC group. Hyperinsulinemia (T3, FINS ≥ 15.22 μIU/mL) increased OR for the incidence of the poor CCC group (OR 2.419, 95% CI 1.780– 3.287) in multivariate analysis. Multivariate logistic regression also revealed that diabetes, HbA1c, HOMA-IR, HDL-C and Syntax score were independent predictors of poor CCC (all P < 0.05).Conclusion: Hyperinsulinemia is a valuable predictor of poor collateral formation in patients with chronic total coronary occlusion.Keywords: coronary collateral, hyperinsulinemia, arteriogenesis, endothelial function

YaLi Wu,1,&ast; WenJuan Chen,1,&ast; Mengfei Guo,1 Qi Tan,1 E Zhou,1 Jingjing Deng,1 Minglei Li,1 Jiangbin Chen,1 Zimo Yang,1 Yang Jin1– 3 1Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Diseases of National Health Commission, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Key Laboratory of Biological Targeted Therapy, the Ministry of Education, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Clinical Research Center for Major Respiratory Diseases in Hubei Province, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Jin, Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China, Email whuhjy@126.comAbstract: Extracellular vesicles (EVs) can contain DNA, RNA, proteins and metabolic molecules from primary origins; they are coated with a phospholipid bilayer membrane and released by cells into the extracellular matrix. EVs can be obtained from various body liquids, including the blood, saliva, cerebrospinal fluid, and urine. As has been proved, EVs-mediated transfer of biologically active molecules is crucial for various physiological and pathological processes. Extensive investigations have already begun to explore the diagnosis and prognosis potentials for EVs. Furthermore, research has continued to recognize the critical role of nucleic acids and proteins in EVs. However, our understanding of the comprehensive effects of metabolites in these nanoparticles is currently limited and in its infancy. Therefore, we have attempted to summarize the recent research into the metabolomics of EVs in relation to potential clinical applications and discuss the problems and challenges that have occurred, to provide more guidance for the future development in this field.Keywords: extracellular vesicles, metabolomics, metabolites, clinical application

Shiqi Wang,1 Chao Xia,2 Qirui Zheng,3 Aiping Wang,4 Qian Tan1 1Department of Burns and Plastic Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, People’s Republic of China; 2Department of Orthopedics, Air Force Hospital of Eastern Theater Command, Nanjing, People’s Republic of China; 3Software Institute, Nanjing University, Nanjing, People’s Republic of China; 4Department of Endocrinology, Air Force Hospital of Eastern Theater Command, Nanjing, People’s Republic of ChinaCorrespondence: Qian Tan, Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People’s Republic of China, Tel +86 25 83106666, Email smmutanqian@sina.com Aiping Wang, Department of Endocrinology, Air Force Hospital of Eastern Theater Command, Nanjing, 210002, People’s Republic of China, Email wap454hospital@163.comBackground: Early detection of hard-to-heal diabetic foot ulcers (DFUs) is vital to prevent a poor prognosis. The purpose of this work was to employ clinical characteristics to create an optimal predictive model of hard-to-heal DFUs (failing to decrease by > 50% at 4 weeks) based on machine learning algorithms.Methods: A total of 362 DFU patients hospitalized in two tertiary hospitals in eastern China were enrolled in this study. The training dataset and validation dataset were split at a ratio of 7:3. Univariate logistic analysis and clinical experience were utilized to screen clinical characteristics as predictive features. The following six machine learning algorithms were used to build prediction models for differentiating hard-to-heal DFUs: support vector machine, the naïve Bayesian (NB) model, k-nearest neighbor, general linear regression, adaptive boosting, and random forest. Five cross-validations were employed to realize the model’s parameters. Accuracy, precision, recall, F1-scores, and AUCs were utilized to compare and evaluate the models’ efficacy. On the basis of the best model identified, the significance of each characteristic was evaluated, and then an online calculator was developed.Results: Independent predictors for model establishment included sex, insulin use, random blood glucose, wound area, diabetic retinopathy, peripheral arterial disease, smoking history, serum albumin, serum creatinine, and C-reactive protein. After evaluation, the NB model was identified as the most generalizable model, with an AUC of 0.864, a recall of 0.907, and an F1-score of 0.744. Random blood glucose, C-reactive protein, and wound area were determined to be the three most important influencing factors. A corresponding online calculator was created (https://predicthardtoheal.azurewebsites.net/).Conclusion: Based on clinical characteristics, machine learning algorithms can achieve acceptable predictions of hard-to-heal DFUs, with the NB model performing the best. Our online calculator can assist doctors in identifying the possibility of hard-to-heal DFUs at the time of admission to reduce the likelihood of a dismal prognosis.Keywords: hard-to-heal, diabetic foot ulcers, machine learning, classification

Yanqiu He,1,&ast; Cheng Hu,1,&ast; Shiyu Liu,1 Mingjie Xu,1 Ge Liang,2 Dan Du,3 Tingting Liu,1 Fei Cai,1 Zhiyao Chen,1 Qingyuan Tan,1 Lihui Deng,1 Qing Xia1 1Pancreatitis Centre, Department and Laboratory of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Advanced Mass Spectrometry Center, Research Core Facility, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lihui Deng, Pancreatitis Centre, Department and Laboratory of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People’s Republic of China, Email denglihui@scu.edu.cnBackground: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas without specific treatment. Shenmai injection (SMI) was reported to eliminate the severity of experimental AP. This study aimed to explore the mechanisms underlying the synergistic protective effects of SMI on AP based on network pharmacology and experimental validation.Methods: Network pharmacology analysis and molecular docking based on identified components were performed to construct the potential therapeutic targets and pathways. The principal components of SMI were detected via ultra-high-performance liquid chromatography-coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF/MS). Effect of SMI and the identified components on cellular injury and IL6/STAT3 signaling was assessed on mouse pancreatic acinar cell line 266– 6 cells. Finally, 4% sodium taurocholate (NaT) was used to induce AP model to assess the effects of SMI in treating AP and validate the potential molecular mechanisms.Results: By searching the TCMSP and ETCM databases, 119 candidate components of SMI were obtained. UHPLC-QTOF/MS analysis successfully determined the representative components of SMI: ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D. Fifteen hub targets and eight related pathways were obtained to establish the main pharmacology network. Subnetwork analysis and molecular docking indicated that the effects of these four main SMI components were mostly related to the interleukin (IL) 6/STAT3 pathway. In vitro, SMI, ginsenoside Rb1, ginsenoside Rg1, ginsenoside Re, and ophiopogonin D increased the cell viability of NaT-stimulated mouse pancreatic acinar 266– 6 cells and decreased IL6 and STAT3 expression. In vivo, 10 mL/kg SMI significantly alleviated the pancreatic histopathological changes and the expression of IL6 and STAT3 in the AP mice.Conclusion: This study demonstrated SMI may exert anti-inflammatory effects against AP by suppressing IL6/STAT3 activation, thus providing a basis for its potential use in clinical practice and further study in treating AP.Keywords: acute pancreatitis, Shenmai injection, network pharmacology, molecular docking, IL6/STAT3 signaling pathway

Zhongjing Wang,1,&ast; Shu Fang,1,2,&ast; Sheng Ding,1 Qin Tan,1 Xuyan Zhang1 1Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, People’s Republic of China; 2School of Medicine, Jianghan University, Wuhan, 430056, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xuyan Zhang, Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, No. 26 of Shengli Street, Jiang’an District, Wuhan, 430014, People’s Republic of China, Tel +86 027 6569 6337, Fax +86 027 8276 1417, Email wish66zh@126.comAbstract: Iron is one of the most important trace elements in life activities. It participates in a variety of important physiological processes in the body through oxidation-reduction reaction. A large number of studies show that iron overload (IO) is closely related to the progression of diabetes and its various chronic complications. However, the mechanism of iron overload in the pathogenesis of diabetes and the mechanism of iron overload in atherosclerosis (AS) are still controversial, and the relationship between iron overload and diabetic lower extremity arterial disease (LEAD) remains still unclear. Some recent reviews and original research articles suggest further studies to explain the complex relationship between iron metabolism and atherosclerosis. This article reviews the relationship between iron overload and diabetes and its relationship with LEAD, and discusses its mechanisms from various aspects, such as lipid peroxidation induced by iron overload, so as to provide clinical diagnosis and treatment ideas for diabetic lower extremity arterial disease. It is hoped that early evaluation, diagnosis and treatment of LEAD will be inspired.Keywords: iron overload, lower extremity arterial disease, atherosclerosis, serum ferritin, type 2 diabetes mellitus

Qian Tan,1,&ast; Zhengkun Cai,2,&ast; Jia Li,3 Jing Li,1 Hongchun Xiang,1 Bocun Li,1 Guowei Cai1 1Department of Acupuncture, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Public Administration, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guowei CaiDepartment of Acupuncture, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaEmail cgw645@163.comObjective: We aim to explore whether acupuncture inhibits inflammation and bone destruction in rat model monosodium iodoacetate (MIA)-induced knee osteoarthritis (KOA) by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography (PET) and micro-computed tomography (CT) imaging.Methods: KOA was induced in rats by intra-articular injection MIA (2 mg/50 μL) through the right knee of the rats. Forty male Sprague Dawley rats weighing 280 to 340 g (12 weeks old) were randomly divided into four groups including Control group, KOA group, KOA plus manual acupuncture group (KOA+MA), KOA plus sham acupuncture group (KOA+SA). The acupuncture treatment lasted for three weeks (one-day rest after six days of treatment). Paw withdrawal threshold test and open-field test were used to assess mechanical allodynia and locomotor activity respectively for once a week. Hematoxylin and eosin (H&E) staining was used to assess the damage of the cartilage, synovium and infrapatellar fat pad (IFP). 18F-FDG PET was performed to quantify joint inflammation. The influence on the subchondral bone in these rats was confirmed by micro-CT.Results: Mechanical hyperalgesia, joint inflammation, and obvious bone destruction were observed in the KOA group. H&E staining of the knee joint found that manual acupuncture played a protective effect in cartilage, synovium and IFP destruction. However, compared with KOA group, the results in sham acupuncture had no significant difference. After manual acupuncture treatment in KOA rats, inflammation was significantly suppressed shown by 18F-FDG PET imaging. Micro-CT analysis of the knee joint revealed that manual acupuncture protected bone by inhibiting osteophyte development and subchondral bone remodeling.Conclusion: The results of 18F-FDG PET and micro-CT showed that manual acupuncture inhibited inflammation and bone destruction, which provides reliable evidence for the effectiveness of acupuncture in hindering development of KOA, and provides reliable evidence for clinical application of acupuncture.Keywords: osteoarthritis, acupuncture, PET, micro-CT, inflammation, bone destruction

Qi Tan,&ast; Limin Duan,&ast; Qi Huang,&ast; Wenjuan Chen,&ast; Zimo Yang, Jiangbin Chen, Yang Jin Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang JinDepartment of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, Hubei, People’s Republic of ChinaTel +86-135-5436-1146Fax +86-27-85755457Email whuhjy@126.comBackground: There is a close relationship among inflammation, glycolysis, and tumors. The IL-1 family includes important inflammatory cytokines, among which IL-1β has been widely studied. In this study, we focused on the effect of IL-1β on glycolysis of lung adenocarcinoma (LUAD) cells in vivo and in vitro and explored its possible mechanisms.Methods: A bioinformatic database and quantitative real-time PCR were used to analyze the expression of glycolysis-related enzyme genes and their correlations with IL1β in human LUAD samples. The human LUAD cell line A549 and Lewis lung carcinoma LLC cell line were stimulated with IL-1β. In vitro treatment effects, including glycolysis level, migration, and invasion were evaluated with a glucose assay kit, lactate assay kit, Western blotting, wound healing, and the transwell method. We established a mouse model of subcutaneous tumors using LLC cells pretreated with IL-1β and analyzed in vivo treatment effects through positron-emission tomography-computed tomography and staining. Virtual screening and molecular dynamic simulation were used to screen potential inhibitors of IL-1β.Results: Our results showed that IL1β was positively correlated with the expression of glycolysis-related enzyme genes in LUAD. Glycolysis, migration, and invasion significantly increased in A549 and LLC stimulated with IL-1β. In vivo, IL-1β increased growth, mean standard uptake value, and pulmonary tumor metastasis, which were inhibited by the glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors. Small molecular compound ZINC14610053 was suggested being a potential inhibitor of IL-1β.Conclusion: IL-1β promotes glycolysis of LUAD cells through p38 signaling, further enhancing tumor-cell migration and invasion. These results show that IL-1β links inflammation to glycolysis in LUAD, and targeting IL-1β and the glycolysis pathway may be a potential therapeutic strategy for lung cancer.Keywords: interleukin 1β, glycolysis, lung adenocarcinoma, p38 signaling

Qiaowen Tan,1 Shaoke Li,2 Juan Niu,3 Shien Liu,2 Yaling Li,1 Yujie Lu,1 Zhihong Wang,1 Wanqun Xu,1 Yalin Wei,1 Zongjun Guo1 1Department of Geriatrics, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of China; 2Department of Medical Imaging, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of China; 3Clinical Psychology Department, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, People’s Republic of ChinaCorrespondence: Zongjun Guo; Shaoke Li Email guozjj@163.com; lsk224@163.comIntroduction: We studied the regulatory mechanism of the habitual brain network in tobacco dependence to provide a theoretical basis for the regulation and cessation of tobacco dependence.Methods: We used resting-state functional magnetic resonance imaging (rs-fMRI) to explore the Fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity (FC) of the habitual brain network in tobacco-dependent subjects and to evaluate the relationship between the FC level and tobacco selection preference behavior. In total, 29 male tobacco-dependent participants and 28 male nonsmoking participants were recruited. rs-fMRI was used to collect blood oxygen level-dependent signals of the participants in the resting and awake states. After rs-fMRI, all subjects completed cigarette/coin selection tasks (task 1 and task 2).Results: Compared with the control group, the tobacco dependence group showed increased fractional amplitude values of fALFF in the left posterior cingulate cortex and right parahippocampus. FC in the tobacco-dependent group was increased in the right inferior temporal gyrus, left middle frontal gyrus, left cingulated gyrus, and bilateral superior frontal gyrus, compared with that in the control group. Moreover, the preference selection behavior was associated with the enhancement of FC about parts of the brain regions in the habitual brain network of the tobacco-dependent participants. Thus, habitual network activity was significantly enhanced in tobacco-dependent participants in the resting state. Moreover, a positive correlation was found between the cigarette selection preference of the smokers and certain brain regions related to the habitual network.Discussion: This suggests that increased activity of the habitual brain network may be essential in the development of tobacco-dependent behavior.Keywords: tobacco dependence, behavioral decision preference, habitual brain network, resting-state functional magnetic resonance imaging, functional connectivity, fractional amplitude of low-frequency fluctuations

Qiang Tan, Ming Chen, Jia Hao, Kun Wei Department of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, Qinhuangdao, Hebei Province, People’s Republic of ChinaCorrespondence: Qiang TanDepartment of Cardiology, Qinhuangdao First Hospital, Hebei Medical University, No. 258 of Wenhua Road, Qinhuangdao, Hebei Province, 066000, People’s Republic of ChinaEmail qhdtanqiang@aliyun.comBackground and Objectives: Hyperinsulinemia plays a key role in the development of cardiovascular impairment in patients with metabolic syndrome. The aim of this study was to evaluate the influence of hyperinsulinemia on long-term clinical outcomes of percutaneous coronary intervention (PCI) in patients without diabetes mellitus who have acute myocardial syndrome (ACS).Methods: Between March 2016 and January 2019, we enrolled 468 patients with ACS and without diabetes mellitus who received primary PCI. Patients were divided into a low-insulin group (n = 157), medium-insulin group (n = 154), and high-insulin group (n = 157) according to tertiles of fasting insulin level. The primary endpoint was major adverse cardiac events (MACE; all-cause death, non-fatal myocardial infarction, target vessel revascularization [TVR]) at 24 months. The secondary endpoint was angina hospitalization.Results: Patients in the high-insulin group had an unfavorable prognosis, with a higher rate of MACE (34.39%) than the low-insulin group (22.29%) and medium-insulin group (23.37%) at 24 months (P < 0.05). This difference was mainly driven by the increase in TVR. The high-insulin group also had a higher rate of angina hospitalization than the low-insulin group. Cox proportional hazards regression showed that high-insulin level (hazard ratio [HR] 1.870, 95% confidence interval [CI] 1.202– 2.909), small-vessel lesion (HR 1.713, 95% CI 1.111– 2.642), bifurcation lesion (HR 3.394, 95% CI 2.033– 5.067), SYNTAX score (HR 1.084, 95% CI 1.039– 1.130), and stent length (HR 1.017, 95% CI 1.002– 1.032) increased the incidence of MACE in patients with ACS and without diabetes who underwent PCI.Conclusion: Hyperinsulinemia might be a valid predictor of clinical outcomes in patients with ACS undergoing PCI.Keywords: percutaneous coronary intervention, hyperinsulinemia, acute myocardial syndrome, major adverse cardiac events

Wei Xi,1,&ast; Qinxuan Tan,2,&ast; Yingyong Hou,3,&ast; Xiaoyi Hu,1 Hang Wang,1 Li Liu,1 Yu Xia,1 Qi Bai,1 Jiajun Wang,1 Jianjun Zhou,2 Jianming Guo1 1Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianming GuoDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail guo.jianming@zs-hospital.sh.cnJianjun ZhouDepartment of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail zhou.jianjun@zs-hospital.sh.cnObjective: Pseudocapsule (PS) of tumor-parenchyma interface (TPI) can be detected by MDCT (ctPS) in renal cell carcinoma (RCC) with exceptions. We aim to study the prognostic implications and histological reflections of no detection of ctPS in RCC.Patients and Methods: A total of 210 RCC patients who had MDCT examination and received nephrectomy in our institution were included in the analysis. Absence or presence of ctPS was recognized, and its associations with overall survival (OS) and progression-free survival (PFS), pathological PS (pPS) and vasculature were studied.Results: A total of 172 (81.9%) patients were recognized to have a ctPS and 38 (18.1%) had no detection of it. They had comparable histology, stage, grade, and necrosis. Patients without a ctPS had significantly shortened overall survival (OS, p = 0.001) and progression-free survival (PFS, p < 0.001), the significance of which persisted in multivariable analysis (OS, HR 3.104, p = 0.003; PFS, HR 3.313, p = 0.001). Nearly all tumors (34/38, 89.4%) without a ctPS actually had a pPS being detected and incompleteness of pPS was also irrelevant (p = 0.739). Compared with ctPS presence, those without a ctPS had significantly thinned pPS (0.36 vs 0.43 mm, p = 0.005). In clear-cell histology, those without a ctPS also contained increased vascular density and cross-sectional area of vessels with long diameter ≥ 200 um in the pPS layer (p = 0.005 and 0.011) and increased vascular density in the 500 um layer outside pPS (p = 0.017).Conclusion: Absence of ctPS on MDCT significantly increases the risk of adverse clinical outcome in RCC. It is the reflection of a thinner pPS and enriched vasculature of TPI rather than absence of pPS itself.Keywords: renal cancer, pseudocapsule, MDCT, prognosis, histological reflection

Yuling Yu,1,&ast; Yuqing Huang,1,&ast; Lin Liu,2 Xiao-Cong Liu,1 Qiuhong Tan,3 Chaolei Chen,1 Jiayi Huang,3 Yingqing Feng,1 Songtao Tang4 1Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 3Guangdong Provincial People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, People’s Republic of China; 4Department of Cardiology, Community Health Center of Liaobu Town, Dongguan, 523400, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Songtao TangDepartment of Cardiology, Community Health Center of Liaobu Town, Dongguan, 523400, Guangdong, People’s Republic of ChinaEmail 3038384760@qq.comYingqing FengDepartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 2nd Zhongshan Road, Yuexiu District, Guangzhou, 510080, People’s Republic of ChinaEmail fengyingqing@gdph.org.cnBackground: Vascular overload index (VOI) is a marker of arterial stiffness and arteriolar resistance, which predicts the increasing risks of cardiovascular and cerebrovascular disease. This study aimed to evaluate the association between VOI and new-onset ischemic stroke in an elderly population with hypertension.Methods: This retrospective cohort study included 3315 hypertensive participants aged 60 years or more. Ischemic stroke was diagnosed according to cranial computed tomography, magnetic resonance imaging of the brain or cerebrovascular angiography. The calculation of VOI was based on systolic and diastolic blood pressure. VOI was divided by quartiles (< 7.88 mmHg, 7.88– 16.10 mmHg, 16.10– 27.14 mmHg, ≥ 27.14 mmHg) and evaluated the association with new-onset ischemic stroke by multivariable Cox regression models.Results: A total of 3315 participants (55.5% female) aged 71.4± 7.20 years were included in the analysis. The median follow-up period was 5.5 years, and 206 participants reached the endpoint, new-onset ischemic stroke. With per standard deviation increment in VOI, the risks of new-onset ischemic stroke increased in non-adjusted model (Hazard ratio [HR], 1.11; 95% confidence interval [CI]: 1.03– 1.22; p = 0.001), adjusted model (HR, 1.11; 95% CI: 1.04– 1.22; p = 0.003) and fully-adjusted model (HR, 1.15; 95% CI: 1.08– 1.26; p< 0.001), respectively. In multivariate fully adjusted model, the risks of ischemic stroke increased in higher quartiles in comparison to the first quartiles (p for trend < 0.001).Conclusion: In an elderly hypertensive population, VOI is significantly associated with the incidence of new-onset ischemic stroke. Elevated VOI is the cardiovascular risk factor and increases the probability of new-onset ischemic stroke.Keywords: vascular overload index, ischemic stroke, hypertension, elderly population, blood vessel

Yongjia Huang,1,* Tingting Wang,2,* Qunyou Tan,3,* Dan He,1,* Mingjun Wu,4,* Jingchuan Fan,4 Jie Yang,1 Cailing Zhong,1 Kailing Li,1 Jingqing Zhang1 1Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing, People’s Republic of China; 2Biochemistry and Molecular Biology Laboratory, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Thoracic Surgery, Daping Hospital of Army Medical University, PLA, Chongqing, People’s Republic of China; 4Institute of Life Science, Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingqing ZhangMedicine Engineering Research Center, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, People’s Republic of ChinaTel +86 13308300303Email zjqrae01@163.comAbstract: Dysfunction in the mitochondria (Mc) contributes to tumor progression. It is a major challenge to deliver therapeutic agents specifically to the Mc for precise treatment. Smart drug delivery systems are based on stimuli-responsiveness and active targeting. Here, we give a whole list of documented pathways to achieve smart stimuli-responsive (St-) and Mc-targeted DDSs (St-Mc-DDSs) by combining St and Mc targeting strategies. We present the formulations, targeting characteristics of St-Mc-DDSs and clarify their anti-cancer mechanisms as well as improvement in efficacy and safety. St-Mc-DDSs usually not only have Mc-targeting groups, molecules (lipophilic cations, peptides, and aptamers) or materials but also sense the surrounding environment and correspondingly respond to internal biostimulators such as pH, redox changes, enzyme and glucose, and/or externally applied triggers such as light, magnet, temperature and ultrasound. St-Mc-DDSs exquisitely control the action site, increase therapeutic efficacy and decrease side effects of the drug. We summarize the clinical research progress and propose suggestions for follow-up research. St-Mc-DDSs may be an innovative and sensitive precision medicine for cancer treatment.Keywords: smart delivery, stimuli-responsive, mitochondria-targeting, tumor microenvironment, cancer therapy

Qian Tan,1,2,* Jing Hu,3,* Yujing Zhou,1,2 Yunxiao Wan,1,2 Chuanlan Zhang,1,2 Xin Liu,1,2 Xingyao Long,1,4 Fang Tan,5 Xin Zhao1 1Chongqing Collaborative Innovation Center for Functional Food, Chongqing Engineering Research Center of Functional Food, Chongqing Engineering Laboratory for Research and Development of Functional Food, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 2College of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People’s Republic of China; 3Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, People’s Republic of China; 4Department of Food Science and Biotechnology, Cha University, Seongnam, 13488, South Korea; 5Department of Public Health, Our Lady of Fatima University, 838 Valenzuela, Philippines*These authors contributed equally to this workCorrespondence: Xin ZhaoChongqing Collaborative Innovation Center for Functional Food, Chongqing University of Education, Xuefu Main Street 9, Chongqing, 400067, People’s Republic of ChinaTel +86-23-6265-3650Email zhaoxin@cque.edu.cnFang TanDepartment of Public Health, Our Lady of Fatima University, 120 McArthur Highway, 838 Valenzuela, PhilippinesTel +86-23-6265-3650Email tanfang@foods.ac.cnAim: The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. Lactococcus lactis subsp. lactis HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation.Methods: Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay.Results: Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner.Conclusion: LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent.Keywords: yak yogurt, lactic acid bacterium, diphenoxylate, constipation, mice

Qin Tan,1,* Yanding Gao,1,* Pin Zhang,2 Yan Huo,3 Yihan Lu,4,5 Weifeng Huang1 1Department of Critical Care, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of General Surgery, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Department of Pharmacy, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Epidemiology, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 5National Health Commission Key Laboratory of Health Technology Assessment, Fudan University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weifeng HuangDepartment of Critical Care, The Sixth People’s Hospital, Shanghai Jiao Tong University, No. 600 Yi Shan Road, Shanghai, 200233, People’s Republic of ChinaEmail breeze-huang@hotmail.comBackground: The effect of different administration routes of omeprazole remains unclear on the recovery in patients with obesity after laparoscopic sleeve gastrectomy (LSG).Methods: We designed a randomized clinical trial enrolling 120 patients with a BMI≥ 32.5 kg/m2 after LSG. They were randomized into two groups to be administered with omeprazole by rapid intravenous injection (group A) or by continuous micropump infusion (group B). The plasma concentration of omeprazole was monitored upon initiating administration. Change in intragastric pH and gastrointestinal symptoms during follow-up served as indicators for therapeutic evaluation.Results: Patients in the two groups showed no difference in the AUC curves (P=0.25), but group A had significantly higher peak concentration (P< 0.001), and shorter time to reach peak concentration after administration (P< 0.001), compared to group B. Before and after the administration of omeprazole, the average change in intragastric pH was much lower in group A (0.031 ± 0.61) than in group B (0.48 ± 0.74) (P=0.004). The incidence of gastrointestinal symptoms was similar between the two groups (P=0.85); however, the average duration of remaining symptoms was longer in group A (3.97 months; 95% CI, 2.90– 5.04) than in group B (2.82 months; 95% CI, 2.01– 3.63) (P=0.04).Conclusion: Continuous micropump infusion of omeprazole may improve the outcomes in patients with obesity after LSG.Trial registration: China Clinical Trial Registration Center (ChiCTR), ChiCTR-IPR-17013365. Registered 13 November 2017. http://www.chictr.org.cn/showproj.aspx?proj=22892.Keywords: obesity, laparoscopic sleeve gastrectomy, omeprazole, gastrointestinal symptoms

Wenxiang Lin,1,2 Libei Zhao,2 Qian Tan,1,2 Ding Lin1,2 1Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of China; 2Department of Ophthalmology, Changsha Aier Eye Hospital, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaTel +86-13787255158Email linding@csu.edu.cnPurpose: Efficacy of norvancomycin (NVCM) through continuous topical ocular instillation drug delivery (CTOIDD) system for treating severe acute bacterial keratitis infection with Staphylococcus aureus was investigated.Methods: Rabbits with bacterial keratitis were treated using CTOIDD with NVCM (n=13), topical NVCM eye drops (n=11), and CTOIDD with saline (n=8). Clinical signs of keratitis in all groups were assessed consecutively for a week. Bacterial quantification of excised corneas was counted on the fourth and eighth days. Histopathologic examinations were performed to assess inflammatory cell infiltration on the eighth day.Results: All signs of bacterial keratitis were alleviated in CTOIDD with NVCM according to criteria, and the CTOIDD-NVCM group had significantly less inflammation than CTOIDD-saline (p< 0.05), and eye drop-NVCM (p< 0.05). Two eyes in the eye drop-NVCM group, four eyes in the CTOIDD-saline group had corneal perforation (CP), while none of the rabbits showed CP in the CTOIDD-NVCM group. Bacterial counts were significantly less in the CTOIDD with NVCM group in comparison to the eye drop-NVCM (p< 0.05), and CTOIDD-saline (p< 0.05) groups. Severe inflammation and marked inflammatory cell infiltration were found in histopathologic examinations in the CTOIDD-saline and eye drop-NVCM groups, while significantly less inflammation was documented in the CTOIDD-NVCM (p< 0.05) group.Conclusion: CTOIDD with NVCM effectively reduced the severity and treated acute bacterial S. aureus keratitis infection in a rabbit model. The presented approach of CTOIDD with NVCM appears to be a promising therapeutic approach for severe acute bacterial keratitis.Keywords: severe acute bacterial keratitis, continuous topical instillation, eye drop, norvancomycin, rabbit eyes

Abstract Background Simulation exercises can functionally validate World Health Organization (WHO) International Health Regulations (IHR 2005) core capacities. In 2018, the Vietnam Ministry of Health (MOH) conducted a full-scale exercise (FSX) in response to cases of severe viral pneumonia with subsequent laboratory confirmation for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to evaluate the country’s early warning and response capabilities for high-risk events. Methods An exercise planning team designed a complex fictitious scenario beginning with one case of severe viral pneumonia presenting at the hospital level and developed all the materials required for the exercise. Actors, controllers and evaluators were trained. In August 2018, a 3-day exercise was conducted in Quang Ninh province and Hanoi city, with participation of public health partners at the community, district, province, regional and national levels. Immediate debriefings and an after-action review were conducted after all exercise activities. Participants assessed overall exercise design, conduction and usefulness. Results FSX findings demonstrated that the event-based surveillance component of the MOH surveillance system worked optimally at different administrative levels. Detection and reporting of signals at the community and health facility levels were appropriate. Triage, verification and risk assessment were successfully implemented to identify a high-risk event and trigger timely response. The FSX identified infection control, coordination with internal and external response partners and process documentation as response challenges. Participants positively evaluated the exercise training and design. Conclusions This exercise documents the value of exercising surveillance capabilities as part of a real-time operational scenario before facing a true emergency. The timing of this exercise and choice of disease scenario was particularly fortuitous given the subsequent appearance of COVID-19. As a result of this exercise and subsequent improvements made by the MOH, the country may have been better able to deal with the emergence of SARS-CoV-2 and contain it.

Maojian Chen,1,* Chanchan Xiao,2,* Wei Jiang,3 Weiping Yang,4 Qinghong Qin,1 Qixing Tan,1 Bin Lian,1 Zhijie Liang,5 Changyuan Wei1 1Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Microbiology and Immunology, School of Medicine and Public Health, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 3Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 4Department of Ultrasound Diagnosis, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 5Department of Gland Surgery, The Fifth Affiliated Hospital of Guangxi Medical University & The First People’s Hospital of Nanning, Nanning, Guangxi 530022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changyuan WeiDepartment of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of ChinaTel/Fax +86 0771 5308593Email changyuanwei@gxmu.edu.cnBackground: As a natural compound extracted from a variety of hot peppers, capsaicin has drawn increasing attention to its anti-cancer effects against multiple human cancers including breast cancer. FBI-1 is a major proto-oncogene negatively regulating the transcription of many tumor suppressor genes, and plays a vital role in tumorigenesis and progression. However, whether FBI-1 is involved in capsaicin-induced breast cancer suppression has yet to be ascertained. This study aimed to investigate the effects of capsaicin on proliferation and apoptosis and its association with FBI-1 expression in breast cancer.Methods: CCK-8 and morphological observation assay were employed to detect cell proliferation. Flow cytometry and TUNEL assay were conducted to detect cell apoptosis. RNA interference technique was used to overexpress or silence FBI-1 expression. qRT-PCR and/or Western blot analysis were applied to detect the protein expression of FBI-1, Ki-67, Bcl-2, Bax, cleaved-Caspase 3, Survivin and NF-κB p65. Xenograft model in nude mice was established to assess the in vivo effects.Results: Capsaicin significantly inhibited proliferation and induced apoptosis in breast cancer in vitro and in vivo, along with decreased FBI-1, Ki-67, Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Furthermore, FBI-1 overexpression obviously attenuated the capsaicin-induced anti-proliferation and pro-apoptosis effect, accompanied with the above-mentioned proteins reversed, whereas FBI-1 silencing generated exactly the opposite response. In addition, as a target gene of FBI-1, NF-κB was inactivated by p65 nuclear translocation suppressed with capsaicin treatment, which was perceptibly weakened with FBI-1 overexpression or enhanced with FBI-1 silencing.Conclusion: This study reveals that FBI-1 is closely involved in capsaicin-induced anti-proliferation and pro-apoptosis of breast cancer. The underlying mechanism may be related to down-regulation of FBI-1-mediated NF-κB pathway. Targeting FBI-1 with capsaicin may be a promising therapeutic strategy in patients with breast cancer.Keywords: capsaicin, breast cancer, proliferation, apoptosis, FBI-1, NF-κB

Zhen Huang,* Qixing Tan,* Qinghong Qin, Qinguo Mo, Changyuan Wei Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinguo Mo; Changyuan WeiDepartment of Breast Surgery, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, People’s Republic of ChinaTel +86-771-5308593; + 86-771-5308593Fax +86-771-5312000Email qgmo135@263.net; weichangyuan@gxmu.edu.cnPurpose: The efficacy of primary site surgery in patients with de novo stage IV breast cancer remains controversial. However, few real-world studies have evaluated the benefits of local surgery on the primary site of stage IV breast cancer in China. The purpose of this study was to investigate the role of local surgery in the de novo stage IV breast cancer.Materials and Methods: Women with metastatic breast cancer at diagnosis were identified from Guangxi medical university cancer hospital (China) database from 2009 to 2017. The clinical and tumor features, surgical treatment, and survival rates were compared between surgical and non-surgical patients.Results: Two hundred forty-three patients were included, of whom 125 underwent primary site surgery. Patients who underwent surgery were more often had small primary tumors, fewer lymph node metastases, and had less visceral involvement. Patients in the surgery group had dramatically longer OS (median 35 vs 22 months, log-rank P=0.006). Stratified survival analysis showed that patients with bone metastasis alone or ≤ 3 metastasis benefit from surgery, while patients with visceral metastasis did not benefit from surgery. In multivariate analysis, surgical treatment, estrogen receptor status, progesterone receptor status and visceral metastases remained independent factors for survival.Conclusion: Surgical resection of the primary site can improve survival in selected de novo stage IV breast cancer patients.Keywords: stage IV breast cancer, surgery, survival

Zhen Huang,* Qinghong Qin,* Longjie Xia,* Bin Lian, Qixing Tan, Yinghua Yu, Qinguo Mo Department of Breast Surgery, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qinguo MoDepartment of Breast Surgery, The Affiliated Tumor Hospital of Guangxi Medical University, No. 71 Hedi Road, Nanning 530021 Guangxi Province, People’s Republic of ChinaTel +86-771-530859Email qgmo135@263.netObjective: To investigate the association between the recurrence score (RS) obtained by Oncotype DX 21-gene test and long non-coding RNA (lncRNA) MALAT1 expression in early and estrogen receptor-positive (ER+) breast cancer.Materials and Methods: The Oncotype DX 21-gene test and MALAT1 expression detection were performed in tumor samples from 76 ER+ and early breast cancer patients with the Surplex liquid chip. The RS value was calculated based on the expression of total 21 genes. The level of MALAT1 was measured in both tumor tissue and para-tumor tissue, and relatively quantified with an internal control gene. Mann–Whitney U-test or Kruskal–Wallis test were used to analyze the association between MALAT1 level and different clinical pathological characteristics, including age, tumor stage, disease grade, lymph node status, Ki-67 expression, and progesterone receptor (PR) status. The association between the RS and different characteristics was analyzed by Wilcoxon rank-sum test. Correlation between two parameters was analyzed by Spearman’s rank correlation analysis.Results: The expression of MALAT1 was more abundant in tumor tissue (2.992 ± 2.256) than that in adjacent normal tissue (1.641± 1.438, Z=− 2.594, p= 0.009), and it was not correlated with any clinical pathological characteristics. According to the old criteria for RS stratification, 52.7% of patients were in low risk (RS< 18), 36.8% of patients were in medium risk (18≤RS≤ 30), and 10.5% of patients were in high risk (RS> 30). While under the new criteria, 18.4% were in low risk group (RS< 11), 63.2% were in a medium risk group (11≤RS≤ 26), and 18.4% were in a high risk group (RS> 26). The Oncotype DX 21-gene results only correlated with Ki-67 expression under both new and old criteria, and it was not related with other cancer characteristics. The expression of lncRNA MALAT1 was significantly correlated with the Oncotype DX 21-gene results under the old criteria.Conclusion: MALAT1 is a novel breast cancer biomarker independent of tumor stage, disease grade and lymph node status. MALAT1 level is associated with the Oncotype DX 21-gene RS value. Therefore, combination of MALAT1 and the Oncotype DX 21-gene test may be used to predict prognosis in ER+ and early stage breast cancer.Keywords: Oncotype DX 21-gene test, MALAT1, long non-coding RNA; lncRNA, breast cancer, risk of recurrence

Pengcheng Liu,1,* Jie Tan,2,* Qiuwen Tan,1 Li Xu,1 Tao He,1 Qing Lv1 1Department of Breast Surgery, Clinical Research Center for Breast, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2Department of Orthopaedic Surgery & Orthopaedic Institute, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing LvDepartment of Breast Surgery, Clinical Research Center for Breast, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu 610041, Sichuan, People’s Republic of ChinaEmail lvqingwestchina@163.comBackground: Accurate lymph node (LN) staging has considerably prognostic and therapeutic value in patients with colorectal cancer (CRC). The purpose of this study is to evaluate the feasibility of applying carbon nanoparticles (CNPs) to track LN metastases in CRC.Methods: Two researchers independently screened publications in PubMed, EMBASE, Cochrane and Ovid MEDLINE databases. The keywords were (carbon nanoparticles OR activated carbon nanoparticles) AND (colon cancer OR rectal cancer OR colorectal cancer). Titles and abstracts of the articles were meticulously read to rule out potential publications. Next, full texts of the ultimately obtained eligible publications were retrieved and analyzed in detail.Results: The search produced 268 publications, and 140 abstracts were identified after a bibliographic review. Finally, 20 studies relevant to our subject were obtained; however, only 14 papers met our inclusion criteria and were included for final review. All studies included have compared the control group with carbon nanoparticles group (control group, defined as nontattooed group; and carbon nanoparticles group, defined as administering carbon nanoparticles during surgery) for their efficacy in intraoperative detecting and positioning. After analysis, appreciably less amount of bleeding (3/5 trials), shorter operation time (2/4 trials), and shorter time to detect lesions and dissect LNs (2/2 trials) were revealed in CNPs group compared to control group. Thirteen studies have recorded the numbers of the harvested LNs in both groups; meanwhile, CNPs group shows superiority to control group in LN retrieval as well (11/13 trials), which also could effectively aid in locating and harvesting more LNs with diameter below 5 mm.Conclusion: The tracing technique for CNPs is a safe and useful strategy both in localizing tumor and tracing LNs in CRC surgery. But there is still a need for more randomized controlled trials to further establish its contribution to patient survival.Keywords: carbon nanoparticles, colorectal cancer, lymph nodes, trace, tumor location

Zongqiu Wang,1,* Jiwen Hou,2,* Yu Shi,3 Qiaowen Tan,1 Lin Peng,1 Zhiying Deng,1 Zhihong Wang,1 Zongjun Guo1 1Department of Geriatrics, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Geriatrics, The Affiliated Hospital of Chengdu University, Chengdu, People’s Republic of China; 3Department of Critical Medicine, Weihai Central Hospital, Weihai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zongjun GuoDepartment of Geriatrics, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong 266003, People’s Republic of ChinaEmail guozjj@163.comObjective: To explore the effects of different lifestyle choices on mild cognitive impairment (MCI) and to establish a decision tree model to analyse their predictive significance on the incidence of MCI.Methods: Study participants were recruited from geriatric and physical examination centres from October 2015 to October 2019: 330 MCI patients and 295 normal cognitive (NC) patients. Cognitive function was evaluated by the Mini-Mental State Examination Scale (MMSE) and Clinical Dementia Scale (CDR), while the Barthel Index (BI) was used to evaluate life ability. Statistical analysis included the χ2 test, logistic regression, and decision tree. The ROC curve was drawn to evaluate the predictive ability of the decision tree model.Results: Logistic regression analysis showed that low education, living alone, smoking, and a high-fat diet were risk factors for MCI, while young age, tea drinking, afternoon naps, social engagement, and hobbies were protective factors for MCI. Social engagement, a high-fat diet, hobbies, living condition, tea drinking, and smoking entered all nodes of the decision tree model, with social engagement as the root node variable. The importance of predictive variables in the decision tree model showed social engagement, a high-fat diet, tea drinking, hobbies, living condition, and smoking as 33.57%, 27.74%, 22.14%, 11.94%, 4.61%, and 0%, respectively. The area under the ROC curve predicted by the decision tree model was 0.827 (95% CI: 0.795∼ 0.856).Conclusion: The decision tree model has good predictive ability. MCI was closely related to lifestyle; social engagement was the most important factor in predicting the occurrence of MCI.Keywords: lifestyle, behaviours habit, mild cognitive impairment, influencing factors, decision tree model

Introduction: Hospitals are a key source of information for the early identification of emerging disease outbreaks and acute public health events for risk assessment, decision-making, and public health response. The objectives of this study were to identify potential facilitators and barriers for reporting of unusual events from the curative sector to the preventive medicine system in Viet Nam. Methods: In 2016, we conducted 18 semi-structured in-depth interviews and 9 focus group discussions with representatives from the curative and preventive medicine sectors in four provinces. We transcribed the interviews and focus group discussions and conducted a thematic analysis of the factors that appeared to affect public health event reporting. Results: We identified five major themes. Firstly, the lack of a legal framework to guide reporting meant there was an over-reliance on internal procedures. Secondly, participants reported the importance of an enabling environment to facilitate reporting such as leadership support and having focal points for reporting. Thirdly, potential benefits for reporting were seen such as support during outbreaks and receiving feedback. Fourthly, some challenges prohibited timely reporting such as not perceiving reporting to be the task of the curative sector and hesitancy to report without laboratory confirmation. Finally, the limited resources and specialist capacities in remote areas hindered timely detection and reporting of unusual events. Discussion: This study identified potential opportunities to promote the detection and reporting of unusual events from health care workers to the public health sector, and thus improving the overall health security system in Viet Nam and beyond.

Libei Zhao, Manqiang Peng, Wenxiang Lin, Qian Tan, Muhammad Ahmad Khan, Ding Lin Department of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, No. 388, Section 2, Furong Middle Road, Changsha City, Hunan Province 410005, People’s Republic of ChinaTel +86 13787255158Email linding@csu.edu.cnPurpose: To explore the feasibility of cyclophosphamide (CP) via a sub-Tenon micro-perfusion system (SMS) in rabbits, and assess its therapeutic efficacy in severe ocular inflammation.Materials and Methods: Distribution and pharmacokinetics of CP were evaluated in vivo, and the concentrations of CP in plasma, vitreous humor, and retina/choroid were quantitated by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) at different time points. After induction of severe experimental uveitis, rabbits were divided into three groups (n=8 in each): the SMS group, subconjunctival injection (SI) group, and control group. Clinical inflammatory score was assessed in rabbits. Electroretinography and histopathology were performed on post-treatment day 8. Statistical analyses were performed using Mann–Whitney and Kruskal–Wallis tests. P-value less than 0.05 was considered significant.Results: The concentrations of CP in vitreous humor and retina/choroid in the SMS group were significantly higher than that of the SI group at 3, 6, 10, and 24 hours (P< 0.01), while plasmatic CP concentrations were comparable at all time points in the SMS group and SI group (P> 0.05). The SMS group showed significantly less inflammation compared to the control group and SI group. Furthermore, the restoration of retinal structure and function were more obvious in the SMS group compared with conventional SI application.Conclusion: Sub-Tenon micro-perfusion of CP exhibited satisfied therapeutic efficacy in rabbits with severe ocular inflammation and may provide a promising alternative for controlling ocular inflammatory disease and immune-mediated ocular diseases.Keywords: cyclophosphamide, sub-Tenon drug delivery, ocular inflammation, treatment, rabbit

Jinbao Wang,1,* Qingjuan Tan,2,* Weishan Wang,1 Jie Yu3 1General Surgery, Linyi Central Hospital, Linyi, Shandong Province, People’s Republic of China; 2Neonatal Intensive Care Unit, Linyi Central Hospital, Linyi, Shandong Province, People’s Republic of China; 3Department of Anal-Colorectal, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie YuDepartment of Anal-Colorectal, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei Province, People’s Republic of ChinaEmail yujie19797@163.comPurpose: To investigate the potential role of the circMTO1/miR-9-5p/NOX4 axis in liver cancer.Materials and Methods: Human genome-wide circrna microarray V2 was used for analyzing the expression profile of circRNAs in human tissue samples. The TargetScan database was used to predict target genes. Gene overexpression and silencing in hepatoma cell lines were achieved by transfecting the cells with suitable constructs. Quantitative real time PCR and Western blotting were used to analyze gene and protein expression levels. CCK-8 analysis was performed to detect cell proliferation and the transwell assay for analyzing cell migration. Annexin V-FITC/PI staining and immunohistochemistry were respectively used to detect apoptosis and protein expression.Results: CircMTO1 were down-regulated in the liver cancer tissues and cell lines compared to their respective normal controls. TargetScan database screening and dual luciferase assay revealed that circMTO1 was a molecular sponge of miR-9-5p, and NOX4 was the target gene of miR-9-5p. Overexpression of circMTO1 and NOX4 inhibited proliferation and migration of hepatoma cells, while the overexpression of miR-9-5p had the opposite effects. In contrast, overexpression of circMTO1 and NOX4 promoted apoptosis, while that of miR-9-5p decreased the cell apoptosis rates.Conclusion: Overexpression of CircMTO1 acts as tumor suppressor in liver cancer by sponging miR-9-5p, which upregulates NOX4.Keywords: circMTO1, miR-9-5p/NOX4 axis, hepatocellular carcinoma, proliferation, apoptosis

Abstract Background In 2016–2017, Vietnam’s Ministry of Health (MoH) implemented an event-based surveillance (EBS) pilot project in six provinces as part of Global Health Security Agenda (GHSA) efforts. This manuscript describes development and design of tools for monitoring and evaluation (M&E) of EBS in Vietnam. Methods A strategic EBS framework was developed based on the EBS implementation pilot project’s goals and objectives. The main process and outcome components were identified and included input, activities, outputs, and outcome indicators. M&E tools were developed to collect quantitative and qualitative data. The tools included a supervisory checklist, a desk review tool, a key informant interview guide, a focus group discussion guide, a timeliness form, and an online acceptability survey. An evaluation team conducted field visits for assessment of EBS 5–9 months after implementation. Results The quantitative data collected provided evidence on the number and type of events that were being reported, the timeliness of the system, and the event-to-signal ratio. The qualitative and subjective data collected helped to increase understanding of the system’s field utility and acceptance by field staff, reasons for non-compliance with established guidelines, and other factors influencing implementation. Conclusions The use of M&E tools for the EBS pilot project in Vietnam provided data on signals and events reported, timeliness of reporting and response, perceptions and opinions of implementers, and fidelity of EBS implementation. These data were valuable for Vietnam’s MoH to understand the function of the EBS program, and the success and challenges of implementing this project in Vietnam.

Min Yu,1,* Liyao Peng,1,* Ping Liu,1 Mingxia Yang,2 Hong Zhou,1 Yirui Ding,1 Jingjing Wang,3 Wen Huang,1 Qi Tan,1 Yanli Wang,1 Weiping Xie,1 Hui Kong,1 Hong Wang1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated Changzhou No.2 People’s Hospital of Nanjing Medical University, Changzhou 213003, People’s Republic of China; 3Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Kong; Hong WangDepartment of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, People’s Republic of ChinaTel +86-25-68136426Fax +86-25-68136269Email konghui@njmu.edu.cn; hongwang@njmu.edu.cnBackground: Endothelial cells dysfunction is one of the hallmark pathogenic features of pulmonary arterial hypertension (PAH). Paeoniflorin (PF) is a monoterpene glycoside with endothelial protection, vasodilation, antifibrotic, anti–inflammatory and antioxidative properties. However, the effects of PF on PAH remain unknown.Methods: Here, we investigated the efficacy of PF in the SU5416/hypoxia (SuHx) rat model of PAH. Human pulmonary arterial endothelial cells (HPAECs) were exposed to 1% O2 with or without PF treatment.Results: Hemodynamics analysis showed that prophylactic treatment with PF (300 mg/kg i.g. daily for 21 days) significantly inhibited chronic hypoxia/SU5416-induced elevations of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index in rats. Meanwhile, PF significantly reduced pulmonary vascular remodeling, as well as alleviated collagen deposition in lungs and right ventricles in SuHx rats. Additionally, PF inhibited SuHx–induced down-regulation of endothelial marker (vascular endothelial cadherin) and up-regulation of mesenchymal markers (fibronectin and vimentin) in lung, suggesting that PF could inhibit SuHx–induced endothelial-to-mesenchymal transition (EndMT) in lung. Further in vitro studies confirmed that PF treatment suppressed hypoxia-induced EndMT in HPAECs, which was abolished by the knockdown of bone morphogenetic protein receptor type 2 (BMPR2) in HPAECs.Conclusion: Taken together, our findings suggest that PF ameliorates BMPR2 down-regulation-mediated EndMT and thereafter alleviates SuHx–induced PAH in rats.Keywords: paeoniflorin, pulmonary arterial hypertension, endothelial-to-mesenchymal transition, BMPR2, hypoxia

Wenxiang Lin,1,2 Libei Zhao,1,2 Xuetao Huang,3 Qian Tan,1,2 Manqiang Peng,1,2 Muhammad Ahmad Khan,1,2 Ding Lin1,2 1Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of China; 2Department of Ophthalmology, Changsha Aier Eye Hospital, Changsha, People’s Republic of China; 3Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Ding LinDepartment of Ophthalmology, Changsha Aier Eye Hospital, Aier School of Ophthalmology, Central South University, Changsha, People’s Republic of ChinaTel +86-13787255158Email linding@csu.edu.cnBackground: The aim of this study was to compare the distribution characteristics and ocular pharmacokinetics of norvancomycin (NVCM) in ocular tissues of the anterior segment between continuous topical ocular instillation and hourly administration of eye drop in rabbits.Methods: Sixty rabbits were randomly divided into two groups: continuous topical ocular instillation drug delivery (CTOIDD) group and eye drop (control) group. In the CTOIDD group, NVCM solution (50 mg/mL) was perfused to the ocular surface using the CTOIDD system at 2 mL/h up to 10 h and the same solution was administered at one drop (50 μL) per hour for 10 h in the control group. Animals (N=6 per time-point per group) were humanely killed at 2, 4, 6, 10, and 24 h to analyze their ocular tissues and plasma. The concentrations of NVCM in the conjunctiva, cornea, aqueous humour, iris, ciliary body and plasma were measured by HPLC with photodiode array detector. The pharmacokinetic parameters were calculated by Kinetica 5.1.Results: The highest concentrations of NVCM for the CTOIDD group and control group were 2105.45± 919.89 μg/g and 97.18± 43.14 μg/g in cornea, 3033.92± 1061.95 μg/g and 806.99± 563.02 μg/g in conjunctiva, 1570.19± 402.87 μg/g and 46.93± 23.46 μg/g in iris, 181.94± 47.11 μg/g and 15.38± 4.00 μg/g in ciliary body, 29.78± 4.90 μg/mL and 3.20± 1.48 μg/mL in aqueous humour, and 26.89± 5.57 μg/mL and 1.90± 1.87 μg/mL in plasma, respectively. The mean NVCM levels significantly increased at all time-points in cornea, iris, and ciliary body (p< 0.05) in the CTOIDD group. The AUC0– 24 values in the CTOIDD group were 27,543.70 μg·h/g in cornea, 32,514.48 μg·h/g in conjunctiva, 8631.05 μg·h/g in iris, 2194.36 μg·h/g in ciliary body and 343.9 μg·h/mL in aqueous humour, which were higher than for the eye drop group in all tissues.Conclusion: Since continuous instillation of NVCM with CTOIDD could reach significantly higher concentrations and was sustained for a longer period compared with hourly administration of eye drop, CTOIDD administered NVCM could be a possible method to treat bacterial keratitis.Keywords: topical drug delivery, ocular tissue, anterior segment, area under the curve, rabbit eye

In our inter-connected world, health-care professionals are the first line of defence to identify emerging diseases and public health events for rapid response. In Vietnam, event-based surveillance (EBS), critical for the early detection of emerging disease outbreaks and acute public health events, has been limited to media-based EBS until recently. In 2017–2018, the Ministry of Health of Vietnam, in collaboration with the World Health Organisation and the US Centres for Disease Control and Prevention, designed, implemented, and evaluated a hospital EBS demonstration pilot in six hospitals in two provinces in Vietnam. After the 9-month implementation period, we conducted a logbook review, eight interviews, and six focus group discussions with hospital and preventive medicine staff, and conducted thematic and descriptive analysis. During the implementation period, 11 signals were reported and confirmed as true events. Of the 11 signals, majority (N = 8, 72.7%) were detected in ICU, followed by the outpatient department (N = 2, 18.2%). The most common signal were clusters of food poisoning (N = 4, 36.4%). All (100%) signals were reported, risk-assessed, and responded to within 24 hours of signal detection. The hospital and preventive medicine staff reported that one of the main benefits of the pilot was their improved mutual relationship. This pilot formalised hospital event-based surveillance through a legal framework, standard operating procedures, a formal feedback mechanism to hospitals to facilitate a two-way conversation, and providing additional training and continued sensitisation. Most importantly, it fostered a trusting relationship between the curative medicine and public health sectors, marking an important step towards advancing the national event-based surveillance system in Vietnam.

Summary: Background: Vietnam has emerged as one of the world's leading success stories in responding to COVID-19. After a prolonged period of little to no transmission, there was an outbreak of unknown source in July, 2020, in the Da Nang region, but the outbreak was quickly suppressed. We aimed to use epidemiological, behavioural, demographic, and policy data from the COVID-19 outbreak in Da Nang to calibrate an agent-based model of COVID-19 transmission for Vietnam, and to estimate the risk of future outbreaks associated with reopening of international borders in the country. Methods: For this modelling study, we used comprehensive data from June 15 to Oct 15, 2020, on testing, COVID-19 cases, and quarantine breaches within an agent-based model of SARS-CoV-2 transmission to model a COVID-19 outbreak in Da Nang in July, 2020. We applied this model to quantify the risk of future outbreaks in Vietnam in the 3 months after the reopening of international borders, under different behavioural scenarios, policy responses (ie, closure of workplaces and schools), and ongoing testing. Findings: We estimated that the outbreak in Da Nang between July and August, 2020, resulted in substantial community transmission, and that higher levels of symptomatic testing could have mitigated this transmission. We estimated that the outbreak peaked on Aug 2, 2020, with an estimated 1060 active infections (95% projection interval 890–1280). If the population of Vietnam remains highly compliant with mask-wearing policies, our projections indicate that the epidemic would remain under control even if a small but steady flow of imported infections escaped quarantine into the community. However, if complacency increases and testing rates are relatively low (10% of symptomatic individuals are tested), the epidemic could rebound again, resulting in an estimated 2100 infections (95% projected interval 1050–3610) in 3 months. These outcomes could be mitigated if the behaviour of the general population responds dynamically to increases in locally acquired cases that exceed specific thresholds, but only if testing of symptomatic individuals is also increased. Interpretation: The successful response to COVID-19 in Vietnam could be improved even further with higher levels of symptomatic testing. If the previous approaches are used in response to new COVID-19 outbreaks, epidemic control is possible even in the presence of low levels of imported cases. Funding: Ministry of Science and Technology (Vietnam). Translation: For the Vietnamese translation of the abstract see Supplementary Materials section.

Jiaowang Tan,1,2 Li Luo,3 Min Zhang,3 Huifen Chen,3 Dingjun Zhang,3 Chendi Dong,3 Bingqing Xia,3 Lizhe Fu,1 Fang Tang,1 Xusheng Liu,1 Qinxiang Tan,2 Yifan Wu11Renal Division, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, People’s Republic of China; 2Renal Division, Beijing University of Chinese Medicine Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 3The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of ChinaCorrespondence: Yifan WuRenal Division, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), No.111, Dade Road, Yuexiu District, Guangzhou 510120, People’s Republic of ChinaTel +86 13 56 032 4448Email wuyifan007@gzucm.edu.cnObjective: The self-reported scale is a widely used method to assess patients’ medication adherence in clinical practice, but there is still a lack of medicine adherence measurement scale for patients with Chronic Kidney Disease (CKD). Therefore, this study aimed to develop a medication adherence measurement scale of traditional Chinese medicine and Western medicine, providing a tool for evaluating medicine adherence of CKD patients.Methods: In the preliminary stage, we formed the prediction scale after three rounds Delphi method and it was filled by 20 patients, who were selected randomly. After pre-investigation and language adaption, we adjusted the prediction measurement scale which included 31 items based on Knowledge-Attitude-Belief Theory. Then, 222 CKD patients in Guangdong Hospital of traditional Chinese Medicine were investigated by this 31-item scale. We screened 31 items by Items analysis theory, including critical ratio, item correlation analysis, internal consistency analysis, principal component analysis and other methods. The left 26 items made up a formal scale. We collected and analyzed data of the 26-item scale and Chinese version of MGL scale, and took their scores correlation analysis as the criterion validity of the 26-item scale. At the same time, we evaluated content validity, Cronbach alpha coefficient and retest reliability of the 26-item scale.Results: We developed a scale with 26 items and 5 dimensions finally. In the validation analysis, the scale had good construct validity and content validity. The Pearson relation index between respective scores of the scale and Chinese version of MGL scale was 0.426, P

Wen Shi,1 Juan Wu,1 Qi Tan,1 Chun-Mei Hu,2 Xia Zhang,2 Hong-Qiu Pan,3 Zhen Yang,4 Meng-Yu He,1 Min Yu,1 Bo Zhang,5 Wei-Ping Xie,1 Hong Wang11Department of Respiratory and Critical Care Medicine, Jiangsu Province Hospital. The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 2Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing, Jiangsu Province, People’s Republic of China; 3Department of Tuberculosis, The Third Hospital of Zhenjiang City, Zhenjiang, Jiangsu Province, People’s Republic of China; 4Department of Respiratory Medicine, Jiangbei Hospital, Nanjing, Jiangsu Province, People’s Republic of China; 5Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USAPurpose: Multidrug-resistant tuberculosis (MDR-TB) remains a challenge of global TB control, with difficulty in early detection of drug-sensitive tuberculosis (DS-TB). We investigate the diagnostic significance of IDO as a potential biomarker to discriminate MDR patients among the TB patients.Patients and methods: Plasma indoleamine 2,3-dioxygenase (IDO) was measured by the ratio of kynurenine (Kyn) to tryptophan (Trp) concentrations, using high performance liquid chromatography-mass spectrometry (LC-MS/MS). Chest computed tomography (CT) imaging signs from TB patients were collected and analyzed in 18 DS-TB patients, 16 MDR-TB patients, 6 lung cancer (LC) patients, and 11 healthy individuals. Lung imaging signs from TB patients were collected and analyzed.Results: We found that plasma IDO activity was significantly higher in the MDR-TB patients than in the DS-TB patients (p=0.012) and in the LC patients (p=0.003). We evaluated the diagnostic significance of plasma IDO activity in discriminating the MDR-TB group from the DS-TB group using a receiver operating characteristic (ROC) curve. With a cutoff level of 46.58 uM/mM, the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for IDO activity were 87.50%, 72.22%, 73.68%, and 86.67%, respectively. Plasma IDO activity was higher in cavity cases than in non-cavity cases (p=0.042), proving a positive correlation between lung cavity number and cavity size (p

Surveillance and outbreak reporting systems in Vietnam required improvements to function effectively as early warning and response systems. Accordingly, the Ministry of Health of Vietnam, in collaboration with the US Centers for Disease Control and Prevention, launched a pilot project in 2016 focusing on community and hospital event–based surveillance. The pilot was implemented in 4 of Vietnam’s 63 provinces. The pilot demonstrated that event-based surveillance resulted in early detection and reporting of outbreaks, improved collaboration between the healthcare facilities and preventive sectors of the ministry, and increased community participation in surveillance and reporting.

The study of distant galaxy groups and clusters at the peak epoch of star formation is limited by the lack of a statistically and homogeneously selected and spectroscopically confirmed sample. Recent discoveries of concentrated starburst activities in cluster cores have opened a new window to hunt for these structures based on their integrated IR luminosities. Here, we carry out a large NOEMA (NOrthern Extended Millimeter Array) program targeting a statistical sample of infrared-luminous sources associated with overdensities of massive galaxies at z > 2, the Noema formIng Cluster survEy (NICE). We present the first result from the ongoing NICE survey, a compact group at z = 3.95 in the Lockman Hole field (LH-SBC3), confirmed via four massive (M∗ ≳ 1010.5 M⊙) galaxies detected in the CO(4-3) and [CI](1-0) lines. The four CO-detected members of LH-SBC3 are distributed over a 180 kpc physical scale and the entire structure has an estimated halo mass of ~1013 M⊙ and total star formation rate of ~4000 M⊙ yr-1. In addition, the most massive galaxy hosts a radio-loud active galactic nucleus with L1.4 GHz, rest = 3.0 × 1025 W Hz-1. The discovery of LH-SBC3 demonstrates the feasibility of our method to efficiently identify high-z compact groups or cluster cores undergoing formation. The existence of these starbursting cluster cores up to z ~ 4 provides critical insights into the mass assembly history of the central massive galaxies in clusters.

This article describes Viet Nam Ministry of Health’s (VMoH) activities to prepare for and respond to the threat Zika virus (ZIKV), including the adaptation of existing surveillance systems to encompass ZIKV surveillance.

Jiangbo Hu,1,* Dilong Chen,2,* Rong Jiang,2 Qunyou Tan,3 Biyue Zhu,4 Jingqing Zhang11Medicine Engineering Research Center, Chongqing Medical University, Chongqing, People's Republic of China; 2Department of Histology and Embryology, Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, 3Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 4West China School of Pharmacy, Sichuan University, Chengdu, People's Republic of China *These authors contributed equally to this workPurpose: The purpose of this study was to assess the improved absorption and in vivo kinetic characteristics of a novel water-in-oil nanoemulsion containing evodiamine–phospholipid nanocomplex (NEEPN) when administered orally.Methods: NEEPN was fabricated by loading an evodiamine–phospholipid nanocomplex into a water-in-oil nanoemulsive system. The gastrointestinal absorption of NEEPN was investigated using an in situ perfusion method. The modified in vivo kinetic characteristics of evodiamine (EDA) in NEEPN were also evaluated.Results: Compared with EDA or conventional nanoemulsions containing EDA instead of evodiamine–phospholipid complex, NEEPN with its favorable in vivo kinetic characteristics clearly enhanced the gastrointestinal absorption and oral bioavailability of EDA; for example, the relative bioavailability of NEEPN to free EDA was calculated to be 630.35%, and the effective permeability of NEEPN in the colon was 8.64-fold that of EDA.Conclusion: NEEPN markedly improved the oral bioavailability of EDA, which was probably due to its increased gastrointestinal absorption. NEEPN also increased efficacy and reduced adverse effects for oral delivery of EDA. Such finding demonstrates great clinical significance as an ideal drug delivery system demands high efficacy and no adverse effects.Keywords: nanoemulsive system, evodiamine–phospholipid, nanocomplexes, gastrointestinal absorption, oral bioavailability, water-in-oil

Qunyou Tan,1,* Rong Jiang,3,* Meiling Xu,2,4,* Guodong Liu,5,* Songlin Li,1 Jingqing Zhang21Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 2Medicine Engineering Research Center, Chongqing Medical University, 3Stem Cells and Tissue Engineering Research, Chongqing Medical University, 4Department of Pharmacy, Chongqing Emergency Medical Center, 5Eighth Department, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workBackground: Pyridostigmine bromide (3-[[(dimethylamino)-carbonyl]oxy]-1-methylpyridinium bromide), a reversible inhibitor of cholinesterase, is given orally in tablet form, and a treatment schedule of multiple daily doses is recommended for adult patients. Nanotechnology was used in this study to develop an alternative sustained-release delivery system for pyridostigmine, a synthetic drug with high solubility and poor oral bioavailability, hence a Class III drug according to the Biopharmaceutics Classification System. Novel nanosized pyridostigmine-poly(lactic acid) microcapsules (PPNMCs) were expected to have a longer duration of action than free pyridostigmine and previously reported sustained-release formulations of pyridostigmine.Methods: The PPNMCs were prepared using a double emulsion-solvent evaporation method to achieve sustained-release characteristics for pyridostigmine. The preparation process for the PPNMCs was optimized by single-factor experiments. The size distribution, zeta potential, and sustained-release behavior were evaluated in different types of release medium.Results: The optimal volume ratio of inner phase to external phase, poly(lactic acid) concentration, polyvinyl alcohol concentration, and amount of pyridostigmine were 1:10, 6%, 3% and 40 mg, respectively. The negatively charged PPNMCs had an average particle size of 937.9 nm. Compared with free pyridostigmine, PPNMCs showed an initial burst release and a subsequent very slow release in vitro. The release profiles for the PPNMCs in four different types of dissolution medium were fitted to the Ritger-Peppas and Weibull models. The similarity between pairs of dissolution profiles for the PPNMCs in different types of medium was statistically significant, and the difference between the release curves for PPNMCs and free pyridostigmine was also statistically significant.Conclusion: PPNMCs prepared by the optimized protocol described here were in the nanometer range and had good uniformity, with significantly slower pyridostigmine release than from free pyridostigmine. This novel sustained-release delivery nanosystem for pyridostigmine might alleviate the need to identify new acetylcholinesterase inhibitors.Keywords: nanosized microcapsules, process optimization, characteristics, sustained-release, pyridostigmine bromide

Qunyou Tan,1,* Dan He,2,* Mingjun Wu,2,* Lin Yang,3 Yong Ren,4 Juan Liu,2 Jingqing Zhang,21Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, 2Medicine Engineering Research Center, Chongqing Medical University, Chongqing, 3Chongqing Institute for Food and Drug Control, Chongqing, 4Center of Drug Discovery, Nanjing Normal University, Nanjing, People's Republic of China*These authors contributed equally to this workBackground: The purpose of this study was to develop, characterize, and investigate a molecular inclusion complex containing rifaldazine with good solubility and antibacterial activity.Methods: Rifaldazine, a lipophilic molecule, was encapsulated into the hydrophobic cavity of ß-cyclodextrin to form a molecular inclusion complex (RAABCD) with good solubility. RAABCD was prepared in a short time using a solid-state grinding method. The inclusion ratio, binding constant, and change in Gibbs free energy were determined by a phase solubility diagram and/or ultraviolet-visible spectroscopy. Differential scanning calorimetry and Fourier transform infrared spectroscopy of RAABCD were performed. Morphological features of RAABCD were observed by photomicroscopy. The most likely optimal configuration for RAABCD was simulated by computer modeling. Broth macrodilution testing was done to investigate the antibacterial activity of RAABCD.Results: The inclusion ratio, binding constant, and change in Gibbs free energy, determined by a phase solubility diagram and/or ultraviolet-visible spectroscopy were 1:1, 288.33/261.33 L/mol, and 32.29/31.73 kJ/mol, respectively. Differential scanning calorimetry and Fourier transformed infrared spectra of RAABCD confirmed the molecular interaction between rifaldazine and ß-cyclodextrin. The morphological difference between irregular and amorphous-shaped RAABCD and columnar-shaped rifaldazine further confirmed the molecular encapsulation of rifaldazine. The most likely optimal configuration for RAABCD was confirmed by computer modeling. Broth macrodilution testing indicated that RAABCD had good antibacterial activity.Conclusion: RAABCD had improved solubility and good activity, and might be a promising alternative for treatment of a range of bacterial infections.Keywords: rifaldazine, cyclodextrin inclusion complex, stoichiometric relationships, differential scanning calorimetry, Fourier transform infrared spectra, computer modeling

Yunming Tao,1,2 Tiehui Hu,1 Zhongshi Wu,1 Hao Tang,1 Yerong Hu,1 Qi Tan,1 Chunlin Wu11Department of Thoracic and Cardiovascular Surgery, Second Xiangya Hospital of Central South University, Changsha; 2Department of Thoracic and Cardiovascular Surgery, Ji'an Central People’s Hospital, Ji'an, Jiangxi Province, People's Republic of ChinaAbstract: Biocompatibility and biomechanical stability are two of the main obstacles limiting the effectiveness of vascular scaffolds. To improve the biomechanical stability and biocompatibility of these scaffolds, we created a heparin-nanomodified acellular bovine jugular vein scaffold by alternating linkage of heparin and dihydroxy-iron via self-assembly. Features of the scaffold were evaluated in vitro and in vivo. Heparin was firmly linked to and formed nanoscale coatings around the fibers of the scaffold, and the amount of heparin linked was about 808 ± 86 µg/cm2 (101 ± 11 USP/cm2) per assembly cycle. The scaffolds showed significantly strengthened biomechanical stability with sustained release of heparin for several weeks in vitro. Importantly, the modified scaffolds showed significantly reduced platelet adhesion, stimulated proliferation of endothelial cells in vitro, and reduced calcification in a subcutaneous implantation rat model in vivo. Heparin nanomodification improves the biocompatibility and biomechanical stability of vascular scaffolds.Keywords: scaffolds, nanomodification, heparin, sustained release, biomechanical stability, biocompatibility

Qunyou Tan,1,* Yi Li,2–4,* Jianyong Wu,2,* Hu Mei,5 Chunjing Zhao,3 Jingqing Zhang21Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, 2Medicine Engineering Research Center, Chongqing Key Laboratory of Biochemical and Molecular Pharmacology, Chongqing Medical University, 3School of Pharmacy, Second Affiliated Hospital, Chongqing Medical University, 4School of Pharmacy, The First People’s Hospital of Chongqing, 5College of Bioengineering, Chongqing University, Chongqing, People’s Republic of China*These authors contributed equally to this work Objective: The purpose of this study was to explore and evaluate the enhanced physical properties and biological activity of a molecular inclusion complex (MICDH) comprising diferuloylmethane (DFM) and hydroxypropyl-β-cyclodextrin.Methods: The preparation conditions of MICDH were optimized using an orthogonal experimental design. The solubility, in vitro release and model fitting, microscopic morphology, molecular structure simulation, anti-lung cancer activity, and action mechanism of MICDH were evaluated.Results: The solubility of DFM was improved 4400-fold upon complexation with hydroxypropyl-β-cyclodextrin. The release rate of DFM was significantly higher from MICDH than from free DFM. MICDH exhibited higher antitumor activity against human lung adenocarcinoma A549 cells than free DFM. More cells were arrested in the S/G2 phase of the cell cycle or were induced to undergo apoptosis when treated with MICDH than when treated with free DFM. Furthermore, increased reactive oxygen species and intracellular calcium ion levels and decreased mitochondrial membrane potential were observed in cells treated with MICDH.Conclusion: MICDH markedly improved the physical properties and antitumor activity of DFM. MICDH may prove to be a preferred alternative to free DFM as a formulation for DFM delivery in lung cancer treatment.Keywords: biological properties, action mechanism, hydroxypropyl-β-cyclodextrin, antitumor activity

Qi Tan1, Weidong Liu1,2, Chenyu Guo1, Guangxi Zhai11Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan; 2Department of Pharmacy, Linyi People's Hospital Affiliated to Shandong University, Linyi, People's Republic of ChinaBackground: The purpose of this study was to investigate lecithin-chitosan nanoparticles as a topical delivery system for quercetin.Methods: Tocopheryl propylene glycol succinate was chosen to be the surfactant for the nanosystem. The mean particle size of the nanoparticles was 95.3 nm, and the entrapment efficiency and drug loading for quercetin were 48.5% and 2.45%, respectively. Topical delivery in vitro and in vivo of the quercetin-loaded nanoparticles was evaluated using quercetin propylene glycol solution as the control.Results: Compared with quercetin solution, the quercetin-loaded nanoparticles showed higher permeation ability, and significantly increased accumulation of quercetin in the skin, especially in the epidermis. Microstructure observation of the skin surface after administration indicated that the interaction between ingredients of the nanoparticles and the skin surface markedly changed the morphology of the stratum corneum and disrupted the corneocyte layers, thus facilitating the permeation and accumulation of quercetin in skin.Conclusion: Lecithin-chitosan nanoparticles are a promising carrier for topical delivery of quercetin.Keywords: quercetin, tocopheryl polyethylene glycol succinate, lecithin, chitosan, nanoparticles, topical delivery

Qi Tan, Hao Tang, Jianguo Hu, Yerong Hu, Xinmin Zhou, Yunming Tao, Zhongshi WuDepartment of Cardiothoracic Surgery Second Xiangya Hospital, Central South University, Changsha 410011, People's Republic of ChinaAbstract: Regeneration deficiency is one of the main obstacles limiting the effectiveness of tissue-engineered scaffolds. To develop scaffolds that are capable of accelerating regeneration, we created a heparin/chitosan nanoparticle-immobilized decellularized bovine jugular vein scaffold to increase the loading capacity and allow for controlled release of vascular endothelial growth factor (VEGF). The vascularization of the scaffold was evaluated in vitro and in vivo. The functional nanoparticles were prepared by physical self-assembly with a diameter of 67–132 nm, positive charge, and a zeta potential of ~30 mV and then the nanoparticles were successfully immobilized to the nanofibers of scaffolds by ethylcarbodiimide hydrochloride/hydroxysulfosuccinimide modification. The scaffolds immobilized with heparin/chitosan nanoparticles exhibited highly effective localization and sustained release of VEGF for several weeks in vitro. This modified scaffold significantly stimulated endothelial cells' proliferation in vitro. Importantly, utilization of heparin/chitosan nanoparticles to localize VEGF significantly increased fibroblast infiltration, extracellular matrix production, and accelerated vascularization in mouse subcutaneous implantation model in vivo. This study provided a novel and promising system for accelerated regeneration of tissue-engineering scaffolds.Keywords: nanoparticle, scaffolds, VEGF, control release, vascularization, regeneration