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Haiyan Zhang,1,* Chaoying Jin,2,* Jiaqing Hua,3,* Zuxiang Chen,4 Wenxin Gao,4 Wenting Xu,4 Li Zhou,4 Letian Shan1 1The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 3College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China; 4The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Letian Shan; Li Zhou, Email letian.shan@zcmu.edu.cn; zhouli@zcmu.edu.cnAbstract: Osteoarthritis (OA) induced microenvironmental alterations are a common and unavoidable phenomenon that greatly exacerbate the pathologic process of OA. Imbalances in the synthesis and degradation of cartilage extracellular matrix (ECM) have been reported to be associated with an adverse microenvironment. Stem cell therapy is a promising treatment for OA, and mesenchymal stem cells (MSCs) are the main cell sources for this therapy. With multispectral differentiation and immunomodulation, MSCs can effectively regulate the microenvironment of articular cartilage, ameliorate inflammation, promote regeneration of damaged cartilage, and ultimately alleviate OA symptoms. However, the efficacy of MSCs in the treatment of OA is greatly influenced by articular cavity microenvironments. This article reviews the five microenvironments of OA articular cavity, including inflammatory microenvironment, senescence microenvironment, hypoxic microenvironment, high glucose microenvironment and high lipid environment, focus on the positive and negative effects of OA microenvironments on the fate of MSCs. In this regard, we emphasize the mechanisms of the current use of MSCs in OA treatment, as well as its limitations and challenges.Keywords: microenvironment, mesenchymal stem cells, osteoarthritis

Yingying Jiang,1,* Siqi Ge,2,* Chunyang Wang,1 Chen Jin,1 Yumei Zhao,1 Qingying Liu3 1Department of Neuropharmacology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neuroepidemiology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 3Department of Pain Medicine, the First Affiliated Hospital of Zhengzhou University, Henan, 450052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingying Liu, Email liuqy1679@163.comBackground: Sleep played an important part in human health, and COVID-19 led to a continuous deterioration of sleep. However, the causal relationship between micronutrient and sleep disorder was not yet fully understood.Methods: In this research, the genetic causal relationship between micronutrient and sleep disorder was analyzed utilizing a two-sample Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) were used as instrumental variables. The analyses were conducted using the MR-Egger, inverse variance weighted, weighted mode, weighted median, simple mode, Cochran’s Q test and leave-one-out.Results: Our results suggested that 8 genetically predicted micronutrients participated in sleep disorders, including liver iron (L-iron) and iron in sleeping too much, spleen iron (S-iron) in sleeplessness/insomnia, trouble falling or staying asleep, sleep duration (undersleepers) and nonorganic sleeping disorders, iron metabolism disorder (IMD) and vitamin B12 deficiency anaemia (VB12DA) in narcolepsy, urine sodium (uNa) in narcolepsy, sleep apnea syndrome and sleep disorder, vitamin D (VD) in sleep duration (oversleepers), 25-Hydroxyvitamin D (25(OH)D) in trouble falling or staying asleep.Conclusion: Our study used Mendelian randomization methods at the SNP level to explore the potential causal relationship among L-iron, iron, S-iron, IMD, uNa, 25(OH)D, VD, VB12DA with certain sleep disorder subtypes. Our results uncovered a micronutrient-based strategy for alleviating sleep disorder symptoms.Keywords: Mendelian randomization, micronutrient, sleep disorder, causality, vitamin

Jiasen Ma,1 Xiuqin Huang,2 Yanping Hu,1 Bing Xu,1 Chunhua Jin1 1Emergency Department, Shaoxing People’s Hospital, Shaoxing, Zhejiang Province, People’s Republic of China; 2Department of Plastic and Cosmetic Surgery, The 72nd Group Military Hospital of the People’s Liberation Army of China, Huzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Chunhua Jin, Emergency Department, Shaoxing People’s Hospital, Shaoxing, Zhejiang Province, People’s Republic of China, Email mjsjch@163.comBackground: Secretoneurin is a neuropeptide with several neuroprotective properties. Here, we discuss the importance of serum secretoneurin in assessing severity and predicting delayed cerebral ischemia (DCI) and functional outcomes following aneurysmal subarachnoid hemorrhage (aSAH).Methods: A prospective cohort study of 167 patients with aSAH and 100 controls was performed to determine serum secretoneurin levels. Severity was reflected by the Hunt-Hess and modified Fisher scores. Prognostic parameters included DCI and poor 6-month prognosis (extended Glasgow outcome scale scores of 1– 4). Univariate analysis followed by multivariate analysis was performed to determine the correlation between severity and prognosis.Results: Compared to controls, patients exhibited a marked elevation in serum secretoneurin levels. Serum secretoneurin levels, which were independently correlated with Hunt-Hess scores and modified Fisher scores, independently predicted DCI and bad 6-month prognosis. Serum secretoneurin levels, which were linearly related to the risk of DCI and poor prognosis under a restricted cubic spline, effectively distinguished the risks under the receiver operating characteristic (ROC) curve. Subgroup analysis for prognosis or DCI prediction revealed no substantial interactions between serum secretoneurin levels and other variables, such as age, sex, hypertension, diabetes, alcohol consumption, and cigarette consumption. In addition, the prognosis model, in which serum secretoneurin, Hunt-Hess scale, and modified Fisher scale were merged, was graphically represented by a nomogram and performed well under the calibration, decision, and ROC curves.Conclusion: Serum secretoneurin levels significantly increased after aSAH, which was intimately correlated with disease severity and independently associated with DCI and worse outcomes, indicating that serum secretoneurin may be a potential prognostic biomarker of aSAH.Keywords: aneurysm, subarachnoid hemorrhage, secretoneurin, delayed cerebral ischemia, prognosis, outcome, severity

Chunhua Jin,1 Xiuqin Huang,2 Yanping Hu,1 Bing Xu,1 Jiasen Ma1 1Emergency Department, Shaoxing People’s Hospital, Shaoxing, Zhejiang Province, People’s Republic of China; 2Department of Plastic and Cosmetic Surgery, The 72nd Group Military Hospital of the People’s Liberation Army of China, Huzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jiasen Ma, Emergency Department, Shaoxing People’s Hospital, Shaoxing, Zhejiang Province, People’s Republic of China, Tel +86 575 88508888, Email sxrmyymjs@163.comBackground: Stanniocalcin-1 (STC1) may harbor anti-inflammatory and anti-oxidative properties, thereby exerting neuroprotective effects. This study was done with the intent to determine the role of serum STC1 in severity assessment and prognosis prediction of severe traumatic brain injury (sTBI).Methods: In this prospective longitudinal cohort study of 104 sTBI patients and 104 healthy individuals (controls), serum STC1 levels were quantified. Severity indicators were Glasgow Coma Scale (GCS) and Rotterdam computed tomography classification. Follow-up time was 180 days and extended Glasgow outcome scale (GOSE) score 1– 4 was deemed as poor prognosis. Multivariate analyses were applied to assess severity correlations and prognosis associations. Discriminative efficiencies were estimated in terms of area under receiver operating characteristic curve (AUC).Results: Patients exhibited significantly higher serum STC1 levels than controls. Serum STC1 levels were substantially elevated in order of GCS scores from 8 to 3, Rotterdam scores from 3 to 6 and 180-day GOSE scores from 8 to 1. Also, serum STC1 levels were independently correlated with GCS scores, Rotterdam scores and 180-day GOSE scores. Serum STC1 levels were independently associated with 180-day death, overall survival and poor prognosis, as well as were efficiently predictive of death and poor prognosis. Prediction model containing GCS scores, Rotterdam scores and serum STC1 levels, as opposed to any of them, showed higher discriminative ability for the risks of death and poor prognosis. Alternatively, serum STC1 levels were linearly correlated with risk of death, overall survival and poor prognosis under restricted cubic spline. Subgroup analysis showed that serum STC1 levels non-statistically significantly interacted with age, gender, hypertension, diabetes mellitus, etc.Conclusion: A significant elevation of serum STC1 levels is highly related to severity and clinical outcome, suggesting that serum STC1 may be a potential prognostic biomarker of sTBI.Keywords: traumatic brain injury, stanniocalcin-1, severity, outcome, biomarkers

Cui Jin, Yongmei Cao, Yingchuan Li Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of ChinaCorrespondence: Yingchuan Li, Department of Critical Care Medicine, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, People’s Republic of China, Email yingchuan_li@tongji.edu.cnIntroduction: The incidence and mortality rates of sepsis-induced acute kidney injury (SAKI) remain high, posing a substantial healthcare burden. Studies have implicated a connection between the development of SAKI and inflammation response, apoptosis, and autophagy. Moreover, evidence suggests that manipulating autophagy could potentially influence the prognosis of this condition. Notably, exosomes derived from bone mesenchymal stem cells (BMSCs-Exo) have exhibited promise in mitigating cellular damage by modulating pathways associated with inflammation, apoptosis, and autophagy. Thus, this study aims to investigate the influence of BMSCs-Exo on SAKI and the potential mechanisms that drive this impact.Methods: The SAKI model was induced in HK-2 cells using lipopolysaccharide (LPS), while rats underwent cecal ligation and puncture (CLP) to simulate the condition. Cell viability was assessed using the CCK-8 kit, and kidney damage was evaluated through HE staining, blood urea nitrogen (BUN), and serum creatinine (SCr) measurements. Inflammatory-related RNAs and proteins were quantified via qPCR and ELISA, respectively. Apoptosis was determined through apoptosis-related protein levels, flow cytometry, and TUNEL staining. Western blot analysis was utilized to measure associated protein expressions.Results: In vivo, BMSCs-Exo ameliorated kidney injury in CLP-induced SAKI rats, reducing inflammatory cytokine production and apoptosis levels. Fluorescence microscope observed the absorption of BMSCs-Exo by renal cells following injection via tail vein. In the SAKI rat kidney tissue, there was an upregulation of LC3-II/LC3-I, p62, and phosphorylated AMP-activated protein kinase (p-AMPK) expressions, indicating blocked autophagic flux, while phosphorylated mammalian target of rapamycin (p-mTOR) expression was downregulated. However, BMSCs-Exo enhanced LC3-II/LC3-I and p-AMPK expression, concurrently reducing p62 and p-mTOR levels. In vitro, BMSCs-Exo enhanced cell viability in LPS-treated HK-2 cells, and exerted anti-inflammation and anti-apoptosis effects which were consistent with the results in vivo. Similarly, rapamycin (Rapa) exhibited a protective effect comparable to BMSCs-Exo, albeit partially abrogated by 3-methyladenine (3-MA).Conclusion: BMSCs-Exo mitigate inflammation and apoptosis through autophagy in SAKI, offering a promising avenue for SAKI treatment. Keywords: exosomes, bone mesenchymal stem cells, acute kidney injury, sepsis, autophagy

Jian Wang,1 Ben Wang,2 Chao Liang,3 Caifei Jin,4 Huiliang Shen1 1Department of Dermatology, Zhejiang Province Dermatology Hospital, Huzhou City, 313200, Zhejiang Province, People’s Republic of China; 2Department of Information Technology, Zhejiang Province Dermatology Hospital, Huzhou City, 313200, Zhejiang Province, People’s Republic of China; 3Department of Surgery, Zhejiang Province Dermatology Hospital, Huzhou City, 313200, Zhejiang Province, People’s Republic of China; 4Department of Medical Technology, Zhejiang Province Dermatology Hospital, Huzhou City, 313200, Zhejiang Province, People’s Republic of ChinaCorrespondence: Huiliang Shen, Department of Dermatology, Zhejiang Province Dermatology Hospital, No. 61, Wuyuan Street, Deqing County, Huzhou City, Zhejiang Province, 313200, People’s Republic of China, Tel +86-13706535666, Email shl.1168@163.comPurpose: This study investigated microbiome and metabolome differences between ulcerated tissues and normal skin from the lower limbs of participants with leprosy.Patients and Methods: Ulcerated tissues and surrounding normal skin were collected from the lower limbs of 28 participants with leprosy who had been cured. The 16S ribosomal DNA sequencing analysis of the samples was conducted with the Illumina NovaSeq platform to analyze the community structure and diversity of microorganisms on the skin surface, followed by non-targeted metabolomic analysis with LC-MS technology. Next, differential metabolites were statistically screened, followed by metabolic pathway analysis. The Spearman method was used to analyze the correlation between differential microbiota and differential metabolites.Results: Compared to normal skin, ulcerated tissues showed a decrease in microbial α diversity (species richness, homogeneity, and sequencing depth), without significant differences (observed species, Chao1, Shannon, Simpson, and Pielou’s evenness index; P > 0.05). Conversely, Jaccard distance demonstrated that sample β-diversity exhibited a certain degree of clustering (P < 0.05), with significant differences between the two groups. The results of LEfSe analysis revealed that compared to the normal skin, the ulcerated tissues had significantly decreased microbial abundance of Flavobacteriaceae, Flavobacteriales, Lachnospiraceae, Lachnospirales, Enterobacterales, Acinetobacter, and Moraxellaceae, which might be associated with the ulcerative state. The Spearman correlation analysis suggested a strong correlation between skin metabolome and skin microbiome.Conclusion: For participants with leprosy sequelae, skin microecology and metabolites are disturbed and species diversity and homogeneity are reduced in lower-limb ulcers, and the types of skin metabolites are dependent on the microbiota.Keywords: leprosy, lower-limb ulcers, 16S rDNA sequencing, metabolome, skin microecology

Qing Su,1 Chen Jin,2 Yi Yang,1 Jingxian Wang,1 Juejin Wang,1 Hao Zeng,1 Yaqing Chen,1 Junxi Zhou,1 Yi Wang1 1Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, People’s Republic of China; 2Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People’s Republic of ChinaCorrespondence: Yi Wang, Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Chashan High Education Zone, Wenzhou, Zhejiang, 325035, People’s Republic of China, Tel +86-577-8669-9358, Email wang.yi@wmu.edu.cnPurpose: Observational studies have reported that autoimmune diseases are closely related to sarcopenia, but the causalities of autoimmune diseases with sarcopenia have not been established. We conducted this Mendelian randomization (MR) study to reveal the causal associations of overall autoimmune disease and five common autoimmune diseases with sarcopenia-related traits.Methods: The publicly available summary-level data of autoimmune diseases and three sarcopenia-related traits were used for analysis. The causal effects of autoimmune diseases on sarcopenia-related traits were first identified in discovery samples using the inverse-variance-weighted method as the primary method, and the robustness of results was examined by additional sensitivity analyses. Replication MR analyses were then conducted using replication samples of five autoimmune diseases. Finally, the possibility of reverse causation was assessed by reverse MR analyses.Results: In both the discovery and replication samples, we identified potential causal effects of rheumatoid arthritis (RA) on appendicular lean mass (ALM) and low grip strength (OR = 0.979, 95% CI: 0.964– 0.995 for ALM; OR = 1.042, 95% CI: 1.013– 1.072 for low grip strength), but not on walking pace. We also found that inflammatory bowel disease (IBD) and type 1 diabetes (T1D) were only causally negatively associated with ALM in the discovery stage (OR = 0.986, 95% CI: 0.974– 0.999 for IBD; OR = 0.987, 95% CI: 0.975– 0.999 for T1D), whereas systemic lupus erythematosus, multiple sclerosis, and overall autoimmune disease were not associated with any of the three sarcopenia-related traits. Additionally, reverse MR analysis only found an association between walking pace and overall autoimmune disease, but this association did not remain in the weighted-median method.Conclusion: This study demonstrates that RA is causally associated with low grip strength and reduced ALM, and that IBD and T1D may be causally negatively related to ALM.Keywords: Mendelian randomization, autoimmune disease, sarcopenia, rheumatoid arthritis, grip strength, appendicular lean mass

Yichun Gu,1,&ast; Anqi Wang,2,&ast; Huan Tang,3 Haode Wang,4 Yuji Jiang,5 Chunlin Jin,1 Haiyin Wang1 1Shanghai Health Development Research Center, Shanghai, People’s Republic of China; 2School of Public Health, Weifang Medical University, Weifang, Shandong, People’s Republic of China; 3School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 4School of Health and Related Research, University of Sheffield, Sheffield, UK; 5Business School, Imperial College London, London, UK&ast;These authors contributed equally to this workCorrespondence: Chunlin Jin; Haiyin Wang, Shanghai Health Development Research Center, Shanghai, People’s Republic of China, Tel +8613162429202 ; +8618917769216, Email jinchunlin@shdrc.org; wanghaiyin@shdrc.orgBackground: In light of the limited availability of healthcare resources, providing universal access to healthcare is a challenging task. As a result, prioritizing healthcare services has emerged as a crucial issue. This study aims to explore the preferences of the public regarding healthcare prioritization for rare and common diseases. By examining public attitudes, this study seeks to inform government decisions concerning resource allocation and distribution within healthcare.Methods: “Social preference” and “rare disease” were searched as MeSH terms in the electronic databases of Ovid Medline, Web of Science, Embase, and Econlit for articles published since their establishment, and the information on the characteristics of the articles and the results of social preferences for rare diseases were analyzed and summarized.Results: The public held predominantly neutral views on the setting of healthcare priorities for rare and common diseases. The results of the included studies showed that with all else being equal, no social preference for rarity was found, but when the public considered the proportional advantage of rare diseases or when the respondents were young, a social preference for rarity existed. In addition, the public weighed attributes such as the health benefits of treatments, the effectiveness of treatment options, the safety of treatment, equity, unmet needs, and disease severity in the process of setting of treatment priorities for rare diseases. Furthermore, in consideration of equity, the public showed a willingness to pay for rare diseases in spite of the high medical costs.Conclusion: International studies on social preferences provide some evidence for the setting of healthcare priorities for rare diseases, and health policymakers should consider social preferences in an integrated manner in order to set healthcare priorities appropriately.Keywords: rare diseases, common diseases, healthcare, priority, social preference, social willingness to pay

Xuebin Tian,1,2,&ast; Yiwen Xie,1,2,&ast; Jingjing Chen,3,&ast; Wanpeng Yin,1,2 Yu Long Zhao,1 Peng Yao,4 Mingqing Dong,4 Changzhong Jin,1,2 Nanping Wu1,2 1Cell Biology Research Platform, Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, People’s Republic of China; 2State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Hospital Office, Shandong Second Provincial General Hospital, Jinan, Shandong, People’s Republic of China; 4Department of Infectious Disease, Zhejiang Qingchun Hospital, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changzhong Jin; Nanping Wu, Email changzhongjin@163.com; flwnp2013@163.comBackground: Microbial translocation (MT) is a characteristic of human immunodeficiency virus (HIV) infection. Whether MT is also a biomarker of different immune responses to antiretroviral therapy (ART) received by people living with HIV (PLWH) is not known.Methods: We examined the presence of MT in a cohort of 33 HIV-infected immunological responders (IRs) and 28 immunological non-responders (INRs) (≥ 500 and < 200 cluster of differentiation (CD)4+ T-cell counts/μL after 2 years of HIV-1 suppression, respectively) with no comorbidities. Plasma samples were used to measure the circulating levels of MT markers. All enrolled study participants had received 2 years of viral-suppression therapy.Results: Levels of lipopolysaccharide (P = 0.0185), LPS-binding protein (P < 0.0001), soluble-CD14 (P < 0.0001), and endogenous endotoxin-core antibody (P < 0.0001) at baseline were significantly higher in INRs than in IRs and were associated with an increased risk of an immunological non-response, whereas the level of intestinal fatty acid-binding protein did not show this association. Analysis of receiver operating characteristic (ROC) curves demonstrated the utility of these individual microbial markers in discriminating INRs after ART in people living with HIV with high sensitivity, specificity, and area under the ROC curve.Conclusion: INRs in HIV infection are characterized by increased MT at baseline. These markers could be used as a rapid prognostic tool for predicting immune responses in people infected with the HIV.Keywords: HIV, immunological non-responders, microbial translocation

Bin Lu,1 Xinling Pan,2 Bin Wang,3 Chenyuan Jin,1 Chenxin Liu,1 Mengqi Wang,4 Yunzhen Shi1 1Department of Infectious Diseases, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang Province, People’s Republic of China; 2Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, People’s Republic of China; 3Department of Emergency, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang Province, People’s Republic of China; 4Department of Neurology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang Province, People’s Republic of ChinaCorrespondence: Yunzhen Shi, Department of Infectious Diseases, Affiliated Dongyang Hospital of Wenzhou Medical University, No. 60 Wuningxi Road, Dongyang, People’s Republic of China, Email syzwylwmc@163.comPurpose: We attempted to establish a model for predicting the mortality risk of sepsis patients during hospitalization.Patients and Methods: Data on patients with sepsis were collected from a clinical record mining database, who were hospitalized at the Affiliated Dongyang Hospital of Wenzhou Medical University between January 2013 and August 2022. These included patients were divided into modeling and validation groups. In the modeling group, the independent risk factors of death during hospitalization were determined using univariate and multi-variate regression analyses. After stepwise regression analysis (both directions), a nomogram was drawn. The discrimination ability of the model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, and the GiViTI calibration chart assessed the model calibration. The Decline Curve Analysis (DCA) was performed to evaluate the clinical effectiveness of the prediction model. Among the validation group, the logistic regression model was compared to the models established by the SOFA scoring system, random forest method, and stacking method.Results: A total of 1740 subjects were included in this study, 1218 in the modeling population and 522 in the validation population. The results revealed that serum cholinesterase, total bilirubin, respiratory failure, lactic acid, creatinine, and pro-brain natriuretic peptide were the independent risk factors of death. The AUC values in the modeling group and validation group were 0.847 and 0.826. The P values of calibration charts in the two population sets were 0.838 and 0.771. The DCA curves were above the two extreme curves. Moreover, the AUC values of the models established by the SOFA scoring system, random forest method, and stacking method in the validation group were 0.777, 0.827, and 0.832, respectively.Conclusion: The nomogram model established by combining multiple risk factors could effectively predict the mortality risk of sepsis patients during hospitalization.Keywords: severe sepsis, mortality risk prediction, nomogram, SOFA, random forest, stacking

Dan Long,1 Ting Yang,1 Jie Chen,1 Ying Dai,1 Li Chen,1 Feiyong Jia,2 Lijie Wu,3 Yan Hao,4 Ling Li,5 Jie Zhang,6 Xiaoyan Ke,7 Mingji Yi,8 Qi Hong,9 Jinjin Chen,10 Shuanfeng Fang,11 Yichao Wang,12 Qi Wang,13 Chunhua Jin,14 Tingyu Li1 1Chongqing Key Laboratory of Child Nutrition and Health, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center of Child Health and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, Changchun, People’s Republic of China; 3Research Center for Child Development and Behavior, Harbin Medical University, Harbin, People’s Republic of China; 4Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 5Department of Children Rehabilitation, Hainan Women and Children’s Medical Center, Haikou, People’s Republic of China; 6Children Health Care Center, Xi’an Children’s Hospital, Xi’an, People’s Republic of China; 7The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 8Department of Child Health Care, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 9Maternal and Child Health Hospital of Baoan, Shenzhen, People’s Republic of China; 10Department of Child Health Care, Shanghai Children’s Hospital, Shanghai, People’s Republic of China; 11Department of Child Health Care, Children’s Hospital Affiliated of Zhengzhou University, Zhengzhou, People’s Republic of China; 12National Health Commission Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Hospital, Changsha, People’s Republic of China; 13Deyang Maternal and Child Health Hospital, Deyang, People’s Republic of China; 14Department of Children Health Care, Capital Institute of Pediatrics, Beijing, People’s Republic of ChinaCorrespondence: Tingyu Li, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China, Tel +86 23 63630913, Fax +86 23 63622754, Email tyli@vip.sina.comPurpose: The present study investigated the age of diagnosis, treatment and demographic factors of Chinese children with autism spectrum disorders (ASD), to provide a scientific basis for the early detection, diagnosis, and intervention of ASD.Patients and Methods: A total of 1500 ASD children aged 2– 7 years old from 13 cities in China were administered questionnaires to examine their diagnosis, treatment, and basic family information. The Childhood Autism Rating Scale (CARS) was used to measure the symptoms and severity of ASD children, and the Children Neuropsychological and Behavior Scale-Revision 2016 (CNBS-R2016) was utilized to measure neurodevelopmental levels of ASD children.Results: We found that for children with ASD, the median (p25, p75) age for the initial detection of social behavioral developmental delay was 24 (18, 30) months, while the age for the initial diagnosis was 29 (24, 36) months and the age for the beginning of intervention was 33 (27, 42) months. Multiple linear regression (MLR) analysis suggested that in children with ASD whose parents were divorced, separated, or widowed, or whose mothers were engaged in physical work, the initial detection of social behavioral developmental delay happened later. For the children with ASD who lived in urban areas, had higher levels of ASD symptom severity or whose parents were not divorced or separated, the age for the initial diagnosis was earlier. For the children with ASD who lived in urban areas or whose mothers had received higher level of education, the earlier age for the beginning of intervention was observed, while for those with ASD whose mothers were engaged in physical work, the age for the beginning of training was later.Conclusion: It is recommended to actively carry out health education of ASD and strengthen the support for ASD families to enhance their rehabilitation level.Keywords: autism spectrum disorders, children, age, influencing factors, multicenter

Zhaoxiang Liu, Luqi Xiao, Chenxi Jin, Jianzhong Xiao, Wenhui Zhao Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of ChinaCorrespondence: Wenhui Zhao, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, People’s Republic of China, Tel +86 10-5611-9057, Fax +86 10-5611-9057, Email zwha01637@btch.edu.cnBackground: Bariatric surgery is an effective therapy for type 2 diabetes mellitus (T2DM) and obesity. Euglycaemic ketoacidosis (EKA) has been reported in patients taking sodium-glucose cotransporter 2 (SGLT2) inhibitors after bariatric surgery. Cases of T2DM complicated with EKA without SGLT2 inhibitors after bariatric surgery are rarely reported.Purpose: To present a case report of a T2DM patient (without SGLT2 inhibitor use) who developed EKA soon after laparoscopic sleeve gastrectomy.Methods: Clinical records and interviews were used.Results: A 35-year-old female patient was diagnosed with T2DM and obesity. The patient underwent laparoscopic sleeve gastrectomy to lose weight and control her blood glucose levels. Her daily fluid intake was 800– 1000 mL, and her daily caloric intake was less than 500 kcal during the first days after the surgery. She was prescribed degludec insulin, metformin and dulaglutide and her blood sugar was lower than 13.9 mmol/L. On postoperative Day 6, the patient complained of fatigue and vomiting. Blood gas analysis and urine analysis supported the diagnosis of ketoacidosis. Fluid resuscitation, insulin and glucose were administered to the patient immediately. On postoperative Day 8, the patient recovered without any symptoms.Conclusion: We report an extremely rare case of T2DM in which the patient developed EKA after laparoscopic sleeve gastrectomy owing to extremely low-calorie intake and dehydration. Physicians should be on alert for ketoacidosis in patients with T2DM after bariatric surgery with an euglycaemic status, even without the use of SGLT2 inhibitors or the presence of stresses, such as infection.Level V: Opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.Keywords: bariatric surgery, euglycaemic ketoacidosis, type 2 diabetes mellitus

Xi-Yu Liu, Chai Jin, Yan Zhou Department of Endocrinology, Dongyang People’s Hospital, Dongyang, Zhejiang, People’s Republic of ChinaCorrespondence: Xi-Yu Liu, Email csuliuxiyu@163.comIntroduction: Higher serum carcinoembryonic antigen (CEA) was found in diabetic patients rather than controls. However, the prevalence of abnormal CEA among diabetic inpatients with a large proportion of poor glycemic control is unclear.Methods: A total of 385 diabetic inpatients were included in this study. We collected information from a large clinical database. Patients with malignant tumors were excluded by examination and follow-up.Results: We found a surprisingly high prevalence (14.3%) of diabetic inpatients with CEA above normal. The proportion of patients with abnormal CEA was significantly different in subgroups with different blood glucose levels, 20.4% in the HbA1c ≥ 9% group, and 8.5% in the HbA1c < 9%, p = 0.000. We found that the CEA levels were correlated with age, body mass index and HbA1c. The regression coefficient of HbA1c was the highest, B = 0.284, p = 0.000. We also found that the CEA levels were higher in diabetic inpatients with BMI < 24 kg/m2 than the overweight or obesity patients. There was a significant difference in the insulin level and C peptide level between the elevated CEA group and the non-elevated CEA group.Conclusion: The elevation of CEA is common in diabetic inpatients, especially those with poor hyperglycemia controlled (HbA1c ≥ 9%). The underlying mechanism may be related to glucose toxicity.Keywords: diabetic patients, CEA, carcinoembryonic antigen, hyperglycemic

Haode Wang,1 Hui Sun,1,2 Chunlin Jin,1 Meifeng Wang,1 Yashuang Luo,1 Wenqian Song,3 Haiyin Wang1 1Shanghai Health Development Research Center, Shanghai Medical Information Center, Shanghai, People’s Republic of China; 2Key Laboratory of Health Technology Assessment, National Health Commission; School of Public Health, Fudan University, Shanghai, People’s Republic of China; 3Shanghai Overseas Rescue and Aid Service Center, Shanghai, People’s Republic of ChinaCorrespondence: Haiyin Wang, Shanghai Health Development Research Center, Minhang District, No. 181 Xinbei Road, Shanghai, 201199, People’s Republic of China, Tel +86- 18917769216, Email why0522@126.comObjective: Shanghai is one of the pioneers proposing family doctor contract service (FDCS). However, there is no quantitative research focusing on the Shanghai experience from a demand-side perspective. This study investigated Shanghai chronic patients’ relative preferences for FDCS using a discrete choice experiment method.Methods: A face-to-face discrete choice experiment (DCE) was performed to elicit the preference with 300 samples. Attributes and levels were extracted from the literature review and focus group consultation with patients. Seven attributes, follow-up frequency, medicine accessibility, family doctor competency, health management, referral convenience, appointment flexibility, and shared decision-making, were decided. Three levels were attached to each attribute. A mixed logit model was used to evaluate the multiple-choice data.Results: A total of 248 patients completed the survey. Patient valued FDCS medicine accessibility (β=0.57, P < 0.05), and high family doctor competency (β= 0.43, P < 0.05), regular health management activities (β=0.36, P < 0.05), high follow-up frequency (β=0.31, P < 0.05) the most. The good doctor-patient shared decision-making atmosphere (β=0.12, P < 0.05), high referral convenience (β=0.06, P < 0.05) and high appointment flexibility (β=0.04, P < 0.05) are valued as less important. No significant preference heterogeneity was identified for patients with different sociodemographic characteristics. Respondents reported other FDCS needs, including online health consultation, specialist services in local institutes, higher reimbursement rates, free rehabilitation guidance for the disabled and personal health management.Conclusion: This research is the first discrete choice experiment FDCS preference research targeting on Chinese urban population. The results suggested that to increase the quality of FDCS, policy-makers should prioritize follow-up frequency, medicine accessibility, family doctor competency and health management. The service package should consider a higher reimbursement rate and rehabilitation guidance for the disabled if extra health-care resources available. Future FDCS policy should consider stated societal preference and be congruent with it.Keywords: primary care, family doctor contract services, urban resident preferences, discrete choice experiment

Heli Yang,&ast; Xin Ji,&ast; Chenggen Jin,&ast; Ke Ji, Ziyu Jia, Xiaojiang Wu, Ji Zhang, Zhaode Bu Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heli YangDepartment of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of ChinaTel/Fax +86-10-88196970Email leighy@163.comPurpose: To establish a pragmatic prognostic nomogram for predicting the survival of elderly patients undergoing gastrectomy for gastric adenocarcinoma.Patients and Methods: Data of elderly patients undergoing gastrectomy for gastric adenocarcinoma between 2004 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database. Prognostic factors were identified by the Kaplan–Meier method and the Cox proportional hazards model. Based on these factors, we developed a nomogram to predict the overall survival (OS) and gastric cancer-specific survival (GCSS). Concordance index (C-index) and calibration curve are employed to assess the predictive accuracy of the model. Decision curve analysis (DCA) and receiver operating characteristic curve (ROC) analysis are applied to further appraise the clinical utility of the model.Results: A total of 8401 cases were incorporated into this research. After univariate and multivariate analyses, nine prognostic factors of OS were identified, including age (P < 0.001), race (P < 0.001), marital status (P < 0.001), tumor site (P < 0.001), tumor size (P = 0.024), differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and M stage (P < 0.001); ten prognostic factors of GCSS were identified, including age (P < 0.001), race (P < 0.001), tumor site (P < 0.001), tumor size (P = 0.002), differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), M stage (P < 0.001), radiotherapy (P < 0.001) and chemotherapy (P < 0.001). The C-index of the constructed nomogram for OS was 0.708 (95% CI: 0.701– 0.715) while for GCSS was 0.745 (95% CI: 0.737– 0.753). The calibration curves of the nomogram predictions and actual observations displayed good agreement for the 3- and 5-year OS and GCSS probabilities. The results of DCA and the area under the curve calculated by ROC analysis showed that the developed model was superior than TNM stage.Conclusion: The nomogram we established could accurately predict the prognosis of individual elderly patients who underwent gastrectomy for gastric adenocarcinoma.Keywords: gastric adenocarcinoma, elderly, gastrectomy, survival, nomogram

Kunpeng Wang,1 Xiongying Miao,2 Fanhua Kong,2 Siqi Huang,3 Jinggang Mo,1 Chong Jin,1 Yanwen Zheng2 1Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, 318000, Zhejiang, People’s Republic of China; 2Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of China; 3Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of ChinaCorrespondence: Yanwen ZhengDepartment of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People’s Republic of ChinaEmail zyw.1018@csu.edu.cnBackground and Aim: Pancreatic cancer is one of the most malignant tumors worldwide. Zuojin pills (ZJP), a traditional Chinese medicine (TCM) formula, which can treat a variety of cancers. However, the active compounds present in ZJP and the potential mechanisms through which ZJP acts against pancreatic cancer have not been thoroughly investigated.Methods: Data on pancreatic cancer-related genes, bioactive compounds, and potential targets of ZJP were downloaded from public databases. Bioinformatics analysis, including protein–protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, was conducted to identify important components, potential targets, and signaling pathways through which ZJP affects pancreatic cancer. The results of this analysis were verified by in vitro experiments.Results: The network pharmacology analysis results showed that 41 compounds and 130 putative target genes of ZJP were associated with anti-pancreatic cancer effects. ZJP may exert its inhibitory effects against pancreatic cancer by acting on key targets such as JUN, TP53, and MAPK1. Moreover, KEGG analysis indicated that the anti-pancreatic cancer effect of ZJP was mediated by multiple pathways, such as the PI3K-AKT, IL-17, TNF, HIF-1, and P53 signaling pathways. Among these, the PI3K-AKT signaling pathway, which included the highest number of enriched genes, may play a more important role in treating pancreatic cancer. The in vitro results showed that ZJP significantly inhibits the cell cycle and cell proliferation through the PI3K/AKT/caspase pathway and that it can induce apoptosis of pancreatic cancer cells, consistent with the results predicted by network pharmacological methods.Conclusion: This study preliminarily investigated the pharmacological effects of ZJP, which appear to be mediated by multiple compounds, targets and pathways, and its potential therapeutic effect on pancreatic cancer. Importantly, our work provides a promising approach for the identification of compounds in TCM and the characterization of therapeutic mechanisms.Keywords: pancreatic cancer, Zuojin pill, network pharmacology, traditional Chinese medicine, proliferation, apoptosis

Ye Song,1,2,&ast; Zhuo Li,1,&ast; Lei Li,3,&ast; Houming Zhou,4 Ting-Ting Zeng,1 Chuan Jin,2 Jin-Rong Lin,2 Sha Gao,2 Yan Li,1 Xin-Yuan Guan,1,3 Ying-Hui Zhu1 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 2Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510000, People’s Republic of China; 3Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People’s Republic of China; 4Department of Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying-Hui ZhuState Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People’s Republic of ChinaTel + 86-20-87342283Email zhuyh@sysucc.org.cnXin-Yuan GuanDepartment of Clinical Oncology, The University of Hong Kong, Room L10-56, 10/F, Laboratory Block, 21 Sassoon Road, Hong Kong, People’s Republic of ChinaTel +86 852-39179782Fax + 852-28169126Email xyguan@hku.hkPurpose: By using integrative RNA sequencing analysis, we identified a novel tumor suppressor, serpin family A member 11 (SERPINA11), which is a serine proteinase inhibitor that belongs to the serpin superfamily. However, the function of SERPINA11 in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the role and molecular mechanism of SERPINA11 in HCC.Methods: Gene expression patterns of SERPINA11 were analyzed in tissue samples of HCC patients by qRT-PCR. In vitro and in vivo experiments were performed to characterize the function and molecular mechanism of SERPINA11 in the tumor metastasis capacity.Results: SERPINA11 was downregulated in approximately 50% of HCC and significantly associated with metastasis and poor outcome of patients. Functional study demonstrated that SERPINA11 could inhibit cell growth, cell migration and tumor metastasis. Mechanistic investigations suggested that SERPINA11 accelerated urokinase-type plasminogen activator (uPA) degradation to suppress extracellular signal-regulated kinase (ERK1/2) phosphorylation, and thereby subdued metastatic capabilities of HCC cells.Conclusion: SERPINA11 plays an important tumor suppressive role in HCC, with possible use as a biomarker and an intervention point for new therapeutic strategies.Keywords: SERPINA11, HCC, metastasis, uPA, ERK

Hanrui Zheng,1,* Qian Xie,2,* Mei Zhan,1 Chaohui Jin,1 Qiu Li3,4 1Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2International Medical Center/Ward of General Practice, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4West China Biomedical Big Data Center, Sichuan University, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chaohui JinDepartment of Pharmacy, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaTel +86-28-85421763Email 695025422@qq.comQiu LiDepartment of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of ChinaTel +86-28-85423262Email fbqiu9@163.comBackground: Helicobacter pylori (H. pylori) eradication therapy has been shown to reduce the risk of gastric cancer in patients who have a family history of gastric cancer in first-degree relatives. The aim of this study was to assess the cost-effectiveness of H. pylori eradication therapy in a select population in the People’s Republic of China.Methods: A Markov model was applied to evaluate the cost-effectiveness of H. pylori eradication therapy. The long-term costs of H. pylori eradication therapy were calculated from the Chinese perspective. Health outcomes were measured by quality-adjusted life years (QALYs). Epidemiological information and health utilities used in the model were collected from published literatures or statistical bureaus. A sensitivity analysis was conducted to explore the influence of parameters on the uncertainty of the model.Results: Compared with the no eradication therapy group, H. pylori eradication therapy prolonged an average of 4.52 QALYs (32.64 QALYs vs 28.12 QALYs) and saved $3227.07 ($2472.83 vs $5699.90). The cost-effectiveness analysis demonstrated that no H. pylori eradication therapy cost more and produced less QALYs. It was dominated by H. pylori eradication therapy. The one-way sensitive analyses proved that the results were robust to the fluctuations of the input parameters.Conclusion: H. pylori eradication therapy not only reduced the risk of gastric cancer in first-degree relatives of patients with gastric cancer but also was an economical strategy with lower costs and greater efficacy.Keywords: Helicobacter pylori, eradication therapy, gastric cancer, cost-effectiveness analysis

Renchi Yang,1 Yongqiang Zhao,2 Xuefeng Wang,3 Jing Sun,4 Runhui Wu,5 Chenghao Jin,6 Jie Jin,7 Depei Wu,8 Pablo Rendo,9 Feifei Sun,10 Jeremy Rupon,9 Francois Huard11,†, Joan M Korth-Bradley,12 Lihong Xu,10 Binyu Luo,10 Yingxue Cathy Liu13 1Thrombosis and Hemostasis Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People’s Republic of China; 2Department of Hematology, Peking Union Medical College Hospital, Beijing, People’s Republic of China; 3Department of Clinical Blood Transfusion, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 5Department of Hematology, Beijing Children’s Hospital and Capital Medical University, Beijing, People’s Republic of China; 6Department of Hematology, Jiangxi Provincial People’s Hospital, Jiangxi, People’s Republic of China; 7Department of Hematology, The First Affiliated Hospital – Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 8Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 9Rare Disease, Pfizer Inc, Collegeville, PA, USA; 10 Pfizer (China) Research & Development Co, Ltd, Shanghai, People’s Republic of China; 11Clinical Pharmacology, Pfizer PIO, Paris, France; 12Pfizer Inc, Collegeville, PA, USA; 13Statistics, Pfizer (China) Research & Development Co, Ltd, Shanghai, People’s Republic of China†Dr. Francois Huard passed away on July 20, 2017.Correspondence: Renchi Yang Email rcyang65@163.comIntroduction: Moroctocog alfa albumin-free cell culture (AF-CC) increases plasma levels of factor VIII (FVIII) activity and, in China, is indicated for the control and prevention of bleeding episodes in patients with hemophilia A. This study aimed to evaluate the efficacy, safety, and recovery data of moroctocog alfa (AF-CC) in patients with hemophilia participating in two open-label studies, both conducted in China.Methods: The authorization study (clinicaltrials.gov identifier NCT00868530) enrolled patients aged ≥ 6 years, previously treated with ≥ 1 exposure day of FVIII replacement therapy. The real-world study (clinicaltrials.gov identifier NCT02492984) enrolled patients of any age who were previously untreated or requiring surgical prophylaxis. In both studies, on-demand treatment was administered over 6 months. Key assessments included response to treatment, FVIII inhibitor development, and recovery.Results: In the authorization study (N = 53; mean age, 23.2 years; severe hemophilia, 23%), response was excellent/good for 90% of infusions at 24 hours. Seven patients developed inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.77 (0.50) and 1.67 (0.45) (IU/dL)/(IU/kg), respectively. In the real-world study (N = 85; mean age, 9.5 years; severe hemophilia, 58%), response was rated as excellent or good for most (87%) on-demand infusions and for all surgical prophylaxis patients (n = 14). Seven patients developed FVIII inhibitors. Mean (SD) FVIII recovery at the initial and final visits was 1.71 (0.50) and 1.68 (0.31) (IU/dL)/(IU/kg), respectively. No new safety signals were observed in either study.Conclusion: On-demand treatment and surgical prophylaxis with moroctocog alfa (AF-CC) is safe and effective for both previously treated and previously untreated Chinese patients with hemophilia A.Keywords: Asian, blood coagulation factor VIII, deficiency, factor VIII, ReFacto, Xyntha

Tingting Yang,1,* Fen Li,2,* Bifan Zhu,2 Yuqian Chen,2 Duo Chen,2 Changying Wang,2 Zhiying Hou,2 Jiajie Xu,2 Shuwei Gu,3 Jiefeng Liu,4 Zhuochun Wu,1 Ying Wang,1 Chunlin Jin2 1School of Public Health/ Key Laboratory of Health Technology Assessment, National Health and Family Planning Commission of the People’s Republic of China, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Health Development Research Center, Shanghai Medical Information Center, Shanghai, People’s Republic of China; 3Jiangxi University of Traditional Chinese Medicine, School of Economics and Management, Nanchang, Jiangxi, People’s Republic of China; 4Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunlin Jin; Ying Wang Email jinchunlin@shdrc.org; wangying1013@fudan.edu.cnBackground: The value of identifying and targeting population demographics at high risk of stroke based on patient-reported outcomes (PROs) with electronic health records (EHRs) in Shanghai is largely undiscovered.Aim: To test the hypothesis that establishing an evidence-based support system composed of PROs integrated with EHRs could be effective at identifying individuals at high risk of suffering from stroke.Methods: The patients included in this study joined the hypertensive patient management system from 2014 to 2018. We merged the Hypertension Patients Management Database and the Diabetes Mellitus Patients Management Database of Shanghai Jiading district, then kept the hypertension patients with or without diabetes. We subsequently performed a screen analysis utilizing EHRs to target the population with any risk factor for stroke, namely, hypertension, diabetes mellitus, obesity, smoking and physical inactivity. We also calculated the distribution of each risk factor and the combinations of risk factors.Results: In the Jiading District of Shanghai, 46,580 hypertensive patients with complete baseline information joined the hypertensive patient management system from 2014 to 2018. The majority of the patients were aged above 60 years old. Physical inactivity (83.24%), smoking (24.07%), diabetes (16.87%), and obesity (12.23%) were highly prevalent in hypertensive participants. Approximately 4377 patients were diagnosed with hypertension exclusively, accounting for 9.70% of the total number of patients in this study. Meanwhile, approximately 52.47% of the patients were diagnosed with two concurrent risk factors, and 38.13% of the patients had hypertension, meaning that 17,762 patients could be labeled as the high-risk population for stroke according to the criteria established by the National Stroke Screening Survey.Conclusion: Our exploratory findings demonstrate the feasibility of pinpointing and targeting populations at high risk of stroke using the EHRs of hypertensive patients.Keywords: hypertension, electronic health records, EHRs, stroke risk factors

Ning Lin,1,* Wentao Li,2,* Xiefeng Wang,2,* Shiqiang Hou,1 Dong Yu,1 Xingyuan Zhao,1 Chunjing Jin,3 Guoquan Yao,1 Wei Yan,2 Yongping You2 1Department of Neurosurgery, Chuzhou Clinical College of Anhui Medical University, The First People’s Hospital Chuzhou, Chuzhou, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 3Laboratory Medicine Center, Affiliated Hospital of Nantong University, Nantong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning LinDepartment of Neurosurgery, Chuzhou Clinical College of Anhui Medical University, The First People’s Hospital Chuzhou, Chuzhou, People’s Republic of ChinaEmail lin2007512@vip.163.comYongping YouDepartment of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of ChinaEmail YYPL9@njmu.edu.cnBackground: Epithelial–mesenchymal Transition (EMT) is involved in various cancers including glioblastoma. Our previous study has shown that miR-340 negatively correlated with EMT process in glioblastoma.Purpose: In the present study, we aim to explore the underlying molecular mechanisms of miR-340 in EMT process of glioblastomas.Materials and Methods: Using RT-qPCR assay, we analyzed the expression of miR-340 in glioma cell lines and normal human glia (NHA) cell line. Using CCK8, Colony formation assays, transwell and Western blot assays, we investigated tumor growth and EMT process. Using luciferase reporter assay, we confirmed a target of miR-340.Results: Our results showed that miR-340 was down-regulated in glioma cell lines (U87, U251 and LN229) compared to NHA cells. MiR-340 overexpression remarkably inhibited cell proliferation and invasion as well as up-regulated E-cadherin expression and down-regulated N-cadherin, Vimentin, ZEB1, Slug and Snail expressions in U251 and LN229 cells. Further studies have confirmed c-MET as a target gene of miR-340. The EMT-inhibitory effect of miR-340 was lost after c-MET expression was restored. We also identified the antitumorigenic activity of miR-340 in vivo.Conclusion: These results demonstrated that miR-340 functioned as a tumor suppressor via targeting EMT process and could be a potential therapeutic candidate for treating glioblastomas.Keywords: miR-340, EMT, c-MET, glioblastoma

Chunmei Jin,1 Rong Shi,1 Xue Jiang,1 Fuxian Zhou,1 Jixiang Qiang,1 Changshan An2 1Department of Clinical Laboratory, Yanbian University Hospital, Yanji, People’s Republic of China; 2Department of Respiratory Medicine, Yanbian University Hospital, Yanji, People’s Republic of ChinaCorrespondence: Changshan An Tel +86-433-2660064Email cs_an2003@aliyun.comIntroduction: Carbapenem-resistant Enterobacteriaceae (CRE) pose a serious threat to clinical patient management and public health, as they are generally resistant to most antibiotics and cause infections with high mortality rates. Klebsiella pneumoniae ranks second among Enterobacteriaceae species that cause nosocomial infections. In this study, we investigated the epidemic characteristics of carbapenem-resistant K. pneumoniae (CRKP) in the pediatric intensive care unit (PICU) of Yanbian University Hospital.Materials and Methods: A total of 14 non-duplicate CRKP strains, collected from March 2015 to November 2019, were subjected to automated microbial identification and antimicrobial susceptibility tests using the Phoenix-100 ID/AST system. The strains were also subjected to genotypic resistance testing, polymerase chain reaction assays to detect genes encoding carbapenemases and other β-lactamases, multi-locus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE)-based homology analysis.Results: Two carbapenemase genes, KPC-2 and NDM-1 (in eight and six strains, respectively), were detected. MLST enabled the division of the strains into two sequence types, ST11 and ST1224 (containing eight and six strains, respectively). PFGE results classified the 14 strains into clonotypes A–D, of which clonotypes A and B belonged to ST11, while clonotypes C and D belonged to ST1224.Conclusion: Our study reveals that epidemics of the KPC-2-ST11 and NDM-1-ST1224 strains occurred in the PICU of Yanbian University Hospital. Surveillance and strict implementation of prevention and control measures are crucial to prevent the occurrence and rapid spread of nosocomial infections.Keywords: Klebsiella pneumoniae, carbapenemase, sequence type 1224, pediatric intensive care unit

Chunmei Jin,1 Fuxian Zhou,1 Qingsong Cui,2 Jixiang Qiang,1 Changshan An3 1Department of Clinical Laboratory, Yanbian University Hospital, Yanji, People’s Republic of China; 2Department of Intensive Care Unit, Yanbian University Hospital, Yanji, People’s Republic of China; 3Department of Respiratory Medicine, Yanbian University Hospital, Yanji, People’s Republic of ChinaCorrespondence: Changshan An Tel +86-0433-2660064Email cs_an2003@aliyun.comBackground: Infections caused by the carbapenem-resistant Enterobacter cloacae (CREC) bring great challenges to the clinical treatment and pose a serious threat to public health. In this study, we investigated the molecular characteristics of CREC in a tertiary hospital.Materials and Methods: A total of 12 non-duplicate CREC strains isolated during the period of November 2016 to July 2019 were subjected to automated microbial identification and antimicrobial susceptibility testing (AST) using the BD Phoenix-100 identification and antimicrobial susceptibility testing (ID/AST) system. The strains were also subjected to phenotypic screening for the detection of antibiotic resistance genes such as the carbapenemase and other β-lactamase genes, with the use of the polymerase chain reaction assay (PCR). Finally, multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE)-based homology analysis were applied.Results: Four types of carbapenemases namely IMP-26, NDM-5, NDM-1, and KPC-2 were identified in 12 CREC strains. IMP-26 was the most prevalent type (6/12 strains, 50 %), followed by NDM-5 (3/12 strains, 25 %). The results of MLST revealed that these 12 strains could be divided into five sequence types (STs) among which ST544 was the dominant type (6/12 strains, 50 %). The PFGE results divided the 12 strains into four clusters.Conclusion: Our study indicated that the epidemics of the IMP-26-producing E. cloacae ST544 strain did occur in the intensive care unit (ICU) of a tertiary hospital. Therefore, early surveillance and strict implementation of control measures are crucial for the prevention of nosocomial infections and transmissions in hospitals.Keywords: Enterobacter cloacae, carbapenemase, IMP-26, ST544

Wenchao Wu,1,2 Jiangqing Wu,1 Qiafan Fu,1 Chenhao Jin,1 Fangyuan Guo,1,2 Qinying Yan,1,2 Qingliang Yang,1,2 Danjun Wu,1,2 Yan Yang,1,2 Gensheng Yang1,21College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China; 2Research Institute of Pharmaceutical Particle Technology, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of ChinaPurpose: Clinical applications of curcumin (Cur) have been greatly restricted due to its low solubility and poor systemic bioavailability. Three-arm amphiphilic copolymer tricarballylic acid-poly (ϵ-caprolactone)-methoxypolyethylene glycol (Tri-CL-mPEG) nanoparticles (NPs) were designed to improve the solubility and bioavailability of Cur. The present study adopted a microchannel system to precisely control the preparation of self-assembly polymeric NPs via liquid flow-focusing and gas displacing method.Methods: The amphiphilic three-arm copolymer Tri-CL-mPEG was synthesized and self-assembled into nearly spherical NPs, yielding Cur encapsulated into NP cores (Cur-NPs). The obtained NPs were evaluated for physicochemical properties, morphology, toxicity, cellular uptake by A549 cells, release in vitro, biodistribution, and pharmacokinetics in vivo.Results: Rapidly fabricated and isodispersed Cur-NPs prepared by this method had an average diameter of 116±3 nm and a polydispersity index of 0.197±0.008. The drug loading capacity and entrapment efficiency of Cur-NPs were 5.58±0.23% and 91.42±0.39%, respectively. In vitro release experiments showed sustained release of Cur, with cumulative release values of 40.1% and 66.1% at pH 7.4 and pH 5.0, respectively, after 10 days post-incubation. The results of cellular uptake, biodistribution, and in vivo pharmacokinetics experiments demonstrated that Cur-NPs exhibited better biocompatibility and bioavailability, while additionally enabling greater cellular uptake and prolonged circulation with possible spleen, lung, and kidney targeting effects when compared to the properties of free Cur.Conclusion: These results indicate that Tri-CL-mPEG NPs are promising in clinical applications as a controllable delivery system for hydrophobic drugs.Keywords: A549 cells, amiphiphilic three-arm copolymer, biodegradable nanoparticles, biodistribution, pharmacokinetics

Jiajun Yin,1 Wei Feng,2 Hongwei Yuan,3 Jianmin Yuan,1 Yue Wu,3 Xiaowei Liu,3 Chunhui Jin,1 Zaohuo Cheng3 1Brain Science Basic Laboratory, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, Wuxi, Jiangsu Province, China; 2Department of Social Prevention and Control, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, Wuxi, Jiangsu Province, China; 3Department of Geriatric Psychiatry, The Affiliated Wuxi Mental Health Center with Nanjing Medical University, Wuxi, Jiangsu Province, China Background and purpose: Lipid metabolism plays an important role in Alzheimer’s disease (AD), and recent evidence suggests that single nucleotide polymorphisms (SNPs) in the StAR-related lipid transfer domain 6 (STARD6) and near the enzyme enoyl CoA hydratase domain containing 3 (ECHDC3) gene are related to plasma lipid levels or lipid traits in AD. Materials and methods: To identify whether the variants in or near the STARD6 and ECHDC3 genes contribute to AD susceptibility, we carried out an association analysis of STARD6 rs10164112 and ECHDC3 rs7920721 in combination with the apolipoprotein E (APOE) ε4 allele in a case–control study (278 cases, 509 controls) in China. Results: We identified that SNP rs10164112 in the STARD6 gene was a risk factor associated with AD and the APOE ε4 carriers (all P

Zhongyi Guo,1 Feng Wang,2 Yang Di,1 Lie Yao,1 Xinzhe Yu,1 Deliang Fu,3 Ji Li,3 Chen Jin1 1Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, China; 2School of Pharmacy & Key Laboratory of Smart Drug Delivery, Fudan University, Shanghai, China; 3Pancreatic Disease Institute, Huashan Hospital, Fudan University, Shanghai, China Purpose: Gemcitabine is currently the standard first-line chemotherapeutic drug for treating pancreatic cancer. However, many factors can contribute to gemcitabine resistance. One of the most important reasons is the low hENT1 expression. In this study, we tested the antitumor effect of gemcitabine-loaded human serum albumin nanoparticle (GEM-HSA-NP) on gemcitabine-resistant pancreatic cancer induced by low hENT1 expression. Materials and methods: S-(4-nitrobenzyl)-6-thioinosine was utilized to inhibit the activity of hENT1 and simulate low hENT1 expression. Growth inhibition assays and cell cycle and apoptosis analyses were performed on human pancreatic cancer cell lines such as BxPC-3 and SW1990. The in vivo antitumor effect was studied by using patient-derived xenograft (PDX) models. The in vivo toxicity assessment was performed on healthy Kunming mice. Results: In in vitro studies, GEM-HSA-NP showed its ability to inhibit cell proliferation, arrest cell cycle and induce apoptosis when tumor cells were resistant to gemcitabine. In in vivo studies, GEM-HSA-NP was more effective than gemcitabine on inhibiting tumor growth whether the expression levels of hENT1 were high or low in PDX models. The in vivo toxicity assessment showed that the biotoxicity of GEM-HSA-NP did not increase compared with gemcitabine. Conclusion: GEM-HSA-NP can overcome gemcitabine resistance induced by low hENT1 expression, which suggests its potential role for the clinical application. Keywords: pancreatic cancer, gemcitabine resistance, albumin nanoparticles, low hENT1 expression, PDX model

Kenzo Iizuka, Cheng Jin, Kokoro Eshima, Mei Hua Hong, Kiyoshi Eshima, Masakazu Fukushima Division of Research and Development, Delta-Fly Pharma Inc., Tokushima, Japan Introduction: Peritoneal disseminated ovarian cancer is one of the most difficult cancers to treat with conventional anti-cancer drugs and the treatment options are very limited, although an intraperitoneal (ip) paclitaxel has shown some clinical benefit. Therefore, treatment of peritoneal disseminated ovarian cancer is a highly unmet medical need and it is urgent to develop a new ip delivered drug regulating the fast DNA synthesis. Methods: We developed a unique RNAi molecule consisting of shRNA against the thymidylate synthase (TS) and a cationic liposome (DFP-10825) and tested its antitumor activity and PK profile in peritoneally disseminated human ovarian cancer ascites models by the luciferase gene-transfected SCID mice. DFP-10825 alone, paclitaxel alone or combination with DFP-10825 and paclitaxel were administered in an ip route to the tumor-bearing mice. The TS expression level was measured by conventional RT-PCR. The anti-tumor activity and host survival benefit by DFP-10825 treatment on tumor-bearing mice were observed as resulting from the specific TS mRNA knock-down in tumors. Results: DFP-10825 alone significantly suppressed the growth of SKOV3-luc tumore ascites cells and further extended the survival time of these tumor-bearing mice. Combination with the ip paclitaxel augmented the antitumor efficacy of DFP-10825 and significantly prolonged the survival time in the tumor-bearing mice. Short-hairpin RNA for TS (TS shRNA) levels derived from DFP-10825 in the ascetic fluid were maintained at a nM range across 24 hours but not detected in the plasma, suggesting that TS shRNA is relatively stable in the peritoneal cavity, to be able to exert its anti-tumor activity, but not in blood stream, indicating little or no systemic effect. Conclusion: Collectively, the ip delivery of DFP-10825, TS shRNA conjugated with cationic liposome, shows a favorable antitumor activity without systemic adverse events via the stable localization of TS shRNA for a sufficient time and concentration in the peritoneal cavity of the peritoneally disseminated human ovarian cancer-bearing mice. Keywords: DFP-10825, thymidylate synthase, short-hairpin RNA, cationic liposome, ip delivery, intraperitoneal dissemination, ovarian cancer

Xinzhe Yu,1 Wenwen Zhu,2 Yang Di,1 Jichun Gu,1 Zhongyi Guo,1 Hengchao Li,1 Deliang Fu,1 Chen Jin1 1Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, 2Institute of Functional Nano & Soft Materials, Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu, China Abstract: Lymphatic metastasis is the major metastatic pattern of pancreatic cancer and considered as an independent risk factor of survival. However, there is still no effective way for the diagnosis and treatment for lymphatic metastases of pancreatic cancer. In this study, using albumin as a carrier of gemcitabine (Gem), further modified by pyropheophorbide-a, we have designed and synthesized a nanoparticle (NP) compound named “pheophorbide-a (P@)-Gem-human serum albumin (HSA)-NPs”. By utilization of its tracer ability of lymphatic metastases, which is triggered by near-infrared irradiation and its visible dying ability, the compound is used for drug delivery tracking, meanwhile as a treating drug, as well as the combined effect of photodynamic therapy and chemotherapy. By the nude mice model of lymphatic metastases of pancreatic cancer (BxPC-3-LN7), we aim to explore the feasibility, effectiveness, and biological safety of diagnosis and treatment for the lymphatic metastases of pancreatic cancer by P@-Gem-HSA-NP, thereby, providing new methods and strategies for the study of nanodrug carrier and research on lymphatic metastases of pancreatic cancer. Keywords: theranostic nanoparticles, chemotherapy, photodynamic therapy, pancreatic cancer, lymphatic metastases, near infrared irradiation

Masakazu Fukushima, Kenzo Iizuka, Cheng Jin, Chun Zhang, Mei Hong, Kiyoshi Eshima Division of Oncology Research and Development, Delta-Fly Pharma Inc., Kawauchi-cho, Tokushima, Japan Abstract: To reduce 5-fluorouracil (5-FU)-induced serious toxicities without loss of antitumor activity, we have developed DFP-11207, a novel fluoropyrimidine, which consists of 1-ethoxymethyl-5-fluorouracil (EM-FU; a precursor form of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-FU degradation), and citrazinic acid (CTA; an inhibitor of 5-FU phosphorylation). In vitro studies of DFP-11207 indicated that it strongly inhibited the degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD) in homogenates of the rat liver, and also inhibited the phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT) in tumor tissues in a similar magnitude of potency by CDHP and CTA, respectively. Especially, DFP-11207 inhibited the intracellular phosphorylation of 5-FU in tumor cells in a dose-dependent manner whereas CTA alone did not protect intracellular 5-FU phosphorylation. These results postulate that DFP-11207 rapidly entered into the cell and the free CTA produced from DFP-11207 inhibited the phosphorylation of 5-FU in the cell. Furthermore, following oral administration of DFP-11207, CTA was found to be highly retained in the gastrointestinal (GI) tract compared to other tissues in rats. Interestingly, EM-FU, the prodrug of 5-FU was found to specifically produce 5-FU by various species of liver microsomes. When DFP-11207 was administered to rats, the plasma level of 5-FU was persisted for a long-time with lower Cmax and longer half-life than that from other 5-FU prodrugs. The antitumor activity of DFP-11207 was evaluated in human tumor xenografts in nude rats and found that DFP-11207 showed an antitumor activity in a dose-dependent fashion and its efficacy is equivalent to reference 5-FU drugs. In striking contrast, DFP-11207 manifested no or less 5-FU-related toxicities, such as a decrease in body weights, GI injury, and myelosuppression, especially thrombocytopenia. Taken together, the preclinical evaluation of DFP-11207 strongly indicates that DFP-11207 be a potential new version of the oral fluoropyrimidine prodrug for further clinical development. Keywords: antimetabolite, 5-FU, citrazinic acid, 5-chloro-2,4-dihydroxypyridine, antitumor activity, myelo-toxicity

BACKGROUND: Unsupervised online cognitive assessments have demonstrated promise as an efficient and scalable approach for evaluating cognition in aging, and Alzheimers disease and related dementias. OBJECTIVES: The aim of this study was to evaluate the feasibility, usability, and construct validity of the Paired Associates Learning task from the Cambridge Neuropsychological Test Automated Battery® in adults enrolled in the Brain Health Registry. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: The Paired Associates Learning task was administered to Brain Health Registry participants in a remote, unsupervised, online setting. In this cross-sectional analysis, we 1) evaluated construct validity by analyzing associations between Paired Associates Learning performance and additional participant registry data, including demographics, self- and study partner-reported subjective cognitive change (Everyday Cognition scale), self-reported memory concern, and depressive symptom severity (Patient Health Questionnaire-9) using multivariable linear regression models; 2) determined the predictive value of Paired Associates Learning and other registry variables for identifying participants who self-report Mild Cognitive Impairment by employing multivariable binomial logistic regressions and calculating the area under the receiver operator curve; 3) investigated feasibility by looking at task completion rates and statistically comparing characteristics of task completers and non-completers; and 4) evaluated usability in terms of participant requests for support from BHR related to the assessment. RESULTS: In terms of construct validity, in participants who took the Paired Associates Learning for the first time (N=14,528), worse performance was associated with being older, being male, lower educational attainment, higher levels of self- and study partner-reported decline, more self-reported memory concerns, greater depressive symptom severity, and self-report of Mild Cognitive Impairment. Paired Associates Learning performance and Brain Health Registry variables together identified those with self-reported Mild Cognitive Impairment with moderate accuracy (areas under the curve: 0.66-0.68). In terms of feasibility, in a sub-sample of 29,176 participants who had the opportunity to complete Paired Associates Learning for the first time in the registry, 14,417 started the task. 11,647 (80.9% of those who started) completed the task. Compared to those who did not complete the task at their first opportunity, those who completed were older, had more years of education, more likely to self-identify as White, less likely to self-identify as Latino, less likely to have a subjective memory concern, and more likely to report a family history of Alzheimers disease. In terms of usability, out of 8,395 received requests for support from BHR staff via email, 4.4% (n=374) were related to PAL. Of those, 82% were related to technical difficulties. CONCLUSIONS: Our findings support moderate feasibility, good usability, and construct validity of cross-sectional Paired Associates Learning in an unsupervised online registry, but also highlight the need to make the assessment more inclusive and accessible to individuals from ethnoculturally and socioeconomically diverse communities. A future, improved version could be a scalable, efficient method to assess cognition in many different settings, including clinical trials, observational studies, healthcare, and public health.