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Zhihua Zhang,1 Yuhong Wang,2 Yankun Zhang,3 Shujun Geng,2 Haifeng Wu,4 Yanxin Shao,5 Guannan Kang6 1Department of Science & Education, Hebei Chest Hospital, Hebei Provincial Key Laboratory of Lung Disease, Shijiazhuang, People’s Republic of China; 2Department of Tuberculosis, Hebei Chest Hospital, Hebei Provincial Key Laboratory of Lung Disease, Shijiazhuang, People’s Republic of China; 3Department of Ophthalmology, Hebei Chest Hospital, Hebei Provincial Key Laboratory of Lung Disease, Shijiazhuang, People’s Republic of China; 4Clinical Laboratory, Hebei Chest Hospital, Hebei Provincial Key Laboratory of Lung Disease, Shijiazhuang, People’s Republic of China; 5Office of Clinical Pharmacological Center, Hebei Chest Hospital, Hebei Provincial Key Laboratory of Lung Disease, Shijiazhuang, People’s Republic of China; 6Department of Tuberculosis, Hebei Chest Hospital, Shijiazhuang, People’s Republic of ChinaCorrespondence: Yanxin Shao, Office of Clinical Pharmacological Center, Hebei Chest Hospital, Hebei Provincial Key Laboratory of Lung Disease, No. 372, Sheng Li North Street, Shijiazhuang, Hebei, 050041, People’s Republic of China, Email shaoyanxin163@163.comBackground: Tuberculosis (TB) is one of the most infectious diseases caused by Mycobacterium tuberculosis (M. tb), and the diagnosis of active tuberculosis (TB) and latent TB infection (LTBI) remains challenging.Methods: Gene expression files were downloaded from the GEO database to identify the differentially expressed genes (DEGs). The ssGSEA algorithm was applied to assess the immunological characteristics of patients with LTBI and TB. Weighted gene co-expression network analysis, protein-protein interaction network, and the cytoHubba plug-in of Cytoscape were used to identify the real hub genes. Finally, a diagnostic model was constructed using real hub genes and validated using a validation set.Results: Macrophages and natural killer cells were identified as important immune cells strongly associated with TB. In total, 726 mRNAs were identified as DEGs. MX1, STAT1, IFIH1, DDX58, and IRF7 were identified as real hub immune-related genes. The diagnostic model generated by the five real hub genes could distinguish active TB from healthy controls or patients with LTBI.Conclusion: Our study may provide implications for the diagnosis and drug development of M. tb infections.Keywords: tuberculosis, latent tuberculosis infection, mycobacterium tuberculosis, immune, diagnostic model

Ying Zhu, Shiyu Geng, Feiye Zhu School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of ChinaCorrespondence: Feiye Zhu, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Email zhufeiye@163.com

Yuxi He,1,* Shike Geng,1,* Qing Mei,1,* Lei Zhang,1,* Tianjun Yang,1 Chunyan Zhu,1 Xiaoqin Fan,1 Yinzhong Wang,1 Fei Tong,1 Yu Gao,1 Xiaowei Fang,1 Renren Bao,2 Ximei Sheng,3 Aijun Pan1– 3 1Department of Intensive Care Unit, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2Department of Intensive Care Unit, the Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Intensive Care Unit, the Training Center of Anhui Provincial Hospital, Wannan Medical College, Wuhu, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aijun Pan; Qing Mei, Department of Intensive Care Unit, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No. 17, Lu Jiang Road, Hefei, Anhui Province, People’s Republic of China, Tel +86-0551-62286175, Email aijunpan868@ustc.edu.cn; meiqing@ustc.edu.cnObjective: To evaluate the diagnostic value and clinical application of metagenomic next-generation sequencing (mNGS) for infections in critically ill patients.Methods: Comparison of diagnostic performance of mNGS and conventional microbiological testing for pathogens was analyzed in 234 patients. The differences between immunocompetent and immunocompromised individuals in mNGS-guided anti-infective treatment adjustment were also analyzed.Results: The sensitivity and specificity of mNGS for bacterial and fungal detection were 96.6% (95% confidence interval [CI], 93.5%– 99.6%) and 83.1% (95% CI, 75.2%– 91.1%), and 85.7% (95% CI, 71.9%– 99.5%) and 93.2% (95% CI, 89.7%– 96.7%), respectively. Overall, 152 viruses were detected by mNGS, but in which 28 viruses were considered causative agents. The proportion of mNGS-guided beneficial anti-infective therapy adjustments in the immunocompromised group was greater than in the immunocompetent group (48.5% vs 30.1%; P=0.008). In addition, mNGS-guided anti-infective regimens with peripheral blood and BALF specimens had the highest proportion (39.0%; 40.0%), but the proportion of patients not helpful due to peripheral blood mNGS was also as high as 22.0%.Conclusion: mNGS might be a promising technology to provide precision medicine for critically ill patients with infection.Keywords: next-generation sequencing, critically ill patients, community-acquired infection, hospital-acquired infection, immunosuppression

Jianli Ge,1,* Shasha Geng,1,* Yang Gao,2 Guangwei Ren,3 Xiaoming Sun,1,4 Hua Jiang1 1Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People’s Republic of China; 2Department of General Practice, Huamu Community Health Service Center, Shanghai, 201204, People’s Republic of China; 3Science and Education Department, Sanlin Community Health Service Center, Shanghai, 200124, People’s Republic of China; 4Department of General Practice, Zhongshan Hospital, Fudan University Medical School, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoming Sun, Fudan University Medical School, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China, Email xm_sun2003@aliyun.com Hua Jiang, Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People’s Republic of China, Email Huajiang2013@tongji.edu.cnBackground: There is a high incidence rate of age-related hearing loss. Severe hearing loss may increase the prevalence of mental illness, cognitive impairment, and even the risk of all-cause death.Purpose: Construction of the three-level and two-stage screening mode for age-related hearing loss of the community and to evaluate its effectiveness.Materials and Methods: A total of 401 participants (aged 60 years or older) from five typical communities were enrolled in the study. The risk factors assessment of age-related hearing loss was completed by using a cross-sectional survey and receiver operating characteristic (ROC) curve. Multiple screening method was adopted and verified by serial and parallel tests, respectively. Based on research data, incorporate risk factors assessment, the Hearing Handicap Inventory for the Elderly Screening Version (HHIE-s) and pure tone audiometry (PTA) were used to construct the screening mode.Results: Multiple screening series testing and multiple screening parallel testing, including risk factors assessment, HHIE-s, and PTA, were used for verification: the sensitivity, specificity, and Kappa index were 70.5% and 9.2%, 95.0% and 71.6%, 0.26 and 0.63, respectively. Finally, the three-level and two-stage screening mode for age-related hearing loss was established. “Three-level” was defined as the risk factors assessment/HHIE-s (high-risk population), PTA (suspect population), and comprehensive hearing loss assessment (confirmed population). “Two-stage” was defined as the population screening by general practitioner in the community and target screening by otolaryngologist of the tertiary hospitals.Conclusion: The three-level and two-stage screening mode for age-related hearing loss consists of the following framework: from population screening to target screening, from suspicious diagnosis to accurate diagnosis, from primary health care to tertiary hospitals. The study objective is to structure a new secondary prevention and treatment mode for age-related hearing loss with primary health care as the core, so as to help the front-end management of healthy aging.Keywords: age-related hearing loss, three-level and two-stage mode, screening, general practitioners, self-management

Liang Wang, Liting Yang, Tao Li, Shanshan Geng Department of Cardiology, Shuyang Hospital of Traditional Chinese Medicine, Shuyang, Jiangsu, People’s Republic of ChinaCorrespondence: Shanshan Geng, Department of Cardiology, Shuyang Hospital of Traditional Chinese Medicine, No. 28, Shanghai Road, Shuyang, Jiangsu, 223600, People’s Republic of China, Tel + 86-052783562463, Email 1594743945@qq.comBackground: Malignant ventricular arrhythmia (MVA) can seriously affect the hemodynamic changes of the body. In this study, we developed and validated a nomogram to predict the in-hospital MVA risk in patients with STEMI after emergency PCI.Methods: The multivariable logistic regression analysis included variables with a P< 0.05 in the univariate logistic regression analysis and investigated the independent predictors affecting in-hospital MVA after PCI in patients with STEMI in the training cohort. The construction of a nomogram model used independent predictors to predict the risk of in-hospital MVA, and C-index, Hosmer-Lemeshow (HL) test, calibration curves, decision curve analysis (DCA), and receiver operating characteristic (ROC) were used to validate the nomogram.Results: Killip class [OR=5.034 (95% CI: 1.596– 15.809), P=0.005], CK-MB [OR=1.002 (95% CI: 1.001– 1.004), P=0.022], serum potassium [OR=0.618 (95% CI: 0.406– 0.918), P=0.020], NLR [OR=1.073 (95% CI: 1.034– 1.115), P< 0.001], and monocyte [OR=1.974 (95% CI: 1.376– 2.925), P< 0.001] were the independent predictors of in-hospital MVA after PCI in patients with STEMI. A nomogram including the 5 independent predictors was developed to predict the risk of in-hospital MVA. The C-index, equivalent to the area under the ROC curve (AUC), was 0.803 (95% confidence interval [CI]: 0.738– 0.868) in the training cohort, and 0.801 (95% CI:0.692– 0.911) in the validation cohort, showing that the nomogram had a good discrimination. The HL test (χ2=8.439, P=0.392 in the training cohort; χ2=9.730, P=0.285 in the validation cohort) revealed a good calibration. The DCA suggested an obvious clinical net benefit.Conclusion: Killip class, CK-MB, serum potassium, NLR, and monocyte were independent factors for in-hospital MVA after PCI in patients with STEMI. The nomogram model constructed based on the above factors to predict the risk of in-hospital MVA had satisfactory discrimination, calibration, and clinical effectiveness, and was an excellent tool for early prediction of the risk of in-hospital MVA after PCI in patients with STEMI.Keywords: ST-segment elevation myocardial infarction, percutaneous coronary intervention, nomogram model, malignant ventricular arrhythmia, circulating inflammatory cells

Haojie Li,1 Zhan Shi,2 Xuejiao Chen,1 Junjie Wang,1 Jiacheng Ding,1 Shuoji Geng,1 Xinyuan Sheng,1 Songhe Shi1 1Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Department of Pharmacy, Zhengzhou People’s Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Songhe Shi, Department of Epidemiology and Health Statistics, College of Public Health, Zhengzhou University, No. 100 Science Avenue, Zhengzhou, Henan, People’s Republic of China, Email ssh@zzu.edu.cnBackground: Non-alcoholic fatty liver disease (NAFLD) represents a large and growing public health problem. Insulin resistance (IR) plays a crucial role in the pathogenesis of NAFLD. The aim of this study was to determine the association of triglyceride-glucose (TyG) index, TyG index with body mass index (TyG-BMI), lipid accumulation product (LAP), visceral adiposity index (VAI), triglycerides/high-density lipoprotein cholesterol ratio (TG/HDL-c) and metabolic score for IR (METS-IR) with NAFLD in older adults and to compare the discriminatory abilities of these six IR surrogates for NAFLD.Methods: This cross-sectional study included 72,225 subjects aged ≥ 60 years living in Xinzheng, Henan Province, from January 2021 to December 2021. The data were collected from the annual health examination dataset. Logistic regression models were used to examine the relationships between the six indicators and NAFLD risk. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory ability of different IR surrogates for NAFLD under the influence of potential risk factors.Results: After adjusting for multiple covariates, compared with the first quintile, the odds ratios (ORs) and 95% confidence intervals (CIs) of the highest quintiles of TyG-BMI were the most obvious (OR:43.02, 95% CI:38.89– 47.72), followed by the METS-IR (OR:34.49, 95% CI:31.41– 37.95). Restricted cubic spline analysis reported that there were non-linear positive association and dose-response relationship between 6 IR surrogates and NAFLD risk. Compared with other IR-related indicators (LAP, TyG, TG/HDL-c and VAI), TyG-BMI showed the highest AUC (AUC:0.8059;95% CI:0.8025– 0.8094). Additionally, METS-IR also had a high predictive performance for NAFLD, and the AUC was greater than 0.75 (AUC:0.7959;95% CI:0.7923– 0.7994).Conclusion: TyG-BMI and METS-IR had pronounced discrimination ability to NAFLD, which are recommended as complementary markers for the assessment of NAFLD risk both in clinic and in future epidemiological studies.Keywords: non-alcoholic fatty liver disease, insulin resistance surrogates, triglyceride-glucose index with body mass index, metabolic score for insulin resistance

Shasha Geng,1,2,&ast; Yang Li,1,2,&ast; Jianli Ge,1,2 Xiaotong Guo,1,2 Yue Liu,1,2 Hua Jiang1,2 1Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yue Liu; Hua Jiang, Email liuyue_5_2009@163.com; huajiang2013@tongji.edu.cnObjective: Hospital-associated venous thromboembolism (VTE) is a major cause of unintended death in hospitalized patients. Standardized and reasonable prevention measures may reduce its occurrence effectively. This study aims to analyze the consistency of VTE risk assessment by physicians and nurses and its potential causes.Methods: A total of 897 patients admitted to Shanghai East Hospital from December 2021 to March 2022 were recruited. The VTE assessment scores of physicians and nurses and the activities of daily living (ADL) scores within the first 24 h of admission were collected for each patient. Cohen’s Kappa values were calculated to assess the inter-rater consistency of these scores.Results: VTE scores were fairly consistent between doctors and nurses in both surgical (Kappa = 0.30, 95% CI: 0.25– 0.34) and non-surgical (Kappa = 0.35, 95% CI: 0.31– 0.38) departments. There was moderate agreement in VTE risk assessment between doctors and nurses in surgical departments (Kappa = 0.50, 95% CI: 0.38– 0.62) while fair agreement in VTE risk assessment between doctors and nurses in non-surgical departments (Kappa = 0.32, 95% CI: 0.26– 0.40). The assessment of the mobility impairment component was fairly consistent between doctors and nurses in the non-surgical departments (Kappa = 0.31, 95% CI: 0.25– 0.37).Conclusion: Due to the poor consistency of VTE risk assessment between doctors and nurses, it is necessary to provide systematic training and develop a standardized assessment process for healthcare professionals to construct a scientific and effective VTE prevention and treatment system.Keywords: venous thromboembolism, risk assessment, consistency, reliability, exploratory study

Le Zhang,1,2,* Fangfang Chen,2,* Shikai Geng,2,* Xiaodong Wang,2 Liyang Gu,2 Yitian Lang,1 Ting Li,2 Shuang Ye2 1Department of Pharmacy, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang Ye; Ting LiDepartment of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of ChinaTel +86-2134506393Fax +86-2163363475Email ye_shuang2000@163.com; leeting007@163.comPurpose: To compare the efficacy, safety, and cost-effectiveness of methotrexate (MTX) plus hydroxychloroquine (HCQ) vs MTX plus leflunomide (LEF) in established rheumatoid arthritis (RA) with inadequate response to MTX monotherapy in a real-world Chinese cohort.Patients and Methods: A prospective RA cohort (n=549) was screened with eligible patients who had inadequate response (disease activity score in 28 joints using erythrocyte sedimentation rate, DAS28-ESR> 3.2) to initial MTX monotherapy and subsequently received either MTX+HCQ or MTX+LEF. Propensity score matching (PSM) was applied to adjust the possible baseline confounders between two groups. The primary outcome was the proportion of patients achieving first remission (DAS28-ESR< 2.6) during follow-up by log rank test. Secondary outcomes were changes of DAS28, glucocorticoids (GCs) exposure, safety, cost-effectiveness, sustained remission, and low disease activity (LDA) rate after 24-month follow-up.Results: Overall, 222 eligible patients were subjected to the aforementioned two treatment protocols (MTX+HCQ, n=102; MTX+LEF, n=120). After PSM adjustment, 97 patients in each group were analyzed. A higher remission rate was observed in the MTX+HCQ group than in the MTX+LEF group (70.1% vs 56.7%, P=0.048). The median time to remission was 11 and 16 months in the two groups, respectively. At the endpoint, more patients achieved remission (46.8% vs 32.5%, P=0.063) and maintained sustained LDA in the HCQ group (53.2% vs 38.6%, P=0.062) and also more patients withdrew GCs in this group (32% vs 16.7%, P=0.053) than those in the LEF group. Safety profiles were non-alarming, with no significant difference between the two groups. The incremental cost-effectiveness ratio yielded by MTX+HCQ over MTX+LEF was $1,111.8 per quality-adjusted life-year (QALY), within the cost-effective threshold set as the per capita gross domestic product (GDP) of China.Conclusion: The MTX+HCQ combination was seemingly superior to MTX+LEF in a real-world cohort of Chinese RA patients with inadequate response to methotrexate monotherapy in respect of the efficacy and cost-effectiveness.Keywords: hydroxychloroquine, leflunomide, methotrexate-resistant, rheumatoid arthritis, efficacy, cost-effectiveness

Binchan He,1,* Shen Geng,2,* Wei Zhou,1 Yuwen Rui,1 Xianmin Mu,3 Chen Zhang,3 Qiang You,3 Xin Su1,2 1Department of Respiratory and Critical Care Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China; 2Department of Respiratory and Critical Care Medicine, Jinling Hospital, Southern Medical University, Guangdong 510000, China; 3Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210002, Jiangsu, China *These authors contributed equally to this work Purpose: ICAM-1 plays a critical role in the development of acute respiratory distress syndrome (ARDS). MK2 regulates the expression of ICAM-1 in human pulmonary microvascular endothelial cells. To explore whether the inhibition of MK2 activation has the same effect in experimental animals, MMI-0100, a peptide-mediated inhibitor of MK2, was used to verify whether MMI-0100 can ameliorate lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1.Methods: In this study, C57BL/6 mice were randomly divided into three groups: a control group, an lipopolysaccharides (LPS) group, and an LPS plus MMI-0100 group. Mice were killed 24 hours after the administration of LPS and MMI-0100. The mouse lung tissue histopathology, wet/dry weight ratio (W/D), and the neutrophil count were used to measure the severity of lung inflammation in mice. The pulmonary microvascular endothelial cells (PMVECs) of the mice were isolated. The mRNA expression of ICAM-1 in mouse PMVECs was determined using RT-PCR, and the protein expression of MK2 and ICAM-1 in mouse PMVECs was analyzed using Western blotting and immunohistochemistry.Results: We found that the level of phosphorylated MK2 in the LPS plus MMI-0100 group was reduced. Compared with the LPS group, the LPS plus MMI-0100 group of mice showed less severe inflammation, including a lower W/D and neutrophil count. The mRNA and protein expression of ICAM-1 in the LPS group was significantly higher than in the control group in mouse PMVECs, and the ICAM-1 level was reduced after the administration of MMI-0100.Conclusion: These data indicate that MMI-0100 ameliorates lung inflammation in a mouse model of ARDS by reducing endothelial expression of ICAM-1. Keywords: pulmonary microvascular endothelial cell, inflammation, acute respiratory distress syndrome

Huijing Wang,1,* Le Zhang,2,* Zhe Liu,1 Xiaodong Wang,1 Shikai Geng,1 Jiaoyu Li,1 Ting Li,1 Shuang Ye1 1Department of Rheumatology, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 2Department of Pharmacy, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China *These authors contributed equally to this work Purpose: The aim of this study was to develop and internally validate a medication nonadherence risk nomogram in a Chinese population of patients with inflammatory rheumatic diseases. Patients and methods: We developed a prediction model based on a training dataset of 244 IRD patients, and data were collected from March 2016 to May 2016. Adherence was evaluated using 19-item Compliance Questionnaire Rheumatology. The least absolute shrinkage and selection operator regression model was used to optimize feature selection for the medication nonadherence risk model. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the least absolute shrinkage and selection operator regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and decision curve analysis. Internal validation was assessed using the bootstrapping validation. Results: Predictors contained in the prediction nomogram included use of glucocorticoid (GC), use of nonsteroidal anti-inflammatory drugs, number of medicine-related questions, education level, and the distance to hospital. The model displayed good discrimination with a C-index of 0.857 (95% confidence interval: 0.807–0.907) and good calibration. High C-index value of 0.847 could still be reached in the interval validation. Decision curve analysis showed that the nonadherence nomogram was clinically useful when intervention was decided at the nonadherence possibility threshold of 14%. Conclusion: This novel nonadherence nomogram incorporating the use of GC, the use of nonsteroidal anti-inflammatory drugs, the number of medicine-related questions, education level, and distance to hospital could be conveniently used to facilitate the individual medication nonadherence risk prediction in IRD patients. Keywords: noadherence, inflammatory rheumatic diseases, Compliance Questionnaire Rheumatology, predictors, nomogram

Yun-liang Wang,1,2,* Jin-feng Li,1,* Yu-tong Wang,3 Chun-yang Xu,2 Lin-lin Hua,2 Xiao-peng Yang,2 Shuang Geng,1 Shan-shan Wang,1 Zhen Wang,1 Hong-lei Yin1 1Neurology Department, 148th Hospital, Zibo, Shandong, 2Neurology Department, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 3Public Health Department, Henan University School of Medicine, Kaifeng, Henan, People’s Republic of China *These authors contributed equally to this work Abstract: Amyloid-β peptide (Aβ) toxicity in Alzheimer’s disease (AD) is associated with the c-Jun N-terminal kinase (JNK) signaling pathway. Curcumin may prevent Aβ fiber formation, slowing AD progression. A model of AD was established in 32 Sprague Dawley rats by injection of 10 μg Aβ1–40 into the right hippocampus. Saline was used in sham control (n=16). Sixteen AD model rats received 300 mg/kg curcumin and another 16 received saline daily for 7 days. Spatial learning and memory were assessed using a Morris water maze. Hippocampus neuron apoptosis and hippocampal levels of JNK-3 and p-JNK-3 were assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling, reverse transcription-polymerase chain reaction and Western blotting. Aβ1–40 injection induced slower spatial learning, memory deficit, neuronal apoptosis and increased JNK-3 expression and phosphorylation (all P

Shupei Qiao,1,* Yufang Zhao,1,* Shuai Geng,2,* Yong Li,1,* Xiaolu Hou,1,3 Yi Liu,1 Feng-Huei Lin,4,5 Lifen Yao,6 Weiming Tian1 1School of Life Science and Technology, Harbin Institute of Technology, 2Department of Pharmacology, Harbin Medical University, 3Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 4Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan; 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan; 6Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China *These authors contributed equally to this work Abstract: Instead of killing cancer stem cells (CSCs), the conventional chemotherapy used for cancer treatment promotes the enrichment of CSCs, which are responsible for tumor growth, metastasis, and recurrence. However, most therapeutic agents are only able to kill a small proportion of CSCs by targeting one or two cell surface markers or dysregulated CSC pathways, which are usually shared with normal stem cells (NSCs). In this study, we developed a novel nondrug delivery system for the dual targeting of CSCs by conjugating hyaluronic acid (HA) and grafting the doublecortin-like kinase 1 (DCLK1) monoclonal antibody to the surface of poly(ethylene glycol) (PEG)–poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs), which can specifically target CD44 receptors and the DCLK1 surface marker – the latter was shown to possess the capacity to distinguish between CSCSs and NSCs. The size and morphology of these NPs were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). This was followed by studies of NP encapsulation efficiency and in vitro drug release properties. Then, the cytotoxicity of the NPs was tested via Cell Counting Kit-8 assay. Finally, the 4T1 CSCs were obtained from the alginate-based platform, which we developed as an in vitro tumor model. Tumor-bearing nude mice were used as in vivo models to systematically detect the ability of NPs to target CSCs. Our results showed that the DCLK1–HA–PEG–PLGA NPs exhibited a targeting effect toward CSCs both in vitro and in vivo. These findings have important implications for the rational design of drug delivery systems that target CSCs with high efficacy. Keywords: alginate, CD44, PEG–PLGA, DCLK1, hyaluronic acid

Abstract The nonlinear Markov branching process with immigration and resurrection (NMBPIR) is considered in this paper. We give the criteria for regularity and uniqueness of NMBPIR, and then investigate the extinction probability and the mean extinction time. Furthermore, we give a condition for the Feller minimal NMBPIR to be recurrence, and provide an example to illustrate our results.

With the in-depth development of economic globalization and the increasingly close ties between countries in the world, how to train international talents has become an important topic. Cross-cultural learning is conducive to broadening the horizons of learners and cultivating international talents. An effective network support environment and the design of cross-cultural learning activities are the keys to the success of cross-cultural learning. As an emerging network software with rich functions, simple development and convenient use, the WeChat Mini Program (WMP) can serve as a network support platform for cross-cultural learning activities. This study developed a cross-cultural learning platform based on the WeChat mini program. Under the guidance of activity theory, this study builds a WMP-based design model of cross-cultural learning activities, including the components of learners, resources, cross-cultural learning community, WMP, rules, role division and activity process. Under the guidance of this model, we designed, implemented and evaluated WMP-based cross-cultural learning activities for Chinese students and international students at Lanzhou University. The research results show that the cross-cultural learning activities designed and implemented under the guidance of the model have a positive impact on learners’ knowledge, abilities and literacies. It is expected that this study will enrich the platform of cross-cultural learning and provide a reference for the design of cross-cultural activities.

Abstract Background Whole genome sequencing (WGS) is becoming increasingly prevalent for molecular diagnosis, staging and prognosis because of its declining costs and the ability to detect nearly all genes associated with a patient's disease. The currently widely accepted variant calling pipeline, GATK, is limited in terms of its computational speed and efficiency, which cannot meet the growing analysis needs. Results Here, we propose a fast and accurate DNASeq variant calling workflow that is purely composed of tools from LUSH toolkit. The precision and recall measurements indicate that both the LUSH and GATK pipelines exhibit high levels of consistency, with precision and recall rates exceeding 99% on the 30x NA12878 dataset. In terms of processing speed, the LUSH pipeline outperforms the GATK pipeline, completing 30x WGS data analysis in just 1.6 h, which is approximately 17 times faster than GATK. Notably, the LUSH_HC tool completes the processing from BAM to VCF in just 12 min, which is around 76 times faster than GATK. Conclusion These findings suggest that the LUSH pipeline is a highly promising alternative to the GATK pipeline for WGS data analysis, with the potential to significantly improve bedside analysis of acutely ill patients, large-scale cohort data analysis, and high-throughput variant calling in crop breeding programs. Furthermore, the LUSH pipeline is highly scalable and easily deployable, allowing it to be readily applied to various scenarios such as clinical diagnosis and genomic research.