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Generative Artificial Intelligence is set to revolutionize healthcare delivery by transforming traditional patient care into a more personalized, efficient, and proactive process. Chatbots, serving as interactive conversational models, will probably drive this patient-centered transformation in healthcare. Through the provision of various services, including diagnosis, personalized lifestyle recommendations, dynamic scheduling of follow-ups, and mental health support, the objective is to substantially augment patient health outcomes, all the while mitigating the workload burden on healthcare providers. The life-critical nature of healthcare applications necessitates establishing a unified and comprehensive set of evaluation metrics for conversational models. Existing evaluation metrics proposed for various generic large language models (LLMs) demonstrate a lack of comprehension regarding medical and health concepts and their significance in promoting patients’ well-being. Moreover, these metrics neglect pivotal user-centered aspects, including trust-building, ethics, personalization, empathy, user comprehension, and emotional support. The purpose of this paper is to explore state-of-the-art LLM-based evaluation metrics that are specifically applicable to the assessment of interactive conversational models in healthcare. Subsequently, we present a comprehensive set of evaluation metrics designed to thoroughly assess the performance of healthcare chatbots from an end-user perspective. These metrics encompass an evaluation of language processing abilities, impact on real-world clinical tasks, and effectiveness in user-interactive conversations. Finally, we engage in a discussion concerning the challenges associated with defining and implementing these metrics, with particular emphasis on confounding factors such as the target audience, evaluation methods, and prompt techniques involved in the evaluation process.

Bingpeng Lin,1,2,* Yufei Fan,2,* Xuechao Yang,2 Janak L Pathak,2 Mei Zhong3 1Department of Orthodontics, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China; 2Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, 510182, People’s Republic of China; 3Department of Prosthodontics, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, 510180, People’s Republic of China*These authors contributed equally to this workCorrespondence: Janak L Pathak; Mei Zhong, Email J.pathak@gzhmu.edu.cn; 2016686043@gzhmu.edu.cnAbstract: Periodontal disease is a common disorder affecting a wide range of people and has a high prevalence globally. Periodontitis comprises a series of inflammatory conditions affecting periodontal support tissue, which could ultimately lead to tooth loss and reduce life quality and add to the financial burden of society. Matrix metalloproteinase-12 (MMP-12) is an elastase that is produced mostly by macrophages and could degrade a wide spectrum of extracellular matrix (ECM) and also contribute to several systematic pathological conditions. Recently, researchers have reported higher expression of MMP-12 in chronic periodontitis patients. However, there are few reports on the role of MMP-12 in periodontitis pathogenicity, and the interaction between MMP-12, periodontal pathogens, and periodontal tissues remains unclear. In this review, we introduce the potentially unique role of MMP-12 in the context of periodontal inflammation earlier, summarize the possible effects of MMP-12 on the pathological process of periodontitis and the interaction of host response under the challenge of various inflammatory factors, and provide possible diagnostic and therapeutic strategies targeting MMP-12 for the management of periodontitis. Future research and policies should focus on and implement effective chairside testing methods to reduce the prevalence of periodontal diseases.Keywords: matrix metalloproteinase-12, periodontitis, dysbiosis, epithelial barrier, immunity, osteoimmunology

Min Fang,1,2 Wei Yin,3 Chunyan Qiu,4 Tao Song,2 Baihua Lin,2 Ying Wang,2 Hanchu Xiong,2 Shixiu Wu1 1Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, People’s Republic of China; 2Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 4National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, People’s Republic of ChinaCorrespondence: Wei Yin, Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China, Email hzyinwei@live.cn Shixiu Wu, Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, People’s Republic of China, Email wushixiu@yeah.netObjective: Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer.Methods: We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people’s Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan–Meier method and further analyzed with multivariate analysis.Results: Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes.Conclusion: The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients.Keywords: triple negative breast cancer, B lymphocytes, T lymphocytes, tumor associated macrophages, multispectral immunofluorescence, prognosis

Fan Jiang, Lingyi Lu, Sihan Wang, Feng Yuan, Lu Cao, Suling Xu,* Bingjiang Lin* Department of Dermatology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang; National Clinical Medical Research Center for Skin and Immune Diseases, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Suling Xu; Bingjiang Lin, Department of Dermatology, The First Affiliated Hospital of Ningbo University, No. 59 Liuting Street, Ningbo, Zhejiang, 315000, People’s Republic of China, Email linbingjiangnb@163.comPurpose: The purpose of this study was to investigate the comprehensive impact of family history of psoriasis, lesion size, disease severity, and the possibility of joint involvement on patients’ quality of life(QoL).Patients and Methods: Data from 5961 patients with psoriasis recruited from 440 hospitals throughout China were analyzed. The effects of family history of psoriasis, Body Surface Area(BSA), Psoriasis Area and Severity Index(PASI), and Psoriasis Epidemiology Screening Tool(PEST) on their Dermatology Life Quality Index(DLQI) were studied using a moderated chained mediated effects test.Results: A total of 912 patients (15.30%) had a family history of psoriasis, and 5071 patients (85.10%) had plaque psoriasis. In patients with plaque psoriasis, the variables of family history, PASI, PEST, and DLQI were positively correlated with each other. Additionally, in patients with other types of psoriasis, PASI was positively correlated with PEST and DLQI. Age was positively correlated with PASI and PEST and negatively correlated with DLQI in patients with plaque psoriasis; their Body Mass Index(BMI) and disease duration were in positive correlation with PASI and PEST. The mediation effect of PASI and PEST between family history and DLQI was remarkable in patients with plaque psoriasis and not in those with other types of psoriasis. BSA moderated the association between family history and PASI in patients with plaque psoriasis.Conclusion: PASI and PEST play a chain mediating role in the relationship between family history and DLQI in patients with plaque psoriasis, and high levels of BSA increase the ability of family history to positively predict PASI in plaque psoriasis, thereby affecting the patient’s QoL.Keywords: plaque psoriasis, PASI, PEST, quality of life, family history

HongKui Chen,1,2,* Xianwei Xie,2,3,* Huazhen Xiao,1,2,* Wenjia Liang,1,2 Zhi-Jie Lin,1,2 Biting Lin,2,3 Kai-Yang Lin,2,3 Chun Chen,4 Yansong Guo1,2 1Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, Fujian Province, 350000, People’s Republic of China; 2Fujian Provincial Key Laboratory of Cardiovascular Disease, Fujian Provincial Center for Geriatrics, Fujian Provincial Clinical Research Center for Severe Acute Cardiovascular Diseases, Fuzhou, Fujian Province, 350000, People’s Republic of China; 3Fujian Heart Failure Center Al liance, Fuzhou, Fujian Province, 350000, People’s Republic of China; 4School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, 350000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yansong Guo; Chun Chen, Email ysguo1234@126.com; chenchun-0428@163.comBackground: As a chronic inflammatory disease, atherosclerosis (AS) and ischemia events are primarily affected by inflammation in AS. PANoptosis has been implicated in many human systemic disorders, including infection, cancer, neurodegeneration, and inflammation. On the other hand, little is understood about PANoptosis’s function in AS.Methods: We used consensus clustering to divide the GSE100927 dataset into two panoptosis-related subgroups. PANoptosis-associated genes were screened by differential analysis and weighted gene co-expression network analysis (WGCNA) and enriched by ClueGO software. Investigating LASSO regression and MCODE to identify AS Diagnostic Markers. Immunoinfiltration analysis and single-cell analysis were used to search for cell types associated with the diagnostic genes. Final validation was performed by polymerase chain reaction (PCR).Results: We classified the GSE100927 dataset into two PANoptosis-related subtypes based on the expression of PANoptosis-related genes (PRGs) using consensus clustering. A total of 36 PANoptosis-associated genes were screened in the differentially expressed genes and WGCNA-related module. 4 hub genes were identified by MCODE and LASSO regression, and 3 AS diagnostic markers (ACP5, CCL3, HMOX1) were screened by external validation set. Immunoinfiltration analysis and single-cell analysis showed that the three diagnostic markers were associated with macrophages, and PCR results demonstrated that ACP5 and HMOX1 could be used as AS diagnostic markers.Conclusion: Our study identified ACP5 and HMOX1 as diagnostic genes for AS that may be associated with PANoptosis. ACP5 and HMOX1 may be involved in the pathogenesis of AS by regulating macrophage PANoptosis.Keywords: atherosclerosis, PANoptosis, macrophage, subtypes

Rafael Robles,1 Nikhil Patel,2 Emily Neag,2 Ajay Mittal,3 Zahra Markatia,2 Kambiz Ameli,2 Benjamin Lin2 1Department of Ophthalmology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; 2Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA; 3Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL, USACorrespondence: Benjamin Lin, Bascom Palmer Eye Institute, University of Miami, 900 NW 17th Street, Miami, FL, 33136, USA, Tel +1 305 326-6000, Fax +1 305 326-6000, Email brl65@miami.eduPurpose: Recent advances in telemedicine have led to increased use of digital ophthalmoscopes (DO) in clinical settings. This review aims to assess commercially available DOs, including smartphone (SP), desktop, and handheld ophthalmoscopes, and evaluate their applications.Methods: A literature review was performed by searching PubMed (pubmed.ncbi.nlm.nih.gov), Web of Science (webofknowledge.com), and Science Direct (sciencedirect.com). All English-language papers that resulted from the search terms “digital ophthalmoscope”, “screening tool”, “glaucoma screening”, “diabetic retinopathy screening”, “cataract screening”, and “papilledema screening” were reviewed. Studies that contained randomized clinical trials with human participants between January 2010 and December 2020 were included. The Risk of Bias in Systematic Reviews (ROBIS) tool was used to assess the methodological quality of each included paper.Results: Of the 1307 studies identified, 35 met inclusion and exclusion criteria. The ROBIS tool determined that 29/35 studies (82.8%) had a low risk of bias, 3/35 (8.5%) had a moderate risk of bias, and 3/35 (8.5%) had a high risk of bias.Conclusion: The continued adoption of DOs remains uncertain because of concerns about the image quality for non-mydriatic eyes and the confidence in data captured from the device. Likewise, there is a lack of guidelines for the use of DOs, which makes it difficult for providers to determine the best device for their practice and to ensure appropriate use. Even so, DOs continue to gain acceptance as technology and practice integration improve, especially in underserved areas with limited access to ophthalmologists.Keywords: fundoscopy, teleophthalmology, diagnostics, screening, referral

Beilei Lin,1,2 Lihong Xue,1 Baoxia An,1 Zhenxiang Zhang,2 Weihong Zhang2 1Nursing Department, Henan Huaxian People Hospital, Anyang City, Henan Province, People’s Republic of China; 2Nursing and Health School, Zhengzhou University, Zhengzhou City, Henan Province, People’s Republic of ChinaCorrespondence: Zhenxiang Zhang; Weihong Zhang, Nursing and Health school, Zhengzhou University, No 100 Science Avenue, Zhengzhou City, People’s Republic of China, Email zhangzx6666@zzu.edu.cn; zwhong306@zzu.edu.cnObjective: To describe the Physical Activity and Exercise (PAE) adherence of stroke survivors in rural regions, additionally, to analyze the influential factors through age stratification.Methods: This is a cross-sectional study. Totally, 596 stroke patients (65.70± 10.76 years) from three rural regions were selected, PAE scale was used for measuring compliance. The influential factors among different age groups were explored separately. This study adheres to the EQUATOR checklist, SROBE.Results: Only 17.8% (106) of participants regularly participated in PAE. Altogether, 42.45% were classified as a young-middle age group, and the rest 57.55% were in the old age group. Positive attitudes and better PAE-relevant knowledge were protective factors for adherence in the young and middle-aged group (OR=0.683; 95% CI 0.173~0.588 and OR=0.939; 95% CI 0.013~0.114), as well as in the old group (OR=0.704; 95% CI 0.193~0.534 and OR=0.929; 95% CI 0.035~0.118); having no home rehabilitation equipment was a strong risk factor for younger patients (OR=16.078; 95% CI 1.235~4.320); however, without hemiplegia can positively affect their adherence (OR=0.891; 95% CI 0.045~0.229). In addition, the presence of a spouse can lead to a better compliance among old patients (OR=0.436; 95% CI − 0.496~-0.165).Conclusion: It is necessary to improve the knowledge of physical activity in rural stroke patients of all ages. It is of great significance to install home rehabilitation equipment to promote exercise for young and middle-aged stroke patients. While for the old stroke patients, we strongly suggest focusing on the role of spouses, which would be more useful in low-income regions.Keywords: stroke, physical activity, exercise, adherence, rural area, influential factors

Bozhu Lin,1 Xiaorong Zhang2 1Gynaecology and Obstetrics Department, Longyan People’s Hospital, Longyan, People’s Republic of China; 2Neonatal Department, Longyan People’s Hospital, Longyan, People’s Republic of ChinaCorrespondence: Xiaorong Zhang, Neonatal Department, Longyan People’s Hospital, No. 31, Denggaoxi Road, Xinluo District, Longyan, 364000, People’s Republic of China, Tel +86-13605936060, Email zhangxiaorong@fjlyrmyy.comBackground: Gestational diabetes mellitus (GDM) is the most common pregnant disorder worldwide. In this study, we aimed to explore whether vitamin E (VE) treatment alone could protect against GDM in a mouse model.Methods: 6-week-old C57BL/6J female mice were fed on high-fat diet for two weeks and continued with high-fat diet after pregnancy to induce GDM. The pregnant mice were orally administrated with 2.5, 25 or 250 mg/kg VE twice per day during pregnancy together with high-fat diet. Oral glucose tolerance test, insulin amounts, oxidative stress and inflammation were then measured.Results: Only 250 mg/kg VE could improve glucose tolerance and insulin level in pregnant mice. VE (250 mg/kg) effectively inhibited GDM-induced hyperlipidemia, and secretion of inflammatory cytokines such as tumor necrosis factor-α and interleukin-6. VE also significantly ameliorated maternal oxidative stress at the late stage of pregnancy, and also improved reproductive outcomes, including increasing the litter size and birth weight in GDM mice. Moreover, VE also activated GDM-reduced nuclear factor-erythroid factor 2-related factor 2 (Nrf2) / heme oxygenase-1 signaling pathway in the maternal liver tissues of GDM mice.Conclusion: Our data clearly demonstrated that 250 mg/kg VE twice a day during pregnancy could significantly ameliorate the symptoms of GDM by alleviating oxidative stress, inflammation, hyperglycemia, and hyperlipidemia through Nrf2/HO-1 signaling pathway in GDM mice. Thus, additional VE supplement might be beneficial to GDM.Keywords: gestational diabetes mellitus, vitamin E, fetus, oxidative stress, Nrf2

Online education is rapidly becoming a significant method of course delivery in higher education. Consequently, instructors analyze student performance in an attempt to better scaffold student learning. Learning analytics can provide insight into online students' course behaviors. Archival data from 167 graduate level education students enrolled in 4 different programs and 9 different online courses were analyzed to determine whether a relationship existed between grades earned and time spent in specific areas within the course: total course time, course modules, document repository, and synchronous online sessions. Time spent in each component did not predict a specific letter grade, but did predict whether or not an A would be achieved. The sample was composed of students from four different graduate education programs: Educational Leadership, Reading, Instructional Design, and Special Education. Variations found among programs did not significantly predict the grade earned in the course. A logistic regression revealed that of all the predictor variables, time spent in synchronous online sessions alone showed as a significant predictor of receiving an A in the course. This is important information for instructors when providing scaffolding for students.

Different thermal demands and preferences between individuals lead to a low occupant satisfaction rate, despite the high energy consumption by HVAC system. This study aims to quantify the difference in thermal demands, and to compare the influential factors which might lead to those differences. With the recently released ASHRAE Database, we quantitatively answered the following two research questions: which factors would lead to marked individual difference, and what the magnitude of this difference is. Linear regression has been applied to describe the macro-trend of how people feel thermally under different temperatures. Three types of factors which might lead to different thermal demands have been studied and compared in this study, i.e. individual factors, building characteristics and geographical factors. It was found that the local climate has the most marked impact on the neutral temperature, with an effect size of 3.5 °C; followed by country, HVAC operation mode and body built, which lead to a difference of more than 1 °C. In terms of the thermal sensitivity, building type and local climate are the most influential factors. Subjects in residential buildings or coming from Dry climate zone could accept 2.5 °C wider temperature range than those in office, education buildings or from Continental climate zone. The findings of this research could help thermal comfort researchers and designers to identify influential factors that might lead to individual difference, and could shed light on the feature selection for the development of personal comfort models.

We analyzed the ASHRAE Global Thermal Comfort Database II to answer a fundamental but overlooked question in thermal comfort studies: how many and which subjective metrics should be used for the assessment of the occupants' thermal experience. We found that the thermal sensation is the most frequently used metrics in Thermal Comfort Database II, followed by thermal preference, comfort and acceptability. The thermal sensation/thermal preference, thermal comfort/air movement acceptability and thermal comfort/thermal preference are the top three most dependent metrics pairs. A principal component analysis confirmed that the personal experience of thermal conditions in built environment is not a one-dimensional problem, but at least a two-dimensional problem, and suggested thermal sensation and thermal comfort should be asked in right-now surveys as the first two Principal Component are majorly constructed by thermal sensation and thermal comfort. To further confirm the predictive power of thermal sensation and comfort, we used logistic regression and support vector machine to predict thermal acceptability and thermal preference with thermal sensation and comfort. The prediction accuracy is 87% for thermal acceptability and 64% for thermal preference. The prediction error might be due to occupants' individual difference and people errors in answering survey. These findings could help the design of chamber experiments, field studies, and human-building interaction interfaces by shedding light on the choice of subjective thermal metrics to effectively and accurately collect information on occupants’ thermal experience.

Injection of carbon dioxide (CO2) into coal seams has been demonstrated as an effective technology for enhanced methane recovery and CO2 storage. However, the impacts of the geochemical reactions between CO2 and coal on the wettability of coal pore surfaces, which influences immiscible multiphase displacement, are not yet well understood. We studied wettability alterations of coal surfaces resulting from reactions with gas, liquid and supercritical (sc)CO2 under varied pressure (1–141 bar) and temperatures (˜25 - 60 °C) through measuring static and dynamic contact angles with anthracite coal plates. We found that reactions with gas CO2 only slightly changed the wettability of coal surfaces from water-wet to intermediate-wet with static contact angles from ˜60˚ to 70°-90°. However, reactions with liquid and scCO2 altered the coal surfaces to strongly CO2-wet, with the contact angles up to 115-180°. We also found that both static and dynamic contact angles increase significantly with increasing pressure. Temperature affects the contact angles reversely especially under supercritical pressure conditions. These relationships of contact angles with pressure and temperature may be explained by the CO2 density dependence on pressure and temperature.

Thermal environment is important for both occupants’ comfort and health. Previously, the impacts of thermal environment were explored in the areas of thermal comfort and public health separately. This paper aims to bridge both disciplines by examining the correlation between comfort temperature and Minimum Mortality Temperature (MMT), which is a key index quantifying the association of health and weather temperature, through literature review and data-driven approach. It was found that the MMT data obtained from the public health area are generally in good agreement with the thermal neutral temperatures from the comfort perspective. The MMT data range from 17.2 °C to 30 °C, which are similar to the thermal neutral temperatures ranging from 19.5 °C to 30 °C based on the global field tests. Moreover, the MMT data demonstrate the potential to capture some complex distribution patterns of the field comfort data. The introduction of the health-temperature data could assist the intensive field experiments and modeling efforts and complement the thermal comfort dataset, which suffers from the problems of limited sample size. Some discrepancies between the two datasets were identified as well. The contextual factors other than the climate factor which may cause such discrepancies, such as socio-economics, population densities, etc. should be analyzed to enable the potential application of the health-temperature data and modeling to thermal comfort and health studies.

Bo Lin,1,2 Eng Wah Teo,1 Tingting Yan1,2 1Centre for Sport and Exercise Sciences, University of Malaya, Kuala Lumpur, Malaysia; 2School of Physical Education, Henan Institute of Science and Technology, Xinxiang, People’s Republic of ChinaCorrespondence: Eng Wah Teo, Email vteo2@um.edu.myBackground: Previous studies showed that smartphone addiction (SA) can lead to reduced physical activity (PA), but only a few studies have explored the impact of SA from psychological perspective closely related to PA. This study aimed to examine the extrinsic and partial psychological factors leading to decrease in PA using structural equation modelling analysis.Methods: We conducted an online survey on 628 males and 1159 female students from 10 universities in Henan Province, China, through a questionnaire survey application “Questionnaire Star”. This study used three models to test the mediating effects of three types of motives (intrinsic motives, body-related motives, and social motives) and self-efficacy, respectively, in the relationship between smartphone addiction and physical activities.Results: Our result confirmed that smartphone addiction leads to lower physical activities. Secondly, self-efficacy mediates smartphone addiction and physical activities, but the mediating effect of all three types of motivation is not significant. Thirdly, smartphone addiction did not affect intrinsic motivation and body-related motivation, but positively affects social motivation. Finally, as the motivation type changes from internal to external, the mediating effect of self-efficacy becomes stronger.Conclusion: This study showed that smartphone addiction lead to increase social motivation and decreased self-efficacy, and is a potential barrier to personal participation in physical activities. Our findings provide a new perspective for future design physical activities interventions in China and worldwide especially among university students where smartphone addiction is a problem.Keywords: smartphone use, smartphone addiction, physical activity, motivation, self-efficacy, physical health

Huiming Han,1,* Zhi Zhao,2,* Yan Lin,1 Baihui Lin,1 Hao Xu,3 Beiwen Zheng3 1School of Basic Medical Sciences, Beihua University, Jilin, Jilin Province, People’s Republic of China; 2Department of Neonatology, Shaanxi Province People’s Hospital, Xi’an, Shaanxi Province, People’s Republic of China; 3Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Beiwen Zheng, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, Zhejiang Province, 310003, People’s Republic of China, Tel +86 571 872 364 23, Fax +86 571 872 364 21, Email zhengbw@zju.edu.cnAbstract: In this study, we describe, for the first time, the co-existence of blaNDM-1and blaOXA-10 in a carbapenem-resistant Citrobacter braakii strain DY2019 isolated from a patient with urinary tract infection in China. We aimed to investigate the genomic context of two β-lactamase-producing plasmids and characterize the transmission mechanism of the carbapenemase-encoding gene. Whole-genome sequencing of strain DY2019 was performed with Nanopore and Illumina platforms, which revealed a chromosome sequence with the length of 4,830,928 bp, an IncC group plasmid pDY2019-OXA (size of 178,134 bp), and a novel IncHI2 group plasmid pDY2019-NDM (length 348,495 bp). A total of 16 antimicrobial resistance genes (ARGs) that confer resistance to nine different antibiotic groups were identified in strain DY2019, and 11 of them were carried by plasmid pDY2019-OXA. These data and analyses suggest that the carbapenem-resistant C. braakii strains may serve as potential reservoir of carbapenemase and highlight the need for further close surveillance of this species in clinical settings.Keywords: Citrobacter braakii, carbapenem-resistant, NDM-1, OXA-10, whole-genome sequencing, urinary tract infection

Classroom teachers sometimes struggle trying to find time during the typical school day to provide the writing instruction students need to be successful. This study examined 29 fifth through twelfth grade classroom teachers' survey responses about their perception of the effectiveness of using an online blogging tool, Kidblog, to plan and provide writing instruction for a struggling writer through survey responses and reflective journal entries. In addition, qualitative data from 16 of the 29 teachers were collected through their journals. After eight weeks of using the blogging tool, teachers perceived the tool to be more effective than they had originally thought it would be. The teachers reported that they were able to evaluate their individual student's writing progress to determine next steps in writing instruction. They perceived that student engagement with the writing process increased during the study. Additionally, using an online format encouraged teachers to incorporate other online tools into their instruction. However, barriers to using the blogging tool were also identified. Teachers reported that they would have liked the opportunity for more face-to-face interaction with their students and they also indicated that students may need strong keyboarding skills to effectively use the Kidblog tool. Additionally, prior to implementing the tool, teachers identified practice should have been provided for the teachers, as some found the blogging software difficult to use.

This study explores K-12 teachers' perceptions of the benefits and barriers to technology integration by either teachers or students in K-12 instruction. The sample was composed of 68 students enrolled in online classes in the graduate studies in education department of a small private liberal arts institution in the southeast. Data was collected using an anonymous, online survey. Open and axial coding was used to identify themes in barriers and benefits in both student and teacher technology use. Even with the emphasis on providing 1:1 technology, availability of technology was most frequently identified barrier, while increased engagement was the most frequently identified benefit. Content instructional issues or teacher knowledge were not as stronger identified barriers or benefits.

Yingjie Ma, Xiaoni Zhong, Bing Lin, Wei He Department of Epidemiology and Health Statistics, School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Xiaoni ZhongDepartment of Epidemiology and Health Statistics, School of Public Health and Management, Chongqing Medical University, 1 Yixue Road, Chongqing, 400016, People’s Republic of ChinaTel +8613308368059Email zhongxiaoni@cqmu.edu.cnPurpose: Low adherence to medication is an important reason why pre-exposure prophylaxis (PrEP) is not effective at reducing the rate of new human immunodeficiency virus (HIV) infections among men who have sex with men (MSM). The intelligent reminder system (IRS) has been designed to improve user compliance, but the intention of MSM to use the IRS remains unclear. This study establishes a theoretical model to analyze the factors influencing their intention to use the IRS.Patients and Methods: Non-probability sampling was used to recruit MSM volunteers in Chongqing and Sichuan, China, and the data were collected from MSM who had used the IRS. A model based on the unified theory of acceptance and use of technology (UTAUT) was established for the data through a structural equation model, and the perceived privacy risk was considered to explore the subjects’ behavior intention.Results: A total of 111 volunteers who had used the IRS filled out a questionnaire. Social influence had the greatest impact on behavior intention (β = 0.360, P < 0.001), followed by performance expectancy (β = 0.331, P < 0.001), and perceived privacy risk had a negative impact on behavior intention (β = − 0.151, P = 0.040). In addition, social influence had an indirect effect on behavior intention (β = 0.182, P = 0.003) and performance expectancy played a mediating role in this indirect effect.Conclusion: Developments in the IRS are required to improve its usefulness and adequately explain its role when recommending it to MSM. It is also important to improve the system’s ability to protect user privacy. Clinical evidence for the effectiveness of the IRS is conducive to its widespread use.Keywords: AIDS, men who have sex with men, behavior intention, medication reminder, structural equation model

Beiyou Lin,1 Weiwei Zheng,2 Xiaofei Jiang1 1Department of Cardiology, Zhuhai People’s Hospital, (Zhuhai hospital affiliated with Jinan University), Zhuhai, Guangdong, 519000, People’s Republic of China; 2Department of Gastrointestinal Surgery, Henan Provincial People’s Hospital & Zhengzhou University People’s Hospital & Henan University People’s Hospital, Zhengzhou, 450003, Henan, People’s Republic of ChinaCorrespondence: Xiaofei JiangDepartment of Cardiology, Zhuhai People’s Hospital, (Zhuhai hospital affiliated with Jinan University), Kangning Road, Xiangzhou District, Zhuhai, 519000, Guangdong, People’s Republic of ChinaEmail xfjzhh@163.comBackground: The reason of high mortality of acute myocardial infarction (AMI) was the lack of exploring the cellular and molecular mechanism of AMI. Therefore, we explored the crosstalk among cells, as well as its potential molecular mechanism of mediating AMI.Methods: The gene expression profile of peripheral blood, endothelial, platelets and mononuclear cells were applied to differentially expressed genes (DEGs) analysis. ClusterProfiler and the package of gene set enrichment analysis (GSEA) were applied to explore the potential functional pathways of DEGs in 3 types of intravascular cells (endothelial, platelets and mononuclear cells) and peripheral blood. Subsequently, we extracted the surface receptors, secreted proteins and extracellular matrix from the up-regulated DEGs to explore their potential interactions mechanism of AMI by crosstalk and pivot analysis.Findings: A total 11 common regulated DEGs (CDEGs) were identified, which might be potential biomarkers for AMI diagnosis. The abnormal pathways involved in DEGs of 3 types of intravascular cells and peripheral blood were shown, which also verified by GSEA. Afterwards, it was found that there was crosstalk in 3 types of intravascular cells and peripheral blood. Furthermore, we constructed a cell–cell interaction map among cells in AMI regulated by exosome lncRNA, which was involved in the development of AMI. Finally, we identified 8 hub genes, which might be potential biomarkers of AMI.Interpretation: The result of this study can not only be used as a reference for subsequent experiments and further exploration, but also contribute to the development of novel cell and molecular therapies.Keywords: AMI, CDEGs, crosstalk, intercellular interaction, platelets

Baiyang Lin,1 Li Bai,2 Shenglong Wang,2 Hong Lin3 1Department of Pneumology, Shanxi Provincial People’s Hospital, Taiyuan, 030000, People’s Republic of China; 2Department of Pneumology, Shanxi Hospital of Integrated Traditional and Western Medicine, Taiyuan, 030000, People’s Republic of China; 3Department of Orthopedics, The Sixth Hospital of Shanxi Medical University, Taiyuan, 030000, People’s Republic of ChinaCorrespondence: Li BaiDepartment of Pneumology, Shanxi Hospital of Integrated Traditional and Western Medicine, No. 13 of Fudong Street, Xinghualing District, Taiyuan, Shanxi Province, 030000, People’s Republic of ChinaTel +86 15935129231Email bailizhh@21cn.comObjective: Chronic obstructive pulmonary disease (COPD) is often associated with sarcopenia, and systemic inflammation is an underlying pathogenesis of COPD. In this study, the effects of interleukin (IL)- 6 and IL-10 levels on sarcopenia in patients with COPD were investigated.Methods: Seventy-three patients (59 males and 14 females), aged 60– 93 years old, who had stable COPD (not including patients with advanced lung decline) were enrolled in this study. The patients were classified according to four stages of lung function, based on the Global Initiative for Chronic Obstructive Lung Disease 2018, and their symptoms were evaluated using the COPD assessment test and mMRC dyspnea Scale. The skeletal muscle index (SMI) was evaluated using a dual-energy X-ray absorptiometry test, and walking pace and handgrip strength were measured to reflect muscle mass and function. The diagnosis of sarcopenia was made according to the Asian Working Group for Sarcopenia and China guide recommendations. The inflammation biomarkers IL-6 and IL-10 were measured by enzyme-linked immunosorbent assay. Albumin (Alb) was measured using the bromocresol green method.Results: Twenty-eight patients (38.36%) were diagnosed with sarcopenia. IL-6 (r = − 0.38, P = 0.001) and IL-10 (r = − 0.38, P = 0.001) were negatively correlated with the SMI, while the IL-10/IL-6 ratio had no correlation with sarcopenia. Multiple regression analysis showed that age (OR = 1.11, P = 0.02) and IL-6 (OR = 1.07, P< 0.05), had a strong correlation with sarcopenia, while IL-10 was not statistically significant in sarcopenia. However, body mass index (OR = 0.54, P = 0.002) had an opposite effect on muscle reduction.Conclusion: The increase of IL-6 might be a factor associated with sarcopenia. However, the relationship between IL-10 and sarcopenia is unclear.Keywords: chronic obstructive pulmonary disease, sarcopenia, cytokine, interleukin-6, interleukin-10

Xiling Hu,1,&ast; Yao Zhang,2,&ast; Bin Yao,2 Beisi Lin,2 Dan Yang,3 Cong Ling,4,&ast; Lingling Gao3,&ast; 1Department of Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China; 3School of Nursing, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Department of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Cong LingDepartment of Neurosurgery, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, Guangdong, 510630, People’s Republic of ChinaTel +86-13580465121Email doctor200@126.comLingling GaoSchool of Nursing, Sun Yat-sen University, No. 74, Zhongshan Er Road, Guangzhou, Guangdong, 510085, People’s Republic of ChinaTel +86 13539965693Email gaoll@mail.sysu.edu.cnPurpose: The purpose of this exploratory qualitative study was to identify the needs and barriers to diabetes dietary education issues in a Chinese context among people with type 2 diabetes and also their family members.Patients and Methods: Nineteen patients with type 2 diabetes and 15 family members were randomly selected from a larger study in Guangzhou. Descriptive phenomenological qualitative inquiry guided this study.Results: Both patients and their family members claimed a variety of needs regarding diabetes dietary information and that it should be patient-centered. In addition, both groups identified the effectiveness and helpfulness of diabetes diet-related health education, but family members reported a lack of professional education. Patients reported that the barriers to diabetes diet-related health education were: 1) patients’ different faculties of memory and acceptance, 2) educators’ methods of explaining the information, 3) lack of advertising and intensity of publicity both inside and outside of the hospital. Family members identified that diabetes diet-related health education assisted them with taking care of patients with diabetes and it was also beneficial for themselves to gain more dietary knowledge and develop healthy dietary habits.Conclusion: It is necessary to make some adjustment to traditional diabetes dietary education. It may be a good strategy to investigate the needs and faculties of memory and acceptance of people with diabetes before starting a diabetes education program. Hospitals should intensify their publicity of diabetes education and make it more attractive to patients with diabetes and their family members. Educators should add information specifically for family members while conducting diabetes education. Tertiary hospitals could provide standardized training regarding diabetes-related health education to community family physicians; in this way, diabetes education could gradually be transferred to them and both groups of clinicians could share in the education.Keywords: diabetes, family members, dietary education, needs, barriers, qualitative

Xiujun Zhang,1,2 Bin Lin,3 Gang Yang,4 Longgen Liu,1,2 Jianchun Lu,1,2 Zhaohui Lu,4 Yuan Xue1,2 1Institute of Hepatology, The Third People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 2Department of Liver Diseases, The Third People’s Hospital of Changzhou, Changzhou, People’s Republic of China; 3Department of Infectious Diseases, The First People’s Hospital of Jintan, Changzhou, People’s Republic of China; 4Department of Respiratory Diseases, The Second People’s Hospital of Wuhu, Wuhu, People’s Republic of ChinaCorrespondence: Zhaohui Lu; Yuan Xue Email lzh1980222@163.com; xueyuan80908@163.comObjective: The present study aimed to investigate the correlation between obesity and virus persistence in patients with COVID-19.Design and Methods: A total of 57 patients with laboratory-confirmed COVID-19 were admitted to two clinical centers, and data were analyzed retrospectively. Among them, 18 patients with body mass index (BMI) ≥ 25 kg/m2 were diagnosed with obesity, and dynamics of viral replication were compared.Results: Eighteen patients were diagnosed with obesity. The correlations between BMI and white blood cell, C-reactive protein, and cycle threshold (Ct) values of ORF1ab were not significant (all P > 0.05). On day 7 after admission, virus clearance was achieved in 13 (33.3%) patients with BMI < 25 kg/m2 and 5 (27.8%) patients with BMI ≥ 25 kg/m2 (χ2 = 0.176, P =0.68). On day 14, the RNA tests were negative in 37 (94.9%) patients with BMI < 25 kg/m2 and 13 (72.2%) patients with BMI ≥ 25 kg/m2 (χ2 = 5.865, P = 0.03). Multivariable analysis showed that only BMI ≥ 25 kg/m2 (P = 0.02) was the independent risk factor for virus clearance on day 14.Conclusion: Obesity may affect the clearance of SARS-CoV-2, and BMI should be assessed in patients with COVID-19, although they are not seriously ill.Keywords: SARS-CoV2, COVID-19, body mass index, obesity, virus clearance

Jiaxiu Liu,1,2 Ruibin Deng,1 Bing Lin,1 Hong Pan,1 Yuwen Gao,1 Jianghong Dai,3 Hao Liang,4 Ailong Huang,5 Xiaoni Zhong1 1School of Public Health and Management, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2School of Medical Information, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Epidemiology and Health Statistics, School of Public Health, Xinjiang Medical University, Xinjiang, People’s Republic of China; 4Department of Epidemiology and Medical Statistics, School of Public Health, Guangxi Medical University, Nanning, People’s Republic of China; 5Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Xiaoni ZhongSchool of Public Health and Management, Chongqing Medical University, 1 Yixue Road, Chongqing, 400016, People’s Republic of ChinaTel +86 13308368059Email zhongxiaoni@cqmu.edu.cnBackground: Men who have sex with multiple men (MSMM) belong to a high-risk group for HIV infection, and pre-exposure prophylaxis (PrEP) is an effective measure to prevent the infection. However, few studies on PrEP adherence by MSMM in China exist. We aimed to explore the protective motivation-related factors for PrEP adherence in an HIV-negative MSMM population in Western China and to provide a reference for future risk management and effective prevention strategies.Methods: Data were collected from a 2-year follow-up cohort study of PrEP in MSM in China. Rogers’ protective motivation theory (PMT) was used to study the PrEP adherence of MSMM, and logistic regression was performed to analyze the influencing factors of PrEP adherence.Results: A total of 496 MSMM were included in the study: 299 (60.28%) of them in the good adherence group and 197 (39.72%) in the poor adherence group. The threat assessment scores of the good and poor adherence groups were 2.15 ± 0.59 and 2.06 ± 0.47, respectively, and the response assessment scores were 2.81 ± 0.62 and 2.74 ± 0.62, respectively. Poor PrEP adherence was associated with on-demand PrEP medication (OR=0.670), students at school (OR=1.837), occasional condom use (OR=1.621), and good HIV knowledge (OR= 0.659). The higher the threat assessment score, the higher the susceptibility; and the lower the response cost, the stronger the protection motivation and the less likely MSMM were to have poor adherence.Conclusion: On-demand PrEP medication is more conducive to adherence. Preventive management should focus on MSMMs who are students at school, those who occasionally use condoms, and those with poor HIV knowledge. Improving threat perception and susceptibility, and controlling and reducing the response cost can effectively improve PrEP adherence, and the subsequent application of PMT during intervention research can provide a reference for HIV prevention in MSMM.Keywords: MSM, multiple sexual partners, PrEP, adherence, protective motivation theory, Western China

Duan X, Lu L, Wang Y, et al. Int J Nanomedicine. 2017;12:6705–6719. The authors have advised that Figures 6, 8 and 9 on pages 6713, 6715 and 6716, respectively, of the published paper are incorrect. The errors were introduced by the Editorial staff during the publication process. The correct figures are shown in Download Article. Read the original article

Qicen Yao,1,* Qingchao Wu,2,* Xiayu Xu,1 Yixi Xing,1 Jin Liang,1 Qianqi Lin,1 Meiqiong Huang,1 Yiling Chen,1 Bo Lin,3 Weifei Chen1 1Department of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China; 2Department of Rheumatology and Immunology, Minda Hospital of Hubei Minzu University, Enshi, Hubei Province, People’s Republic of China; 3Department of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weifei ChenDepartment of Rheumatology and Immunology, The Second Affiliated Hospital of Hainan Medical University, 368 Yehai Boulevard, Haikou City, Hainan Province, People’s Republic of ChinaEmail chenwf130@163.comBo LinDepartment of Pharmacy, The Second Affiliated Hospital of Hainan Medical University, 368 Yehai Boulevard, Haikou City, Hainan Province, People’s Republic of ChinaEmail linbo13518072160@163.comPurpose: Resveratrol (Res) is a natural polyphenolic compound found in several plants and reported as a promising biological molecule with effective anti-fibrosis and anti-inflammatory activities. However, the underlying mechanism of Res on systemic sclerosis (SSc) remains unclear. In the study, we identified the key cellular signaling pathways involved in the Res regulatory process on SSc.Methods: Res-targeted genes interaction network was constructed using the STITCH database, and the shared Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in both SSc and Res-targeted genes were then identified. The top five enriched KEGG pathways were visualized by GOplot. KEGG pathways associated with Res-targeted genes were established by Pathway Builder Tool 2.0. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of sirtuin 1 (SIRT1), mammalian targeted of rapamycin (mTOR), and cytokines.Results: Enrichment analysis of Res-targeted genes showed 79 associated pathways, 27 of which were also involved in SSc. Particularly, SIRT1/mTOR signaling was found as one of the crucial regulatory pathways. In vitro results suggested that SIRT1-mediated mTOR degradation ameliorated bleomycin (BLM)-induced fibrosis and inflammation. Res was capable of elevating the SIRT1 level in fibroblasts and partially reversing mTOR-dependent induction of fibrosis and inflammation.Conclusion: These results indicated that Res is a feasible and effective choice for SSc and therapeutic target of mTOR could be a potential alternative for treatment of SSc.Keywords: resveratrol, systemic sclerosis, SIRT1, mTOR, signaling

Yongli Wang,1,2 Janet Krska,3 Beilei Lin,1 Yongxia Mei,1 Barbra Katusiime,3 Yawen Guo,1 Zhenxiang Zhang1 1School of Nursing and Health, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Peking University People’s Hospital, Beijing, People’s Republic of China; 3Medway School of Pharmacy, The Universities of Kent and Greenwich at Medway, Chatham, Kent, UKCorrespondence: Zhenxiang ZhangSchool of Nursing and Health, No. 100 Science Avenue, Zhengzhou, Henan, People’s Republic of ChinaTel +86 13303816666Fax +86 371-86565001Email zhangzx6666@126.comBackground: The Living with Medicines Questionnaire (LMQ-3) is a reliable, valid instrument used to assess the medication-related burden of patients with chronic disease using long-term medication, but it has not been used in China.Purpose: To translate and cross-culturally adapt the LMQ-3 into Chinese and assess its reliability and validity among elderly patients with chronic disease.Methods: After translation and back-translation, views from an expert group and cognitive interviews with elderly persons using multiple medicines were used to ensure the cultural relevance of the LMQ-3. Then, 412 participants aged 60– 92 years were recruited from three communities in Zhengzhou to complete the instrument. Item analysis, internal consistency, content validity, exploratory factor analysis (EFA) and reliability testing were performed.Results: Item analysis identified nine items for possible removal, which were discussed with the originating team. Internal consistency testing confirmed the suitability of removing two of these items, which concurred with the views of the expert group and cognitive interviews. All other items were retained, but four were modified for clarification without changing their meaning, resulting in a 39-item instrument. EFA of this 39-item measure yielded an eight-factor model, similar to the English version. Cronbach’s alpha of the Chinese version of LMQ-3 (C-LMQ-3) for elderly patients with chronic diseases was 0.855, and alpha values for the eight domains ranged from 0.822 to 0.932. Test–retest reliability was satisfactory, with ICC values for the eight domain scores ranging from 0.751 to 0.881.Conclusion: With only minor modifications compared to the English version, the 39-item C-LMQ-3 is a valid tool, with adequate reliability, which can be used to assess the medication-related burden of long-term use of multiple medicines in elderly patients in China.Keywords: reliability, cultural adaptation, medicine burden, patient-reported outcome, multi-morbidity, Living with Medicines Questionnaire

Le-jing Lian,1 Bin Lin,2 Xiao Cui,1 Jie He,1 Zhe Wang,1 Xiao-dong Lin,1 Wei-jian Ye,1 Rui-jie Chen,1 Wei Sun1 1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, People’s Republic of China; 2Department of Clinical Pharmacy, Changxing People’s Hospital, Changxing 313100, People’s Republic of ChinaCorrespondence: Wei Sun; Rui-jie Chen Tel +8613968803162; +8613806890233Email 33sunwei@163.com; crj@wzhealth.comPurpose: Precise and timely detection of methotrexate (MTX) concentration played a key role in high-dose MTX individualization therapy in acute lymphoblastic leukemia (ALL) children to avoid serious adverse effects or nonresponse. This report described a sensibility and validation of ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for therapeutic drug monitoring (TDM) of methotrexate concentration in children’s plasma.Methods: One-step protein precipitation of samples was accomplished by adding 200 μL of acetonitrile to 100 μL of plasma sample. The separation of plasma samples was carried out on a ZORBAX Eclipse Plus C18 Rapid Resolution HD column with gradient elution using a mobile phase constituted of acetonitrile and 1% formic acid. The detection was executed by electrospray ionization (ESI) of triple quadrupole tandem mass spectrometer (TQMS) in the multiple reaction monitoring (MRM) mode with the transitions m/z 455.2 → 307.9 for methotrexate and m/z 458.2 → 311.2 for IS, separately. Linear concentration range of the calibration curve was 44– 11,000 nmol/L and 44 nmol/L was the lower limit of quantification.Results: The methotrexate elution time was at 1.577 min, and the overall running time was only 3.3 min. The intra- and interday precision for all the analysis results was within 11.24%, and mean recoveries rate of methotrexate exceeded 87.98%.Conclusion: The described and fully validated UHPLC-MS/MS method was successfully applied in clinical TDM after infusion of high-dose methotrexate 1– 5 g/m2 to 41 childpatients.Keywords: high-dose methotrexate, UHPLC-MS/MS, therapeutic drug monitoring, children, acute lymphoblastic leukemia

Shubin Wang, Binhui Lin, Wei Liu, Guojun Wei, Zongguang Li, Naichun Yu, Xiang Xue, Guangrong Ji Department of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, Xiamen City, Fujian, People’s Republic of ChinaCorrespondence: Guangrong JiDepartment of Orthopedic Surgery, Xiang’an Hospital of Xiamen University, No. 2000, Xiang’an East Road, Xiang’an District, Xiamen City, Fujian Province 361000, People’s Republic of ChinaTel +86-13945107257Fax + 0954-2683908Email 15755188821@163.comPurpose: The long-term survival rate of osteosarcoma, which is the most common type of primary malignant bone tumor, has stagnated in past decades. Acacetin is a natural flavonoid compound that has antioxidative and anti-inflammatory effects and exhibits extensive therapeutic effects on various cancers. In this study, the anticancer potential of acacetin and the underlying molecular mechanisms were examined in human osteosarcoma cells (SJSA and HOS).Materials and Methods: HOS and SJSA cell lines were exposed to different concentrations of acacetin. Cell proliferation and viability were assessed by CCK-8 and colony-formation assays. Hoechst 33258 fluorescent staining was employed to detect apoptosis. Cell apoptosis was measured by an annexin V-FITC/PI assay by flow cytometry. The alteration in the mitochondrial membrane potential was detected by a JC-1 Assay Kit. Apoptosis-related protein expression was determined by Western blotting. Intracellular reactive oxygen species (ROS) production was detected by fluorescence microscopy and flow cytometry. Subsequently, the activation of the ROS/JNK signaling pathway was investigated.Results: Acacetin could inhibit proliferation and induce apoptosis in SJSA and HOS cells. The acacetin treatment resulted in the activation of caspase-3, − 8, and − 9 and cleaved PARP. Further studies showed that acacetin-induced apoptosis was attributed to ROS. In addition, we found that acacetin induced the activation of the downstream c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, after treatment with the ROS scavenger GSH and the JNK inhibitor SP600125, the apoptosis-inducing effect triggered by acacetin was significantly attenuated.Conclusion: The results of the present study indicate that acacetin may induce apoptosis to inhibit cell growth by activating the ROS/JNK signaling pathway in SJSA and HOS cells, suggesting that acacetin may be a promising candidate for the management of osteosarcomas.Keywords: acacetin, osteosarcoma, apoptosis, ROS/JNK activation

Jialiang Wen,* Lizhi Lin,* Bangyi Lin, Erjie Xia, Jinmiao Qu, Ouchen Wang Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ouchen WangDepartment of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaTel +86 13957706099Email woc@wmu.edu.cnIntroduction: Breast cancer (BC) is one of the most prevalent malignancies in women and its incidence has increased steadily over recent years (0.3% per year). However, the mechanism of BC tumorigenesis remains elaborate elucidation. With the aid of RNA sequencing technology, we discovered that immortalization-upregulated protein (IMUP) is overexpressed in BC tissues compared to normal breast tissues. Our study is to understand the role of IMUP in BC.Methods: We validated the upregulation of IMUP from multiple public databases. By using quantitative real-time polymerase chain reaction (qRT-PCR), we proved that IMUP is overexpressed in BC tissues and cell lines. We performed proliferation, migration, invasion and apoptosis assays to explore the function of IMUP in BC cell lines (MCF-7 and MDA-MB-231). Besides, we investigated the effect of IMUP silencing on epithelial–mesenchymal transition using Western blotting and qRT-PCR.Results and Discussion: We validated that IMUP expression in BC tissues and cell lines is higher than that in the normal control group. The clinical analysis showed that IMUP is associated with lymph node metastasis and the outcome of neoadjuvant taxol-based therapy. The loss of function assay demonstrated that, with silencing IMUP, the capacities of proliferation, migration, and invasion of BC cell lines were impaired, while the apoptosis rate of cells increased. Meanwhile, the downregulation of IMUP could hinder the procession of epithelial–mesenchymal transition.Conclusion: Our study proved that IMUP plays a vital role in BC and acts as a potential target and marker in future therapy.Keywords: immortalization-upregulated protein, IMUP, breast cancer, BC, progression, epithelial–mesenchymal transition, EMT

Network-wide traffic measurement is of interest to network operators to uncover global network behavior for the management tasks of traffic accounting, debugging or troubleshooting, security, and traffic engineering. Increasingly, sophisticated network measurement tasks such as anomaly detection and security forensic analysis are requiring in-depth fine-grained flow-level measurements. However, performing in-depth per-flow measurements (e.g., detailed payload analysis) is often an expensive process. Given the fast-changing Internet traffic landscape and large traffic volume, a single monitor is not capable of accomplishing the measurement tasks for all applications of interest due to its resource constraint. Moreover, uncovering global network behavior requires network-wide traffic measurements at multiple monitors across the network since traffic measured at any single monitor only provides a partial view and may not be sufficient or accurate. These factors call for coordinated measurements among multiple distributed monitors. In this paper, we present a centralized optimization framework, LEISURE (Load- EqualIzed mea SUREment), for load-balancing network measurement workloads across distributed monitors. Specifically, we consider various load-balancing problems under different objectives and study their extensions to support both fixed and flexible monitor deployment scenarios. We formulate the latter flexible monitor deployment case as an MILP (Mixed Integer Linear Programming) problem and propose several heuristic algorithms to approximate the optimal solution and reduce the computation complexity. We evaluate LEISURE via detailed simulations on Abilene and GEANT network traces to show that LEISURE can achieve much better load-balanced performance (e.g., 4.75 × smaller peak workload and 70 × smaller variance in workloads) across all coordinated monitors in comparison to a naive solution (uniform assignment) to accomplish network-wide traffic measurement tasks under the fixed monitor deployment scenario. We also show that under the flexible monitor deployment setting, our heuristic solutions can achieve almost the same load-balancing performance as the optimal solution while reducing the computation times by a factor up to 22.5 × in Abilene and 800 × in GEANT.

Xin Nie,1,2 Cong Liu,3 Qian Guo,1,2 Ming-jun Zheng,1,2 Ling-ling Gao,1,2 Xiao Li,1,2 Da-wo Liu,1,2 Lian-cheng Zhu,1,2 Juan-juan Liu,1,2 Bei Lin1,2 1Department of Obstetrics and Gynaecology, Shengjing Hospital Affiliated to China Medical University, Liaoning, China; 2Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Liaoning, China; 3Department of Obstetrics and Gynaecology, Wuxi Materal and Child Health Hospital, Jiangsu, China Background: Transmembrane protein with epidermal growth factor-like and two follistatin-like domains 1 (TMEFF1) has an anticarcinogenic effect in brain tumors. However, little is known about the role of TMEFF1 in epithelial ovarian cancer (EOC).Materials and methods: TMEFF1 expression in EOC was detected by immunohistochemistry; its relationship with clinical pathological parameters and its influence on prognosis were analyzed. The MTT, scratch, Transwell assays, and flow cytometry were used to assess the malignant behavior of ovarian cancer cell. Changes in node proteins in MAPK and PI3K/AKT signaling pathways and the expression of epithelial–mesenchymal transformation markers were measured by Western blot. The regulatory effect of p53 on TMEFF1 was verified by chromatin immunoprecipitation (ChIP) assay and Western blot.Results: TMEFF1 expression was higher in the EOC group than in the borderline and benign tumor groups and normal ovary group; its high expression was significantly related to International Federation of Gynecology and Obstetrics stage (P=0.024) and independently predicted shorter overall survival (P