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Yong-Fang Li,1,* Qin-Yi Wang,1,* Lu-Lu Xu,2 Chun Yue,2 Li Hu,2 Na Ding,1 Yan-Yi Yang,2 Xiao-Li Qu,1 Zhi-Feng Sheng1,2 1National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, Department of Metabolism and Endocrinology, Health Management Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2Health Management Center, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhi-Feng Sheng, Tel +86-13574806523, Email shengzhifeng@csu.edu.cnPurpose: Fragility fractures, the most serious complication of osteoporosis, affect life quality and increase medical expenses and economic burden. Strategies to identify populations with very low bone mineral density (T-scores

Longlong Hu,1 Huihui Bao,1,2 Xiao Huang,1 Wei Zhou,1,2 Tao Wang,1,2 Lingjuan Zhu,1,2 Xi Liu,3 Minghui Li,1,3 Xiaoshu Cheng1,2 1Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Center for Prevention and Treatment of Cardiovascular Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Center of Cardiovascular Medicine, Inner Mongolia People’s Hospital, Hohhot, Inner Mongolia, People’s Republic of ChinaCorrespondence: Minghui LiCenter of Cardiovascular Medicine, Inner Mongolia People’s Hospital, No. 20 Zhaowuda Road, Hohhot, Inner Mongolia, 010017, People’s Republic of China, Tel +8615389819973, Fax +86-791-86262262, Email 15389819973@163.comXiaoshu ChengDepartment of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, Jiangxi, 330006, People’s Republic of China, Tel +8613607089128, Fax +86-791-86262262, Email xiaoshumenfan126@163.comBackground: Several recent studies have shown the relationship between the triglyceride glucose (TyG) index and the risk of stroke in the general population and in a few patient cohorts; however, the role of the TyG index on stroke risk in elderly hypertensive patients has not been determined. Thus, we aimed to investigate the association of the TyG index with first stroke and first ischemic stroke in elderly individuals with hypertension.Methods: We included 8487 elderly subjects with hypertension from the China H-type Hypertension Registry Study for the current analysis. The TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). Outcomes were the first stroke and first ischemic stroke.Results: During a median follow-up of 1.72 years, the first stroke was diagnosed in 82 patients (0.97%), and the first ischemic stroke was diagnosed in 48 patients (0.57%). Multivariable Cox proportional hazards models revealed that the TyG index was positively associated with the risk of first stroke (per 1-unit increment; HR: 1.72; 95% CI: 1.07, 2.76) and first ischemic stroke (HR: 2.31; 95% CI: 1.32, 4.05). When the TyG index was assessed as quartiles, significantly higher risks of first stroke (HR: 1.90; 95% CI: 1.04, 3.45) and first ischemic stroke (HR: 2.45; 95% CI: 1.16, 5.20) were found in participants in quartile 4 compared with those in quartiles 1– 3.Conclusion: The TyG index is potentially useful in the early identification of elderly hypertensive patients at high risk of experiencing a first stroke.Keywords: triglyceride glucose index, stroke, ischemic stroke, hypertension

Bing Huang,1– 4 Hui Yan,2 Limei Hu,1,3,4 Guiqiu Cao,2 Guipeng Wang,2 Jing Meng,2 Wanting Li,5 Gang Liu,2 Juan Wang,2 Wenqing Le,5 Hong Jiang1,3,4 1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Cardiology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China; 3Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, People’s Republic of China; 4Hubei Key Laboratory of Cardiology, Wuhan, Hubei, People’s Republic of China; 5Department of Critical Care, Wuhan Hankou Hospital, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Hong JiangDepartment of Cardiology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuchang District, Wuhan City, Hubei Province, 430060, People’s Republic of ChinaTel +86 2788041911Fax +86 2788042292Email hong-jiang@whu.edu.cnGuiqiu CaoDepartment of Cardiology, Fifth Affiliated Hospital of Xinjiang Medical University, No. 118 Henan Road, Xinshi District, Urumqi, Xinjiang, 830000, People’s Republic of ChinaTel/Fax +86 09917598403Email 809624056@qq.comBackground: Increasing numbers of patients have recovered from severe coronavirus disease 2019 (COVID-19) in Wuhan, China. This study aimed to evaluate the association of psychological distress with resting palpitations in recovered patients.Methods: In this prospective cohort study, consecutive patients who recovered from severe COVID-19 and complained of resting palpitations were included. Dynamic electrocardiogram (ECG) was continuously monitored for 2 hours while patients were at rest. A survey using a palpitation frequency scale and the Hospital Anxiety and Depression Scale (HADS) was administered to all participants.Results: Of the 289 consecutive patients who recovered from severe COVID-19, 24 patients (8.3%) suffered resting palpitation symptoms, and 22 patients were finally included. Two-hour Holter monitoring showed that 18 (81.8%) patients had tachyarrhythmias, of which the most common was sinus tachycardia (17/22, 77.3%). However, patients with sinus tachycardia showed a similar frequency of palpitation episodes compared to those without sinus tachycardia. Anxiety (68.2%) and depression (59.1%) were prevalent among these recovered patients. Patients with anxiety or depression symptoms had a higher frequency of palpitation episodes than those without anxiety or depression symptoms. In addition, both the HADS-anxiety score (r =0.609, P< 0.01) and HADS-depression score (r =0.516, P=0.01) were positively related to the frequency of palpitation episodes.Conclusion: Symptoms of resting palpitations, manifested mainly by sinus tachycardia, are not uncommon in patients who recovered from severe COVID-19. Psychological distress (anxiety and depression) may be responsible, at least in part, for resting palpitation symptoms.Keywords: coronavirus disease 2019, palpitations, sinus tachycardia, anxiety, depression

Xue Tian,1,&ast; Feiyue Yang,2,&ast; Fenghu Li,1 Li Ran,1 Jianying Chang,1 Jiehui Li,1 Wei Hong,3 Lang Shan,1 Yanjun Du,1 Lili Hu,1 Fan Mei,1 Mingyuan He,1 Yongxia Li,1 Heran Wang,1 Kai Zuo,1 Bo Zhou,4 Shuying Chen,1 Wanli Mao1 1Department of Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 2Department of Gynecologic Oncology, Guizhou Provincial People’s Hospital, Guiyang, 550004, People’s Republic of China; 3Department of Radiotherapy, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 4Surgical Department of Gynecological Oncology, The Affiliated Hospital of Guizhou Medical University, The Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fenghu Li; Li Ran Email 769654418@qq.com; ranli171@hotmail.comPurpose: To examine the clinical significance of unoperated cervical cancer patients treated with different neoadjuvant chemotherapy (NACT) schemes followed by concurrent chemotherapy and radiotherapy (CCRT).Methods: This retrospective analysis included women with locally advanced cervical cancer treated with NACT-CCRT between September 2011 and September 2014. Neoadjuvant chemotherapy included paclitaxel plus cisplatin (TP group; 62 patients) or paclitaxel plus loplatin (TL group; 58 patients), which were administered three weekly, and cisplatin or loplatin, which were administered weekly for synchronous chemotherapy. External beam radiation therapy (50.4– 56.35 Gy/28 f, 180– 215 cGy/f, 5 f/w) was followed by intracavitary brachytherapy (5 Gy per fraction, mostly 5 fractions, Ir192 based).Results: One hundred twenty women were included in the analysis. The complete/partial response rate was 99.2% after treatment. The one-year, three-year, and five-year survival rates were 99.2%, 82.5%, and 70.8%, respectively. In the TP and TL groups, the three-year and five-year survival rates were 85.5% vs 77.6% and 75.8% vs 65.5%, respectively, with no significant difference. The 5-year overall survival (OS) rates between patients with stage IIB and stage IIIB disease were not significantly different (69.2% vs 64.7%). In the TP group, grade 3 or 4 digestive reactions were more frequent than those in the TL group. Leukopenia, neutropenia, and thrombocytopenia were more common in the TL group. No significant difference was found in anemia, radiation enteritis, radiation proctitis, or radiation cystitis between the groups.Conclusion: Lobaplatin may be used as an alternative drug for patients with severe digestive system reactions or contraindications to cisplatin, but hematological toxicity must be considered, particularly in dose-intensive schemes. Neoadjuvant chemotherapy followed by concurrent chemotherapy and radiotherapy (NACT-CCRT) warrants further prospective study in cervical cancer patients with a wide range of tumor invasion (eg, mass size ≥ 5 cm or stage IIIB).Keywords: cervical cancer, neoadjuvant chemotherapy, survival benefit, side effects

Shutian Zhang,1,&ast; Li Hu,2,&ast; Chengzhi Han,1 Renhui Huang,1 Kokwin Ooi,1 Xinyi Qian,1 Xiaorong Ren,1 Dechang Chu,3 Haili Zhang,3 Dongshu Du,4 Chunmei Xia1 1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200240, People’s Republic of China; 3College of Agriculture and Bioengineering, Heze University, Heze, 274000, People’s Republic of China; 4School of Life Science, Shanghai University, Shanghai, 200444, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunmei XiaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, People’s Republic of ChinaTel +86 21 54237612-805Email cmxia@fudan.edu.cnDongshu DuSchool of Life Science, Shanghai University, Shanghai, 200444, People’s Republic of ChinaEmail sdhzdds@163.comPurpose: Oxidative/nitrosative stress, neuroinflammation and their intimate interactions mediate sympathetic overactivation in hypertension. An immoderate inflammatory response is characterized not only by elevated proinflammatory cytokines (PICs) but by increases in mitochondrial dysfunction, reactive oxygen species (ROS), and nitric oxide (NO). Recent data pinpoint that both the phospholipid and lipid droplets (LDs) are potent modulators of microglia physiology.Methods: Stress rats underwent compound stressors for 15 days with PLIN2-siRNA or scrambled-siRNA (SC-siRNA) administrated into the rostral ventrolateral medulla (RVLM). Lipids were analyzed by mass spectroscopy-based quantitative lipidomics. The phenotypes and proliferation of microglia, LDs, in the RVLM of rats were detected; blood pressure (BP) and myocardial injury in rats were evaluated. The anti-oxidative/nitrosative stress effect of phosphatidylethanolamine (PE) was explored in cultured primary microglia.Results: Lipidomics analysis showed that 75 individual lipids in RVLM were significantly dysregulated by stress [PE was the most one], demonstrating that lipid composition changed with stress. In vitro, prorenin stress induced the accumulation of LDs, increased PICs, which could be blocked by siRNA-PLIN2 in microglia. PLIN2 knockdown upregulated the PE synthesis in microglia. Anti-oxidative/nitrosative stress effect of PE delivery was confirmed by the decrease of ROS and decrease in 3-NT and MDA in prorenin-treated microglia. PLIN2 knockdown in the RVLM blocked the number of iNOS+ and PCNA+ microglia, decreased BP, alleviated cardiac fibrosis and hypertrophy in stressed rats.Conclusion: PLIN2 mediates microglial polarization/proliferation via downregulating PE in the RVLM of stressed rats. Delivery of PE is a promising strategy for combating neuroinflammation and oxidative/nitrosative stress in stress-induced hypertension.Keywords: lipid droplets, PLIN2, phosphatidylethanolamine, lipidomics, microglial expansion, neuroinflammation, stress, RVLM, oxidative/nitrosative stress

Xiang He,1,2,&ast; Lei Zhang,1,2,&ast; Lingjuan Hu,1,3,&ast; Shengbin Liu,1,2 Anying Xiong,1,2 Junyi Wang,1,2 Ying Xiong,4 Guoping Li1,2 1Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, The Third People’s Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, 610031, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Chengdu Third People’s Hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China; 3Department of Respiratory Disease, Renshou County People’s Hospital, Renshou, 620550, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Sichuan Friendship Hospital, Chengdu, 610000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guoping Li; Ying Xiong Email lzlgp@163.com; ly65110@126.comBackground: Exposure to air pollutants cause exacerbation of asthma, but the experimental evidence and the mechanisms still need to be collected and addressed.Methods: Asthma model was constructed by ovalbumin (OVA) combined with or without airborne fine particulate matter 2.5 (PM2.5) exposure. Lung sections were stained by hematoxylin-eosin staining (H&E) and Masson’s trichrome. RNA-seq and gene set enrichment analysis (GSEA) was performed to identify the key pathway. TdT mediated dUTP Nick End Labeling (TUNEL) assay, real-time qPCR, Western blot, immunofluorescence and lentivirus transfection were applied for mechanism discovery.Results: In this study, we found PM2.5 aggravated airway inflammation in OVA-induced asthmatic mice. RNA-seq analysis also showed that epithelial mesenchymal transition (EMT) was enhanced in OVA-induced mice exposed to PM2.5 compared with that in OVA-induced mice. In the meantime, we observed that apoptosis was significantly increased in asthmatic mice exposed to PM2.5 by using GSEA analysis, which was validated by TUNEL assay. By using bioinformatic analysis, Fas associated via death domain (FADD), a new actor in innate immunity and inflammation, was identified to be related to apoptosis, EMT and tight junction. Furthermore, we found that the transcript and protein levels of tight junction markers, E-cadherin, zonula occludens (ZO)-1 and Occludin, were decreased after PM2.5 exposure in vivo and in vitro by using RT-qPCR and immunofluorescence, with the increased expression of FADD. Moreover, down-regulation of FADD attenuated PM2.5-induced apoptosis and tight junction disruption in human airway epithelial cells.Conclusion: Taken together, we demonstrated that PM2.5 aggravated epithelial tight junction disruption through apoptosis mediated by up-regulation of FADD in OVA-induced model.Keywords: asthma, epithelial tight junction disruption, PM2.5, FADD, apoptosis

Longhao Hu,1,&ast; Xi Yang,2,3,&ast; Jing Yin,1 Xuan Rong,1 Xinlei Huang,1 Peiquan Yu,3 Zhiqiang He,1 Yi Liu1– 3 1Department of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 2School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China; 3Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi LiuDepartment of Biophysics, School of Life Sciences, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of ChinaTel/Fax +86-516-83262084Email cbpeliuyinew@163.comPurpose: The aim was to evaluate the antimicrobial potential of AgNPs synthesized with Artemisia argyi leaf extract and investigate the antimicrobial synergistic effects of AgNPs combined with domiphen and provide an efficient and broad-spectrum combination drug strategy.Methods: AgNPs synthesized with Artemisia argyi leaf extract were studied using UV–vis spectroscopy, FTIR spectroscopy and particle size analysis. Then, Artemisia argyi leaf extract-synthesized AgNPs and domiphen were tested against Acinetobacter baumannii (ATCC 19606), Staphylococcus aureus (ATCC 6538), Escherichia coli (8099) and Candida albicans (ATCC 10231), respectively. Then, we explore synergistic antimicrobial effect and synergistic anti-biofilm effect through combined drug susceptibility test and combined drug minimum biofilm eradication concentration (MBEC50) test.Results: Characteristic absorption bands of AgNPs were found near 430 nm in the UV–vis spectrum. Particle size analysis results revealed that the average particle size of Artemisia argyi leaf extract-synthesized AgNPs was 77.6 nm. Artemisia argyi leaf extract-synthesized AgNPs showed high antimicrobial activity against the above four strains. Minimum inhibitory concentration (MIC) of Artemisia argyi leaf extract-synthesized AgNPs against strains was 1 μg/mL for Acinetobacter baumannii, 2 μg/mL for Staphylococcus aureus, Escherichia coli and Candida albicans. MBEC50 of Artemisia argyi leaf extract-synthesized AgNPs against strains was 2 μg/mL for Acinetobacter baumannii, 4 μg/mL for Staphylococcus aureus, 1/2 μg/mL for Escherichia coli and 2 μg/mL for Candida albicans. The combination of Artemisia argyi leaf extract-synthesized AgNPs and domiphen has synergistic antimicrobial effect and synergistic anti-biofilm effect. Fractional inhibitory concentration (FIC) was ≤ 0.5.Conclusion: Artemisia argyi leaf extract-synthesized AgNPs had antimicrobial activity against the above four strains. The combination of Artemisia argyi leaf extract-synthesized AgNPs and domiphen has synergistic antimicrobial effects to reduce the dosage of each antimicrobial drugs. Artemisia argyi leaf extract-synthesized AgNPs and domiphen have synergistic anti-biofilm effects.Keywords: AgNPs, domiphen, synergy, pathogenic biofilm, combination medication

Li Hu,1,2 Wipa Sae-Sia,2 Luppana Kitrungrote2 1Breast Surgery Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Faculty of Nursing, Prince of Songkla University, Hatyai, Songkhla, ThailandCorrespondence: Li Hu Email 13765156895@163.comBackground: Pressure injury (PI) remains a critical health issue worldwide. The global incidence of hospital-acquired PI is 8.4%, and among intensive-care unit (ICU) patients, it is even higher, ranging from 6.60% to 36.80%. It is important to investigate ICU nurses’ PI prevention knowledge, attitudes, and practices (KAP).Aim: The aim of this study was to describe the level of Chinese ICU nurses’ knowledge, attitudes, and self-reported practices of PI prevention.Materials and Methods: From March 31 to April 30, 2019, we recruited a total of 510 ICU nurses into the current study using convenience sampling. The Modified Pressure Ulcer Knowledge Assessment Tool version 2.0, Attitudes toward Pressure Ulcer Prevention instrument, and Questionnaire to evaluate nurses’ Adherence to Recommendations for Preventing Pressure Ulcers were used for data collection. We used one-way analysis of variance, Student’s t-test, and the Mann–Whitney U-test to assess differences in knowledge, attitudes, and self-reported practices of PI prevention among ICU nurses, whom we categorized by their demographic characteristics.Results: Mean scores of participants’ knowledge, attitude, and their self-report practice were 65.82 ± 9.29, 76.65 ± 8.62, and 83.35 ± 13.55, respectively. Participants with bachelor’s degrees or higher, who worked in tertiary hospitals, and who had received training on PI prevention over the last year had higher scored on PI prevention knowledge (all P < 0.05). Participants who had received training on PI prevention over the last year scored higher on attitude than those who had not received such training over the last year (P = 0.001).Conclusion: ICU nurses surveyed in this study did not demonstrate an acceptable level of knowledge about PI prevention, while their attitudes and self-reported practices were acceptable. Continuing education or in-service training should be provided to enhance ICU nurses’ knowledge of PI prevention.Keywords: intensive-care unit nurse, knowledge, attitude, practice, pressure injury prevention

Wenjing Cao,1 Lin Hu,2 Yongmei He,3 Ping Yang,4 Xiaoling Li,5 Shunwang Cao6 1Nursing School of Xiang Nan University, Chenzhou, Hunan, People’s Republic of China; 2School of Public Health of Xiang Nan University, Chenzhou, Hunan, People’s Republic of China; 3Department of Nursing, The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, People’s Republic of China; 4Department of Gastroenterology, The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, People’s Republic of China; 5Rehabilitation School of Xiang Nan University, Chenzhou, Hunan, People’s Republic of China; 6Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Shunwang CaoDepartment of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of ChinaTel +86 15625053283Email cswang2010@163.comBackground: Midwives have a high risk of work-related musculoskeletal disorders (WMSDs), which are the leading cause of pain and disability. However, the association between job stress and WMSDs among midwives has not been studied. The aim of this project was to specifically describe relationships between the job stress and WMSDs among a sample of hospital midwives in Chenzhou, Hunan Province, China.Methods: We conducted a cross-sectional study among a sample of 769 eligible midwives in the city of Chenzhou in Hunan Province, China from May 2018 to January 2019. All participants completed a questionnaire regarding the presence and severity of different pain symptoms and job stress assessed by the Korean occupational stress scale.Results: A total of 597 participants responded (77.6%), and 491 (82.2%) reported that they had experienced WMSDs at some time over a 12-month period. The most common pain site was low back (72.7%), followed by the neck (52.8%) and shoulders (42.7%). We revealed that various aspects of job stress were associated with WMSDs in the current study, namely “Owing to my workload, I always feel time pressure” (OR, 2.05; 95% CI: 1.28– 3.28), “My job has become increasingly overbearing” (OR, 2.34; 95% CI: 1.46– 3.77), “My work requires long lasting concentration” (OR, 3.50; 95% CI: 2.13– 5.74), “I have to do various jobs simultaneously”, (OR, 3.15; 95% CI: 1.93– 5.14)), “My work requires creativity” (OR, 2.15; 95% CI: 1.31– 3.54), “My work requires a high level of skill or knowledge” (OR, 2.83; 95% CI: 1.67– 4.80), “My supervisor is helpful in getting the job done” (OR, 0.53; 95% CI: 0.33– 0.84), “I have someone who understands my difficulties at work” (OR, 0.53; 95% CI: 0.34– 0.85), “Undesirable changes (ie, downsizing) will come to my job” (OR, 3.28; 95% CI: 2.01– 5.77), “My company provides me with sufficient organizational support” (OR, 0.47; 95% CI: 0.29– 0.74), “Departments cooperate each other without conflicts” (OR, 0.50; 95% CI: 0.32– 0.80), “I am provided with the opportunity to develop my capacity” (OR, 0.57; 95% CI: 0.36– 0.91) and “My company climate is authoritative and hierarchical” (OR: 3.21; 95% CI: 1.97-5.23).Conclusion: Overall, this study suggests that job stress has an important influence on WMSDs among a sample of hospital midwives in Chenzhou, Hunan Province, China. Given the multifaceted nature of identified risk, a comprehensive approach to reduce this risk is clearly required and a job stress management program will be essential.Keywords: midwife, work-related musculoskeletal disorders, job stress

Linjun Hu,1,&ast; Xingli Shan,1,&ast; Dongdong Han,1 Zhaoxia Guo,2 Huina Wang,2 Zejun Xiao3 1Department of Urology, Cancer Hospital of HuanXing Chaoyang District Beijing, Beijing, People’s Republic of China; 2Acornmed Biotechnology Co., Ltd, Beijing, People’s Republic of China; 3Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zejun XiaoDepartment of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaEmail xiaozejun1968@163.comAbstract: Penile squamous cell carcinoma (pSCC) is a rare disease in developed countries. pSCC causes a severe health problem and social burden in developing countries. We reported a 49-year-old male recurrent pSCC patient with medium PD-L1 expression and low TMB. The patient obtained complete response after multimodal therapy (MMT). The clinical manifestation is a recurrence in the right groin with nearly ruptured pSCC. He had partial resection of penile cancer plus bilateral groin lymph node dissection and pelvic lymph node dissection during the first operation. Pathology of the recurrent tumor showed fibrous tissue with cancer infiltration and necrosis. We used MMT, including resection of palliative right inguinal metastases, four cycles of paclitaxel+bleomycin+cisplatin, and continuous sintilimab to treat the patient. The patient had a complete response (CR) after four cycles of therapy and sustained CR for 18 months with continuous sintilimab, showing a good tolerance and acceptable toxicity. This is the first case presenting a complete response in a relapsed pSCC patient. These results suggest that MMT is worth exploring.Keywords: pSCC, immunotherapy, chemotherapy, multimodal treatment, case report

Li Hu, Lei Fang, Zhiping Zhang, Zhilong Yan Department of Gastroenterology, Ningbo No.1 Hospital, Ningbo, People’s Republic of ChinaCorrespondence: Zhilong YanDepartment of Gastroenterology, Ningbo No.1 Hospital, 59 Liuting Street, Haishu District, Ningbo, 315000, Zhejiang Province, People’s Republic of ChinaEmail yanzhilong@nbu.edu.cnBackground: Colorectal cancer (CRC) is one of the leading causes of cancer-related death around the world, becoming a severe public health problem. Mounting evidence has proven that circRNAs act as pivotal modulators in the initiation and development of CRC. Although the function of circTADA2A has been explored in osteosarcoma and breast cancer, the specific role of circTADA2A in CRC remains unknown.Methods: Bioinformatics analysis based on GEO datasets was used to evaluate the dysregulated circRNAs in CRC. CCK-8 and transwell assays were used to detect the functions of CRC cells. qRT-PCR and Western blot were performed to evaluate the expression of RNAs and proteins. Luciferase assay and RNA pull down experiment were carried out to verify the interaction between miR and its targets.Results: CircTADA2A was downregulated in CRC tissues compared with normal samples. CircTADA2A exhibited greater stability than its linear form when exposed to RNase R and actinomycin D treatment. qRT-PCR analysis validated the lower expression level of circTADA2A in CRC. The loss-of-function and gain-of-function assays indicated that circTADA2A exerted the inhibitory role in CRC cell proliferation and migration. Mechanistically, circTADA2A functioned as a sponge of miR-1229. Further experiments manifested that circTADA2A regulated BCL2L10 expression via competitively binding to miR-1229. More importantly, the tumor suppressor role of circTADA2A in the malignant behaviors of CRC cells was mediated by BCL2L10.Conclusion: circTADA2A suppressed cell proliferation and migration in CRC through regulation of miR-1229/BCL2L10 axis, which suggested that circTADA2A might represent a novel potential target for the treatment of CRC.Keywords: colorectal cancer, circTADA2A, miR-1229, BCL2L10

Xingwei Cao,1,&ast; Qiaoshi Zhong,1,&ast; Yinjuan Guo,2,3 Yaping Hang,1 Yanhui Chen,1 Xueyao Fang,1 Yanping Xiao,1 Hongying Zhu,1 Hong Luo,1 Fangyou Yu,2,3 Longhua Hu1 1Jiangxi Provincial Key Laboratory of Medicine, Clinical Laboratory of the Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Clinical Laboratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China; 3Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200082, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Longhua Hu; Fangyou Yu Email longhuahu@163.com; wzjxyfy@163.comIntroduction: Polymyxin resistance caused by the plasmid-mediated mcr-1 gene in gram-negative bacilli poses a huge threat to our health. In recent years, many regions have reported that mcr-1 and β-lactamase genes can coexist in a single strain.Methods: In this study, 107 nonduplicate Klebsiella pneumoniae (K. pneumoniae) isolates were collected from a tertiary hospital in Jiangxi, China. Antimicrobial susceptibility testing of isolates was performed using gram-negative susceptibility cards on the VITEK system. The minimum inhibitory concentrations (MICs) of polymyxin B was detected using the microdilution broth method. The presence of resistance genes was assessed using polymerase chain reaction (PCR). We subjected isolates to genotyping using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) and analyzed the transferability of plasmids with filter mating and electroporation. Subsequently, whole-genome sequencing was performed for plasmids.Results: Of the 107 K. pneumoniae isolates, 15 (14.0%) were resistant to polymyxin B. All polymyxin B-resistant isolates harbored at least one of the extended-spectrum β-lactamase genes tested. Only one isolate simultaneously harbored mcr-1, blaNDM− 5, blaCTX-M-55, and blaSHV-27 genes. MLST results showed that 15 carbapenem-resistant K. pneumoniae isolates belonged to five sequence types (STs). PFGE results displayed nine different PFGE clusters. Conjugation and transformation experiments and sequencing analysis showed that the strain had three plasmids, and mcr-1, blaNDM− 5, and blaCTX-M-55 were located on different plasmids.Conclusion: The present study demonstrated for the first time the coexistence of mcr-1, blaNDM− 5, and blaCTX-M-55 in a K. pneumoniae ST485 isolate. The three plasmids carrying the mcr-1, blaNDM− 5, and blaCTX-M-55 genes can be transmitted in Enterobacteriaceae strains, which may lead to more severe bacterial resistance.Keywords: Klebsiella pneumoniae, polymyxin B, mcr-1, blaNDM-5, blaCTX-M-55, plasmid

Lingfei Hu, Yinping Liu, Chaobing Wei, Huixiang Jin, Lixin Mei, Changfan Wu Department of Ophthalmology, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, People’s Republic of ChinaCorrespondence: Changfan Wu Tel +86- 13909632351Email wuchangfan1971@sohu.comAim: In the present study, we performed bioinformatics studies and in vitro functional assays to explore the underlying role of serpin family H member 1 (SERPINH1) in the diabetic retinopathy.Methods: Common differentially expressed genes (DEGs) between diabetic retinal tissues and normal retinal tissues were analyzed using Gene Expression Omnibus (GEO) database. The proliferation and migration of human retinal endothelial cells (HRECs) was evaluated by MTS, EdU and wound healing assays, respectively; the miRNA and mRNAs expression levels of hub genes in HRECs were determined using quantitative real-time PCR (qRT-PCR). Protein levels were determined using a Western blot assay.Results: A total of 189 common DEGs were screened between two GEO datasets (GSE60436 and GSE94019), and ten potential hub genes that may link to the progression of diabetic retinopathy were detected. The qRT-PCR results showed that collagen, type I, alpha 1 (COL1A1), Collagen, type I, alpha 2 (COL1A2) and serpin family H member 1 (SERPINH1) mRNA expression levels were up-regulated in the HRECs after being exposed to high glucose for 48 h. Silence of SERPINH1 repressed the high glucose-induced increase in proliferation and migration of HRECs. SERPINH1 was a target of miR-29b and was suppressed by miR-29 in HRECs. SERPINH1 overexpression promoted HREC proliferation and migration. Furthermore, miR-29b suppressed HREC proliferation and migration under high-glucose stimulation, which was significantly attenuated by enforced expression of SERPINH1.Conclusion: In conclusion, by performing the integrated bioinformatics analysis, the present study suggested that 3 hub genes (COL1A1, COL1A2 and SERPINH1) may be associated with diabetic retinopathy pathophysiology. Further mechanistic studies indicated that miR-29b/SERPINH1 signaling participated in high glucose-induced enhancement in the proliferation and migration of HRECs.Keywords: diabetic retinopathy, bioinformatics analysis, HRECs, SERPINH1, proliferation, migration

Yuchen Xia,1,2 Guihua Wang,2 Manli Jiang,3 Xueting Liu,3 Yan Zhao,4 Yinghui Song,5 Binyuan Jiang,3 Demao Zhu,4 Ling Hu,6 Zhao Zhang,6 Ting Cao,6 Ji Ming Wang,7 Jinyue Hu3 1Graduate School, Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Department of Oncology, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China; 3Medical Research Center, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China; 4Department of Pathology, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China; 5Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Hunan Normal University, Changsha, Hunan, People’s Republic of China; 6Department of Clinical Laboratory, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of China; 7Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, 21702, USACorrespondence: Jinyue HuMedical Research Center, Changsha Central Hospital, University of South China, Changsha, Hunan, 410004, People’s Republic of ChinaTel +86-731-85667664Fax +86-731-85668157Email jinyueh@yahoo.comGuihua WangDepartment of Oncology, Changsha Central Hospital, University of South China, Changsha, Hunan, People’s Republic of ChinaTel +86-731-85667664Fax +86-731-85668157Email wangguihua8890@163.comIntroduction: Glutathione reductase (GSR) provides reduced glutathione (GSH) to maintain redox homeostasis. Inhibition of GSR disrupts this balance, resulting in cell damage, which benefits cancer therapy. However, the effect of GSR inhibition on the tumorigenicity of human cervical cancer is not fully understood.Materials and Methods: Tissue microarray analysis was employed to determine GSR expression in cervical cancer tissues by immunohistochemical staining. Cell death was measured with PI/FITC-annexin V staining. mRNA levels were measured via quantitative RT-PCR. Protein expression was measured by Western blotting and flow cytometry. STAT3 deletion was performed with CRISPR/Cas9 technology. GSR knockdown was achieved by RNA interference. Reactive oxygen species (ROS) levels were measured by DCF staining. GSR enzymatic activity was measured with a GSR assay kit. The effect of GSR inhibition on the growth of tumors formed by cervical cancer cells was investigated using a xenograft model.Results: The expression of GSR was increased in human cervical cancer tissues, as shown by immunohistochemical staining. GSR knockdown by RNA interference in human cervical cancer cell lines resulted in cell death, suggesting the ability of GSR to maintain cancer cell survival. The STAT3 inhibitor 6-nitrobenzo[b]thiophene 1,1-dioxide (Stattic) also inhibited the enzymatic activity of GSR and induced the death of cervical cancer cells. More importantly, Stattic decreased the growth of xenograft tumors formed by cervical cancer cells in nude mice. Mechanistically, tumor cell death induced by Stattic-mediated GSR inhibition was ROS-dependent, since the ROS scavengers GSH and N-acetyl cysteine (NAC) reversed the effect of Stattic. In contrast, pharmacological and molecular inhibition of STAT3 did not induce the death of cervical cancer cells, suggesting a STAT3-independent activity of Stattic.Conclusion: Stattic inhibits the enzymatic activity of GSR and induces STAT3-independent but ROS-dependent death of cervical cancer cells, suggesting its potential application as a therapeutic agent for human cervical cancers.Keywords: Stattic, glutathione reductase, cell death, cervical cancer, reactive oxygen species, tumor growth

Lina Gao,1 Lei Zhang,1 Fengjun He,1 Jing Chen,1 Meng Zhao,1 Simin Li,1 Hao Wu,1 Yumeng Liu,1 Yinan Zhang,1,2 Qineng Ping,3 Lihong Hu,1,2 Hongzhi Qiao1,2,4 1Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 3Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 4Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of ChinaCorrespondence: Hongzhi Qiao; Lihong HuState Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, People’s Republic of ChinaEmail qiaohz@njucm.edu.cn; lhhu@njucm.edu.cnBackground: BF211, a derivative of bufalin (BF), shows significantly improved solubility and potent antitumor efficiency compared to BF. Unfortunately, the unwanted toxicity such as cardiotoxicity caused by unspecific distribution has hindered its clinical use.Methods: PEGylated BF211 liposomes (BF211@Lipo) were designed and optimizely prepared based on the pre-prescription research. In vitro and in vivo cardiotoxicity was evaluated. In vivo pharmacokinetics and biodistribution of BF211@Lipo were investigated. In vivo antitumor activity and toxicity were evaluated in HepG2 cell xenograft models. The rapid-release triggered by Poloxamer 188 (P188) was assessed in vitro and in vivo.Results: The optimized BF211@Lipo displayed a spherical morphology with a size of (164.6 ± 10.3) nm and a high encapsulation efficiency of (93.24 ± 2.15) %. The in vivo concentration–time curves of BF211 loaded in liposomes showed a prolonged half-life in plasma and increased tumor accumulation. No obvious abnormality in electrocardiograms was observed in guinea pigs even at 9 mg/kg. Moreover, to improve the efficient release of BF211@Lipo, a surfactant-assisted rapid-release strategy was developed, and the release-promoting mechanism was revealed by the fluorescence resonance energy transfer (FRET) and fluorescence nanoparticle tracking analysis (fl-NTA) technology. Sequential injection of BF211@Lipo and P188 could ignite the “cold” liposomes locally in tumor regions, facilitating the burst release of BF211 and enhancing the therapeutic index.Conclusion: Our progressive efforts that begin with preparation technology and dosage regimen enable BF211 to like a drug, providing a promising nano platform to deliver the cardiac glycosides and alleviate the side effects by decreasing unspecific biodistribution.Keywords: bufalin derivative, liposome, rapid-release, antitumor, cardiotoxicity

Dong Zhang,1– 3,* Weifen Zhang,1,2,* Xinghan Wu,1 Qian Li,1,2 Zhiyi Mu,1,2 Fengshuo Sun,1,2 Mogen Zhang,1 Guoyan Liu,3 Linlin Hu1,2 1Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang, 261053, People’s Republic of China; 2College of Pharmacy, Weifang Medical University, Weifang, 261053, People’s Republic of China; 3Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoyan Liu; Linlin Hu Tel/Fax +86 15715369896Email wfliuguoyan@126.com; hull@wfmc.edu.cnPurpose: Malignant melanoma is one of the most devastating types of cancer with rapid relapse and low survival rate. Novel strategies for melanoma treatment are currently needed to enhance therapeutic efficiency for this disease. In this study, we fabricated a multifunctional drug delivery system that incorporates dacarbazine (DTIC) and indocyanine green (ICG) into manganese-doped mesoporous silica nanoparticles (MSN(Mn)) coupled with magnetic resonance imaging (MRI) and photothermal imaging (PI), for achieving the superior antitumor effect of combined chemo-photothermal therapy.Materials and Methods: MSN(Mn) were characterized in terms of size and structural properties, and drug loading and release efficiency MSN(Mn)-ICG/DTIC were analyzed by UV spectra. Photothermal imaging effect and MR imaging effect of MSN(Mn)-ICG/DTIC were detected by thermal imaging system and 3.0 T MRI scanner, respectively. Then, the combined chemo-phototherapy was verified in vitro and in vivo by morphological evaluation, ultrasonic and pathological evaluation.Results: The as-synthesized MSN(Mn) were characterized as mesoporous spherical nanoparticles with 125.57± 5.96 nm. MSN(Mn)-ICG/DTIC have the function of drug loading-release which loading ratio of ICG and DTIC could reach to 34.25± 2.20% and 50.00± 3.24%, and 32.68± 2.10% of DTIC was released, respectively. Manganese doping content could reach up to 65.09± 2.55 wt%, providing excellent imaging capability in vivo which the corresponding relaxation efficiency was 14.33 mM− 1s− 1. And outstanding photothermal heating ability and stability highlighted the potential biomedical applicability of MSN(Mn)-ICG/DTIC to kill cancer cells. Experiments by A375 melanoma cells and tumor-bearing mice demonstrated that the compound MSN(Mn)-ICG/DTIC have excellent biocompatibility and our combined therapy platform delivered a superior antitumor effect compared to standalone treatment in vivo and in vitro.Conclusion: Our findings demonstrate that composite MSN(Mn)-ICG/DTIC could serve as a multifunctional platform to achieve a highly effective chemo-photothermal combined therapy for melanoma treatment.Keywords: Mn-doped mesoporous silica, drug delivery, magnetic resonance imaging, combination therapy

Liheng Chen,1 Jiawei Sun,2,3 Qiaohong Wang,1 Lingzhen Hu,1 Yi Zhang,1 Huibin Ma,2,3 Xize Jia,4,5 Xuyan Yang1 1Department of Rheumatology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310009, People’s Republic of China; 2School of Information and Electronics Technology, Jiamusi University, Jiamusi, People’s Republic of China; 3Integrated Medical Research School, Jiamusi University, Jiamusi, People’s Republic of China; 4Institute of Psychological Sciences, Hangzhou Normal University, Hangzhou, People’s Republic of China; 5Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, People’s Republic of ChinaCorrespondence: Xize JiaInstitute of Psychological Sciences, Hangzhou Normal University, Hangzhou, People’s Republic of ChinaEmail jiaxize@hznu.edu.cnXuyan YangDepartment of Rheumatology, Second Affiliated Hospital, College of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, People’s Republic of ChinaEmail hangzhouyxy@zju.edu.cnPurpose: In this study, we seek to investigate dynamic changes of brain activity in non-neuropsychiatric systemic lupus erythematosus (non-NPSLE) patients with inactive disease.Patients and Methods: Thirty-one non-NPSLE patients with inactive disease and 20 matched healthy controls underwent the blood oxygenation level-dependent fMRI examination. Dynamic regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) were used to analyze the brain activity in typical band (0.01– 0.08 Hz), slow-4 (0.027– 0.073 Hz) and slow-5 (0.01– 0.027 Hz). Pearson’s correlation analysis was performed to correlate dynamic regional homogeneity (dReHo) and dynamic fractional amplitude of low-frequency fluctuations (dfALFF) values for clusters of voxels where significant group differences were found with clinical variables in non-NPSLE patients with inactive disease.Results: In typical band, non-NPSLE patients showed increased dReHo in left middle occipital gyrus (MOG) compared to healthy controls. Meanwhile, patients showed decreased dfALFF in right superior frontal gyrus (SFG) and bilateral middle frontal gyrus (MFG) in typical band. In slow-4, increased dReHo in left MOG was found in non-NPSLE patients. In slow-5, non-NPSLE patients showed increased dReHo in left MOG, left calcarine fissure and surrounding cortex, right precentral gyrus (PreCG) and left postcentral gyrus (PoCG). Meanwhile, non-NPSLE patients showed decreased dfALFF in left SFG, right MFG, and right PreCG in slow-5. Moreover, the glucocorticoid dose showed significantly negative correlations with dReHo values in right PreCG in slow-5, left PoCG in slow-5, and left MOG in typical band.Conclusion: dReHo and dfALFF abnormalities in different frequency bands may be the key characteristics in the pathogenesis mechanism of non-NPSLE.Keywords: systemic lupus erythematosus, non-neuropsychiatric systemic lupus erythematosus, dynamic fractional amplitude of low-frequency fluctuations, dynamic regional homogeneity, frequency bands, resting-state functional magnetic resonance imaging

Li Zhang,1,* Xin-Mei Yang,2,* Jing Chen,3 Lei Hu,4 Fan Yang,5 Yue Zhou,5 Bei-Bei Zhao,1 Wei Zhao,2,5,* Xiao-Fan Zhu1,* 1Department of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, People’s Republic of China; 2Department of Clinical Pharmacy, Clinical Trial Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People’s Republic of China; 3Pediatric Hematology & Oncology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, People’s Republic of China; 5Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Fan ZhuDepartment of Pediatric, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of ChinaTel/Fax +86 22 2390 9001Email xfzhu@ihcams.ac.cnWei ZhaoDepartment of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, No. 44, Wenhua West Road, Jinan, Shandong Province, People’s Republic of ChinaTel/Fax +86 531 8838 3308Email zhao4wei2@hotmail.comBackground: An oral tetra-arsenic tetra-sulfide (AS4S4) formula has been recommended as an outpatient post-remission treatment for Chinese adults with acute promyelocytic leukemia (APL) but limited data are available for children. In this exploratory study, we aimed to evaluate the pharmacokinetics and safety of the AS4S4 formula in children.Methods: Eleven newly diagnosed and one relapsed pediatric patient (4– 14 years of age) treated with the AS4S4 formula were included. Blood samples were collected from 12 children, and drug concentrations were quantified by ICP-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM software. Toxic effects were graded according to the NCI-CTCAE, Version 3.Results: A total of 107 arsenic concentrations (0.1– 75.0 μg L− 1) were used for population pharmacokinetic analysis. The median (range) of estimated weight-normalized CL and volume distribution at steady-state were 45.26 (35.63– 82.18) L h− 1 kg− 1 and 230.37 (85.96– 495.68) L kg− 1, respectively. No patients discontinued AS4S4 treatment owing to adverse events, and there were no drug-related adverse events over grades 3– 4. All newly diagnosed APL patients were in MCR with a median follow-up of 28 months (range, 23 to 37 months). Both the estimated 3-year EFS and OS rates were 100%.Conclusion: The pharmacokinetics and safety oral AS4S4 formula was evaluated for the first time in pediatric APL. The pharmacokinetic assessment demonstrated that the dosing regimen of 60 mg/kg/d TID resulted in a higher steady-state through concentration in children than that which was achieved in adults. The results of this study indicate that the AS4S4 formula is safe in newly diagnosed pediatric APL patients.Keywords: acute promyelocytic leukemia, Realgar-Indigo Naturalis Formula, pediatric, safety, population pharmacokinetics

Lei Zhang,1,* Fengjun He,1,* Lina Gao,1 Minghui Cong,1 Juan Sun,2 Jialu Xu,2 Yutong Wang,2 Yang Hu,1 Sajid Asghar,3 Lihong Hu,1,2 Hongzhi Qiao1,2,4 1Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2State Key Laboratory Cultivation Base for TCM Quality and Efficacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 3Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan; 4Jiangsu Engineering Research Center for Efficient Delivery System of TCM, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hongzhi Qiao; Lihong HuSchool of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Nanjing, 210023, People’s Republic of ChinaEmail qiaohz@njucm.edu.cn; lhhu@njucm.edu.cnBackground: Exosomes are a type of membrane vesicles secreted by living cells. Recent studies suggest exosome-like nanovesicles (ELNVs) from fruits and vegetables are involved in tissue renewal process and functional regulation against inflammatory diseases or cancers. However, there are few reports on ELNVs derived from medicinal plants.Methods: ELNVs derived from Asparagus cochinchinensis (Lour.) Merr. (ACNVs) were isolated and characterized. Cytotoxicity, antiproliferative and apoptosis-inducing capacity of ACNVs against hepatoma carcinoma cell were assessed. The endocytosis mechanism of ACNVs was evaluated on Hep G2 cells in the presence of different endocytosis inhibitors. In vivo distribution of ACNVs was detected in healthy and tumor-bearing mice after scavenger receptors (SRs) blockade. PEG engineering of ACNVs was achieved through optimizing the pharmacokinetic profiles. In vivo antitumor activity and toxicity were evaluated in Hep G2 cell xenograft model.Results: ACNVs were isolated and purified using a differential centrifugation method accompanied by sucrose gradient ultracentrifugation. The optimized ACNVs had an average size of about 119 nm and showed a typical cup-shaped nanostructure containing lipids, proteins, and RNAs. ACNVs were found to possess specific antitumor cell proliferation activity associated with an apoptosis-inducing pathway. ACNVs could be internalized into tumor cells mainly via phagocytosis, but they were quickly cleared once entering the blood. Blocking the SRs or PEGylation decoration prolonged the blood circulation time and increased the accumulation of ACNVs in tumor sites. In vivo antitumor results showed that PEGylated ACNVs could significantly inhibit tumor growth without side effects.Conclusion: This study provides a promising functional nano platform derived from edible Asparagus cochinchinensis that can be used in antitumor therapy with negligible side effects.Keywords: exosome, exosome-like nanovesicles, Asparagus cochinchinensis, engineering exosome, antitumor

ChengCheng Yue,1,* WeiHua Shen,2,* LiFen Hu,1,3,4 YanYan Liu,1,3,4 YaHong Zheng,1 Ying Ye,1,3,4 Yuhao Zhang,5 JiaBin Li1,3,4,6 1Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Special Clinic, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Anhui Center for Surveillance of Bacterial Resistance, Hefei, Anhui, People’s Republic of China; 4Institute of Bacterial Resistance, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 5Anhui Medical University, Hefei, Anhui, People’s Republic of China; 6Department of Infectious Diseases, The Chaohu Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: JiaBin Li; LiFen HuDepartment of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of ChinaTel +86-551-62922713; +86-551-62922258Fax +86-551-62922281Email lijiabin@ahmu.edu.cn; lifen.hu@163.comPurpose: Our aim was to investigate in vitro biofilm formation by S. maltophilia and the effects of antibacterial agents used to prevent biofilm formation.Methods: Two trimethoprim/sulfamethoxazole-resistant S. maltophilia strains were isolated from the pleural effusion of a patient with cancer. The minimum inhibitory concentrations (MICs) of amikacin, azithromycin, cefoperazone/sulbactam, and tigecycline were determined. The checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A crystal violet biofilm assay and confocal laser scanning microscopy (CLSM) were used to observe biofilm formation. In vitro effects of azithromycin combined with tigecycline on biofilms of S. maltophilia strains were tested.Results: The two S. maltophilia isolates were confirmed to produce strong biofilms. Crystal violet biofilm assay and CLSM analysis of S. maltophilia biofilm were in the initial adhesive stage after 2 h incubation. Biofilm was in the exponential phase of growth at 12 h and reached maximal growth at 36– 48 h. Compared with tigecycline or azithromycin alone, the combination of tigecycline and azithromycin increased the inhibiting effect S. maltophilia biofilm biomass after incubation for 12 h. Compared with the control group, in almost all strains treated with tigecycline and azithromycin, the biofilm was significantly suppressed significance (P< 0.001). We found that 2x MIC azithromycin combined with 1x MIC tigecycline had the best inhibiting effect against the biofilm, the biofilm inhibition rates of three strains were all over 60%, the biofilm thickness was inhibited from 36.00 ± 4.00 μm to 8.00 μm, from 40.00 μm to 6.67± 2.31 μm, and from 32.00 μm to 13.33 ± 2.31 μm in SMA1, SMA2 and ATCC17666, respectively.Conclusion: Azithromycin combined with tigecycline inhibited biofilm formation by S. maltophilia. Our study provides an experimental basis for a possible optimal treatment strategy for S. maltophilia biofilm-related infections.Keywords: Stenotrophomonas maltophilia, azithromycin, tigecycline, biofilm, trimethoprim/sulfamethoxazole

Tao Tian,1 Xiangyang Fu,2 Liangliang Hu,1 Xiaofeng Yang,1 Peng Sun,1 Fengfeng Sun1 1Department of Urology, Zaozhuang Municipal Hospital, Zaozhuang, 277100, Shandong, People’s Republic of China; 2Zaozhuang Yicheng District People’s Hospital, Zaozhuang, Shandong, 277300, People’s Republic of ChinaCorrespondence: Fengfeng SunDepartment of Urology, Zaozhuang Municipal Hospital, No. 41 Longtou Road, Shizhong District, Zaozhuang, 277100, Shandong, People’s Republic of ChinaTel + 86 0632 3288037Email sunff00@163.comPurpose: Renal carcinoma (RC) originates in the renal tubular epithelial system, among which renal cell carcinoma (RCC) is the most frequent one. The forkhead activin signal transducer 1 (FAST1) has been shown to interfere with tumor progression as an oncogene, while its role in RC is limited. Therefore, this paper explored the prognostic significance, specific effects, and related mechanisms of FAST1 on RC.Patients and Methods: Cell colony formation assay, cell counting kit-8 (CCK8) assay, flow cytometry and Transwell assay were used to test cell proliferation, viability, apoptosis, migration and invasion, respectively. Western blot (WB) was employed to determine the protein level of FAST1.Results: Our study confirmed that FAST1 was up-regulated in RC tissues and cell lines, and its overexpression often represented a poor prognosis of RC patients. Meanwhile, the in vitro experiments showed that overexpressing FAST1 facilitated RC cell viability, proliferation, migration, invasion and epithelial-mesenchymal transition (EMT), and repressed cell apoptosis. In addition, the in vivo experiments illustrated that the up-regulation of FAST1 strengthened tumor growth. On the contrary, knocking down FAST1 had the opposite effects. Mechanistically, The TGF-β/Smad pathway contributed to RC evolvement and was activated by FAST1 both in vitro and in vivo.Conclusion: This article suggests that FAST1 exerts a carcinogenic role in RC by regulating the TGF-β/Smad signaling.Keywords: forkhead activin signal transducer 1, TGF-β/Smad pathway, renal carcinoma

Ling Hu,* Ting Li,* Yi Zou, Xiao-Ling Yin, Hui Gan Department of Endocrinology, The Third Affiliated Hospital of Nanchang University, Nanchang 330000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ling HuDepartment of Endocrinology, The Third Affiliated Hospital of Nanchang University, No. 128 of Xiangshan North Road, Donghu District, Nanchang 330000, People’s Republic of ChinaTel +86 13970075119Email drhu_hl1172@163.comObjective: This study aimed to explore the clinical value of the fracture risk assessment tool (FRAX) in the fracture risk prediction of Chinese patients after replacing rheumatoid arthritis (RA) with type 2 diabetes mellitus (T2DM) in the FRAX algorithm.Methods: A total of 1,047 patients with T2DM from the Endocrinology Department of the Third Affiliated Hospital of Nanchang University were enrolled in this study. Dual-energy X-ray absorptiometry (DXA) was then used to detect their bone density. RA in the FRAX algorithm was replaced with T2DM, and the new RA-adjusted FRAX was used to assess the fracture risk of the patients.Results: The sensitivity, specificity, and Youden’s index of the RA-adjusted FRAX to the treatment opinions on T2DM-associated hip fractures were 0.4761, 0.9642, and 0.4403, respectively, while the sensitivity, specificity, and Youden’s index of RA-adjusted FRAX to the treatment opinions on T2DM-associated major bone osteoporotic fractures were 0.0080, 1.0000, 0.0080, respectively. The DXA and RA-adjusted FRAX both showed acceptable consistency in the treatment recommendations for hip fractures in patients with T2DM (κ = 0.49) but had poor consistency in treatment recommendations for major bone osteoporotic fractures (κ = 0.010). The body mass index (BMI) scores, femoral neck-bone mineral densities, and number of males in the same treatment opinion group were significantly higher than in the different treatment opinions group (P < 0.001).Conclusion: RA-adjusted FRAX is a useful clinical tool for evaluation of hip fracture risk for Chinese patients with T2DM, and the accuracy of fracture risk prediction for male patients with T2DM and patients with T2DM with high BMI scores or high femoral neck-bone mineral density is higher.Keywords: type 2 diabetes mellitus, FRAX, fracture risk, bone mineral density, osteoporosis

Eleanna Makris,1 Lucy Hu,1 Graham B Jones,1,2 Justin M Wright1 1TRD Innovation Group, Novartis Pharmaceuticals, East Hanover, NJ 07936, USA; 2Clinical and Translational Science Institute, Tufts University Medical Center, Boston, MA 02111, USACorrespondence: Graham B Jones Email graham.jones@novartis.comIntroduction: Heart failure remains a substantive contributor to patient morbidity and mortality rates worldwide and represents a significant burden on the healthcare ecosystem. Faced with persistent physical symptoms and debilitating social consequences, patients follow complex treatment regimens and often have difficulty adhering to them.Purpose: In this manuscript, we review factors which contribute to low adherence rates and advance potential single- and multi-factor-based interventions. It is hoped that these observations can lead to improvements in managed care of this vulnerable population of patients.Methods: A narrative review of the primary literature was performed on contributing factors with primary focus on the period 2015– 2020 using available databases and search engines. Adherence pain points identified were mapped against a series of potential solutions which are presented.Results: Enhancement of treatment adherence relies on two approaches viz. single-factor and multi-factor solutions. Single factors identified include electronic reminders, enhanced health education, financial incentives, gamification strategies, community drivers, persona-based modeling, and burden relief of poly pharmacy. Multi-factor solutions combine two or more of the seven approaches offering the potential for flexible interventions tailored to the individual.Discussion and Conclusion: Heart failure patients with poor adherence have increased mortality, hospitalization needs, and healthcare costs. This review highlights current single-factor and multi-factor adherence methods. Against a backdrop of diversity of approaches, multi-factor solutions cast the widest net for positively influencing adherent behaviors. A key enabler lies in the development and leveraging of patient personas in the synthesis of successful intervention methods. Deployable solutions can also be envisioned in clinical trials where adherence tracking represents an essential component.Keywords: heart failure, cardiac disease, treatment adherence, intervention, connected health

Yi Zou,1 Ling Hu,1 Wenjun Zou,2 Honglin Li3 1Department of Endocrinology, The Third Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2General Surgery, Nanchang Third Hospital, Nanchang, People’s Republic of China; 3Department of Biochemistry, Medical College of Georgia, Augusta, GA, USACorrespondence: Ling HuDepartment of Endocrinology, The Third Affiliated Hospital of Nanchang University, No. 128 Xiangshan North Road, Nanchang 330000, Jiangxi Province, People’s Republic of ChinaTel +86 791-88862350Email hul@medmail.com.cnBackground: Leptin, an adipokine, has effects on the cardiovascular system with both protective and harmful role. This study aimed to assess the relationship between leptin and 3-month prognosis in ischemic stroke patients with type 2 diabetes.Patients and Methods: As a prospective single-center observational study, we collected consecutive first-ever acute ischemia stroke with type 2 diabetes mellitus from February 2019 to February 2020. Serum samples were obtained at admission, and leptin serum levels were tested by the ELISA method. Logistic regression models were used to assess leptin’s prognostic value to predict the functional outcome and mortality within three months.Results: Finally, two hundred and eleven patients were included, and the mean leptin serum level was 16.8 (SD. 6.9) ng/mL. At admission, 53.6% of those included patients (N=113) were defined as severe stroke (NIH Stroke Scale [NIHSS]> 5). In multivariable models adjusted for other factors, leptin levels< 11.6ng/mL (lowest quartile, Q1) related to severe stroke and the risk increased 175% (odds ratios [OR] =2.75; 95% confidence interval [CI]=2.13– 3.38; P=0.002). Serum leptin levels on admission in patients with poor outcomes and nonsurvivors were significantly reduced (P< 0.001 and P< 0.001). Leptin levels < 11.6ng/mL (lowest quartile, Q1) related to a higher risk of poor functional impairment (OR=5.13; 95% CI =3.25– 6.86; P< 0.001) and mortality (OR=3.19; 95% CI =2.03– 4.25; P< 0.001).Conclusion: The data shows that leptin serum level is a useful prognostic biomarker in ischemic stroke patients with type 2 diabetes, and this relationship is negative.Keywords: leptin, adipokine, ischemic stroke, type 2 diabetes, prognosis

Long Hu,1 Wei Lin,2 Tiancheng Xu,1 Dongjie Liang,1 Guangze Xiang,1 Rujie Zheng,1 Changzuan Zhou,1 Qinxue Dai,3 Danyun Jia3 1Department of Cardiovascular Medicine, The Heart Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of China; 2Department of Pediatric Intensive Care Unit, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang, People’s Republic of China; 3Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, People’s Republic of ChinaCorrespondence: Danyun Jia; Qinxue DaiDepartment of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang, Ouhai District, Wenzhou City 325000, Zhejiang Province, People’s Republic of ChinaTel/Fax +86-577-88581162Email 529365150@qq.com; 653091408@qq.comBackground: Admission lactate level has been reported as a useful marker of mortality. In this study, we compared the relative value of different lactate indices to predict survival in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).Methods: This was a retrospective observational study including consecutive patients with STEMI undergoing primary PCI who admitted to the Coronary Care Unit of the First Affiliated Hospital of Wenzhou Medical University between 2014 and 2017. The predictive value of lactate indices for mortality was compared using receiver operator characteristic (ROC) analysis, and DeLong’s test was used to compare the AUC. We compared the AUC between GRACE score and GRACE score + lactate index.Results: A total of 1080 patients were included. Fifty-nine died in 30 days and 68 died in 180 days. Most lactate indices (Lacadm, Lac24max, Lac24min and Lac24tw) were significantly lower in survivors (all P< 0.001). In Cox proportional hazards model, each lactate index showed as an independent factor of 30-day and 180-day mortality except LacΔ. Kaplan–Meier curves demonstrated that the patients of higher lactate indices group had higher rates of mortality (all P< 0.0001, except LacΔ P=0.0485). In receiver operator characteristic analysis, Lac24max was significantly larger than Lacadm(P< 0.001) while the AUC value for Lacadm was similar to Lac24min and Lac24tw. Lac24tw improved the predictive probability of 30-day mortality (P=0.0415). Lac24max improved the predictive probability of GRACE score for both 30-day and 180-day mortality (P< 0.05).Conclusion: In patients with STEMI undergoing primary PCI, most lactate indices are all associated with 30-day and 180-day mortality except LacΔ. In prediction of both 30-day and 180-day mortality, Lac24max is superior to Lacadm and significantly enhances the ability of risk stratification and prognostic evaluation when adding Lac24max to the GRACE score.Keywords: STEMI, lactate indices, hyperlactatemia, mortality