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Jie Ding,1,&ast; Fu-Ping Chen,1,&ast; Ya-Ying Song,1,&ast; Hong-Yan Li,1 Xi-Wen Ai,1 Yi Chen,1 Lu Han,1 Xia-Jun Zhou,1 De-Sheng Zhu,1 Yang-Tai Guan1,2 1Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, People’s Republic of China; 2Department of Neurology, Pu Nan Branch of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this work Correspondence : Yang-Tai Guan; De-Sheng ZhuDepartment of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Tel +86-13386271865; +86-13564719779, Fax +86-21-68383482, Email yangtaiguan@sina.com; deshengzhu2008@sina.comBackground: The relationship between serum low-density lipoprotein cholesterol (LDL-C) and the risk of relapse in neuromyelitis optica spectrum disorder (NMOSD) remains uncertain. We aimed to examine the association between serum LDL-C level and relapse in NMOSD patients.Methods: We conducted an analysis of the prospective observational NMOSD cohort study with consecutive 184 hospitalized NMOSD patients from department of neurology. Blood samples were collected to measure LDL-C level upon admission. Primary and relapse were evaluated during hospitalization. The relationship between serum LDL-C level and relapse were analyzed by linear curve fitting analyses. Crude and adjusted odds ratios (OR) of LDL-C for relapse with 95% confidence intervals were analyzed using multiple logistic regression models. ROC curve analysis was used to identify the target lipid-lowering value of LDL-C and the probability of relapse was evaluated by the Kaplan–Meier Plot.Results: Over a mean disease course of 100± 87 days, 59.24% (n=109) participants developed relapse with higher LDL-C than the primary group (n=75) (p< 0.001). Adjusted smoothed plots suggested that there were linear relationships between serum LDL-C level and relapse (p< 0.001). The OR (95% CI) between serum LDL-C level and relapse were 2.67 (1.76– 4.04, p< 0.001), and 2.38 (1.48– 3.83, p< 0.001) respectively in NMOSD patients before and after adjusting for potential confounders. The target LDL-C lowering values were 2.795 mmol/L with potential benefits to prevent relapse in NMOSD.Conclusion: In this sample of NMOSD patients, we found that the elevated serum LDL-C was independently and positively associated with the relapse, and serum LDL-C should be well-controlled to prevent the relapse of NMOSD.Keywords: neuromyelitis optica spectrum disorder, NMOSD, low-density lipoprotein cholesterol, relapse, multivariate analysis

Hong-Yan Li,1,2 Hao-Yu Wang,3 Yi-Fei Duan,2,4 Yu Gou,2,4 Xiao-Qin Liu,2,4 Zheng-Xiang Gao2,4 1West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan, People’s Republic of China; 3Department of Radiology, The First People’s Hospital of Liangshan Yi Autonomous Prefecture, Xichang, Sichuan, People’s Republic of China; 4Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Zheng-Xiang Gao, Email GAOZX84@163.comAbstract: Neurosyphilis is a central nervous system infection caused by Treponema pallidum that imitates various neurological and mental disorders. Therefore, patients with this disease are prone to misdiagnoses. Here, we report a case of neurosyphilis with a psychotic disorder as the main manifestation. A young girl exhibited mental and behavioural abnormalities after a heartbreak, which manifested as alternating low mood, emotional irritability, and a lack of interest in social relations, followed by memory loss. The cerebrospinal fluid protein - Treponema pallidum particle agglutination test was positive, the toluidine red unheated serum test titre was 1:4, the white blood cell count was 5 × 10^6/L, the cerebrospinal fluid protein level was 0.97 g/L, and the brain CT was abnormal. After admission, the possibility of neurosyphilis was considered and the patient received intravenous penicillin G treatment. The patient’s clinical symptom ms improved. This case emphasises that doctors should maintain clinical suspicion of Treponema pallidum infection in adolescent patients with mental abnormalities.Keywords: neurosyphilis, case report, psychotic disorder, Treponema pallidum, syphilis

Zi-Jing Chu,1 Xin Yin,2 Guang-Ying Zhu,3 Shan-Shan Yu,4 Hong-Yan Li2 1Department of Hepatology, The First Hospital of Jilin University, Changchun, People’s Republic of China; 2Department of Nursing, The First Hospital of Jilin University, Changchun,People’s Republic of China; 3Department of Mental Health Branch, The First Hospital of Jilin University, Changchun, People’s Republic of China; 4Department of Hematology, The First Hospital of Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Xin Yin, Department of Nursing, The First Hospital of Jilin University, No. 1 of Xinmin Street, Chaoyang District, Changchun, 130021, People’s Republic of China, Tel +86 0431-88783361, Email yinxin10@jlu.edu.cnObjective: The purpose of this study was to explore the real inner experience and nursing needs of adolescent patients who suffered from school bullying, and to develop a treatment plan to restore adolescent mental health.Methods: Using the maximum difference sampling method, 15 adolescent patients were interviewed by psychologists and nurses, and the interview results were analyzed by topic induction.Results: Among the 15 participants, 12 (80%) felt helpless, 13 (86.7%) had serious negative emotions, and 10 (66.7%) felt anxious about personal growth. Based on the semi-structured interviews, the psychological states of participants were summarized into three themes: Helplessness, Severe negative emotions, and Anxiety about personal growth. Under the theme of serious negative emotions, it was further divided into three sub-themes: Frustration and Distrust, Rebellion, Insecurity and depression. These themes reflected the significant impact of school bullying on the psychological status of the participants.Conclusion: The internal experience of adolescent patients with mental disorders caused by school bullying mainly includes helplessness, serious negative emotions and anxiety about personal growth. It is recommended to evaluate and diagnose patients’ existing and potential health problems individually during clinical treatment and care. On the basis of comprehensive assessment, psychological counseling should be provided and support from family and school should be sought to promote positive mental health and personal growth of adolescents.Keywords: school bullying, adolescents, psychological experience, qualitative research, nursing

Yang Chen,1 Hui-Yi Li,1 Jian-Shu Liu,1 Dao-long Jiang,1 Hao-nan Zheng,2 Xue-Song Dong1 1Department of Emergency, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China; 2No.105 Phase, The First Clinical College of China Medical University, Shenyang, 110001, People’s Republic of ChinaCorrespondence: Xue-Song Dong, Department of Emergency, The First Hospital of China Medical University, No. 155 of Nanjing North Street, Heping District, Shenyang, 110001, People’s Republic of China, Tel +86 024-26111099 ; +86 024-83282011, Email dongxunsongdxs0@126.comBackground: We established a diquat-induced human kidney-2 cells (HK-2 cells) apoptosis model in this study to identify differentially expressed microRNAs (miRNAs) and signaling pathways involved in diquat poisoning via gene sequencing and bioinformatics analysis and explored the related therapeutic benefits.Methods: The effects of diquat on the viability and apoptosis of HK-2 cells were explored using the CCK-8 and Annexin V-FITC/PI double staining methods. Total RNAs were extracted using the TRizol method and detected by Illumina HiSeq 2500. Bioinformatics analysis was performed to explore differentially expressed (DE) miRNAs, their enriched biological processes, pathways, and potential target genes. The RT-qPCR method was used to verify the reliability of the results.Results: Diquat led to HK-2 cell injury and apoptosis played an important role, hence an HK-2 cell apoptosis model in diquat poisoning was established. Thirty-six DE miRNAs were screened in diquat-treated HK-2 cells. The enriched biological process terms were mainly cell growth, regulation of apoptotic signaling pathway, extrinsic apoptotic signaling pathway, and Ras protein signal transduction. The enriched cellular components were mainly cell-cell junction, cell-substrate junction, ubiquitin ligase complex, and protein kinase complex. The enriched molecular functions were mainly Ras GTPase binding, ubiquitin-like protein transferase activity, DNA-binding transcription factor binding, ubiquitin-protein transferase activity, nucleoside-triphosphatase regulator activity, transcription coactivator activity, and ubiquitin-like protein ligase binding. Signaling pathways such as MAPK, FoxO, Ras, PIK3-Akt, and Wnt were also enriched.Conclusion: These findings aid in understanding the mechanisms of diquat poisoning and the related pathways, where DE miRNAs serve as targets for gene therapy.Keywords: apoptosis, biological processes, diquat, HK-2 cells, microRNA

Yi-Tong Zhang,&ast; Hui-Yao Li,&ast; Xiao-Tong Sun, Xue-Wei Tong, Yong-Yan Shan, Yu-Xin Xu, Sheng-Dan Pu, Xin-Yuan Gao Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin-Yuan Gao, Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin, 150001, People’s Republic of China, Email 15124768260@163.comBackground: Diabetic retinopathy (DR) is strongly associated with cardiovascular disease, which is a risk factor for sudden cardiac death (SCD). The index of cardiac electrophysiological balance (iCEB) and the frontal QRS-T angle are recommended to predict the risk of ventricular arrhythmias more than other ECG parameters. However, the relationships between these two markers and DR have not yet been explored. The aim of this study was to investigate the variation in the iCEB, corrected iCEB (iCEBc) and frontal QRS-T angle in different stages of DR and determine whether there are associations between these markers and DR.Methods: The sample comprised 665 patients with Type 2 diabetes mellitus (T2DM) who were classified into three groups: no DR (NDR), mild to moderate non-proliferative DR (NPDR), and vision-threatening DR (VTDR). Twelve-lead ECG was performed and the QT, QTc, QRS duration, iCEB, iCEBc and frontal QRS-T angle were recorded and compared across the groups.Results: The VTDR group had a significantly higher iCEBc and frontal QRS-T angle than the NDR and NPDR groups. After controlling for confounding variables, the correlations between the iCEBc (OR=2.217, 95% CI=1.464– 3.358, P< 0.001), frontal QRS-T angle (OR=1.017, 95% CI=1.008– 1.025, P< 0.001) and DR risk remained (P< 0.05). Subjects in the fourth iCEBc quartile (adjusted OR=2.612, 95% CI=1.411– 4.834, p=0.002) had a much higher chance of developing DR compared to those in the first quartile. In comparison to the first frontal QRS-T angle quartile, subjects in the third (adjusted OR=1.998, 95% CI=1.167– 3.422, P=0.012) and fourth (adjusted OR=2.430, 95% CI=1.420– 4.160, P=0.001) frontal QRS-T angle quartiles had significantly greater risks of DR.Conclusion: With the progression of DR, the iCEBc and frontal QRS-T angle increase. An increased iCEBc and frontal QRS-T angle are associated with an increased risk of DR.Keywords: type 2 diabetes mellitus, diabetic retinopathy, index of cardiac electrophysiological balance, iCEB, frontal QRS-T angle, ventricular arrhythmia

Hong Liu,1,&ast; Si-chong Qian,2,&ast; Yong-feng Shao,1 Hai-yang Li2 On behalf of the Additive Anti-inflammatory Action for Aortopathy & Arteriopathy (5A) Investigators Group1Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China; 2Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong-feng Shao, Department of Cardiovascular Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China, Email yfshaojph@sina.com Hai-yang Li, Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, People’s Republic of China, Email ocean0203@163.comBackground: Acute type A aortic dissection (ATAAD) is a heterogeneous systemic inflammatory response syndrome. Identification of distinct inflammatory phenotypes may allow more precise therapy and improved care. We aim to investigate whether distinct inflammatory subphenotypes exist in ATAAD patients and respond differently to pharmacotherapies.Methods: Retrospective analysis of data sets was conducted from the Additive Anti-inflammatory Actions for Aortopathy & Arteriopathy (5A) III study. Inflammatory subphenotypes were derived among 2008 ATAAD patients who received surgical repair at 11 Chinese hospitals (2016– 2020) using latent class analysis applied to 14 laboratory signatures within 6 hours of hospital admission. Outcomes included operative mortality (Society of Thoracic Surgeons definition), derived subphenotype frequency, and the potential consequences of phenotype frequency distributions on the treatment effects.Results: The median (interquartile range) age of patients was 54 (45– 62) years, and 1423 (70.9%) were male. A two-class (two subphenotype) model was an improvement over a one-class model (P

Hai-Hua Chuang,1– 3 Chao-Yung Wang,4 Li-Pang Chuang,5 Yu-Shu Huang,6 Hsueh-Yu Li,7 Tuan-Jen Fang,7 Rong-Ho Lin,2 Li-Ang Lee3,7 1Department of Family Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 2Department of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan; 3School of Medicine, National Tsing Hua University, Hsinchu, Taiwan; 4Department of Cardiology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 5Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 6Department of Child Psychiatry, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 7Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, TaiwanCorrespondence: Li-Ang Lee, Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, No. 5, Fuhsing Street, Guishan District, Taoyuan, 33305, Taiwan, Tel +886 33281200 ext. 3972, Fax +886 33979361, Email 5738@cgmh.org.twBackground: Obstructive sleep apnea (OSA) and obesity are both directional risk factors of hypertension. Chronic intermittent hypoxemia (IH) is a commonly observed pathophysiological mechanism involved in multiple comorbidities of OSA. However, their interactions are not well understood in children. This study aimed to investigate the associations of IH indexes (oxygen desaturation index 3% [ODI3], mean peripheral oxygen saturation [SpO2], least SpO2, and time with SpO2 < 85%), apnea-hypopnea index, and weight status with hypertension in a sample of pediatric OSA patients.Methods: The medical records of 365 pediatric OSA patients were retrospectively reviewed in this cross-sectional study. Demographics, anthropometrics, standard in-laboratory polysomnography, and nocturnal blood pressure were collected. Multivariate logistic regression with forward selection was used to identify independent predictors of hypertension.Results: Multivariate logistic regression analysis showed that ODI3 (odds ratio [OR] = 1.02, 95% confidence interval [CI] = 1.01– 1.03) and body mass index z-score (OR = 1.34, 95% CI = 1.12– 1.60) were independent continuous predictors of pediatric hypertension, whilst severe OSA (OR = 2.62, 95% CI = 1.60– 4.29) and overweight/obesity (OR = 2.63, 95% CI = 1.59– 4.34) were independent categorical predictors. Traditional risk factors including male sex (OR = 2.33, 95% CI = 1.02– 5.33), late childhood/adolescence (OR = 1.98, 95% CI = 1.01– 3.88), and overweight/obesity (OR = 2.97, 95% CI = 1.56– 5.67) combined with sleep hypoxemia (least SpO2 ≤ 95%) (OR = 2.24, 95% CI = 1.16– 4.04) predicted hypertension (R2 = 0.21) in the severe IH subgroup (n = 205), while the no/mild IH subgroup (n = 160) had an entirely different predictor, severe OSA (OR = 3.81, 95% CI = 1.49– 9.74) (R2 = 0.07).Conclusion: The close relationships among IH, overweight/obesity, and hypertension highlight the importance of reducing IH and body weight in children with OSA.Keywords: children, oxygen desaturation index, intermittent hypoxemia, obesity, obstructive sleep apnea, predictive model

Ming-Shao Tsai,1– 4,&ast; Hung-Chin Chen,1,&ast; Hsueh-Yu Li,2,5 Yao-Te Tsai,1,2 Yao-Hsu Yang,4,6,7 Chia-Yen Liu,4 Yi‑Chan Lee,2,8 Cheng-Ming Hsu,1,2 Li-Ang Lee2,5,9 1Department of Otolaryngology – Head and Neck Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi, 613, Taiwan; 2Faculty of Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 4Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, 613, Taiwan; 5Department of Otolaryngology – Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; 6Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, 613, Taiwan; 7School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 8Department of Otolaryngology – Head and Neck Surgery, Keelung Chang Gung Memorial Hospital, Keelung, 204, Taiwan; 9School of Medicine, National Tsing Hua University, Hsinchu, 300, Taiwan&ast;These authors contributed equally to this workCorrespondence: Li-Ang Lee, Department of Otolaryngology – Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, No. 5, Fu-Hsing Street, Gueishan District, Taoyuan City, 33305, Taiwan, Tel +886 3 3281200 ext. 3968, Fax +886 3 3979361, Email 5738@cgmh.org.twPurpose: We executed the presented retrospective cohort study with the purpose of probing the risk of severe acute respiratory infection (SARI) following influenza in patients with sleep apnea.Materials and Methods: We executed this real-world study by gathering Taiwan National Health Insurance Research Database (NHIRD) data. From a database containing 1 million individuals sampled at random from the NHIRD, we identified all patients aged 20 years or older with a sleep apnea diagnosis between 1997 and 2013 as the study group. We established a comparison cohort of individuals without sleep apnea by randomly matching patients with respect to monthly income, gender, urbanization level, and age at a 1:4 ratio. Follow-up was performed until death or the end of 2015 for both groups. We determined the study outcome to be the occurrence of influenza-associated SARI.Results: We enrolled 6508 and 26,032 patients into the study and comparison groups, respectively. A significantly higher cumulative incidence of influenza-associated SARI was discovered in the study group (p < 0.001). In our multivariate analysis, sleep apnea, chronic obstructive pulmonary disease, and coronary artery disease were independent risk factors for influenza-associated SARI. The hazard ratio of sleep apnea for influenza-associated SARI was 1.98 (95% CI: 1.26– 3.10) after adjustment for all comorbidities, gender, age, monthly income, and urbanization level.Conclusion: Sleep apnea increased the risk of influenza-associated SARI. We suggest that physicians be cautious about the development of severe influenza illness in patients with sleep apnea. Vaccination and early oseltamivir administration should be actively considered in this group of patients.Keywords: sleep apnea, sleep disturbance, influenza, severe acute respiratory infection

Xin Li,&ast; Hui-Yao Li,&ast; Zi-Wei Yu, Yi-Tong Zhang, Xue-Wei Tong, Xin-Yuan Gao The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin-Yuan GaoDepartment of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, People’s Republic of ChinaTel +86 13904517001Email 15369337970@163.comBackground and Aim: Obesity often coexists with diabetes, especially abdominal obesity, recognized as a risk factor for diabetic complications. Diabetic retinopathy (DR), as one of the most common microvascular complications of diabetes, may be associated with these indices. Lipid accumulation product (LAP) and Chinese visceral obesity index (CVAI) are novel visceral obesity indicators, which have been proven to be an influential factor predicting type 2 diabetes (T2DM). However, the correlation among LAP, CVAI, and DR still lacks systematic research in T2DM. The study aimed to explore the relationship among LAP, CVAI levels in different DR stages of T2DM patients and the diagnostic efficacy of LAP and CVAI for DR.Methods: A total of 263 participants were recruited in this cross-sectional study. We enrolled 169 patients with T2DM, divided into the non-DR group (NDR, n = 61), non-proliferative DR group (NPDR, n = 55), and proliferative DR group (PDR, n = 53). And we also enrolled 94 healthy control participants. We collected demographic, anthropometric, and biochemical data on each subject. LAP and CVAI are calculated according to different formulas for men and women.Results: Compared with the control group, LAP and CVAI were significantly higher (P < 0.05). After adjusting for confounding factors, LAP (OR: 1.029, 95CI%: 1.010– 1.049, P < 0.05), WC (OR: 1.073, 95CI%: 1.009– 1.141, P < 0.05) and CVAI (OR: 1.017, 95CI%: 1.000– 1.033, P < 0.05) were all associated with an increased risk of DR. Furthermore, increased LAP (OR: 1.020, 95% CI: 0.100– 0.290) is associated with DR severity (P < 0.001). Moreover, the LAP had the most significant area under the receiver operating characteristics (ROC) curve (AUC) (AUC = 0.728, 95% CI: 0.653– 0.804).Conclusion: A high LAP is associated with an increased risk of DR in T2DM patients, and the LAP index appears to be a good predictor of DR risk and severity in patients with T2DM, compared with BMI, WC, and CVAI.Keywords: lipid accumulation product, LAP, Chinese visceral obesity index, CVAI, diabetic retinopathy, DR, abdominal/visceral obesity

Hao JF, Chen P, Li HY, Li YJ, Zhang YL. Cancer Manag Res. 2020;12:13347–13356 The Editor and Publisher of Cancer Management and Research are retracting the published article. An investigation found images from Figure 5 had been duplicated. Specifically, The image for Figure 5C, 769-P, miR-214-3p-mimics+pcDNA3.1-HCP5 has been duplicated with the same image for Figure 5C, 769-P, miR-214-3p-inhibit+si-HCP5#1. The authors cooperated with the investigation and provided data associated with the reported study. However, despite the authors’ assistance, a satisfactory explanation for how the images came to be duplicated could not be provided, and the validity of the published work could not be verified. The decision was made to retract the article and the authors agree with this. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

I-Chun Kuo,1,2 Li-Jen Hsin,1,2 Li-Ang Lee,1,2 Tuan-Jen Fang,1,2 Ming-Shao Tsai,2,3 Yi-Chan Lee,2,4 Shih-Chieh Shen,2,5 Hsueh-Yu Li1,2 1Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Tao-yuan City, Taiwan; 2College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; 3Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi City, Taiwan; 4Departments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Keelung Branch, Keelung City, Taiwan; 5Departments of Otolaryngology-Head & Neck Surgery, New Taipei City Municipal Tucheng Hospital, New Taipei City, TaiwanCorrespondence: Hsueh-Yu LiDepartments of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Tao-yuan City, TaiwanTel +886-3-328-1200 ext.3966Fax +886-3-397-9361Email hily38@cgmh.org.twObjective: This study aims to explore the factors that contribute to epiglottic collapse (EC) in patients with obstructive sleep apnea (OSA).Methods: This study enrolled 35 patients (34 males; median age, 39 years; median apnea–hypopnea index (AHI), 55.4 events/h; median body mass index (BMI), 26.9 kg/m2). EC (epiglottis attaching onto the posterior pharyngeal wall) was diagnosed by drug-induced sleep computed tomography (DI-SCT). Three dimensions were assessed for comparison between the EC and non-EC (NEC) groups that included anatomical measurement: epiglottic length and angle, endoscopic classification of epiglottis obstructing the glottis (Type I, none; Type II, partial; and Type III, total), and dynamic hyoid movement during DI-SCT (Δ hyoid = √(x2 + y2), maximal displacement of hyoid in x and y axes during sleep breathing cycle).Results: EC was found in 12 patients (34%). No difference in age, gender, AHI, and BMI between the two groups was noted. The anatomical measurement revealed that epiglottis length was significantly different between the EC and NEC groups (21.2 vs 15.8 mm; p < 0.001), with a cutoff value of 16.6 mm (sensitivity, 100%; specificity, 65.2%). The EC group patients showed larger hyoid movement than the NEC group patients (Δ hyoid, 4.8 vs 3.0 mm; p = 0.027). By contrast, epiglottic angle and endoscopic classification revealed an insignificant difference between the two groups.Conclusion: Epiglottis is a potential collapse site among multilevel obstruction in moderate to severe OSA patients. Epiglottic length is highly sensitive in predicting EC, with the cutoff value of 16.6 mm. Hyoid movement plays a role in contributing to EC in OSA patients.Keywords: obstructive sleep apnea, epiglottic collapse, drug-induced sleep computed tomography, epiglottic length, hyoid bone movement

Chin-Kuo Chen,1,2 Shih Chieh Shen,1– 3 Li-Ang Lee,1,2 Ming-Hui Sun,2,4 Ning-Hung Chen,2,5 Li-Pang Chuang,2,5 Hsueh-Yu Li1,2 1Department of Otolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital (Linkou), Taoyuan City, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan City, Taiwan; 3Department of Otolaryngology-Head and Neck Surgery, New Taipei Municipal Tucheng Hospital, New Taipei City, Taiwan; 4Department of Ophthalmology, Chang Gung Memorial Hospital (Linkou), Taoyuan City, Taiwan; 5Department of Pulmonary and Critical Care Medicine, Sleep Center, Chang Gung Memorial Hospital (Linkou), Taoyuan City, TaiwanCorrespondence: Hsueh-Yu Li; Shih Chieh ShenDepartment of Otolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital (Linkou), 33, No. 5, Fushing Street, Gueishan Shiang, Taoyuan City, TaiwanTel +886-3-3281200 ext.3966Fax +886-3-3979361Email hyli38@cgmh.org.tw; b9102083@cgmh.org.twPurpose: Obstructive sleep apnea (OSA) is characterized by recurring hypoxic-apneic events during sleep, and labyrinthine vascular compromise is a pathophysiologic hallmark of idiopathic sudden sensorineural hearing loss (ISSNHL). Some reports have discussed the relationship between OSA and hearing impairment; however, few have examined hearing prognosis in OSA and patients without OSA with ISSNHL. We aimed to investigate clinical manifestations of ISSNHL in patients with OSA, including severity of hearing loss and response to treatment.Patients and Methods: A case-control study was conducted by extracting data from the sleep center and cochlea center databases of the Chang Gung Memorial Hospital. A retrospective chart review was performed to include confirmed adult OSA patients diagnosed with unilateral ISSNHL. Age and sex-matched patients without OSA with ISSNHL were enrolled as controls. Pure-tone average (PTA) thresholds were measured at specific frequencies. Changes in PTA before and after standard treatment with oral prednisolone (1mg/kg/day for 5 days, then tapered) and between participants with OSA and without OSA were compared. Standard treatment was given to all ISSNHL patients.Results: Twenty-eight out of 8500 (0.33%) OSA patients experienced subsequent ISSNHL in 9 years. Patients with OSA (n=28) had poorer high-frequency perception in the unaffected ear than the patients without OSA (n=120), although the difference was not significant. Hearing in the affected ear among patients with OSA was comparable to that patients without OSA at individual frequencies and average, suggesting no difference in hearing loss in the affected ear between the two groups. In terms of high-frequencies (4000 and 8000 Hz) perception, patients with OSA had significantly poorer responses to steroid treatment than patients without OSA.Conclusion: ISSNHL may be one of the auditory complications associated with OSA. Patients with OSA had poorer prednisolone related hearing improvement in high frequencies than patients without OSA. Despite study limitations, OSA-related hypoxia and snoring noise is hazardous to hearing and standard treatments with CPAP is suggested in OSA patients for both holistic and auditory health.Keywords: obstructive sleep apnea, idiopathic sudden sensorineural hearing loss, high-frequency, hypoxemia, pure-tone average, frequencies

Hai-Hua Chuang,1– 3 Chi-Hung Liu,4 Chao-Yung Wang,5 Yu-Lun Lo,6 Guo-She Lee,7,8 Yi-Ping Chao,4,9 Hsueh-Yu Li,10 Terry BJ Kuo,11 Cheryl CH Yang,11 Liang-Yu Shyu,12 Li-Ang Lee10,11 1Department of Family Medicine, Chang Gung Memorial Hospital, Taipei Branch and Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 2Department of Industrial Engineering and Management, National Taipei University of Technology, Taipei, Taiwan; 3Genomic Medicine Institute & Obesity Institute, Geisinger Medical, Danville, PA, USA; 4Department of Neurology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 5Department of Cardiology, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 6Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 7Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan; 8Department of Otolaryngology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan; 9Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan, Taiwan; 10Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Linkou Main Branch, Chang Gung University, Taoyuan, Taiwan; 11Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan; 12Department of Biomedical Engineering, Chung Yuan Christian University, Taoyuan, TaiwanCorrespondence: Li-Ang LeeDepartments of Otorhinolaryngology-Head and Neck Surgery, Sleep Center, Chang Gung Memorial Hospital, Linkou Main Branch, No. 5, Fu-Hsing Street, Guishan District, Taoyuan, 33305, TaiwanTel +886 33281200 ext. 3972Fax +886 33979361Email 5738@cgmh.org.twBackground: Obstructive sleep apnea (OSA) and snoring have been reported to be modifiable risk factors for thick carotid intima-media thickness (CIMT) and carotid atherosclerosis, which are closely linked to cardiovascular disease.Methods: This cross-sectional study prospectively recruited 70 participants with OSA and without a history of carotid artery disorder, who primarily sought surgical Intervention. OSA and snoring were assessed with the Epworth Sleepiness Scale, Snore Outcomes Survey, polysomnography, and snoring sound recording. The carotid arteries were evaluated with ultrasonography and divided into three types of carotid artery profiles (normal carotid artery, thick CIMT, or significant carotid atherosclerosis). Multivariate linear/logistic/categorical regressions were performed with the forward selection approaches/logistic least absolute shrinkage and selection operator, as appropriate.Results: Normalized snoring sound energy (301– 850 Hz) was independently associated with the carotid intima-media thickness (regression coefficient [β] = 0.01, standard error [SE] = 0.004, P = 0.03; R2 = 0.067) and type of carotid profile (β = 0.40, SE = 0.09, P < 0.001; R2 = 0.156). Normalized snoring sound energy (4– 300 Hz) (β = − 0.10, SE = 0.04, P = 0.01) and female sex (β = 1.90, SE = 0.94, P = 0.04) were independently related to the presence of carotid stenosis (R2 = 0.159). The optimal regression model of the type of carotid artery profile included normalized snoring sound energy (301– 850 Hz) (β = 0.33, SE = 0.14, P = 0.03), snoring time (β = 0.26, SE = 0.13, P = 0.047), female sex (β = 0.26, SE = 0.13, P = 0.047), and increased age (β = 0.20, SE = 0.10, P = 0.04) under the control of the Snore Outcomes Survey score, 3% oxygen desaturation index, snoring sound energy (4– 1500 Hz), normalized snoring sound energy (851– 1500 Hz), cigarette smoking, and hyperlipidemia (R2 = 0.427).Conclusion: Our findings suggested that snoring sound characteristics are associated with carotid artery profiles among early OSA patients who cannot be noticed by ultrasound because organic changes of the carotid artery have not yet started. Future studies are warranted to verify the clinical significance of the results.Keywords: atherosclerosis, common carotid artery, categorical regression, obstructive sleep apnea, snoring, ultrasound

Cai-Tao Chen,1 Chun-Xiao Shan,2 Jun Ran,3 Lei-Miao Yin,1 Hai-Yan Li,4 Yu Wang,1 Yu-Dong Xu,1 Jing-Lei Guo,5 Yang-Lin Shi,1 Yan-Jiao Chen,1 Yong-Qing Yang1 1Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China; 3Chongqing Hospital of Traditional Chinese Medicine, Chongqing, People’s Republic of China; 4Shanghai First Rehabilitation Hospital, Shanghai, People’s Republic of China; 5School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Yong-Qing Yang; Yan-Jiao ChenLaboratory of Molecular Biology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, 650 South Wanping Road, Shanghai, 200030, People’s Republic of ChinaTel +86-21-54592134; +86-21-64395975Fax +86-21-64395975Email yyq@shutcm.edu.cn; cyjb1018@163.comPurpose: Cyclophilin A (CypA) inhibits CD4+ T cell signal transduction via interleukin-2-inducible T-cell kinase (Itk), a tyrosine kinase required for T helper (Th) 2 cells function. Furthermore, mice with CypA silencing developed allergic diseases associated with increased Th2 cytokines production. CD4+ T cells with a Th2-cytokine pattern have been demonstrated to have a pivotal role in the pathogenesis of asthma. However, the effects of CypA in regulating immunity in asthma and in relieving asthmatic symptoms in vivo are entirely unknown.Methods: Recombinant CypA protein (rCypA) was generated and purified. Ovalbumin (OVA)-challenged asthmatic rats model and acetylcholine chloride (ACh)-induced contraction of tracheal spirals were established. The pulmonary resistance (RL) value of asthmatic rats in vivo and the isometric tension of tracheal spirals ex vivo were recorded by MFLab 3.01 software. The levels of Th1 and Th2 cytokines and the quantities of immunoglobulin (IgA, IgG, IgM and IgE) in the supernatants of rat spleen lymphocytes were detected and analysed by bio-plex Suspension Array System and ELISA, respectively. CD4+ T cells were separated by MicroBeads, and the levels of interleukin (IL)-4 and interferon-γ (IFN-γ) were detected by ELISA.Results: rCypA (10 ng/kg) significantly reduced RL within 2– 7 min in OVA-challenged asthmatic rats in vivo, and there were no significant differences compared with terbutaline (TB) and hydrocortisone (HC). Furthermore, rCypA (10 ng/mL) significantly reduced the isometric tension in the ACh-induced contraction of the tracheal spiral ex vivo, and the effect of rCypA was better than that of TB. Additionally, rCypA suppressed the secretion of both Th1 and Th2 cytokines, and the suppressive effects of rCypA were stronger than those of HC, especially on Th2 cytokines.Conclusion: These findings indicate that CypA may serve as a potential novel therapeutic strategy for asthma.Keywords: cyclophilin A, asthma, Th2 cytokines, immunoregulation

Jun-Feng Hao,1,* Pei Chen,2,* He-Yi Li,3 Ya-Jing Li,1 Yu-Ling Zhang2 1Department of Nephrology and Blood Purification Center, Jin Qiu Hospital of Liaoning Province (Geriatric Hospital of Liaoning Province), Shenyang City, Liaoning Province 110000, People’s Republic of China; 2Department of Basic Medical Sciences, Jiangsu College of Nursing, Huai’an, Jiangsu Province 223000, People’s Republic of China; 3Department of Ophthalmology, Jin Qiu Hospital of Liaoning Province (Geriatric Hospital of Liaoning Province), Shenyang City, Liaoning Province 110000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu-Ling Zhang Tel +86-15162920912Email yulingzhang2009@163.comBackground: Recent researches have shown that long non-coding RNA (LncRNA) is often disordered and acts in many carcinomas. Clear cell renal cell carcinoma (ccRCC) is the main reason for carcinoma-related deaths, which are mainly caused by the metastasis. HCP5 is a newly discovered LcnRNA. Early studies have found that HCP5 acts in neoplasm metastasis, but the mechanism of HCP5 in ccRCC is still unclear.Methods: The expression of HCP5 in human renal cell carcinoma (RCC) was detected by real-time quantitative PCR. The biological effect of LncRNAs in proliferation, migration, invasion and metastasis of RCC cells was explored by gain-of-function and loss-of-function tests. The molecular mechanism of LncRNAs was explored by RNA immunoprecipitation and Western blot.Results: qRT-PCR revealed that HCP5 was enhanced in neoplasm tissues of ccRCC patients and correlated with the metastatic characteristics of RCC. Over-expression of HCP5 promoted the proliferation, migration and invasion of renal carcinoma cells. The deletion of HCP5 inhibited the proliferation, migration and invasion of RCC in vitro and the metastasis of RCC in vivo. Mechanically, HCP5 inhibited the growth and metastasis of ccRCC cells by regulating miR-214-3p/MAPK1 axis.Conclusion: HCP5, as a key LncRNA, can promote ccRCC metastasis by regulating miR-214-3p/MAPK1 axis and may be a biomarker and be helpful for judging the prognosis of ccRCC.Keywords: HCP5, miR-214-3p, MAPK1, clear cell renal cell carcinoma

Zi-Wei Yu,* Rong Liu,* Xin Li, Ying Wang, Yu-Hong Fu, Hui-Yao Li, Yue Yuan, Xin-Yuan Gao Department of Endocrinology, The First Clinical Hospital of Harbin Medical University, Harbin 150001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-Yuan Gao Tel +86 13904517001 Email 15369337970@163.comPurpose: Diabetic retinopathy (DR) can increase the risk of mild cognitive impairment (MCI), which has been confirmed by previous researches. With the frequent occurrence of MCI in patients with DR, the early detection of MCI has become a research hot-spot. The aim of this study was to investigate the relationship between neuron-specific enolase (NSE) and MCI in patients with DR.Patients and Methods: A total of 124 patients with DR, including 56 MCI patients and 68 normal cognition patients, were recruited in this cross-sectional study. The demographic and clinical data of patients were collected through questionnaires. Serum NSE was measured using electrochemiluminescence immunoassay. The Minimum Mental State Examination (MMSE) scale was used to evaluate the cognitive function of the participants.Results: Compared with the normal cognition group, serum NSE levels and HbA1c levels in the MCI group were higher, while MMSE scores and educational level were lower (P< 0.05). Serum NSE levels were significantly negatively correlated with MMSE total score, attention and calculation score, and language score (P< 0.05). After adjusting for confounding factors, serum NSE still increased the MCI risk in DR patients (OR:1.606, 95CI%:1.264– 2.041, P< 0.001). The areas under the receiver operating characteristics (ROC) curves (AUC) of the crude model and the adjusted model were 0.75 and 0.73, respectively.Conclusion: A high serum NSE level is an independent risk factor for MCI in DR patients. In addition, serum NSE is expected to be a potential biomarker in DR patients with MCI.Keywords: neuron-specific enolase, mild cognitive impairment, type 2 diabetes mellitus, diabetic retinopathy

Shi Zuo,1,* Wei Zou,2,3,* Rong-Min Wu,4 Jing Yang,5 Jian-Nan Fan,2 Xue-Ke Zhao,5 Hai-Yang Li1 1Department of Hepatobiliary Surgery, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Department of Sports Medicine, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 3Department of Orthopedics, The Fourth People’s Hospital of Guiyang, Guizhou, People’s Republic of China; 4Department of Ultrasonography, The Maternity Hospital of Guizhou, Guiyang, Guizhou, People’s Republic of China; 5Department of Infectious Disease, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hai-Yang LiDepartment of Hepatobiliary Surgery, The Hospital Affiliated to Guizhou Medical University, No.28, Guiyi Street, Guiyang, Guizhou 550004, People’s Republic of ChinaEmail haiyangli666@sohu.comJian-Nan FanDepartment of Sports Medicine, The Hospital Affiliated to Guizhou Medical University, No.28, Guiyi Street, Guiyang, Guizhou 550004, People’s Republic of ChinaEmail publetscientific@126.comObjective: Osteoarthritis (OA) is characterized by progressive matrix destruction of articular cartilage. This study aimed to investigate the potential antioxidative and chondroprotective effects and underlying mechanism of Icariin (ICA) in interleukin-1 beta (IL-1β)-induced extracellular matrix (ECM) degradation of OA cartilage.Methods: Human chondrocyte cell line HC-A was treated with different doses of ICA, and then MTT assay and PI staining were used to estimate ICA-induced chondrocyte apoptosis. Intracellular ROS and superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured after treatment by IL-1β with or without ICA. The mRNA and protein expression levels of redox transcription factor Nrf2 and the downstream effector SOD-1, SOD-2, NQO-1 and HO-1 were assayed to explore the detailed mechanism by which ICA alleviates ECM degradation. Finally, to expound the role of Nrf2 in ICA-mediated chondroprotection, we specifically depleted Nrf2 in human chondrocytes and then pretreated them with ICA followed by IL-1β.Results: ICA had no cytotoxic effects on human chondrocytes and 10−9 M was selected as the optimum concentration. ROS induced by IL-1β could drastically activate matrix-degrading proteases and ICA could significantly rescue the matrix degradation and excess ROS generation caused by IL-1β. We observed that ICA activated the Nrf2/ARE pathway, consequently upregulating the generation of GPX and SOD. Ablation of Nrf2 abrogated the chondroprotective and antioxidative effects of ICA in IL-1β-treated chondrocytes.Conclusion: ICA alleviates IL-1β-induced matrix degradation and eliminates ROS by activating the Nrf2/ARE pathway.Keywords: icariin, Nrf2 signaling, ROS, human chondrocyte, ECM degradation

Wenshan Lin,*,1 Hong-Yan Li,*,2 Shujun Lin,1 Tianbiao Zhou11Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, People’s Republic of China; 2Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workBackground: As one of the therapeutic drugs for idiopathic membranous nephropathy (IMN), tacrolimus (TAC) has not been fully vindicated for its efficacy and tolerability. A meta-analysis was performed to detect the efficacy and safety of TAC plus glucocorticoid vs cyclophosphamide (CTX) plus glucocorticoid in therapy of patients with IMN.Methods: A literature search with a pre-defined search strategy was conducted using English databases (PubMed, EMBASE, ClinicalKey and the Cochrane Library) and Chinese databases (China National Knowledge International, Wanfang, Chinese Scientific Journal Database (VIP)) from inception to Nov 19, 2018. Any high-quality randomized controlled trials (RCTs) comparing the effectiveness or safety of TAC with CTX in IMN patients were included. Data were extracted by two authors independently and analyzed using RevMan 5.3.Results: Four randomized controlled studies were included. In this analysis, we did not find that the statistically significant difference between TAC and CTX groups on 6-month and 12-month treatment complete remission (CR) was evident (6-month: OR=1.53, 95% CI: 0.85–2.76, P=0.15; 12-month: OR=2.17, 95% CI: 0.56–8.44, P=0.27). But TAC had better 6-month total remission (TR; total CR plus partial remission [PR]) than CTX (6-month: OR=2.62, 95% CI: 1.38–4.96, P=0.003; 12-month: OR=1.74, 95% CI: 0.29–10.48, P=0.54), and got a lower proteinuria after 6-month treatment (OR=−0.80, 95% CI: −1.53 to −0.07, P=0.03). TAC had a lower incidence rate on leucopenia than CTX, but had a tendency towards higher blood creatinine. In the meantime, tremor in TAC group was higher than that in CTX group. The differences on other adverse effects such as gastrointestinal syndrome, infection, herpes zoster, hypertension, liver function disorder and hyperglycemia were also analyzed. However, none of them were statistically significant.Conclusion: TAC treatment could get high value of TR and had low value of proteinuria level when compared with those in CTX on 6-month treatment in therapy of patients with IMN.Keywords: tacrolimus, idiopathic membranous nephropathy, complete remission, CR, total remission, TR, meta-analysis

Shujun Lin,1 Hong-Yan Li,2 Tianbiao Zhou,1 Wenshan Lin11Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, People’s Republic of China; 2Department of Nephrology, Huadu District People’s Hospital of Guangzhou, Southern Medical University, Guangzhou 510800, People’s Republic of ChinaIntroduction: The efficacy of cyclosporine A (CsA) in the treatment of idiopathic membranous nephropathy (IMN) is unclear. This meta-analysis was conducted to assess the efficacy and the safety of CsA in the treatment of IMN in Asians.Methods: We searched the Pubmed, China Biomedical Database, CNKI, Wanfang Data, VIP, and EMBASE (November 30, 2018) systematically to identify the appropriate randomized controlled trials (RCTs) reporting the efficacy and the safety of CsA and glucocorticoid (GC) treatment vs other immunosuppressants and GC on patients with IMN in Asian populations.Results: The CsA treated group entered complete remission (CR) faster (3 months) than a cyclophosphamide (CTX) group. While the CsA group lower inefficacy rates and higher total remission (TR, CR, or partial remission) than the CTX group in the total treatment (3 months, 6 months, and 12 months), it had a higher relapse rate. As for the CsA group vs the tacrolimus (TAC) group, the TAC had a significant effect in increasing the CR and the TR, with decreased no remission. With the therapeutic regimens of CsA+GC vs CTX+GC, the CsA exhibited better efficacy in lowering the proteinuria levels only at 12 months, not at 3 months or 6 months. Severe events like leucopenia, hemorrhagic cystitis, and alopecia were observed in the CTX group. Gingival hyperplasia, hirsutism, and elevated blood pressure were reported only in the CsA group. Gastrointestinal syndrome, liver function lesion, happened more frequently in the CTX group, and elevated uric acid was more common in the CsA group.Conclusions: In brief, the CsA has better efficacy than the CTX group in the Asian population, with mild adverse effects but higher relapse rates in short-term treatment.Keywords: idiopathic membranous nephropathy, cyclosporine A, cyclophosphamide, mycophenolate mofetil, tacrolimus

Wei Zheng,1 Xin-Ni Luo,1 Hai-Yan Li,1 Xiao-Yin Ke,1 Qing Dai,1 Chan-Juan Zhang,1 Xiang-Yang Zhang,1,2 Yu-Ping Ning1 1The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China; 2Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA Background: Region-specific differences in the prevalence of insomnia symptoms in outpatient clinics in China have received little systematic study. This study was conducted preliminarily to examine region-specific differences in the risk of insomnia symptoms in Chinese outpatients. Method: In total, 4,399 adult outpatients (urban vs rural residents: 1,768 vs 2,631) who completed three questions focusing on insomnia symptoms were included. Their sociodemographic and clinical information were collected with standardized questionnaires. Results: The prevalence of self-reported insomnia symptoms in urban residents (23.4%) was more frequent than the prevalence in rural residents (21.2%). The estimated prevalence of insomnia symptoms was significantly lower in rural than urban residents after adjusting for the potential confounders (P=0.015). Similarly, more urban (22.9%) than rural (13.4%) residents with insomnia symptoms had significantly higher treatment rates (χ2=14.9, P

Zhan Wang,1,* Shu Li,2,* Yong Li,1 Nong Lin,1 Xin Huang,1 Meng Liu,1 Weibo Pan,1 Xiaobo Yan,1 Lingling Sun,1 Hengyuan, Li,1 Binghao Li,1 Hao Qu,1 Yan Wu,1 Peng Lin,1 Zhaoming Ye1 1Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, Hangzhou, China; 2Key Laboratory of Cancer Prevention and Intervention, Key Laboratory of Molecular Biology in Medical Sciences, National Ministry of Education, Department of Hematology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Cancer Institute, Hangzhou, China *These authors contributed equally to this work Background: Primary bone sarcomas of the hands or feet are rare lesions and poorly documented. Moreover, the prognostic determinants of bone sarcomas of the hands or feet have not been reported. Materials and methods: The Surveillance, Epidemiology, and End Results (SEER) program database was used to screen patients with bone sarcomas of the hands or feet from 1973 to 2013, with attention paid to chondrosarcoma, Ewing sarcoma, and osteosarcoma. The prognostic values of overall survival (OS) and cancer-specific survival (CSS) were assessed using Cox proportional hazards regression model with univariate and multivariate analyses. The Kaplan–Meier method was used to obtain OS and CSS curves. Results: A total of 457 cases were selected from the SEER database. Chondrosarcoma was the most common form of lesion in hands or feet or both, followed by Ewing sarcoma and osteosarcoma. The 5- and 10-year OS rates of the entire group were 75.7% and 66.1%, respectively. The 5- and 10-year CSS rates were 78.7% and 73.7%, respectively. Multivariate analysis revealed that age under 40 years, localized stage, low grade, surgical treatment, and first primary tumor were associated with improved OS, and decade of diagnosis, stage, grade, and surgery were independent predictors of CSS. However, no significant differences were observed in OS and CSS among patients with different primary tumor locations and tumor subtypes. Additionally, the most significant prognostic factor was whether metastasis had occurred at the time of initial diagnosis. Conclusion: Among patients with primary bone sarcomas of the hands or feet, younger age (

Yinglai Huang,1,2,* Lin Pan,3,* Khalil Helou,2 Qisheng Xia,3 Toshima Z Parris,2 Hongyan Li,3 Bo Xu,3 Hon Li3 1Division of Breast and Endocrine Surgery, Department of Surgery, Borås Hospital, Borås, 2Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; 3Department of Biochemistry and Molecular Biology, China-Japan Friendship Hospital, Beijing, People’s Republic of China *These authors contributed equally to this work Background/purpose: The aim of this study was to test the hypothesis that mechanical ventilation (MV) during cancer surgery induces lung stroma/tissue milieu changes, creating a favorable microenvironment for postoperative lung metastatic tumor establishment.Materials and methods: In Protocol A, female BALB/c mice were divided into an MV group and a control (no MV) group, both of which were anesthetized and subjected to intravenous injection of green fluorescent protein (GFP)-labeled mouse mammary carcinoma cell line (4T1) cells. After 24 h, the lung tissue was removed and the number of GFP-labeled 4T1 cells was calculated. In Protocol B, the clinically relevant mouse model of spontaneous breast cancer lung metastasis was used with surgical resection of the primary tumor to investigate the MV event that dictates postoperative lung metastasis. Female BALB/c mice were inoculated in the mammary fat pad with 4T1 cells. After 14-d growth, mice were anesthetized and divided into an MV group and a control (no MV) group during surgical procedures (mastectomy). Metastatic tumor burden was assessed two weeks after mastectomy by both macroscopic metastatic nodule count, hematoxylin–eosin histology, immunohistochemistry for the macrophage marker (CD68), and epithelial cell adhesion molecule (EpCAM).Results: MV was associated with a significant increase in the number of circulating breast tumor cells (GFP-labeled 4T1 cells) remaining in the microvasculature of the lung (P

Jun-Zi Wu,1 Gareth R Williams,2 He-Yu Li,1 Dongxiu Wang,3 Huanling Wu,1 Shu-De Li,4 Li-Min Zhu1 1College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, People’s Republic of China; 2UCL School of Pharmacy, University College London, London, UK; 3Central Laboratory, Environmental Monitoring Center of Kunming, 4School of Basic Medical Sciences, Kunming Medical University, Kunming, People’s Republic of China Abstract: Glucose- and temperature-sensitive polymers of a phenylboronic acid derivative and diethylene glycol dimethacrylate (poly(3-acrylamidophenyl boronic acid-b-diethylene glycol methyl ether methacrylate); p(AAPBA-b-DEGMA)) were prepared by reversible addition–fragmentation chain transfer polymerization. Successful polymerization was evidenced by 1H nuclear magnetic resonance and infrared spectroscopy, and the polymers were further explored in terms of their glass transition temperatures and by gel permeation chromatography (GPC). The materials were found to be temperature sensitive, with lower critical solution temperatures in the region of 12°C–47°C depending on the monomer ratio used for reaction. The polymers could be self-assembled into nanoparticles (NPs), and the zeta potential and size of these particles were determined as a function of temperature and glucose concentration. Subsequently, the optimum NP formulation was loaded with insulin, and the drug release was studied. We found that insulin was easily encapsulated into the p(AAPBA-b-DEGMA) NPs, with a loading capacity of ~15% and encapsulation efficiency of ~70%. Insulin release could be regulated by changes in temperature and glucose concentration. Furthermore, the NPs were non-toxic both in vitro and in vivo. Finally, the efficacy of the formulations at managing blood glucose levels in a murine hyperglycemic diabetes model was studied. The insulin-loaded NPs could reduce blood glucose levels over an extended period of 48 h. Since they are both temperature and glucose sensitive and offer a sustained-release profile, these systems may comprise potent new formulations for insulin delivery. Keywords: diethylene glycol methyl ether methacrylate, 3-acrylamidophenylboronic acid, nanoparticle, thermosensitive, glucose sensitive, insulin delivery

Minzhi Zhao,* Haiyun Li,* Yan Ma, He Gong, Shu Yang, Qiaojun Fang, Zhiyuan Hu Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Abraxane (Abr), a US Food and Drug Administration-approved albumin-bound nanoparticle applied for the treatment of non-small-cell lung cancer, has been reported to be more effective than paclitaxel (PTX). To further understand the molecular mechanisms that produce this superior drug efficacy of Abr, a quantitative proteomic approach has been applied to investigate the global protein expression profiles of lung cancer cell A549 treated with Abr and PTX. Only one protein, namely, glucosamine 6-phosphate N-acetyltransferase 1 (GNA1), showed significant differential expression (P

Haiying Li,1 Tingting Pan,1 Ying Cui,1 Xiaxia Li,1 Jiefang Gao,1 Wenzhi Yang,1 Shigang Shen2 1Key Laboratory of Pharmaceutical Quality Control of Hebei Province, College of Pharmacy, 2Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, People’s Republic of China Abstract: The objective of this work was to prepare an oil/water glimepiride (GM) microemulsion (ME) for oral administration to improve its solubility and enhance its bioavailability. Based on a solubility study, pseudoternary phase diagrams, and Box–Behnken design, the oil/water GMME formulation was optimized and prepared. GMME was characterized by dynamic laser light scattering, zeta potential, transmission electron microscopy, and viscosity. The in vitro drug release, storage stability, pharmacodynamics, and pharmacokinetics of GMME were investigated. The optimized GMME was composed of Capryol 90 (oil), ­Cremophor RH40 (surfactant), and Transcutol (cosurfactant), and increased GM solubility up to 544.6±4.91 µg/mL. The GMME was spherical in shape. The particle size and its polydispersity index were 38.9±17.46 nm and 0.266±0.057, respectively. Meanwhile, the GMME was physicochemically stable at 4°C for at least 3 months. The short-term efficacy in diabetic mice provided the proof that blood glucose had a consistent and significant reduction at a dose of 375 µg/kg whether via IP injection or IG administration of GMME. Compared with the glimepiride suspensions or glimepiride-meglumine complex solution, the pharmacokinetics of GMME in Wistar rats via IG administration exhibited higher plasma drug concentration, larger area under the curve, and more enhanced oral bioavailability. There was a good correlation of GMME between the in vitro release values and the in vivo oral absorption. ME could be an effective oral drug delivery system to improve bioavailability of GM. Keywords: glimepiride, microemulsion, solubility, pharmacodynamics, pharmacokinetics

Zhizeng Wang,1 Dejuan Zhi,2 Yang Zhao,1 Hailong Zhang,2 Xin Wang,2 Yi Ru,1 Hongyu Li1,2 1MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, People's Republic of China; 2Institute of Microbiology and Biochemical Pharmacy, School of Pharmaceutics, Lanzhou University, Lanzhou, People's Republic of China Abstract: Although high melamine (MEL) intake has been proven to cause serious health problems, MEL is sometimes illegally added to milk products and animal feed, arousing serious food safety concerns. A satisfactory method of detecting MEL in onsite or in-home testing is in urgent need of development. This work aimed to explore a rapid, convenient, and cost-effective method of identifying MEL in milk products or other food by colloidal selenium-based lateral flow immunoassay. Colloidal selenium was synthesized by L-ascorbic acid to reduce seleninic acid at room temperature. After conjugation with a monoclonal antibody anti-MEL, a test strip was successfully prepared. The detection limit of the test strip reached 150 µg/kg, 1,000 µg/kg, and 800 µg/kg in liquid milk, milk powder, and animal feed, respectively. No cross-reactions with homologues cyanuric acid, cyanurodiamide, or ammelide were found. Moreover, the MEL test strip can remain stable after storage for 1 year at room temperature. Our results demonstrate that the colloidal selenium MEL test strip can detect MEL in adulterated milk products or animal feed conveniently, rapidly, and sensitively. In contrast with a colloidal gold MEL test strip, the colloidal selenium MEL test strip was easy to prepare and more cost-efficient. Keywords: melamine, selenium nanoparticles, test strip, milk, animal feed, dairy food

Yuan-Yuan Diao1,2,*, Hao-Ying Li3,*, Ying-Hua Fu4, Min Han1, Yu-Lan Hu1, Hong-Liang Jiang5, Yasuo Tsutsumi6, Qi-Chun Wei7, Da-Wei Chen2, Jian-Qing Gao1 1Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou; 2School of Pharmacy, Shenyang Pharmaceutical University, Shenyang; 3Biomanufacturing Research Centre, Department of Mechanical and Electrical Engineering, Soochow University, Suzhou; 4Department of Pharmaceutics, Jiaxing University College of Medicine, Jiaxing; 5Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, People's Republic of China; 6Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan; 7Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, Zhejiang University School of Medicine, Hangzhou, People's Republic of China, *These authors contributed equally to this workBackground: Multidrug resistance remains a major obstacle to successful cancer chemotherapy. Some chemical multidrug resistance inhibitors, such as ciclosporin and verapamil, have been reported to reverse resistance in tumor cells. However, the accompanying side effects have limited their clinical application. In this study, we have developed a novel drug delivery system, ie, a polyethyleneglycol-polycaprolactone (PEG-PCL) copolymer micelle encapsulating doxorubicin, in order to circumvent drug resistance in adriamycin-resistant K562 tumor cells.Methods: Doxorubicin-loaded diblock copolymer PEG-PCL micelles were developed, and the physicochemical properties of these micelles, and accumulation and cytotoxicity of doxorubicin in adriamycin-resistant K562 tumor cells were studied.Results: Doxorubicin-loaded micelles were prepared using a solvent evaporation method with a diameter of 36 nm and a zeta potential of +13.8 mV. The entrapment efficiency of doxorubicin was 48.6% ± 2.3%. The micelles showed sustained release, increased uptake, and cellular cytotoxicity, as well as decreased efflux of doxorubicin in adriamycin-resistant K562 tumor cells.Conclusion: This study suggests that PEG-PCL micelles have the potential to reverse multidrug resistance in tumor cells.Keywords: doxorubicin, polyethylene glycol, polycaprolactone, adriamycin-resistant K562 tumor cells, multidrug resistance, micelles

Soil erosion delivers enormous amounts of macro-nutrients including nitrogen (N) and phosphorus (P) from land to rivers, potentially sustaining water column bioavailable nutrient levels for decades. In this study, we represent erosional N and P fluxes in the Energy Exascale Earth System Model (E3SM) and apply the model to the continental United States. We estimate that during 1991-2019 soil erosion delivers 775 Gg yr-1 (1 Gg = 109 g) of particulate N (PN) and 328 Gg yr-1 of particulate P (PP) on average to the drainage basins of the northern Gulf of Mexico, including the Mississippi/Atchafalaya River and other rivers draining to the Texas Gulf and the Eastern Gulf. Our model simulation shows that in these rivers PP is the dominant P constituent and over 55% of P exported by erosion comes from soil P pools that could become bioavailable within decades. More importantly, we find that during 1991-2019 erosional N and P fluxes increase at rates of about 15 Gg N yr-1 and 6 Gg P yr-1, respectively, due to increased extreme rains in the Mississippi/Atchafalaya river basin, and this intensification of erosional N and P fluxes drive the significant increase of riverine PN and PP yields to the northern Gulf of Mexico. With extreme rains projected to increase with warming, erosional nutrient fluxes in the region would likely continue to rise in the future, thus complicating the effort of reducing eutrophication in the inland and coastal waters.

Recent publications have argued that there are potentially serious consequences for researchers in recognising distinct genera in the terminal fusarioid clade of the family Nectriaceae. Thus, an alternate hypothesis, namely a very broad concept of the genus Fusarium was proposed. In doing so, however, a significant body of data that supports distinct genera in Nectriaceae based on morphology, biology, and phylogeny is disregarded. A DNA phylogeny based on 19 orthologous protein-coding genes was presented to support a very broad concept of Fusarium at the F1 node in Nectriaceae. Here, we demonstrate that re-analyses of this dataset show that all 19 genes support the F3 node that represents Fusarium sensu stricto as defined by F. sambucinum (sexual morph synonym Gibberella pulicaris). The backbone of the phylogeny is resolved by the concatenated alignment, but only six of the 19 genes fully support the F1 node, representing the broad circumscription of Fusarium. Furthermore, a re-analysis of the concatenated dataset revealed alternate topologies in different phylogenetic algorithms, highlighting the deep divergence and unresolved placement of various Nectriaceae lineages proposed as members of Fusarium. Species of Fusarium s. str. are characterised by Gibberella sexual morphs, asexual morphs with thin- or thick-walled macroconidia that have variously shaped apical and basal cells, and trichothecene mycotoxin production, which separates them from other fusarioid genera. Here we show that the Wollenweber concept of Fusarium presently accounts for 20 segregate genera with clear-cut synapomorphic traits, and that fusarioid macroconidia represent a character that has been gained or lost multiple times throughout Nectriaceae. Thus, the very broad circumscription of Fusarium is blurry and without apparent synapomorphies, and does not include all genera with fusarium-like macroconidia, which are spread throughout Nectriaceae (e.g., Cosmosporella, Macroconia, Microcera). In this study four new genera are introduced, along with 18 new species and 16 new combinations. These names convey information about relationships, morphology, and ecological preference that would otherwise be lost in a broader definition of Fusarium. To assist users to correctly identify fusarioid genera and species, we introduce a new online identification database, Fusarioid-ID, accessible at www.fusarium.org. The database comprises partial sequences from multiple genes commonly used to identify fusarioid taxa (act1, CaM, his3, rpb1, rpb2, tef1, tub2, ITS, and LSU). In this paper, we also present a nomenclator of names that have been introduced in Fusarium up to January 2021 as well as their current status, types, and diagnostic DNA barcode data. In this study, researchers from 46 countries, representing taxonomists, plant pathologists, medical mycologists, quarantine officials, regulatory agencies, and students, strongly support the application and use of a more precisely delimited Fusarium (= Gibberella) concept to accommodate taxa from the robust monophyletic node F3 on the basis of a well-defined and unique combination of morphological and biochemical features. This F3 node includes, among others, species of the F. fujikuroi, F. incarnatum-equiseti, F. oxysporum, and F. sambucinum species complexes, but not species of Bisifusarium [F. dimerum species complex (SC)], Cyanonectria (F. buxicola SC), Geejayessia (F. staphyleae SC), Neocosmospora (F. solani SC) or Rectifusarium (F. ventricosum SC). The present study represents the first step to generating a new online monograph of Fusarium and allied fusarioid genera (www.fusarium.org).

This study provides an overview of the coupled high-resolution Version 1 of the Energy Exascale Earth System Model (E3SMv1) and documents the characteristics of a 50-year-long high-resolution control simulation with time-invariant 1950 forcings following the HighResMIP protocol. In terms of global root-mean-squared error metrics, this high-resolution simulation is generally superior to results from the low-resolution configuration of E3SMv1 (due to resolution, tuning changes, and possibly initialization procedure) and compares favorably to models in the CMIP5 ensemble. Ocean and sea ice simulation is particularly improved, due to better resolution of bathymetry, the ability to capture more variability and extremes in winds and currents, and the ability to resolve mesoscale ocean eddies. The largest improvement in this regard is an ice-free Labrador Sea, which is a major problem at low resolution. Interestingly, several features found to improve with resolution in previous studies are insensitive to resolution or even degrade in E3SMv1. Most notable in this regard are warm bias and associated stratocumulus deficiency in eastern subtropical oceans and lack of improvement in El Niño. Another major finding of this study is that resolution increase had negligible impact on climate sensitivity (measured by net feedback determined through uniform +4K prescribed sea surface temperature increase) and aerosol sensitivity. Cloud response to resolution increase consisted of very minor decrease at all levels. Large-scale patterns of precipitation bias were also relatively unaffected by grid spacing.

This work documents the first version of the U.S. Department of Energy (DOE) new Energy Exascale Earth System Model (E3SMv1). We focus on the standard resolution of the fully coupled physical model designed to address DOE mission-relevant water cycle questions. Its components include atmosphere and land (110-km grid spacing), ocean and sea ice (60 km in the midlatitudes and 30 km at the equator and poles), and river transport (55 km) models. This base configuration will also serve as a foundation for additional configurations exploring higher horizontal resolution as well as augmented capabilities in the form of biogeochemistry and cryosphere configurations. The performance of E3SMv1 is evaluated by means of a standard set of Coupled Model Intercomparison Project Phase 6 (CMIP6) Diagnosis, Evaluation, and Characterization of Klima simulations consisting of a long preindustrial control, historical simulations (ensembles of fully coupled and prescribed SSTs) as well as idealized CO2 forcing simulations. The model performs well overall with biases typical of other CMIP-class models, although the simulated Atlantic Meridional Overturning Circulation is weaker than many CMIP-class models. While the E3SMv1 historical ensemble captures the bulk of the observed warming between preindustrial (1850) and present day, the trajectory of the warming diverges from observations in the second half of the twentieth century with a period of delayed warming followed by an excessive warming trend. Using a two-layer energy balance model, we attribute this divergence to the model's strong aerosol-related effective radiative forcing (ERFari+aci = −1.65 W/m2) and high equilibrium climate sensitivity (ECS = 5.3 K).

Despite recent advances in land surfacemodeling and remote sensing, estimates of the global water budget are still fairly uncertain. This study aims to evaluate the water budget of the Amazon basin based on several state-ofthe- art land surface model (LSM) outputs. Water budget variables (terrestrial water storage TWS, evapotranspiration ET, surface runoff R, and base flow B) are evaluated at the basin scale using both remote sensing and in situ data. Meteorological forcings at a 3-hourly time step and 18 spatial resolution were used to run 14 LSMs. Precipitation datasets that have been rescaled to matchmonthly Global Precipitation Climatology Project (GPCP) andGlobal Precipitation Climatology Centre (GPCC) datasets and the daily Hydrologie du Bassin de l'Amazone (HYBAM) dataset were used to perform three experiments. The Hydrological Modeling and Analysis Platform (HyMAP) river routing scheme was forced with R and B and simulated discharges are compared against observations at 165 gauges. Simulated ET and TWS are compared against FLUXNET and MOD16A2 evapotranspiration datasets andGravity Recovery and ClimateExperiment (GRACE)TWSestimates in two subcatchments of main tributaries (Madeira and Negro Rivers).At the basin scale, simulated ET ranges from 2.39 to 3.26mmday-1 and a low spatial correlation between ET and precipitation indicates that evapotranspiration does not depend on water availability over most of the basin. Results also show that other simulated water budget components vary significantly as a function of both the LSM and precipitation dataset, but simulated TWS generally agrees with GRACE estimates at the basin scale. The best water budget simulations resulted from experiments using HYBAM, mostly explained by a denser rainfall gauge network and the rescaling at a finer temporal scale.