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Yi-Hung Lai,1,2 Ming-Ju Wu,3 Hsin-Hua Chen,4,5 Shih-Ping Lin,4,6 Chun-Yi Wu,3,4 Chun-Shih Chin,4,7 Cheng-Hsien Lin,4,8 Sz-Iuan Shiu,4,9 Ying-Cheng Lin,4,9 Hui-Chi Chen,1 Shu-Chin Hou,1 Ching-Wein Chang1 1Department of Nursing, Taichung Veterans General Hospital, Taichung, Taiwan; 2Department of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan; 3Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 4Division of General Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 5Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 6Division of Infection, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 7Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 8Division of Hematology and Oncology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 9Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, TaiwanCorrespondence: Ching-Wein Chang, Department of Nursing, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 40705, Taiwan, Email wen6081@gmail.comObjective: A huddle is a short, regular meetings to discuss existing or emerging patient safety issues. Hospital administrators can encourage healthcare staff to voluntarily examine the potential occurrence and severity of risks, thereby enhancing awareness of patient safety. The purpose of this study is to explore the effects of huddle intervention on patient safety culture among medical team members and related factors.Methods: We used a one-group pretest-posttest research design and convenience sampled 109 members of the general internal medicine ward team members from a medical center in central Taiwan. They participated 2 times per week in 15-min huddles from 08:15 to 08:30 in the morning, which lasted for a total of 4 weeks. The process was based on submitted ideas, approved ideas, research ideas and standardization, and data on the safety attitudes questionnaire (SAQ) were collected during the huddles’ intervention pretest and posttest.Results: After the huddle intervention, we found significantly improved scores for safety attitude, teamwork climate (76.49± 16.13 vs 83.26± 13.39, p < 0.001), safety climate (75.07± 16.07 vs 82.63± 13.72, p < 0.001), job satisfaction (73.67± 19.84 vs 83.39± 17.21, p < 0.001), perceptions of management (77.87± 19.99 vs 84.86± 16.03, p < 0.001) and working conditions (78.96± 18.16 vs 86.18± 14.90, p < 0.001). Correlation analyses on the differences between pretest and posttest showed that age had a significant correlation with safety climate (r = 0.22, p = 0.022) and working conditions (r = 0.20, p = 0.035). The number of times to participate in a huddle had a significant correlation with teamwork climate (r = 0.33, p =< .001), safety climate (r = 0.30, p = 0.002), job satisfaction (r = 0.19, p = 0.043), and work conditions (r = 0.28, p = 0.003).Conclusion: Huddles improve clinical team members’ understanding of different dimensions and relate factors of safety attitudes. Implementation of the huddles involved standardized process will help hospital administrators understand the steps to parallel expansion to other wards.Keywords: huddle, patient safety, patient care team

Yen-Ching Lin,1,&ast; Chia-Hsuin Chang,1– 3,&ast; Wei-Ju Su,4,5 Chin-Hui Yang,4 Jann-Tay Wang1,2 1Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 2Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 3Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 4Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan; 5Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chia-Hsuin Chang, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan, Tel +886-2-23123456, Fax +886-2-2392-0456, Email chiahsuin@yahoo.comPurpose: Early studies showed that the risks of mRNA vaccine-associated myocarditis and pericarditis are low but with substantial variation across studies. Study characteristics, ethnicity, vaccine types, dose intervals, and SARS-CoV-2 infection prevalence may influence the rates of myocarditis and pericarditis after mRNA vaccination in population-based studies.Methods: We comprehensively searched MEDLINE for relevant articles published before November 30, 2022. We also searched the websites of health authorities in several countries for unpublished surveillance data on myocarditis and pericarditis after mRNA vaccination. The outcome of interest was the incidence of myocarditis and pericarditis developed after mRNA vaccination for COVID-19.Results: A total of 17 studies form 10 countries were included for review. We noted that considerable heterogeneity in study characteristics, including surveillance method, case definition, and observation period, may partially be responsible for the widely varied reported rates. Studies from countries that adopted active surveillance reported higher rates than those using passive surveillance. Compared to BNT162b2 vaccine, mRNA-1273 may have a higher risk of myocarditis only in young men after the second dose. Our comparison of sex-, age-, vaccine type-, and dose-specific rates of myocarditis across countries did not support the hypothesis that individuals with recent SARS-CoV-2 infection and young Asian males were at higher risk. We also could not find sufficient evidence to conclude whether extending the between-dose interval could reduce myocarditis incidence following mRNA vaccination.Conclusion: Differences in the study characteristics must be fully considered when comparing the risks of mRNA vaccine-related myocarditis and pericarditis in different countries.Keywords: COVID-19, mRNA vaccine, myocarditis, population-based study, surveillance data

Yin-Han Wang,1 Tsung-Ming Yang,2,3 Ming-Szu Hung,2– 4 Yu-Ching Lin,2– 4 Tien-Pei Fang,1,3 Tzu-Tzu Kuo,5,&ast; Mark D Griffiths,6 Chung-Ying Lin7– 10,&ast; 1Department of Respiratory Therapy, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi, Taiwan; 3Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 4Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Division of Respiratory Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan; 6International Gaming Research Unit, Psychology Department, Nottingham Trent University, Nottingham, UK; 7Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 10Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chung-Ying Lin, Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Tel +886-6-2353535 ext. 5106, Fax +886-6-2367981, Email cylin36933@gmail.com Tzu-Tzu Kuo, Division of Respiratory Medicine, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan, Email ed101231@gmail.comPurpose: Inhaled medication adherence is an important issue for patients with chronic obstructive pulmonary disease (COPD) because adhering to inhaled medications could substantially improve their health. However, patients with COPD may not be always adhere to the prescribed inhaled medications. Therefore, understanding the underlying reasons for patients with COPD adhering to inhaled medications is important. The present study used Theory of Planned Behavior (TPB) as a theoretical framework to develop the Intention of Inhaled Medication Adherence Scale (IMAS) and assess its psychometric properties.Patients and Methods: After reviewing papers using the TPB to design psychometric scales and the TPB scale development guidelines, 28 items were generated for expert evaluation. Eight experts reported that the 28 items all had good content validity (content validity index ranged from 0.88 to 1.00 at item-level; and from 0.981 to 0.987 at scale-level) comprising four factors. Following initial development, 235 patients with COPD (mean age 73.12 years; 93.6% males) completed the IMAS via interview with a respiratory therapist and a research assistant. The four-factor structure of the IMAS was evaluated using confirmatory factor analysis (CFA).Results: Nine IMAS items were removed because of low factor loadings or offending estimates. The 19-item IMAS was confirmed as having a four-factor structure supported by the CFA results (comparative fit index=1.00; Tucker-Lewis index=1.00; root mean square error of approximation=0.00; standardized root mean square residual=0.06).Conclusion: The 19-item IMAS had satisfactory psychometric properties in construct validity. The 19-item IMAS is an instrument that could help healthcare providers understand potential factors associated with adherence to inhaled medications among people with COPD.Keywords: adherence, confirmatory factor analysis, COPD, psychometrics

Yu-Chen Lin,1 Wei-Yang Lee2 1Department of Psychiatry, Veteran General Hospital-Taichung, Taichung, 407, Taiwan, Republic of China; 2Department of Psychiatry, Cheng Gung Memorial Hospital, Taoyuan City, 333, Taiwan, Republic of ChinaCorrespondence: Wei-Yang Lee, Department of Psychiatry, Cheng Gung Memorial Hospital, Linkou, No. 5, Fuxing St., Guishan District, Taoyuan City, 333, Taiwan, Republic of China, Tel +886 988067722, Email wayne2859750@gmail.comPurpose: Caregivers’ responses have an impact on children’s emotional and behavioral development. The inability of caregivers to perceive their own emotions affects their responses to children. This study aims to examine the relationship between a mother’s difficulties in emotional expression and children’s emotional and behavioral disorders.Patient and Methods: A total of 78 cases, aged between 3 and 15 years old, were included in this study. The mothers completed the Taiwan version of the “Toronto Alexithymia Scale” (TAS) and “Children’s Behavior Checklist” (CBCL) questionnaires, which served as research tools. TAS consists of three factors: difficulty in distinguishing emotions (Factor 1, F1), difficulty in expressing feelings (Factor 2, F2), and an externally oriented thinking style (Factor 3, F3). CBCL represents a child’s behavior profile. The Mann–Whitney test and correlation analyses were used for follow-up analysis.Results: Our analysis revealed that F1, F2, F3, and total scores of TAS (TAS-Total) correlate positively with the somatic complaint subscale of CBCL (F1: p = 0.003; F2: p = 0.002; F3: p = 0.034, TAS-Total p=0.002). Additionally, TAS-F1 was positively correlated with the internalizing problems subscale of CBCL (p = 0.020) and the withdrawn (WD) subscale of CBCL (p = 0.044). We also found a significant association between TAS-F1 and WD of CBCL in boys alone (p = 0.022). However, we observed a negative association between TAS-F3 and the social problems subscale of CBCL in boys alone (p = 0.038).Conclusion: Mothers with alexithymic features are more likely to have children who internalize emotions, leading to withdrawal and somatic expression. Boys tend to exhibit withdrawal traits associated with internalization. This study provides initial evidence of a partial correlation between maternal alexithymia and children’s emotional and behavioral disorders, emphasizing the importance of investigating caregivers’ emotional traits for a better understanding of children’s development in the future.Keywords: maternal alexithymia, childhood behavioral disturbance, external and internal problem, children’s behavior checklist, Toronto alexithymia scale

Meng-Chin Ho,1 Ying-Shan Chung,2,3 Yu-Ching Lin,1,4 Ming-Szu Hung,1,4,5 Yu-Hung Fang1,3 1Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Puzi City, Chiayi County, Taiwan, Republic of China; 2Department of Pharmacy, Chang Gung Memorial Hospital, Puzi City, Chiayi County, Taiwan, Republic of China; 3Department of Nursing, Chang Gung University of Science and Technology, Puzi City, Chiayi County, Taiwan, Republic of China; 4Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi City, Chiayi County, Taiwan, Republic of China; 5School of Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, Republic of ChinaCorrespondence: Yu-Hung Fang, Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi branch, No. 6, W. Sec., Jiapu Road, Puzi City, Chiayi County, 61363, Taiwan, Republic of China, Tel +886-5-362-1000 ext. 2762, Fax +886-5-362-3005, Email 8902062@gmail.comPurpose: Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib. Afatinib had a wider soluble pH range, with possible fewer interactions with antacids. However, clinical data were limited. Thus, this study aimed to evaluate the negative impact of PPIs on afatinib.Patients and Methods: This retrospective cohort study included patients who are newly diagnosed with non-small cell lung cancer (NSCLC) from 2014 to 2019 using the Chang Gung Research Database. We identified patients who were treated with first-line afatinib and analyzed the association between the PPI and afatinib treatment outcomes.Results: A total of 1418 patients were treated with first-line afatinib and followed up for 6 years. First-line afatinib was administered to 918 eligible patients, and 330 had afatinib with PPIs. The combination use of PPIs and afatinib significantly decreased the overall survival (OS) compared with that of patients using afatinib only (median OS: 33.2 and 25.1 months, p < 0.01) and multivariate analyses (Combination use: hazard ratio: 1.29; 1.05– 1.59, p = 0.01). The percentages of patients who were able to receive 2nd line therapy also significantly decreased in afatinib with PPI cohort.Conclusion: The concurrent use of PPIs was associated with lower OS in patients with EGFR-mutant lung cancer under the first-line afatinib treatment but not associated with TTF.Keywords: proton-pump inhibitor, epidermal growth factor receptor tyrosine kinase inhibitor, non-small cell lung cancer, afatinib, Chang Gung Research Database

Ying-Shan Chung,1,2 Yu-Ching Lin,3,4 Ming-Szu Hung,3– 5 Meng-Chin Ho,3 Yu-Hung Fang2,3 1Department of Pharmacy, Chang Gung Memorial Hospital, Puzi City, Taiwan, Republic of China; 2Department of Nursing, Chang Gung University of Science and Technology, Puzi City, Taiwan, Republic of China; 3Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Puzi City, Taiwan, Republic of China; 4Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi City, Taiwan, Republic of China; 5School of Medicine, College of Medicine, Chang Gung University; Guishan Township, Taoyuan, Taiwan, Republic of ChinaCorrespondence: Yu-Hung Fang, Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, No. 6, W. Sec., Jiapu Road, Puzi City, Chiayi County, 61363, Taiwan, Republic of China, Tel +886-5-362-1000 ext. 2762, Fax +886-5-362-3005, Email 8902062@gmail.comAim: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs)-associated Clostridioides difficile infection (CDI) among lung cancer patients have been reported in case reports and adverse events reporting system databases in the United States and Japan, but clinical data remained insufficient. This study aims to evaluate CDI in lung cancer patients receiving EGFR-TKIs.Methods: We conducted a retrospective cohort study using multi-institutional electronic medical records database. We included patients aged older than 20 years diagnosed with lung cancer and treated with EGFR-TKIs (gefitinib, erlotinib, afatinib). We defined EGFR-TKI initiation date as the index date and occurrence of diarrhea with CDI or without CDI as the event date. We followed patients from the index date until the event date, ICU admission, death, or 12/31/2019.Results: We included 2242 diarrhea patients, 51 were EGFR-TKI with CDI cohort, and 2191 were diarrhea without CDI cohort. Patients who were concurrently taking antibiotics (hazard ratio [HR], 3.30; 95% CI, 1.67– 6.5) and systemic steroids (HR, 4.9; 95% CI, 2.65– 9.06) had an increased risk of CDI. First-generation EGFR-TKIs tended to be associated with an increased risk of CDI compared with afatinib (HR, 1.81, 95% CI, 0.94– 3.47). EGFR-TKI with CDI had a higher ICU admission rate (HR, 3.42, 95% CI, 1.98– 5.91) and mortality rate (HR, 2.34, 95% CI, 1.67– 3.28) than diarrhea without CDI.Conclusion: Patients with CDI had higher ICU admission rates and mortality rates than those without CDI. Concurrent use of antibiotics and systemic steroids were risk factors for CDI among patients with lung cancer receiving EGFR-TKIs. Afatinib was not associated with a higher risk of CDI than first-generation EGFR-TKIs.Keywords: Clostridioides difficile infection, CDI, epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs, lung cancer

Yu-Ching Lin,1,2,&ast; Chung-Ying Lin,3– 6,&ast; Chia-Wei Fan,7 Chieh-Hsiu Liu,8 Daniel Kwasi Ahorsu,9 Duan-Rung Chen,10 Hui-Ching Weng,3,11 Mark D Griffiths12 1Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 6Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Department of Occupational Therapy, AdventHealth University, Orlando, FL, USA; 8Department of Geriatrics and Gerontology, Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong; 10Institute of Health Behaviors and Community Sciences, National Taiwan University, Taipei, Taiwan; 11Institute of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 12International Gaming Research Unit, Psychology Department, Nottingham Trent University, Nottingham, UK&ast;These authors contributed equally to this workCorrespondence: Hui-Ching Weng, Institute of Allied Health Sciences and Institute of Gerontology, College of Medicine, National Cheng Kung University, 1 University Road, East District, Tainan City, 70101, Taiwan, Tel +886-6-2353535 ext. 5986, Fax +886-6-3028175, Email hc6127@mail.ncku.edu.twPurpose: The present study compared two nationally representative cohort datasets concerning Taiwan residents’ healthy behaviors, subjective health outcomes, generalized trust, and accessibility to health promotion resources.Patients and Methods: The Taiwan Social Change Survey (TSCS) was conducted in two waves ten years apart: 2011 cohort (n = 1021; 48.4% males) and 2021 cohort (n = 1425; 47.4%) cohorts. Descriptive statistics were calculated to compare the two TSCS datasets. Then, multiple regression models were constructed with health outcome as the dependent variable, and demographics and other key components as independent variables.Results: The 2011 TSCS cohort showed higher prevalence for cigarette smoking (30.8% vs 25.2%; p=0.002), alcohol drinking (52.5% vs 24.3%; p< 0.001), exercise habits (52.7% vs 48.0%; p=0.02), and better fruit and vegetable accessibility (Mean=3.91 vs 3.82; p=0.04). The 2021 TSCS cohort reported higher body mass index (Mean=24.20 vs 23.63; p< 0.001), less residency in urban areas (22.4% vs 31.1%; p< 0.001), better jogging accessibility (4.14 vs 4.05; p=0.006), higher generalized trust (2.26 vs 2.17; p=0.001), and greater internet usage (3.43 vs 2.89; p< 0.001). The regression model showed that exercise habits (standardized coefficient=0.20 and 0.10; p< 0.001) and generalized trust (standardized coefficient=0.11 and 0.11; p=0.004 and < 0.001) were consistently associated with health outcomes in both cohorts. Additionally, internet use (standardized coefficient=− 0.07; p=0.026) and alcohol drinking behaviors (standardized coefficient=− 0.07; p=0.0022) were negatively associated with health outcomes in the 2021 cohort.Conclusion: The present study demonstrated the trends and changes over 10 years regarding multiple health-related components among Taiwan residents. The study’s findings provide insight into education promotion programs to reduce unhealthy behaviors as well as enhancing generalized trust building and developing healthy behaviors for Taiwan residents.Keywords: health behavior, health promotion, COVID-19, Taiwan, trust

Hao-Wei Chung,1– 3 Hui-Min Hsieh,4– 7 Chung-Hsiang Lee,1 Yi-Ching Lin,5,8– 10 Yu-Hsiang Tsao,5 Huang-Wei Wu,3 Fu-Chen Kuo,11,12 Chih-Hsing Hung1,3,13– 15 1Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 2Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; 3Department of Pediatrics, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan; 4Department of Public Health, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 6Department of Community Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 7Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Division of Pharmacology and Toxicology, Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 9Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 10Doctoral Degree Program of Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 11Department of Obstetrics & Gynecology, E-Da Hospital, Kaohsiung, Taiwan; 12School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 13Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 14Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 15Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Fu-Chen Kuo, School of Medicine, College of Medicine E-Da Hospital, I-Shou University, No. 1, Yida Road, Yanchao Shiang, Kaohsiung, 824, Taiwan, Tel/Fax +886-7-6150940, Email ed100418@edah.org.tw Chih-Hsing Hung, Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, No. 482, Shanming Road, Siaogang District, Kaohsiung City, 812, Taiwan, Tel +886-7-3121101-6506, Fax +886-7-3213931, Email pedhung@gmail.comPurpose: Both air pollutant exposure and neonatal jaundice (NJ) have known effects on childhood asthma, but a higher total serum bilirubin (TSB) level has been associated with lung protection. This study aimed to assess whether prenatal/postnatal exposure to ambient air pollutants is related to the development of asthma in infants with NJ.Patients and Methods: A nested case–control retrospective study was performed using the data of infants with NJ in the Kaohsiung Medical University Hospital Research Database. Data on average ambient air pollution concentrations within six months, the first year and second year after birth, and in the first, second and third prenatal trimesters were collected. NJ was defined as TSB levels ≥ 2 mg/dl with the diagnosis less than one-month-old. Asthma was defined as a diagnosis with medication use. We constructed conditional logistic regression models to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).Results: Exposure to NO and SO2 at all six time points in the study was significantly associated with an increased risk of preschool asthma in infants with NJ. The overall peak OR (95% CI) of SO2, PM2.5, PM10, NO, NO2, and NOX were 1.277 (1.129– 1.444), 1.057 (1.023– 1.092), 1.035 (1.011– 1.059), 1.272 (1.111– 1.455), 1.168 (1.083– 1.259) and 1.104 (1.051– 1.161), respectively. Fetuses in the first and second trimester were most vulnerable to ambient air pollutant exposure such as SO2 PM2.5, NO, NO2 and NOX during the prenatal period. Exposure to all six ambient air pollutants during the first and second years after birth significantly affected preschool asthma in NJ infants.Conclusion: In different time windows, prenatal and postnatal exposure to SO2, PM2.5, PM10, NO, NO2, and NOX were associated with preschool asthma in NJ infants. The relatively high impact of NO and SO2 exposure in infants with NJ requires further studies and prevention measures.Keywords: 1000 days, air pollution, SO2, neonatal hyperbilirubinemia, asthma

Chang-Hung Kuo,1,2 Mei-Lan Tsai,3 Chung-Hsiang Li,2,4 Hui-Pin Hsiao,4 Mei-Chyn Chao,4 Ming-Sheng Lee,4 Yi-Ching Lin,5– 8 Chih-Hsing Hung3,4,9 1Ta-Kuo Clinic, Kaohsiung, Taiwan; 2Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; 3Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 6Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Ph.D. Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 8Substance and Behavior Addiction Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; 9Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, TaiwanCorrespondence: Chih-Hsing HungDepartment of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, No. 482, Shanming Road, Siaogang District, Kaohsiung, 812, TaiwanTel +886-7-3121101-6506Fax +886-7-3213931Email pedhung@gmail.comPurpose: Asthma causes a substantial morbidity and mortality burden in children and the pathogenesis of childhood asthma is not completely understood. Macrophages are heterogeneous with divergent M1/M2 polarization phenotypes in response to various stimulations during the inflammatory process. We aimed to investigate the pattern of macrophage polarization and its association with severity and exacerbation in asthmatic children.Patients and Methods: Normal and asthmatic children aged 4– 18 years were enrolled for 12 months. Children with asthma were further subgrouped according to their severity and the requirement for hospitalization during exacerbations. Clinical data were obtained from medical records. Peripheral blood samples were collected to analyze macrophage polarization, including M1, M2, and subsets, by flow cytometry.Results: Fifty-one asthmatic cases and 27 normal controls were included in this study. The level of PM-2K+CD14+ but not PM-2K+CD14− was decreased in asthmatic children. The levels of M2a (CCR7−CXCR1+), M2b (CCR7−CD86+), and M2c (CCR7−CCR2+) subsets, but not M1 (CCR7+CD86+), were increased in asthmatic children. The levels of M1 were decreased, but the levels of M2c were increased, in children with moderate asthma compared to those with mild asthma. The levels of PM-2K+CD14+ cells and M1 subsets were decreased, but the M2c subset cells were increased in asthmatic children requiring hospitalization during exacerbations.Conclusion: Macrophage polarization may be involved in the pathogenesis of childhood asthma and is a potential biomarker of childhood asthma disease severity.Keywords: M2 macrophage polarization, asthma severity, asthma exacerbation, childhood asthma hospitalization

Yu-Hung Fang,1 Meng-Jer Hsieh,2,3 Ming-Szu Hung,1,4,5 Yu-Ching Lin,1,3– 5 Liang-Tseng Kuo,5,6 Mong-Liang Lu,7 Bor-Show Tzang,8– 10 Vincent Chin-Hung Chen5,11 1Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; 2Department of Respiratory Therapy, College of Medicine, Chang Gung University, Chiayi, Taiwan; 3Division of Pulmonary Infection and Critical Care Medicine, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; 4Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 5Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Division of Sports Medicine, Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan; 7Department of Psychiatry, Wan Fang Hospital, and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan; 9Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan; 10Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 11Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, TaiwanCorrespondence: Vincent Chin-Hung ChenDepartment of Psychiatry, Chang Gung Memorial Hospital, Chiayi Branch, No. 6, W. Sec., Jiapu Road, Puzi City, Chiayi County 61363, Taiwan, Republic of ChinaTel +886-5-3621000 ext. 2315Email cch1966@gmail.comBackground: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) concentrations were reported to decrease in patients with advanced cancer. However, the clinical significance of DHEA and DHEAS concentrations in patients with NSCLC receiving chemotherapy (CT) has not been sufficiently documented.Objective: To evaluate the correlation between mental health and hormone concentrations on patients with advanced non-small-cell lung cancer (NSCLC).Materials and Methods: The present study was a cross-sectional analysis based on a self-reported psychological investigation. Salivary samples were collected from 22 patients with advanced NSCLC after CT and 17 healthy controls. The concentrations of DHEA, DHEAS, and cortisol were analyzed to investigate their associations with the results of self-reported questionnaires on psychological health.Results: Patients with advanced NSCLC exhibited significantly higher Patient Health Questionnaire (PHQ-9) and Startle, Physiological arousal, Anger, and Numbness-Chinese version (SPAN-C) scores, poorer health conditions, lower sleep quality, and more severe fatigue after CT than did healthy controls, and salivary concentrations of DHEA and DHEAS were significantly lower among patients after CT than among controls. DHEAS concentrations were negatively associated with depression scores (PHQ-9, r = − 0.496, P = 0.019) and fatigue scores (Brief Fatigue Inventory-Taiwan, r = − 0.562, P = 0.006).Conclusion: Patients with advanced NSCLC after CT had lower DHEA and DHEAS concentrations than did controls. Lower DHEAS concentrations were associated with higher fatigue and depression scores.Keywords: cancer-related fatigue, chemotherapy, DHEA, DHEAS, lung cancer

Te-Fu Tsai,1,2 Po-Chun Chen,3,4 Yi-Chia Lin,1,2 Kuang-Yu Chou,1,2 Hung-En Chen,1 Chao-Yen Ho,1,5 Ji-Fan Lin,3 Thomas I-Sheng Hwang1,2,6 1Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 2Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan; 3Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 4Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan; 5Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 6Department of Urology, Taipei Medical University, Taipei, TaiwanCorrespondence: Thomas I-Sheng HwangDivision of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11102, TaiwanTel +886-2-28332211 Ext 2065Fax +886-2-28389404Email thomashwang0828@gmail.comPo-Chun Chen Email blibra1002@gmail.comPurpose: Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells.Materials and Methods: After miconazole treatment, the p62-KEAP1-NRF2 activation was analyzed by qPCR and Western blot. The nuclear translocation indicating NRF2 activation was further confirmed by immunofluorescence. Finally, the ROS production was detected by CM-H2DCFDA staining.Results: We demonstrate in this study that miconazole dramatically increases NRF2 activation in bladder cancer cells, in a dose- and time-dependent manner. Interestingly, levels of expression of p62, a noncanonical pathway that mediates NRF2 activation, appeared to increase in accordance with NRF2. We also investigated levels of the negative regulator kelch-like ECH-associated protein 1 (KEAP1), which is involved in NRF2 activation. As expected, a decrease in KEAP1 expression was found after miconazole exposure. Confirmation of NRF2 nuclear translocation was monitored by immunofluorescence. Miconazole-induced generation of reactive oxygen species (ROS) promoted NRF2 activation. Pretreatment of bladder cancer cells with ROS scavengers abolished NRF2 expression and nuclear translocation, indicating that miconazole activates the noncanonical p62-KEAP1-NRF2 pathway, which is regulated by ROS production.Conclusion: Our study elucidates the mechanisms through which miconazole stimulates NRF2 which may contribute to cancer chemopreventive effects.Keywords: miconazole, NRF2, p62, KEAP1, bladder cancer

Yu-Hung Fang,1 Yao-Hsu Yang,2–5 Meng-Jer Hsieh,6,7 Ming-Szu Hung,8,9 Yu-Ching Lin1,8 1Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 2Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 3Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 4Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei City, Taiwan, R.O.C; 5School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C; 6Department of Respiratory Therapy, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.C; 7Division of Pulmonary Infection and Critical Care Medicine, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Puzi City, Chiayi County, Taiwan, R.O.C; 8Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Puzi City, Chiayi County, Taiwan, R.O.C; 9School of Medicine, College of Medicine, Chang Gung University, Guishan Township, Taoyuan County, Taiwan, R.O.CCorrespondence: Yu-Ching LinDivision of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, No.6, W. Sec., Jiapu Road, Puzi City, Chiayi County 61363, Taiwan, R.O.CTel +886 5 362 1000 Ext 2762Fax +886 5 362 3005Email lin0927@cgmh.org.twPurpose: Concurrent proton pump inhibitor (PPI) use might reduce the plasma concentration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Clinically, the adverse effect of PPIs on patients with non-small cell lung cancer (NSCLC) treated with first-line EGFR TKIs remains controversial. This study was conducted to evaluate whether the combined use of gefitinib with PPIs affected NSCLC outcomes.Patients and methods: We performed a nationwide cohort study of patients newly diagnosed with NSCLC between 1997 and 2013 using the Taiwan Cancer Registry and Taiwan National Health Insurance databases. We identified patients who were treated with first-line EGFR TKIs and analyzed the association between use of PPIs and TKI treatment outcome. We defined the coverage ratio of PPIs as duration of PPI treatment in days divided by duration of TKIs in days. Patients who exhibited an overlap of >20% between PPI and TKI usage days were defined as having a high coverage ratio.Results: A total of 1278 patients were treated with first-line gefitinib, 309 of which took PPIs at the same time and 145 had a high PPI coverage ratio. Patients had similar time to failure regardless of their PPI coverage ratio during gefitinib treatment. However, higher PPI coverage ratio significantly decreased overall survival (OS) compared with that of patients with a lower PPI coverage ratio or no PPI treatment in univariate analysis (median OS, 13.5, 16.7, and 21.8 months, respectively, p

Yi-Chun Lin,1 Shih-Wei Li,2 Shin-Yen Ku,3 Hui-Ting Hsieh,3 Mei-Hui Lin,3 Shu-Yin Chang,3 Wei-Wei Wu,3 Na-Lee Sun,3 Shu-Hsing Cheng,1,4 Chien-Yu Cheng1,51Department of Internal Medicine, Division of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; 3Comprehensive HIV Care Center, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan; 4School of Public Health, Taipei Medical University, Taipei, Taiwan; 5School of Public Health, National Yang-Ming University, Taipei, TaiwanBackground and aims: We aimed to evaluate the efficacy and tolerability of grazoprevir/elbasvir in patients with chronic genotype 1 hepatitis C virus (HCV) and HIV co-infection who experienced peginterferon alfa plus ribavirin (PegIFN/RBV) (clinicaltrials.gov NCT03098121).Methods: This non-randomized, open-label trial study was conducted in Taoyuan General Hospital. HIV-infected patients were screened for HCV antibody since June 1, 2012, and HCV and HIV co-infected patients were tested for HCV RNA. The subjects who experienced PegIFN/RBV were enrolled in the study, and of whom with chronic genotype 1a or 1b received grazoprevir 100 mg and elbasvir 50 mg in a fixed-dose combination tablet once daily with or without ribavirin for 12 to 16 weeks.Results: Of 2,419 HIV-infected patients, 40 patients with chronic genotype 1 HCV and HIV co-infection who failed PegIFN/RBV treatment were enrolled. Sixteen patients had genotype 1a and 24 patients had genotype 1b, with or without cirrhosis. The median age was 42 (41–47) years, and 5 patients (12.5%) were diagnosed with liver cirrhosis (child Pugh score A). The median CD4 count was 504 cells/μL (321–689). All patients (100%) had HIV viral load 10 IU/mL (3.98–7.12). At the end of treatment, all patients (100%, 40/40) had undetectable HCV viral load, and 95.0% (38/40) of patients achieved sustained virologic response at 12 weeks.Conclusion: Grazoprevir/elbasvir was effective in genotype 1 patients co-infected with HIV with or without cirrhosis. This finding is consistent with that of previous trials of this regimen in monoinfected population.Keywords: hepatitis C, grazoprevir and elbasvir, PEGylated interferon plus ribavirin, direct-acting antiviral, HCV genotype 1, HCV/HIV co-infection

Yai-Ping Hsiao,1 Chung-Hsiung Huang,2 Yu-Chin Lin,3 Tong-Rong Jan1 1Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan; 2Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan; 3Department of Medicinal Botanicals and Health Applications, College of Biotechnology & Bioresources, Da-Yeh University, Changhua, Taiwan Background: Medicinal preparations of iron oxide nanoparticles (IONPs) have been used as MRI contrast agents for the diagnosis of hepatic tumors and the assessment of neuroinflammation and blood–brain barrier integrity. However, it remains mostly unclear whether exposure to IONPs affects neuroinflammation under disease conditions. The present study aims to investigate the impact of IONPs on autoimmune-mediated neuroinflammation using a murine model of experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis.Methods: Mice were either left untreated or immunized with myelin oligodendrocyte glycoprotein on day 0 followed by two injections of pertussis toxin for EAE induction. The EAE mice were intravenously administered with a single dose of the carboxydextran-coated IONPs, ferucarbotran (20 mg Fe/kg) and/or saline (as vehicle) on day 18. Symptoms of EAE were daily monitored until the mice were killed on day 30. Tissue sections of the brain and spinal cord were prepared for histopathological examinations. Iron deposition, neuron demyelination and inflammatory cell infiltration were examined using histochemical staining. The infiltration of microglial and T cells, and cytokine expression were examined by immunohistochemical staining and/or reverse transcription polymerase chain reaction (RT-PCR).Results: Iron deposition was detected in both the brain and spinal cord of EAE mice 3 days post-ferucarbotran treatment. The clinical and pathological scores of EAE, percentage of myelin loss and infiltration of inflammatory cells into the spinal cord were significantly deteriorated in EAE mice treated with ferucarbotran. Furthermore, ferucarbotran treatment increased the number of CD3+, Iba-1+, IL-6+, Iba-1+TNF-α+ and CD3+IFN-γ+ cells in the spinal cord of EAE mice.Conclusion: A single exposure to ferucarbotran exacerbated neuroinflammation and disease severity of EAE, which might be attributed to the enhanced activation of microglia and T cells. These results demonstrated that the pro-inflammatory effect of ferucarbotran on the central nervous system is closely associated with the deterioration of autoimmunity. Keywords: experimental autoimmune encephalomyelitis, ferucarbotran, iron oxide nanoparticles, microglia, neuroinflammation, T cell, multiple sclerosis

Jian-Hong Chen,1,2,* Po-Hsin Tsai,1,2,* Yin-Chou Lin,2,3 Chih-Ken Chen,1,2 Ching-Yen Chen1,2 1Department of Psychiatry, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan, Republic of China; 2School of Medicine, Chang Gung University, Taoyuan, Taiwan, Republic of China; 3Department of Rehabilitation, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan, Republic of China *These authors contributed equally to this work Objective: To examine the effect of mindfulness-based training on performance and mental health among a group of elite athletes. Methods: This study aimed to evaluate the effect of mindful sport performance enhancement (MSPE) on mental health, flow state, and competitive state anxiety using a 4-week workshop. We recruited an amateur baseball team (N=21) in Taiwan, and collected information by self-reported questionnaires administered before, immediately after, and at a 4-week follow-up. The primary outcome was to evaluate sports performance by flow state and competitive state anxiety, which included self-confidence, somatic anxiety, and cognitive anxiety. The secondary outcome was to explore whether MSPE intervention can improve anxiety, depression, sleep disturbance, and eating disorders.Result: After the workshop and follow-up 1 month later, we found improvements in flow state (P=0.001; P=0.045), cognitive anxiety in competitive anxiety (P=0.056; P=0.008), global eating disorder (P=0.009; P

Te-Fu Tsai,1,* Ji-Fan Lin,2,* Kuang-Yu Chou,1 Yi-Chia Lin,1 Hung-En Chen,1 Thomas I-Sheng Hwang1,3–5 1Department of Urology, 2Central Laboratory, 3Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, 4Department of Urology, Taipei Medical University, 5Division of Urology, School of Medicine, Fu-Jen Catholic University, Taipei, Taiwan, Republic of China *These authors contributed equally to this work Introduction: miR-99a-5p, known to play an important role in mammalian target of rapamycin (mTOR) regulation, is downregulated in human bladder cancer. The study aimed to investigate the anticancer activity of miR-99a-5p and the possible mechanism associated with mTOR in bladder cancer cells. Materials and methods: Vectors expressing miR-99a-5p were transfected into human urinary bladder urothelial carcinoma (5637 and T24) cells. The level of miR-99a-5p was monitored by microRNA (miRNA) quantitative polymerase chain reaction (QPCR). Luciferase reporter assays were performed to verify the direct binding of miR-99a-5p to mTOR transcripts. The mTOR transcripts and protein levels were measured by QPCR and Western blot, respectively. Cell viability of miR-99a-5p-transfected cells was detected by tetrazolium salt (WST-1). Inhibition of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) signaling was detected by the phosphorylation of mTOR and AKT using Western blot. The ability of miR-99a-5p to enhance RAD001-induced apoptosis was determined as the expression of cleaved caspase 3 and levels of DNA fragmentation. Results: Transfection of miR-99a-5p-expressing vector elevated the expression level of miR-99a-5p up to sixfold compared to vector-only controls. The results from luciferase assay verified that miR-99a-5p directly binds to the predicted sequence in the 3' untranslated region (3'-UTR) of mTOR. The levels of mTOR RNA and protein were decreased in miR-99a-5p-transfected cells. Dual inhibition of mTORC1 and mTORC2 by miR-99a-5p was confirmed by the decreased phosphorylation of mTOR (at Ser2448 and Ser2481), phospho-rpS6 and phospho-4EBP1. The phosphorylation of AKT was significantly inhibited in miR-99a-5p-transfected cells upon RAD001 treatment. Enforced expression of miR-99a-5p potentiated RAD001-induced apoptosis in these cells. Conclusion: This is the first study showing that miR-99a-5p markedly inhibits the growth of bladder cancer cells via dual inhibition of mTORC1 and mTORC2. Our data demonstrated that forced expression of miR-99a-5p inhibits the feedback of AKT survival pathway and enhances the induction of apoptosis in RAD001-treated bladder cancer cells. Keywords: apoptosis, bladder cancer, miR-99a-5p, mTOR, RAD001

Jrhau Lung,1 Kuan-Liang Chen,2 Chien-Hui Hung,3 Chih-Cheng Chen,4,5 Ming-Szu Hung,5–7 Yu-Ching Lin,5–7 Ching-Yuan Wu,8 Kuan-Der Lee,9 Neng-Yao Shih,10 Ying Huang Tsai11,12 1Department of Medical Research and Development, Chang Gung Memorial Hospital, Chiayi, 2Department of Endodontics, ChiMei Medical Center, Tainan, 3Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, 4Division of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, 5Department of Medicine, Chang Gung University, Taoyuan, 6Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, 7Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, 8Department of Chinese Medicine; Chang Gung Memorial Hospital, Chiayi, 9Department of Hematology and Oncology, Taipei Medical University Hospital, Taipei, 10National Institute of Cancer Research, National Health Research Institutes, Tainan, 11Department of Respiratory Care, College of Medicine, Chang Gung University, Taoyuan, 12Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan Abstract: Unlimited growth of cancer cells requires an extensive nutrient supply. To meet this demand, cancer cells drastically upregulate glucose uptake and metabolism compared to normal cells. This difference has made the blocking of glycolysis a fascinating strategy to treat this malignant disease. α-enolase is not only one of the most upregulated glycolytic enzymes in cancer cells, but also associates with many cellular processes or conditions important to cancer cell survival, such as cell migration, invasion, and hypoxia. Targeting α-enolase could simultaneously disturb cancer cells in multiple ways and, therefore, is a good target for anticancer drug development. In the current study, more than 22 million chemical structures meeting the criteria of Lipinski’s rule of five from the ZINC database were docked to α-enolase by virtual screening. Twenty-four chemical structures with docking scores better than that of the enolase substrate, 2-phosphoglycerate, were further screened by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties prediction. Four of them were classified as non-mutagenic, non-carcinogenic, and capable of oral administration where they showed steady interactions to α-enolase that were comparable, even superior, to the currently available inhibitors in molecular dynamics (MD) simulation. These compounds may be considered promising leads for further development of the α-enolase inhibitors and could help fight cancer metabolically. Keywords: α-enolase inhibitor, virtual screening, molecular dynamics simulation, glycolysis, metabolism

Yu-Hung Fang,1 Chien-Chin Hsu,2 Meng-Jer Hsieh,3,4 Ming-Szu Hung,1,5,6 Ying-Huang Tsai,1,3 Yu-Ching Lin1,4–6 1Department of Pulmonary and Critical Care Medicine, Division of Thoracic Oncology, Chang Gung Memorial Hospital, Puzi, 2Department of Nuclear Medicine, Chang Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung, 3Department of Respiratory Therapy, College of Medicine, Chang Gung University, Guishan, 4Department of Pulmonary and Critical Care Medicine, Division of Pulmonary Infection and Critical Care Medicine, Chang Gung Memorial Hospital, 5Department of Respiratory Care, Chang Gung University of Science and Technology, Puzi, 6Department of Medicine, College of Medicine, Chang Gung University, Guishan, Taiwan, Republic of China Purpose: Hypertrophic pulmonary osteoarthropathy (HPOA) is a rare disease that most commonly occurs secondary to lung cancer. However, the clinical significance of HPOA remains unclear. The aim of this study was to evaluate the impact of HPOA on patients with lung cancer in Taiwan.Patients and methods: Data regarding lung cancer patients who demonstrated findings of HPOA on bone scintigraphy between 2010 and 2016 were retrospectively analyzed. Pathological confirmation of cases was conducted at Chiayi and Kaohsiung Chang Gang Memorial Hospital. Clinical characteristics, including gender, smoking status, histology subtype, clinical stage, and epidermal growth factor receptor (EGFR) status were investigated.Results: We identified 69 lung cancer patients with typical HPOA findings on bone scintigraphy. Among them, 56 were male (81.2%) and 51 were ex-smokers or current smokers (73.9%). Adenocarcinoma was the most common histology subtype (n=42, 60.9%). Of 34 patients subjected to EGFR mutation analysis, only 4 (11.8%) had EGFR-tyrosine kinase inhibitor (EGFR-TKI)-sensitive mutations.Conclusion: Male, smoking, and adenocarcinoma were the most common clinical characteristics of lung cancer patients with HPOA in our cohort. However, the proportion of EGFR-TKI-sensitive mutation cases was extremely low. Keywords: EGFR, lung cancer, hypertrophic pulmonary osteoarthropathy, bone scintigraphy

Chencai Wang,1 Chao-Hsiung Hsu,1,2 Zhao Li,1 Lian-Pin Hwang,2 Ying-Chih Lin,2 Pi-Tai Chou,2 Yung-Ya Lin1 1Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA; 2Department of Chemistry, National Taiwan University, Taipei, Taiwan Abstract: Magnetic resonance (MR) nano-theranostic hyperthermia uses magnetic nanoparticles to target and accumulate at the lesions and generate heat to kill lesion cells directly through hyperthermia or indirectly through thermal activation and control releasing of drugs. Preclinical and translational applications of MR nano-theranostic hyperthermia are currently limited by a few major theoretical difficulties and experimental challenges in in vivo conditions. For example, conventional models for estimating the heat generated and the optimal magnetic nanoparticle sizes for hyperthermia do not accurately reproduce reported in vivo experimental results. In this work, a revised cluster-based model was proposed to predict the specific loss power (SLP) by explicitly considering magnetic nanoparticle aggregation in in vivo conditions. By comparing with the reported experimental results of magnetite Fe3O4 and cobalt ferrite CoFe2O4 magnetic nanoparticles, it is shown that the revised cluster-based model provides a more accurate prediction of the experimental values than the conventional models that assume magnetic nanoparticles act as single units. It also provides a clear physical picture: the aggregation of magnetic nanoparticles increases the cluster magnetic anisotropy while reducing both the cluster domain magnetization and the average magnetic moment, which, in turn, shift the predicted SLP toward a smaller magnetic nanoparticle diameter with lower peak values. As a result, the heating efficiency and the SLP values are decreased. The improvement in the prediction accuracy in in vivo conditions is particularly pronounced when the magnetic nanoparticle diameter is in the range of ~10–20 nm. This happens to be an important size range for MR cancer nano-theranostics, as it exhibits the highest efficacy against both primary and metastatic tumors in vivo. Our studies show that a relatively 20%–25% smaller magnetic nanoparticle diameter should be chosen to reach the maximal heating efficiency in comparison with the optimal size predicted by previous models. Keywords: nano-theranostics, hyperthermia, magnetic resonance, magnetic nanoparticle, specific loss power

Ji-Fan Lin,1 Yi-Chia Lin,2 Te-Fu Tsai,2,3 Hung-En Chen,2 Kuang-Yu Chou,2,3 Thomas I-Sheng Hwang2–4 1Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, 2Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, 3Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, 4Department of Urology, Taipei Medical University, Taipei, Taiwan Purpose: Cisplatin-based chemotherapy is the first line treatment for several cancers including bladder cancer (BC). Autophagy induction has been implied to contribute to cisplatin resistance in ovarian cancer; and a high basal level of autophagy has been demonstrated in human bladder tumors. Therefore, it is reasonable to speculate that autophagy may account for the failure of cisplatin single treatment in BC. This study investigated whether cisplatin induces autophagy and the mechanism involved using human BC cell lines.Materials and methods: Human BC cells (5637 and T24) were used in this study. Cell viability was detected using water soluble tetrazolium-8 reagents. Autophagy induction was detected by monitoring the levels of light chain 3 (LC3)-II and p62 by Western blot, LC3-positive puncta formation by immunofluorescence, and direct observation of the autophagolysosome (AL) formation by transmission electron microscopy. Inhibitors including bafilomycin A1 (Baf A1), chloroquine (CQ), and shRNA-based lentivirus against autophagy-related genes (ATG7 and ATG12) were utilized. Apoptosis level was detected by caspase 3/7 activity and DNA fragmentation.Results: Cisplatin decreased cell viability and induced apoptosis of 5637 and T24 cells in a dose- and time-dependent manner. The increased LC3-II accumulation, p62 clearance, the number of LC3-positive puncta, and ALs in cisplatin-treated cells suggested that cisplatin indeed induces autophagy. Inhibition of cisplatin-induced autophagy using Baf A1, CQ, or ATG7/ATG12 shRNAs significantly enhanced cytotoxicity of cisplatin toward BC cells. These results indicated that cisplatin induced protective autophagy which may contribute to the development of cisplatin resistance and resulted in treatment failure. Mechanistically, upregulation of beclin-1 (BECN1) was detected in cisplatin-treated cells, and knockdown of BECN1 using shRNA attenuated cisplatin-induced autophagy and subsequently enhanced cisplatin-induced apoptosis.Conclusion: Collectively, the study results indicated that cisplatin-induced autophagy is mediated by BECN1 in BC cells. Therefore, combinative treatment using cisplatin and autophagy inhibitors could potentially overcome cisplatin resistance related to autophagy induction. Keywords: autophagy inhibition, autophagy related genes, apoptosis, cisplatin resistance, human urinary bladder urothelial carcinoma, lentiviral-based shRNA

Cho-I Lin,1 Yu-Ching Lin,1–3 Wei-Chih Lien,1 Pei-Chun Hsieh,1 Sheng-Han Lin,1 Ta-Shen Kuan1,2 1Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan Introduction: Punding is a complex stereotyped behavior, characterized by excessiveness, non-goal orientation, and repetitiveness. It is mostly associated with Parkinson’s disease, and very few cases in non-Parkinson’s disease have been reported. We report a case of punding associated with supratentorial ischemic stroke.Case presentation: We present a 70-year-old man with left posterior cerebral artery infarction with quetiapine-induced punding manifesting as repetitive unidirectional body turning. Remission of punding behavior ensued after cessation of quetiapine and administration of clonazepam.Conclusion: This case describes the clinical course of quetiapine-induced punding in a patient with left posterior cerebral artery infarction. It suggests clonazepam may serve as a treatment option for poststroke punding. Keywords: punding, stereotyped behavior, stroke, quetiapine, clonazepam

Yueh-Feng Lu,1 Yu-Chin Lin,2 Kuo-Hsin Chen,3,4 Pei-Wei Shueng,1 Hsin-Pei Yeh,1 Chen-Hsi Hsieh1,5,6 1Division of Radiation Oncology, Department of Radiology, 2Division of Oncology and Hematology, Department of Medicine, 3Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, 4Department of Electrical Engineering, Yuan-Ze University, Taoyuan, 5Department of Medicine, 6Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Abstract: Treatment for bilateral breast cancer with chest wall and abdominal skin invasion normally involves conventional radiotherapy (RT); however, conventional RT provides inadequate target volume coverage and excessive treatment of large volumes of normal tissue. Helical tomotherapy (HT) has the ability to deliver continuous craniocaudal irradiation that suppresses junction problems and provides good conformity of dose distribution. A 47-year-old female with stage IV bilateral breast cancer with chest wall and pectoralis major muscle invasion, lymphadenopathy, bilateral pleural effusion, and multiple bone metastases received chemotherapy and target therapy beginning in January 2014; 4 months after the initiation of chemotherapy, computed tomography revealed progression of chest and abdominal wall invasion. A total dose of 70.2 Gy was delivered to both breasts, the chest wall, the abdominal wall, and the bilateral supraclavicular nodal areas in 39 fractions via HT. The total planning target volume was 4,533.29 cm3. The percent of lung volume receiving at least 20 Gy (V20) was 28%, 22%, and 25% for the right lung, left lung, and whole lung, respectively. The mean dose to the heart was 8.6 Gy. Follow-up computed tomography revealed complete response after the RT course. Grade 1 dysphagia, weight loss, grade 2 neutropenia, and grade 3 dermatitis were noted during the RT course. Pain score decreased from 6 to 1. No cardiac, pulmonary, liver, or intestinal toxicity developed during treatment or follow-up. Concurrent HT with or without systemic treatment could be a safe salvage therapy for chemorefractory locally advanced breast cancer patients with extensive cutaneous metastasis. Keywords: bilateral breast cancer, cutaneous metastasis, helical tomotherapy, palliative, toxicity

Ji-Fan Lin,1 Yi-Chia Lin,2,3 Shan-Che Yang,1 Te-Fu Tsai,2,3 Hung-En Chen,2 Kuang-Yu Chou,2,3 Thomas I-Sheng Hwang2–4 1Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 2Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; 3Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; 4Department of Urology, Taipei Medical University, Taipei, Taiwan Background: Mammalian target of rapamycin (mTOR), involved in PI3K/AKT/mTOR pathway, is known to play a central role in regulating the growth of cancer cells. The PI3K/AKT/mTOR pathway enhances tumor survival and proliferation through suppressing autophagy, which sustains energy homeostasis by collecting and recycling cellular components under stress conditions. Conversely, inhibitors of the mTOR pathway such as RAD001 induce autophagy, leading to promotion of tumor survival and limited antitumor efficacy. We thus hypothesized that the use of autophagy inhibitor in combination with mTOR inhibition improves the cytotoxicity of mTOR inhibitors in bladder cancer.Materials and methods: The cytotoxicity of RT4, 5637, HT1376, and T24 human bladder cancer cells treated with RAD001 alone or combined with autophagy inhibitors (3-methyladenine (3-MA), bafilomycin A1 (Baf A1), chloroquine, or hydroxychloroquine) was assessed using the WST-8 cell viability kit. The autophagy status in cells was analyzed by the detection of microtubule-associated light chain 3 form II (LC3-II), using immunofluorescent staining and Western blot. Acidic vesicular organelle (AVO) formation in treated cells was determined by acridine orange vital staining. Inhibition of mTOR pathway by RAD001 was monitored by using a homemade quantitative polymerase chain reaction gene array, while phospho-mTOR was detected using Western blot. Induced apoptosis was determined by measurement of caspase 3/7 activity and DNA fragmentation in cells after treatment.Results: Advanced bladder cancer cells (5637, HT1376, and T24) were more resistant to RAD001 than RT4. Autophagy flux detected by the expression of LC3-II showed RAD001-induced autophagy. AVO formation was detected in cells treated with RAD001 and was inhibited by the addition of 3-MA or Baf A1. Cotreatment of RAD001 with autophagy inhibitors further reduced cell viability and induced apoptosis in bladder cancer cells.Conclusion: Our results indicate that simultaneous inhibition of the mTOR and autophagy pathway significantly enhances apoptosis, and it is suggested to be a new therapeutic paradigm for the treatment of bladder cancer. Keywords: autophagy, apoptosis, bladder cancer, chloroquine, RAD001

Yao-Hong Guo,1 Ta-Shen Kuan,1,2 Pei-Chun Hsieh,1 Wei-Chih Lien,1 Chun-Kai Chang,1 Yu-Ching Lin1–3 1Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan Abstract: Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a newly recognized, potentially fatal, but treatable autoimmune disease. Good outcome predictors include milder severity of symptoms, no need for intensive care unit admission, early aggressive immunotherapy, and prompt tumor removal. We report a case of a young girl aged 3 years 2 months and diagnosed as recalcitrant anti-NMDA receptor encephalitis without any underlying neoplasm. The patient had initial symptoms of behavioral changes that progressed to generalized choreoathetosis and orofacial dyskinesia, which resulted in 6 months of hospitalization in the pediatric intensive care unit. One year after initial onset of the disease, she had only achieved the developmental age of an infant aged 6–8 months in terms of gross and fine motor skills, but she resumed total independence in activities of daily living after receiving extensive immunotherapy and 28 months of rehabilitation. Our brief review will help clinical practitioners become more familiar with this disease and the unique rehabilitation programs. Keywords: anti-NMDA receptor encephalitis, autoimmune encephalitis, rehabilitation, cognition deficits

Chen-Hsi Hsieh,1–3 Pei-Wei Shueng,1,4 Li-Ying Wang,5 Li-Jen Liao,6 Yu-Chin Lin,7 Ying-Shiung Kuo,8 Wu-Chia Lo,6 Chien-Fu Tseng,8 Hui-Ju Tien,1 Hsiu-Ling Chou,9,10 Yen-Ping Hsieh,11 Le-Jung Wu,1 Yu-Jen Chen3,12–14 1Department of Radiation Oncology, Far Eastern Memorial Hospital, 2Department of Medicine, 3Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 4Department of Radiation Oncology, National Defense Medical Center, 5School and Graduate Institute of Physical Therapy, College of Medicine, National Taiwan University, 6Department of Otolaryngology, 7Division of Medical Oncology and Hematology, Department of Internal Medicine, 8Department of Dentistry and Oral Surgery, 9Department of Nursing, Far Eastern Memorial Hospital, 10Department of Nursing, Oriental Institute of Technology, Taipei, 11Department of Senior Citizen Service Management, National Taichung University of Science and Technology, Taichung, 12Department of Radiation Oncology, 13Department of Medical Research, Mackay Memorial Hospital, 14Graduate Institute of Sport Coaching Science, Chinese Culture University, Taipei, Taiwan Background: The outcome of postoperative high- and intermediate-risk oral cavity cancer (OCC) patients receiving helical tomotherapy (HT) remains limited. Materials and methods: Between November 2006 and November 2012, 53 postoperative high- and intermediate-risk OCC patients treated with HT were enrolled. Results: The 4-year locoregional, local, and regional control rates were 66%, 76.4%, and 94.3%, respectively. The 4-year locoregional control rates of oral tongue and buccal mucosa cancer were 88.3% and 37.1%, respectively (P=0.012). Eleven (20.8%) patients experienced locoregional failure. In-field failure occurred in six of 53 (11.3%) in the primary area and three of 53 (5.7%) in the regional lymph-node area. No marginal failure was noted. Two of 53 (3.8%) experienced out-of-field failure. The rates of grade 3 dermatitis, mucositis, and dysphagia were 11%, 34%, and 13%, respectively. No grade 3 xerostomia was noted. Grade 2 xerostomia was 33% at month 6 and declined to 0 at month 48. A rate of 56% of grade 2 trismus at month 6 was noted, and declined to around 30% after 2 years. No grade 3 trismus was noted after 2 years. Conclusion: HT as a postoperative modality provided satisfying results, especially for xerostomia and trismus, and was impressive in high- and intermediate-risk OCC patients receiving postoperative HT. Keywords: concurrent chemoradiation, helical tomotherapy, locoregional control rate, oral cavity cancer, trismus

Yu-Chih Lin,1 Liang-Yi Lin,2 Ming-Yi Gao,3 Yi-Ping Fang31Department of Environmental Engineering and Health, Yuanpei University, 2Institute of Environmental Engineering, National Chiao Tung University, 3Department of Biotechnology, Yuanpei University, Hsinchu, TaiwanAbstract: Mesoporous silica nanoparticles (MSNs) were synthesized as a promising drug delivery carrier due to the large surface area and porous characteristics. Our previous study successfully recycled wastes from the liquid crystal display (LCD) industry as the silica precursor. In this study, we substantiated the possibility of applying this material as a drug carrier. MSNs synthesized from the extraction of wastes from the manufacture of LCD panels were characterized as having an average diameter of 100 nm, a surface area of 788 m2/g, a uniform pore size distribution of 3.8 nm, and a pore volume of up to 1.04 cm3/g. Methotrexate and camptothecin were entrapped in MSNs at about 33.88% and 75.12%, respectively. The cell viability assay demonstrated that MSNs at 1 µg/mL had no significant influence on human lung fibroblast (WI-38) cells or ovarian cancer (ES-2) cells. A lactate dehydrogenase assay also indicated no inflammation occurred. Moreover, a hemolytic erythrocyte test indicated that the dose range of

Pei-Chun Hsieh,1 Shu-Min Chen,1–3 Yao-Hong Guo,1 Ta-Shen Kuan,1,2 Wei-Jang Yen,1 Wen-Chen Chang,1 Yu-Ching Lin1–3 1Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; 2Department of Physical Medicine and Rehabilitation, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; 3Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan, Republic of China Abstract: Dystonia is a rare manifestation of multiple sclerosis (MS), but it always interferes with the functional performance and quality of life. We report a rare case of long-lasting paroxysmal dystonia associated with MS. The patient was a 40-year-old woman with relapsing- remitting MS for 6 years. During the latest attack of MS, she suffered from long-lasting paroxysmal dystonia in her left hand. Despite treatment with pulse high-dose intravenous methylprednisolone, interferon, and baclofen, along with occupational therapy, the dystonia persisted and significantly bothered her daily activities. Finally, she was treated with oral acetazolamide (250 mg, three times a day for 4 days), which was very effective for the control of her dystonia. The dystonic movement subsided without recurrence in a follow-up of 17 months. We advocate this effective and safe treatment for patients with paroxysmal dystonia associated with MS. Keywords: multiple sclerosis, dystonia, acetazolamide, movement disorders, rehabilitation

Nonlinear wave mixing in solids with ultrafast x-rays can provide insight into complex electronic dynamics of materials. Here, tabletop-based attosecond noncollinear four-wave mixing (FWM) spectroscopy using one extreme ultraviolet (XUV) pulse from high harmonic generation and two separately timed few-cycle near-infrared (NIR) pulses characterizes the dynamics of the Na+ L2,3 edge core-excitons in NaCl around 33.5 eV. An inhomogeneous distribution of core-excitons underlying the well-known doublet absorption of the Na+ Γ point core-exciton spectrum is deconvoluted by the resonance-enhanced nonlinear wave mixing spectroscopy. In addition, other dark excitonic states that are coupled to the XUV-allowed levels by the NIR pulses are characterized spectrally and temporally. Approximately

The purpose of this paper is to introduce and study two new hybrid proximal-point algorithms for finding a common element of the set of solutions to a generalized equilibrium problem and the sets of zeros of two maximal monotone operators in a uniformly smooth and uniformly convex Banach space. We established strong and weak convergence theorems for these two modified hybrid proximal-point algorithms, respectively.

This work reports a precise measurement of the reactor antineutrino flux using 2.2 million inverse beta decay (IBD) events collected with the Daya Bay near detectors in 1230 days. The dominant uncertainty on the neutron detection efficiency is reduced by 56% with respect to the previous measurement through a comprehensive neutron calibration and detailed data and simulation analysis. The new average IBD yield is determined to be (5.91±0.09)×10-43 cm2/fission with total uncertainty improved by 29%. The corresponding mean fission fractions from the four main fission isotopes U235, U238, Pu239, and Pu241 are 0.564, 0.076, 0.304, and 0.056, respectively. The ratio of measured to predicted antineutrino yield is found to be 0.952±0.014±0.023 (1.001±0.015±0.027) for the Huber-Mueller (ILL-Vogel) model, where the first and second uncertainty are experimental and theoretical model uncertainty, respectively. This measurement confirms the discrepancy between the world average of reactor antineutrino flux and the Huber-Mueller model.

Scanning tunneling microscopy (STM) at 5 K is used to study WSe2 layers grown on epitaxial graphene which is formed on Si-terminated SiC(0 0 0 1). Specifically, a partial hydrogenation process is applied to intercalate hydrogen at the SiC-graphene interface, yielding areas of quasi-free-standing bilayer graphene coexisting with bare monolayer graphene. We find that an abrupt and structurally perfect homojunction (band-edge offset ∼0.25 eV) is formed when WSe2 overgrows a lateral junction between adjacent monolayer and quasi-free-standing bilayer areas in the graphene. The band structure modulation in the WSe2 overlayer arises from the varying work function (electrostatic potential) of the graphene beneath. Scanning tunneling spectroscopy measurements reveal that this effect can be also utilized to create WSe2 quantum dots that confine either valence or conduction band states, in agreement with first-principles band structure calculations.

A search for a time-varying νe signal was performed with 621 days of data acquired by the Daya Bay Reactor Neutrino Experiment over 704 calendar days. The time spectrum of the measured νe flux normalized to its prediction was analyzed with a Lomb-Scargle periodogram, which yielded no significant signal for periods ranging from 2 hours to nearly 2 years. The normalized time spectrum was also fit for a sidereal modulation under the Standard Model Extension (SME) framework to search for Lorentz and CPT violation (LV-CPTV). Limits were obtained for all six flavor pairs ēμ,ēτ, μτ, ēē,μμ and ττ by fitting them one at a time, constituting the first experimental constraints on the latter three. Daya Bay's high statistics and unique layout of multiple directions from three pairs of reactors to three experimental halls allowed the simultaneous constraint of individual SME LV-CPTV coefficients without assuming others contribute negligibly, a first for a neutrino experiment.

Neutrons produced by cosmic ray muons are an important background for underground experiments studying neutrino oscillations, neutrinoless double beta decay, dark matter, and other rare-event signals. A measurement of the neutron yield in the three different experimental halls of the Daya Bay Reactor Neutrino Experiment at varying depth is reported. The neutron yield in Daya Bay's liquid scintillator is measured to be Yn=(10.26±0.86)×10-5, (10.22±0.87)×10-5, and (17.03±1.22)×10-5 μ-1 g-1 cm2 at depths of 250, 265, and 860 meters-water-equivalent. These results are compared to other measurements and the simulated neutron yield in Fluka and Geant4. A global fit including the Daya Bay measurements yields a power law coefficient of 0.77±0.03 for the dependence of the neutron yield on muon energy.

The Daya Bay Experiment consists of eight identically designed detectors located in three underground experimental halls named as EH1, EH2, EH3, with 250, 265 and 860 meters of water equivalent vertical overburden, respectively. Cosmic muon events have been recorded over a two-year period. The underground muon rate is observed to be positively correlated with the effective atmospheric temperature and to follow a seasonal modulation pattern. The correlation coefficient α, describing how a variation in the muon rate relates to a variation in the effective atmospheric temperature, is found to be αEH1 = 0.362±0.031, αEH2 = 0.433±0.038 and αEH3 = 0.641±0.057 for each experimental hall.

Bonner Spheres have been used widely for the measurement of neutron spectra with neutron energies ranged from thermal up to at least 20 MeV . A Bonner Sphere neutron spectrometer (BSS) was developed by extending a Berthold LB 6411 neutron-dose-rate meter. The BSS consists of a 3He thermal-neutron detector with integrated electronics, a set of eight polyethylene spherical shells and two optional lead shells of various sizes. The response matrix of the BSS was calculated with GEANT4 Monte Carlo simulation. The BSS had a calibration uncertainty of ± 8.6% and a detector background rate of (1.57 ± 0.04) × 10-3 s-1. A spectral unfolding code NSUGA was developed. The NSUGA code utilizes genetic algorithms and has been shown to perform well in the absence of a priori information.

We have measured the muon flux and production rate of muon-induced neutrons at a depth of 611 m water equivalent. Our apparatus comprises three layers of crossed plastic scintillator hodoscopes for tracking the incident cosmic-ray muons and 760 L of a gadolinium-doped liquid scintillator for producing and detecting neutrons. The vertical muon intensity was measured to be Iμ=(5.7±0.6)×10-6 cm-2 s-1 sr-1. The yield of muon-induced neutrons in the liquid scintillator was determined to be Yn=(1.19±0.08(stat)±0.21(syst))×10-4 neutrons/(μ·g·cm-2). A fit to the recently measured neutron yields at different depths gave a mean muon energy dependence of 0.76±0.03 for liquid-scintillator targets.

We developed a highly sensitive, reliable and portable automatic system (H3) to monitor the radon concentration of the underground experimental halls of the Daya Bay Reactor Neutrino Experiment. H3 is able to measure radon concentration with a statistical error less than 10% in a 1-h measurement of dehumidified air (R.H. 5% at 25°C) with radon concentration as low as 50 Bq/m3. This is achieved by using a large radon progeny collection chamber, semiconductor α-particle detector with high energy resolution, improved electronics and software. The integrated radon monitoring system is highly customizable to operate in different run modes at scheduled times and can be controlled remotely to sample radon in ambient air or in water from the water pools where the antineutrino detectors are being housed. The radon monitoring system has been running in the three experimental halls of the Daya Bay Reactor Neutrino Experiment since November 2013.

Background: Creatinine secretion, as quantified by the ratio of creatinine clearance (CrCl) to glomerular filtration rate (GFR), may introduce another source of error when using serum creatinine concentration to estimate GFR. Few studies have examined dete

Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer