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Yen-Hao Chen,1– 4 Wan-Ting Huang,5 Wen-Chin Lee,6 Ching-Mei Chen,5 Fu-Jen Cheng,7 Chia-Te Kung,7 Chin-Chou Wang,8 Liang-Jen Wang,9 Yu-Che Ou,10 Shau-Hsuan Li1 1Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 2School of Medicine, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan; 3School of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan; 4Department of Nursing, School of Nursing, Fooyin University, Kaohsiung, 831, Taiwan; 5Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 6Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Department of Occupational Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 9Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 10Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, TaiwanCorrespondence: Shau-Hsuan Li, Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City, 833, Taiwan, Email lee.a0928@msa.hinet.netBackground: The aim of this study was to investigate the role of phthalate in patients with esophageal squamous cell carcinoma (ESCC).Methods: A total of 116 ESCC patients and 58 controls without any known histories of malignancies were enrolled. All eight urine phthalate metabolites were measured to assess phthalate levels. Clinical and urine phthalate metabolite profiles were compared between subgroups to identify differences, and the effects of phthalates on clinical ESCC outcomes were also examined.Results: The concentrations of some urine phthalate metabolites were higher in the ESCC group than in the control group, including mono-(3-carboxypropyl) phthalate (MCPP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-n-butyl phthalate (MnBP). Higher concentrations of urine phthalate metabolites were associated with clinical T3–T4 status. Patients with higher concentration of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and MEOHP had lower 1-year and 2-year overall survival (OS) rates than those with lower concentrations of these metabolites in our univariate analysis. Multivariate analysis showed that urinary MEHP of ≥ 3 μg/L and clinical stage IVB were independent prognostic factors for worse OS.Conclusion: The results of our study showed that urine phthalate metabolites are elevated in ESCC patients and associated with advanced tumor stage, and that a high urinary concentration of MEHP is an independent prognostic factor of worse OS.Keywords: phthalate, esophageal cancer, squamous cell carcinoma, survival

Kuo-Feng Hua,1,2,* Hsien-Ta Hsu,3,4,* May-Shu Huang,5,6 Hsiao-Wen Chiu,1 Wei-Ting Wong,1 Chien-Hsiu Peng,1 Yu-Bei Lin,1 Ann Chen,7 Chien-Chun Wang,8,9 Chung-Hua Hsu,10,11 Chun-Hsien Wu,12 Wen-Yu Lin,1,12 Chen-Lung Ho,13 Lan-Hui Li14 1Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; 2Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; 3Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 4School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan; 5Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 6Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 7Department of Pathology, Hualien Tzu Chi Hospital, Hualien, Taiwan; 8Infectious Disease Division, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 9Kunming Prevention and Control Center, Taipei City Hospital, Taipei, Taiwan; 10Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan; 11Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 12Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 13Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan; 14Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Lan-Hui Li, Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, 100, Kunming Street, Wanhua District, Taipei City, 108203, Taiwan, Tel +886-2-23703739 # 1438, Fax +886-2-23885259, Email A1525@tpech.gov.twPurpose: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, crucial in infectious and inflammatory diseases by regulating IL-1β, presents a target for disease management. Neisseria gonorrhoeae causes gonorrhea in over 87 million people annually, with previous research revealing NLRP3 inflammasome activation in infected macrophages. No natural products have been reported to counteract this activation. Exploring honokiol, a phenolic compound from Chinese herbal medicine, we investigated its impact on NLRP3 inflammasome activation in N. gonorrhoeae-infected macrophages.Methods: Honokiol’s impact on the protein expression of pro-inflammatory mediators was analyzed using ELISA and Western blotting. The generation of intracellular H2O2 and mitochondrial reactive oxygen species (ROS) was detected through specific fluorescent probes (CM-H2DCFDA and MitoSOX, respectively) and analyzed by flow cytometry. Mitochondrial membrane integrity was assessed using specific fluorescent probes (MitoTracker and DiOC2(3)) and analyzed by flow cytometry. Additionally, the effect of honokiol on the viability of N. gonorrhoeae was examined through an in vitro colony-forming units assay.Results: Honokiol effectively inhibits caspase-1, caspase-11 and GSDMD activation and reduces the extracellular release of IL-1β, NLRP3, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in N. gonorrhoeae-infected macrophages. Detailed investigations have demonstrated that honokiol lowers the production of H2O2 and the phosphorylation of ERK1/2 in N. gonorrhoeae-infected macrophages. Importantly, the phosphorylation of JNK1/2 and p38 and the activation of NF-κB remain unaffected. Moreover, honokiol reduces the N. gonorrhoeae-mediated generation of reactive oxygen species within the mitochondria, preserving their integrity. Additionally, honokiol suppresses the expression of the pro-inflammatory mediator IL-6 and inducible nitric oxide synthase induced by N. gonorrhoeae independently of NLRP3. Impressively, honokiol exhibits in vitro anti-gonococcal activity against N. gonorrhoeae.Conclusion: Honokiol inhibits the NLRP3 inflammasome in N. gonorrhoeae-infected macrophages and holds great promise for further development as an active ingredient in the prevention and treatment of symptoms associated with gonorrhea.Keywords: Neisseria gonorrhoeae, honokiol, NLRP3 inflammasome, mitochondria, bactericiide

Xin-Mei Hu,1,* Can-Can Wang,1,* Yu Xiao,1 Yu Liu,1 Hong-Ri Huang,2 Peng Jiang,1 Ying-Kai Wang,1 Yun-Jin Lin,1 Liang-Cheng Li,3 Zhong-Quan Qi1 1Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Research and Development, Guangxi Taimei Rensheng Biotechnology Co., Ltd, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Quan Qi, Guangxi University, Da-Xue-Dong Road No. 100, Xixiangtang District, Nanning, Guangxi Zhuang Autonomous Region, 530004, People’s Republic of China, Tel +8613806001271, Email yxyyz@gxu.edu.cn Liang-Cheng Li, Xiamen University, No. 4221-115, Rm 355, Xiang’an District, Xiang’an, Xiamen Fujian Province, 361102, People’s Republic of China, Tel +8618359206906, Email lchli2013@xmu.edu.cnPurpose: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future.Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection.Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group.Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.Keywords: exosomes, cynomolgus monkeys, safety, immunotoxicity

Hsiao-Mei Hsu,1 Hsin-I Tsai,2– 4 Wei-Chen Lee,4,5 Chih-Chi Wang,6,7 Ming-Chin Yu,3,4,8 Shi-Ming Lin,4,9 Chun-Yen Lin,4,9 Chi-Huan Wu,4,9 Chao-Wei Lee3– 5 1Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 2Department of Anesthesiology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 3Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan; 4College of Medicine, Chang Gung University, Taoyuan, Taiwan; 5Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 7Division of General Surgery, Department of Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan; 8Department of Surgery, New Taipei Municipal Tu-Cheng Hospital (Built and Operated by Chang Gung Medical Foundation), New Taipei City, Taiwan; 9Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan, TaiwanCorrespondence: Chao-Wei Lee, Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou Medical Center, Guishan, No. 5, Fuxing St., Guishan District, Taoyuan City, 33305, Taiwan, Tel +886-975366192, Email alanchaoweilee@hotmail.comAbstract: Surgical resection remains one of the most effective curative therapies for HCC. However, the majority of patients have advanced unresectable diseases upon presentation. It is of paramount importance to raise the resectability of patients with HCC. The remarkable objective response rate reported by Phase III IMbrave150 trial has led to the concept of “Atezo/Bev followed by curative conversion (ABC conversion)” for initially unresectable HCC. With this revolutionary treatment strategy, the concept of surgical resection for HCC should be amended. The current opinion illustrated three extended surgical concepts, which could be integrated into clinical practice in the era of immune checkpoint inhibitors (ICI).Keywords: hepatocellular carcinoma, liver resection, surgery, immune checkpoint inhibitors, immunotherapy

Yi-Cheng Li,1,2 Yia-Ling Chang,3 Fang-Yih Liaw,2,4 Chih-Chia Wang,2,4 Yaw-Wen Chang2,4 1Department of Family Medicine, Hualien Armed Forces General Hospital, Hualien, Taiwan, Republic of China; 2School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China; 3Department of Nursing, Tri-Service General Hospital Penghu Branch, National Defense Medical Center, Penghu, Taiwan, Republic of China; 4Department of Family and Community Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of ChinaCorrespondence: Yaw-Wen Chang, School of Medicine, National Defense Medical Center, No. 161, Sec. 6, Minquan E. Road, Neihu District, Taipei City, 11490, Taiwan, Republic of China, Email yawwenc@office365.ndmctsgh.edu.twBackground: The Discharge Planning Curriculum (DPC) is a 4-hour course for penultimate-year medical students at a tertiary teaching hospital in Taiwan. The course begins with a 30-minute introduction, followed by the students shadowing discharge planning case managers as they visit patients on the wards. After patient visits, the students engaged in a 1-hour case discussion. Our research assessed the effectiveness of the DPC for medical students.Methods: This mixed methods study recruited medical students participating in family medicine rotations between October 2017 and May 2018. To determine the impact of the DPC, we quantitatively analyzed questionnaire responses to measure changes in self-efficacy, attitude toward discharge planning, and course satisfaction before and after completing the DPC. Additionally, we conducted qualitative focus group interviews to gain insight into the students’ learning experiences and applied thematic analysis to the interview data.Results: Our study found two quantitative results: 1) The DPC significantly improved self-efficacy and attitude toward discharge planning (p < 0.001). 2) The medical students acquired knowledge about home care, assistive device application, long-term care facility referral, home rehabilitation, and home care services, and more than 95% of the students reported being satisfied with the course. In addition, the focus group interviews revealed that medical students learned several aspects of discharge planning through the curriculum, including an understanding of various aspects of discharge planning through the curriculum, the importance of early discharge planning, the roles of doctors and case managers, and the challenges faced in the process.Conclusion: The DPC helped medical students understand different team members’ roles in discharge planning and appreciate the challenges that case managers face in this process. The DPC improved medical students’ attitudes toward discharge planning. The curriculum can be a valuable tool in training future healthcare providers in effective transitional care.Keywords: continuity of patient care, curriculum evaluation, interdisciplinary training, patient discharge, undergraduate medical education

Jade Winjei Hwang,1 Shao Ju Chien,2 Chih-Chi Wang,3 Kuang-Che Kuo,4 Kuo-Shu Tang,5 Yu Lee,1 Yi-Chun Chen,6 Mao-Hung Lo,2 Ing-Kit Lee,6 Seng-Kee Chuah,7 Chien-Te Lee,8 Chia-Te Kung,9 Liang-Jen Wang10 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 2Division of Pediatric Cardiology, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung, 83301, Taiwan; 3Division of General Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 4Division of Pediatric Infection, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan; 5Division of Pediatric Emergency, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan; 6Division of Infectious Disease, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 7Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 8Department of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 9Department of Emergency, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan; 10Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, TaiwanCorrespondence: Liang-Jen Wang, Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, No. 123, Ta-Pei Road, Kaohsiung, Taiwan, Tel +886-7-7317123 Ext 8753, Fax +886-7-7326817, Email wangliangjen@gmail.comBackground: Vaccinating adolescents is a vital strategy to enhance population protection without imposing overly restrictive measures on our daily lives during the COVID-19 pandemic. As teenagers gain more independence, their willingness to get vaccinated may depend on their own understanding of the pandemic, vaccines, and mental well-being, as well as that of their caregivers. Our study aimed to examine how Taiwanese adolescents and their caregivers perceive COVID-19 vaccination and assess their mental health status.Methods: We invited a total of 138 vaccinated adolescents and their caregivers to complete several questionnaires, including the Drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S), Impact of Event Scale (IES), and Chinese Health Questionnaire (CHQ).Results: Among the adolescents, 76.8% considered the BNT162b2 vaccine (Pfizer-BioNTech) as the ideal option for COVID-19 vaccination, while 27.5% of caregivers expressed acceptance of any available vaccine. Adolescents scored higher than caregivers in terms of vaccine value (p< 0.001) and autonomy (p< 0.001), but lower in knowledge (p< 0.001), as assessed by the DrVac-COVID19S subscales. The adolescents’ intention to get vaccinated against COVID-19 (DrVac-COVID19S total score) showed a positive correlation with their perception of the pandemic’s impact (IES scores, r=0.214, p=0.012) and their caregivers’ vaccination intention (r=0.371, p< 0.001). Furthermore, adolescents’ mental health demonstrated a positive association with the mental health of their caregiver (CHQ total scores, r=0.481, p< 0.001).Conclusion: During the COVID-19 outbreak, caregivers have encountered heightened levels of mental stress, and this stress has been found to be positively correlated with the mental stress experienced by adolescents and their intentions regarding vaccination. These findings can serve as crucial references for healthcare providers and governments when formulating vaccination policies for adolescents in the future.Keywords: adolescent, autonomy, caregivers, vaccine, psychosomatic, SARS-Cov-2

Hong-Xia Yu,1,&ast; Guo-Shuai Lin,1,&ast; Ji-Fan Zhang,2 Cong-Cong Wang,1 Xiang-Jun Long,1 Mao-Mao Zhao1 1Department of Infection, Yuhuangding Hospital, Yantai, People’s Republic of China; 2Department of Critical Care Medicine, Liaocheng People’s Hospital, Liaocheng, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Mao-Mao Zhao, Department of Infection, Yuhuangding Hospital, No. 20 of Yuhuangding East Road, Zhifu District, Yantai, People’s Republic of China, Tel +86 13863872227, Fax +86 6240341, Email zhaomm295@126.comObjective: This study was designed to analyze the clinical characteristics, etiological characteristics, drug resistance, and empirical use of antibiotics for community-acquired pyogenic liver abscess (PLA) to provide a basis for rational and effective empirical treatment of PLA in the local area.Methods: The clinical data, etiological characteristics, drug resistance, and empirical anti-infective therapy schemes of 606 patients with PLA were collected and analyzed retrospectively.Results: The included patients were mainly males, with a male-to-female ratio of 1.3:1. The average age of the patients was 60.3 ± 14.1 years. The underlying diseases were diabetes and biliary tract disease, accounting for 38.7% and 22.3%, respectively. The main clinical manifestations were fever (92.9%), abdominal pain (44.7%), and nausea (33.3%). Imaging findings: the proportion of patients with a single lesion was 74.7%, and 67% of the patients had involvement in the right lobe of the liver. The main pathogen was Klebsiella pneumoniae accounted for 74.9% in blood culture and 84.1% in pus culture, mainly extended-spectrum β-lactamase. In 272 strains negative for extended-spectrum β-lactamase (ESBLs), 100% were resistant to ampicillin and less than 50% were sensitive to nitrofurantoin. Only 36 ESBL-positive strains had higher than 80% sensitivity to carbapenems, β-lactamase inhibitor compound, and amikacin. Patients treated with different treatment methods showed significantly different average length of hospital stay (14 [9– 21] vs 13 [8– 18]). Empirical anti-infective therapy: Beta-lactamase complex, carbapenems, cephalosporins, and quinolones were used in 280 (37.6%), 180 (29.7%), 180 (29.7%), and 147 (24.3%) patients, respectively.Conclusion: Patients with community-acquired PLA in this area are mainly males, and the underlying diseases are mainly diabetes and hepatobiliary system disease. The main clinical manifestation is fever, so patients with fever of unknown cause should pay attention to possible liver abscesses. Based on drug sensitivity tests, the empirical use of antibiotics is somewhat unreasonable.Keywords: liver abscess, Klebsiella pneumoniae, epidemiological, community

Chiung-Zuei Chen,1 Chau-Chyun Sheu,2 Shih-Lung Cheng,3,4 Hao-Chien Wang,5 Meng-Chih Lin,6 Wu-Huei Hsu,7 Kang-Yun Lee,8 Diahn-Warng Perng,9 Hen-I Lin,10 Ming-Shian Lin,11 Sheng-Hao Lin,12 Jong-Rung Tsai,13 Chin-Chou Wang,6 Cheng-Yi Wang,10 Tsung-Ming Yang,14 Ching-Lung Liu,15 Tsai-Yu Wang,16 Ching-Hsiung Lin12,17,18 1Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 3Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 4Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, 110, Taiwan; 9Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 10Department of Internal Medicine, Cardinal Tien Hospital, Fu-Jen Catholic University, Taipei, 242, Taiwan; 11Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 600, Taiwan; 12Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 13Division of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan City, Taiwan; 15Division of Chest Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, 104, Taiwan; 16Pulmonary Disease Research Centre, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, TaiwanCorrespondence: Ching-Hsiung LinDivision of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground and Aim: Chronic obstructive pulmonary disease (COPD) is frequently underdiagnosed because of the unavailability of spirometers, especially in resource-limited outpatient settings. This study provides real-world evidence to identify optimal approaches for COPD case finding in outpatient settings.Methods: This retrospective study enrolled individuals who were at risk of COPD (age ≥ 40 years, ≥ 10 pack-years, and ≥ 1 respiratory symptom). Eligible participants were examined using various COPD case-finding tools, namely the COPD Population Screener (COPD-PS) questionnaire, a COPD prediction (PCOPD) model, and a microspirometer, Spirobank Smart; subsequently, the participants underwent confirmatory spirometry. The definition and confirmation of COPD were based on conventional spirometry. Receiver operating characteristic curve (ROC), area under the curve (AUC), and decision curve analyses were conducted, and a clinical impact curve was constructed.Results: In total, 385 participants took part in the study [284 without COPD (73.77%) and 101 with COPD (26.23%)]. The microspirometer exhibited a higher AUC value than did the COPD-PS questionnaire and the PCOPD model. The AUC for microspirometry was 0.908 (95% confidence interval [CI] = 0.87– 0.95), that for the PCOPD model was 0.788 (95% CI = 0.74– 0.84), and that for the COPD-PS questionnaire was 0.726 (95% CI = 0.67– 0.78). Decision and clinical impact curve analyses revealed that a microspirometry-derived FEV1/FVC ratio of < 74% had superior clinical utility to the other measurement tools.Conclusion: The PCOPD model and COPD-PS questionnaire were useful for identifying symptomatic patients likely to have COPD, but microspirometry was more accurate and had higher clinical utility. This study provides real-world evidence to identify optimal practices for COPD case finding; such practices ensure that physicians have convenient access to up-to-date evidence when they encounter a symptomatic patient likely to have COPD.Keywords: COPD, COPD case-finding, PCOPD model, COPD-PS questionnaire, microspirometry, spirometry

Yu Lee,1 Pao-Yen Lin,1 Meng-Chih Lin,2 Chin-Chou Wang,2 Hung-I Lu,3 Yung-Che Chen,2 Mian-Yoon Chong,4 Chi-Fa Hung11Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 3Department of Cardiothoracic Vascular Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung, Kaohsiung, Taiwan; 4Chang Gung Memorial Hospital, Chiayi, and Chang Gung University School of Medicine, Kaohsiung, TaiwanObjective: The aim of this study was to assess morbidity and associated factors in patients with lung cancer (LC).Methods: This study used a cross-sectional design with consecutive sampling. Study subjects were recruited from the LC outpatient clinic and inpatient ward in a medical center from March 2016 to February 2018. Patients with LC were enrolled and assessed using the Mini International Neuropsychiatric Interview, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Brief Fatigue Inventory, Numeric Pain Rating Scale, and the List of Threatening Experiences Questionnaire.Results: One hundred and four patients were included in the study. The most prevalent psychiatric disorder was depressive disorder (25.0%), followed by adjustment disorder (17.3%), alcohol use disorder (3.8%), and insomnia disorder (3.8%). Fifty percent of patients had a psychiatric diagnosis. Using logistic regression analysis, it was found that severity of fatigue (OR=1.77; 95% CI, 1.03–3.03; p

Yun Shan Chen,*,1 Fen Liu,*,1 Yi Hong Luo,1 Yue Fan,1 Fang Gui Xu,1 Pin Li,1 Bei Zhou,1 Xiu Yu Pan,1 Chi Chiu Wang,2–4 Long Cui1,41Department of Obstetrics and Gynaecology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, People’s Republic of China; 2Reproduction and Development Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; 3School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong; 4Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong*These authors contributed equally to this workBackground: The role of endothelin receptor type B (EDNRB) isoform 3 involved in Temozolomide (TMZ)-induced melanoma cell death has not yet been elucidated.Methods: The subcellular localization of EDNRB isoform 3 was determined by confocal and immunoblotting assays. Silencing EDNRB isoform 3 was performed by CRISPR/Cas9. Apoptosis was assessed by annexin V/propium iodide staining and caspases 3/7/9 activity. Mitochondrial membrane potential, reactive oxygen species and mitochondrial Ca2+ were measured by flow cytometry. Apoptosis protein array was applied.Results: Confocal and immunoblot analyses indicate mitochondrial localization of EDNRB isoform 3 and the first N-terminal (1–22) amino acids are sufficient for its mitochondrial targeting. EDNRB isoform 3 depleted A375 cells significantly confers chemoresistance with mitochondrial depolarization, reduced reactive oxygen species, enhanced mitochondrial Ca2+ uptake and decreased caspase 9 activation. Additionally, apoptosis array shows that lack of EDNRB isoform 3 has relatively lower expression of phosphorylation of p53 at S392 and a slightly higher expression of Paraoxonase 2.Conclusion: Our findings raise the possibility of targeting EDNRB isoform 3 as a new therapeutic strategy in combination with TMZ for melanoma treatment.Keywords: melanoma, Temozolomide, mitochondrial targeting sequence, apoptosis, reactive oxygen species

Chien-Chih Wu,1,2 Chih-Hsun Tai,1 Wen-You Liao,2 Chi-Chuan Wang,2 Ching-Hua Kuo,2 Shu-Wen Lin,1,3 Shih-Chi Ku41Department of Pharmacy, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; 2School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; 4Division of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanCorrespondence: Shih-Chi KuDivision of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung Shan S. Road, Taipei, TaiwanTel +886 22 356 2905Fax +886 22 358 2867Email scku1015@gmail.comBackground: Augmented renal clearance (ARC) is common in critically ill patients and could result in subtherapeutic antibiotic concentration. However, data in the Asian population are still lacking. The aim of this study was to explore the incidence and risk factors of ARC and its effect on β-lactam pharmacokinetics/pharmacodynamics (PK/PD) in Asian populations admitted to a medical ICU. In addition, we evaluated the appropriateness of using three estimated glomerular filtration (eGFR) formulas [Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] as screening tools.Methods: We measured 2-, 8-, and 24-hr creatinine clearance (CLCr) and calculated eGFR by using three formulas for each. ARC was defined as CLCr24hr >130 mL/min/1.73 m2. Concentrations at the mid-dosing interval and prior to the next dose were collected if patients received the β-lactam antibiotic of piperacillin/tazobactam, cefepime, and meropenem, to determine the PK/PD index of fT > MIC. Multiple logistic regression analysis was conducted to identify the risk factors for ARC. Pearson correlation coefficient and the Bland and Altman method were applied to assess the accuracy of CLCr2hr, CLCr8hr, and eGFR for predicting ARC.Results: Of 100 patients, 46 (46%) manifested ARC. Younger age (4MIC (33% vs 75%, p MIC (23% vs 69%, p4MIC (3% vs 25%, p

Meng-Jer Hsieh,1,2 Shu-Yi Huang,1 Tsung-Ming Yang,1 Chi-Wei Tao,3 Shih-Lung Cheng,4 Chao-Hsien Lee,5 Ping-Hung Kuo,6 Yao-Kuang Wu,7,8 Ning-Hung Chen,9 Wu-Huei Hsu,10 Jeng-Yuan Hsu,11 Ming-Shian Lin,12 Chin-Chou Wang,13 Yu-Feng Wei,14 Ying-Huang Tsai1,2 1Department of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chang-Gung Medical foundation, Chiayi, Taiwan; 2Department of Respiratory Therapy, School of Medicine, Chang-Gung University, Taoyuan, Taiwan; 3Department of Internal Medicine, Cheng Hsin General Hospital, Taipei, Taiwan; 4Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan; 6Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 7Division of Pulmonary Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 8School of Medicine, Tzu Chi University, Hualien, Taiwan; 9Department of pulmonary and critical care medicine, LinKou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 11Division of Chest Medicine, Taichung Veterans General Hospital, Taiwan; 12Dpartment of Internal Medicine, Ditmanson Medical Foundation, Chia-Yi Cristian Hospital, Chia-Yi, Taiwan; 13Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang-Gung Medical Foundation, Kaohsiung, Taiwan; 14Department of Internal Medicine E-Da Hospital, I-Shou University, Kaohsiung, Taiwan Background: This nationwide study was performed to evaluate the evolution of distributions of patients with COPD according to the 2011 and 2017 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines and to assess the concordance between the prescribed medications and the pharmacological management recommended by the two distinct classification systems in Taiwan.Subjects and methods: Data were retrospectively retrieved from stable COPD patients in 11 participating hospitals across Taiwan. Patients were grouped according to GOLD 2011 and 2017 guidelines respectively. Definitions of undertreatment and overtreatment were based on the pharmacological recommendations in the individual guidelines.Results: A total of 1,053 COPD patients were included. The percentages of patients in GOLD 2011 groups A, B, C and D were 18.4%, 40.6%, 6.7% and 34.2%, respectively. When reclassified according to the GOLD 2017, the percentages of group A and B increased to 23.3% and 63.2%, and groups C and D decreased to 1.9% and 11.6%, respectively. Up to 67% of patients in GOLD 2011 groups C and D were reclassified to GOLD 2017 groups A and B. The pharmacological concordance rate was 60.9% for GOLD 2011 and decreased to 44.9% for GOLD 2017. Overtreatment was found in 29.5% of patients according to GOLD 2011 and the rate increased to 46.1% when classified by the GOLD 2017. The major cause of overtreatment was unnecessary inhaled corticosteroids and the main cause of undertreatment was a lack of maintenance long-acting bronchodilators.Conclusion: The distribution of COPD patients in Taiwan was more uneven with the GOLD 2017 than with the GOLD 2011. A pharmacological discordance to the guidelines was identified. Updated guidelines with reclassification of COPD patients resulted in more discordance between prescribed medications and the guidelines. Physicians should make proper adjustments of the prescriptions according to the updated guidelines to ensure the mostly appropriate treatment for COPD patients. Keywords: chronic obstructive pulmonary disease, GOLD guidelines, inhaled corticosteroids, long-acting bronchodilators

Ming-Kung Wu,1 Li-Wen Hsu,2 Kuang-Tzu Huang,3 Chih-Che Lin,2 Chih-Chi Wang,2 Ting-Lung Lin,2 Wei-Feng Li,2 Shigeru Goto,2 Chao-Long Chen,2 Chien-Chih Chen1 1Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Background: Living donor liver transplantation (LDLT) has been developed as one of gold standard treatments for end-stage liver disease. Mental health is a required selection criterion for adult living liver donors and may influence the quality of life after operation. Patients and methods: A total of 1,210 potential living donor candidates for liver transplantation (LT) underwent psychosocial evaluation that included a semi-structured interview, multi-choice self-reported inventory (Beck Depression Inventory-2nd edition [BDI-II], Beck Anxiety Inventory [BAI]), and the family APGAR (Adaptability, Partnership, Growth, Affection, Resolve) index. The test results were compared by family relationships, and subgroups were classified based on the donation type: 1) parents to children, 2) grown children to parents, 3) siblings to siblings, 4) spouses to spouses, and 5) other relatives to other relatives. Results: The BDI-II (P < 0.001) and BAI differed considerably according to the donation type in potential donor candidates. Compared with other subgroups, parents donating to their children suffered the most severe psychological stress before LDLT and exhibited more depressive (P < 0.001) and anxiety symptoms. However, the stress associated with grown children donating to their parents, siblings, and spouses was not significantly higher than it was for other relatives. Furthermore, a significant negative correlation existed between family APGAR scores and the severity of depression and anxiety (P < 0.001) among potential donor candidates. Conclusion: These results indicate the importance of understanding potential donor candidates’ psychological characteristics before LT. Greater anxiety and depression may be exhibited by parent donors due to the distress from fears of death or illness of the recipients, or their guilty feeling for their child. Additionally, family dysfunction also revealed more depression and anxiety. Such donor candidates should be given more extensive pre-donation counseling for minimizing pre-LDLT psychological stress. Keywords: living donor candidates, psychosocial evaluation, depression, anxiety, family function, family relationship

Chien-Chuan Wang,1,2 Huang-Chi Lin,2,3 Mu-Hong Chen,4,5 Nai-Ying Ko,6,7 Yu-Ping Chang,8 I-Mei Lin,9 Cheng-Fang Yen2,3 1Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; 2Department of Psychiatry, Graduate Institute of Medicine and Department of Psychiatry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 4Division of Child and Adolescent Psychiatry, Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 5Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan; 6Department of Nursing, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 7Nursing Department and Center for Infection Control, National Cheng Kung University Hospital, Tainan, Taiwan; 8School of Nursing, The State University of New York, University at Buffalo, Buffalo, NY, USA; 9Department of Psychology, College of Humanities and Social Science, Kaohsiung Medical University, Kaohsiung, Taiwan Objective: This study examined the differences in the current levels of depression, anxiety, and physical pain in emerging adulthood among gay and bisexual men with various experiences of traditional and cyber homophobic bullying based on gender role nonconformity and sexual orientation and the moderating effects of family and peer support.Methods: A total of 500 gay or bisexual men (age 20–25 years) in Taiwan were recruited from August 2015 to July 2017. The levels of depression, anxiety, and physical pain among gay or bisexual men who had experienced both traditional and cyber homophobic bullying (n=109), only traditional or cyber bullying (n=173), and neither traditional nor cyber bullying during childhood (n=218) were compared. The moderating effects of family and peer support on the effects of homophobic bullying victimization on depression, anxiety, and physical pain were also examined.Results: Victims of any type of homophobic bullying in childhood had more severe depression, anxiety, and physical pain in emerging adulthood than nonvictims. Victims of both traditional and cyber homophobic bullying had more severe anxiety in adulthood than victims of only traditional or cyber homophobic bullying. Family but not peer support in childhood moderated the effects of homophobic bullying victimization on current levels of anxiety and physical pain in emerging adulthood among gay and bisexual men.Conclusion: The results of the present study support that early prevention and intervention for homophobic bullying and enhancement of family support are essential to reduce mental health problems in emergent adults among gay and bisexual men. Keywords: sexual minority, homophobia, harassment, gender role nonconformity, sexual orientation

Jiayang He,1 Ping Fang,2 Xiang Zheng,2 Chenchen Wang,2 Tenghui Liu,2 Bowen Zhang,2 Jian Wen,2 Ren-ai Xu3 1Department of Pharmacy, The First Hospital of Jiaxing, Jiaxing, Zhejiang, China; 2Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, Zhejiang, China; 3Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China Aim: The aim of this study was to study the effect of celecoxib on agomelatine metabolism in vitro and in vivo. Methods: Ten healthy male Sprague–Dawley rats were randomly divided into 2 groups: Group A (control group) and Group B (30 mg/kg celecoxib). Then a single dose of 20 mg/kg agomelatine was administered orally 30 min after administration of celecoxib. In an in vitro study, celecoxib with a series of concentrations was added to an incubation mixture containing recombinant human CYP2C9, human or rat liver microsomes to determine the half-maximal inhibitory concentration on the metabolism of agomelatine. Moreover, a mechanism study was performed to determine the inhibitory effect of celecoxib on CYP2C9. Results: The results showed that a single dose of 30 mg/kg celecoxib significantly increased the area under the concentration-time curve and maximum concentration of agomelatine. In addition, celecoxib inhibited the metabolism of agomelatine in the in vitro studies, which was determined to be by a competitive mechanism on CYP2C9. Those results indicated that celecoxib has an inhibitory effect on the metabolism of agomelatine both in vivo and in vitro. Conclusion: Thus, more attention should be paid when celecoxib is administered combined with agomelatine. Keywords: agomelatine, liver microsomes, pharmacokinetics, celecoxib, CYP2C9

Kelsey Lipman,1 Chenchao Wang,2–4 Kang Ting,2 Chia Soo,4 Zhong Zheng2 1David Geffen School of Medicine, 2Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA; 3First Hospital of China Medical University, Shenyang, China; 4Division of Plastic and Reconstructive Surgery, Department of Orthopaedic Surgery, Orthopaedic Hospital Research Center, University of California, Los Angeles, CA, USA Abstract: Both acute and chronic tendinopathy result in high morbidity, requiring management that is often lengthy and expensive. However, limited and conflicting scientific evidence surrounding current management options has presented a challenge when trying to identify the best treatment for tendinopathy. As a result of shortcomings of current treatments, response to available therapies is often poor, resulting in frustration in both patients and physicians. Due to a lack of understanding of basic tendon-cell biology, further scientific investigation is needed in the field for the development of biological solutions. Optimization of new delivery systems and therapies that spatially and temporally mimic normal tendon physiology hold promise for clinical application. This review focuses on the clinical importance of tendinopathy, the structure of healthy tendons, tendon injury, and healing, and a discussion of current approaches for treatment that highlight the need for the development of new nonsurgical interventions. Keywords: tendinopathy, tendon injury, tendon repair, healing

Ching-Chi Yen,1 Yi-Chen Chen,1 Ming-Tsang Wu,2 Chia-Chi Wang,1,3 Yu-Tse Wu1,4 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 2Chinese Medicine Department, Ditmanson Medical Foundation, Chiayi Christian Hospital, Chiayi City, Taiwan; 3PhD Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Background: Andrographolide (AG), a compound with low water solubility, possesses various pharmacological activities, particularly anti-inflammatory activity. However, its low oral bioavailability is a major obstacle to its potential use. This study developed and optimized an AG-loaded nanoemulsion (AG-NE) formulation to improve AG oral bioavailability and its protective effects against inflammatory bowel disease. Methods: A high-pressure homogenization technique was used to prepare the AG-NE and solubility, viscosity, and droplet size tests were conducted to develop the optimized AG-NE composed of α-tocopherol, ethanol, Cremophor EL, and water. The permeability was assessed using everted rat gut sac method and in vivo absorption and anti-inflammatory effect in rats was also evaluated. The plasma concentration of AG was determined using our validated high performance liquid chromatography method, which was used to generate a linear calibration curve over the concentration range of 0.1–25 µg/mL in rat plasma (R2>0.999).Results: The optimized AG-NE had a droplet size of 122±11 nm confirmed using transmission electron microscopy and a viscosity of 28 centipoise (cps). It was stable at 4 and 25°C for 90 days. An ex vitro intestinal permeability study indicated that the jejunum was the optimal site for AG absorption from the optimized AG-NE, which was 8.21 and 1.40 times higher than that from an AG suspension and AG ethanol solution, respectively. The pharmacokinetic results indicate that the absorption of AG from AG-NE was significantly enhanced in comparison with that from the AG suspension, with a relative bioavailability of 594.3%. Moreover, the ulcer index and histological damage score of mice with indomethacin-induced intestinal lesions were significantly reduced by AG-NE pretreatment. Conclusion: We conclude that the developed AG-NE not only enhanced the oral bioavailability of AG in this study but may also prove to be an effective formulation of AG for preventing gastrointestinal inflammatory disorders. Keywords: andrographolide, nanoemulsion, intestinal permeability, oral bioavailability

Yu-Feng Wei,1,2 Ying-Huang Tsai,3 Chin-Chou Wang,4 Ping-Hung Kuo5 On behalf of the TOLD Study Group 1Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, 2Institute of Biotechnology and Chemical Engineering, I-Shou University, Kaohsiung, 3Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, 4Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China Purpose: A low body mass index (BMI) is a poor prognostic marker of acute exacerbations and mortality in patients with COPD. However, the impact of overweight and obesity on COPD-related outcomes is uncertain. The aim of this study was to examine whether a high BMI is associated with the frequent exacerbator phenotype (≥2/year) in Taiwanese patients with COPD. Patients and methods: Data were obtained from the Taiwan Obstructive Lung Disease study, a retrospective, observational nationwide survey of COPD patients conducted at 12 hospitals in Taiwan. Multivariate logistic regression models were used to explore the association between BMI and other factors with the frequency of COPD exacerbations in these patients. Results: Among the whole study cohort (n=1,096), 735 (67.1%) had no exacerbations and 148 (13.5%) were frequent exacerbators in the previous year. The BMI values of the patients with 0, 1, and ≥2 exacerbations were 23.6, 23.5, and 22.6 kg/m2, respectively. In all, 256 (23.4%) and 196 (17.9%) patients were overweight (27 kg/m2 > BMI ≥24 kg/m2) and obese (BMI ≥27 kg/m2), respectively. Even after adjusting for multiple factors, overweight and obesity were associated with the frequency of exacerbations (odds ratio [95% confidence interval] 0.49 [0.28–0.87, P=0.015] and 0.49 [0.26–0.94, P=0.033], respectively). Conclusion: Our results suggest that overweight and obesity are associated with a lower frequency of COPD exacerbations in Taiwan. Keywords: acute exacerbation, COPD, obesity, overweight

Liang-Wen Hang,1,2 Jeng-Yuan Hsu,3 Chee-Jen Chang,4 Hao-Chien Wang,5,6 Shih-Lung Cheng,7,8 Ching-Hsiung Lin,9 Ming-Cheng Chan,3 Chin-Chou Wang,10 Diahn-Warng Perng,11 Chong-Jen Yu5,6 On behalf of the Taiwan COPD Consortium 1Department of Respiratory Therapy, College of Health Care, China Medical University, 2Sleep Medicine Center, Department of Pulmonary and Critical Care Medicine, China Medical University Hospital, 3Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 4Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou Branch, Guishan Township, Taoyuan County, 5Department of Internal Medicine, National Taiwan University Hospital, 6Department of Internal Medicine, National Taiwan University, College of Medicine, Taipei, 7Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, 8Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li City, Taoyuan County, 9Division of Chest Medicine, Changhua Christian Hospital, Changhua City, Changhua County, 10Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 11Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China Background and objectives: COPD and obstructive sleep apnea (OSA) share similar pathological processes and cardiovascular sequelae. Coexisting OSA in COPD – “overlap syndrome” – has worse prognosis than either condition alone, and appropriate treatment improves survival. Our objectives were to ascertain the frequency at which COPD coexists with the risk of OSA in Taiwan and to compare the risk factors, COPD symptoms, and life quality metrics between COPD subgroups with versus without risk of OSA. Methods: We conducted a random cross-sectional national telephone survey of adults >40 years old in Taiwan. Participants fulfilling an epidemiological case definition of COPD completed a questionnaire to assess COPD symptoms and OSA risk, comorbidities, and performance of daily activities. Data from COPD cohorts with and without risk of OSA were analyzed and compared. Results: Of 6,600 interviews completed, 404 subjects fit the epidemiological case definition of COPD – an overall prevalence of 6.1% in this national sample. Data on OSA risk were available for 292 of this COPD cohort, of whom 29.5% were at risk of OSA. Compared to those without risk of OSA, those with risk of OSA were significantly more likely to have hypertension or cardiovascular disease and diabetes, had significantly higher body mass index and COPD Assessment Test scores, and reported impaired work performance and leisure activities. Conclusion: Among adults in Taiwan who fulfill epidemiologic criteria for COPD, 29.5% have coexisting risk of OSA. Comorbid hypertension or cardiovascular disease and diabetes are common and significantly more prevalent among the COPD population at risk of OSA than those who are not. OSA screening is warranted in patients with COPD with those risk factors that are more prevalent in COPD with risk of OSA than without, to target early interventions to reduce adverse cardiovascular sequelae from overlap syndrome. Keywords: cardiovascular risk, COPD, coexistent, obstructive sleep apnea, OSA, overlap syndrome

Guan-Cheng Huang,1–3 Shih-Yu Chen,4 Po-Wei Tsai,5 Jerome G Ganzon,5 Chia-Jung Lee,6 Her-Shyong Shiah,7 Ching-Chiung Wang4,5 1School of Medicine, College of Medicine, Taipei Medical University, Taipei, 2Division of Hematology and Oncology, Department of Internal Medicine, Yuan’s General Hospital, 3Department of Leisure and Recreation Industry Management, College of Humanities and Management, Fooyin University, Kaohsiung, 4Graduate Institute of Pharmacognosy, College of Pharmacy, 5School of Pharmacy, College of Pharmacy, 6PhD Program for Clinical Drug Discovery of Chinese Herbal Medicine, College of Pharmacy, Taipei Medical University, 7Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan Abstract: Dang-Gui-Bu-Xue-Tang (DBT), a combination of Angelicae Sinensis Radix and Astragali Radix, is a widely used herbal decoction in traditional Chinese medicine primarily to promote or invigorate the “blood”. In this study, we explored this ancient formulation and provide evidence of its blood-toning properties. We used the improvement iron uptake as promote or invigorate the “blood” indicator. Ferritin formation of Caco-2 cells in vitro assay and diet-induced anemia (DIA) in rat model were used to prove its improvement iron uptake and ameliorating effects. Finally, the iron–DBT interactions were measured by iron-bind­ing assay. We first demonstrated DBT increased uptake of ferrous iron through the biosynthesis of ferritin by Caco-2 cells and determined which complementary treatment would provide optimum results. Thereafter, effects of the treatment on improving the bioavailability of absorbed iron in the form of hemoglobin (Hb) were established using a DIA-animal model. The results showed that DBT slightly improved Hb levels compared with the baseline Hb and pretreatment with DBT for 2 hours prior to supplementation with ferrous sulfate provided the greatest gain in Hb levels in DIA rats. However, DBT and ferrous sulfate were co-treated with Caco-2 cell or DIA rats, the ferritin formation and Hb levels both were decreased. In iron-bind­ing assay, the DBT extract influenced the free Fe(II) type in the FeSO4 solution. Therefore, we suggest that complementary treatment with DBT and iron supplementation can have a strong ameliorating effect on iron-deficiency anemia in clinical settings, but needs a 2-hour interval of DBT administration prior to ferrous sulfate treatment. Keywords: Dang-Gui-Bu-Xue-Tang, ferulic acid, iron uptake, ferritin, iron-deficiency anemia, herb–drug interaction

Shih-Lung Cheng,1,2 Ming-Cheng Chan,3 Chin-Chou Wang,4 Ching-Hsiung Lin,5 Hao-Chien Wang,6 Jeng-Yuan Hsu,3 Liang-Wen Hang,7,8 Chee-Jen Chang,9 Diahn-Warng Perng,10,* Chong-Jen Yu6,* On behalf of the Taiwan COPD Consortium 1Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, 2Department of Chemical Engineering and Materials Science, Yuan Ze University, Chung-Li City, Taoyuan County, 3Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 4Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 5Division of Chest Medicine, Changhua Christian Hospital, Changhua City, Changhua County, 6Department of Internal Medicine, National Taiwan University Hospital, Taipei, 7Department of Pulmonary and Critical Care Medicine, Sleep Medicine Center, China Medical University Hospital, 8Department of Respiratory Therapy, College of Health Care, China Medical University, Taichung, 9Biostatistical Center for Clinical Research, Chang Gung Memorial Hospital, Linkou Branch, Guishan Township, Taoyuan County, 10Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China *These authors contributed equally to this work Objectives: To determine the prevalence of COPD in Taiwan and to document the disease characteristics and associated risk factors.Methods: We conducted a random cross-sectional national survey of adults older than 40 years in Taiwan. Respiratory health screening questions identified subjects with diagnosed COPD or whose reported symptoms also fulfilled an epidemiological case definition; these were eligible to complete the survey, which also included indices of symptom severity and disability and questions on comorbidities, medical treatments, smoking habits, and occupations potentially harmful to respiratory health. Subjects with diagnosed COPD were subdivided by smoking status. Subjects who fulfilled the case definition of COPD and smoked were designated as “possible COPD”. Participants who did not fit the case definition of COPD were asked only about their personal circumstances and smoking habits. Data from these groups were analyzed and compared.Results: Of the 6,600 participants who completed the survey, 404 (6.1%) fulfilled the epidemiological case definition of COPD: 137 with diagnosed COPD and 267 possible COPD. The most common comorbidities of COPD were hypertension or cardiovascular diseases (36.1%). Subjects with definite COPD had significantly higher COPD Assessment Test scores than the possible COPD group (14.6±8.32 vs 12.6±6.49, P=0.01) and significantly more comorbid illnesses (P=0.01). The main risk factors contributing to health care utilization in each COPD cohort were higher COPD Assessment Test scores (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.04–1.26), higher modified Medical Research Council Breathlessness Scale scores (OR 1.97, 95% CI 1.11–3.51), and having more than one comorbidity (OR 5.19, 95% CI 1.05–25.61).Conclusion: With estimated prevalence of 6.1% in the general population, COPD in Taiwan has been underdiagnosed. Symptoms and comorbidities were independent risk factors for health care utilization in subjects with definite or possible COPD. There is an urgent need to raise awareness of the importance of early evaluation and prompt treatment for subjects with chronic airway symptoms. Keywords: Asia, COPD, epidemiology, health care utilization, risk factors

Wan-Chun Huang,1 Ying-Huang Tsai,2 Yu-Feng Wei,3 Ping-Hung Kuo,4 Chi-Wei Tao,5 Shih-Lung Cheng,6 Chao-Hsien Lee,7 Yao-Kuang Wu,8 Ning-Hung Chen,9 Wu-Huei Hsu,10 Jeng-Yuan Hsu,11 Chin-Chou Wang,12 Ming-Shian Lin1,131Division of Pulmonary Medicine, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, 2Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, 3Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, 4Department of Internal Medicine, National Taiwan University Hospital, 5Department of Internal Medicine, Cheng-Hsin General Hospital, 6Division of Thoracic Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, 7Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, 8Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Taipei, 9Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou, 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, 11Division of Chest Medicine, Taichung Veterans Genera Hospital, Taichung, 12Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 13Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan, Republic of ChinaBackground: COPD is an important public health challenge with significant heterogeneity of clinical presentation and disease progression. Clinicians have been trying to find phenotypes that may be linked to distinct prognoses and different therapeutic choices. Not all patients with COPD present with wheezing, a possible clinical phenotype that can help differentiate patient subgroups.Methods: The Taiwan Obstructive Lung Disease study was a retrospective, multicenter research study to investigate the treatment patterns of COPD after the implementation of the Global Initiative for Chronic Obstructive Lung Disease 2011 guidelines. Between November 2012 and August 2013, medical records were retrieved from patients with COPD aged ≥40 years; patients diagnosed with asthma were excluded. Demographic data, lung function, symptom scores, and acute exacerbation were recorded and analyzed, and the differences between patients with and without wheezing were evaluated.Results: Of the 1,096 patients with COPD, 424 (38.7%) had the wheezing phenotype. The wheezing group had significantly higher COPD Assessment Test scores (12.4±7.8 versus 10.5±6.7, P

Ming-De Chen,1,2 Hsien-Yu Tsai,1 Chih-Chung Wang,3 Yee-Pay Wuang1,4 1Department of Occupational Therapy, Kaohsiung Medical University, 2Department of Rehabilitation, Kaohsiung Municipal Ta-Tung Hospital, 3Department of Rehabilitation Medicine, 4Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Background: This study aimed to investigate the effects of table tennis training (TTT) versus standard occupational therapy (SOT) on visual perception and executive functions in school-age children with mild intellectual disabilities and borderline intellectual functioning. Subjects and methods: Children (n=91) were randomly assigned to intervention with either SOT (n=46, 20 females, mean age =10.9±3.9 years) or TTT (n=45, 21 females, mean age =10.6±3.6 years), while another 41 (18 females, mean age =10.7±4.0 years) served as controls. Both the SOT and TTT programs were administered 60 minutes per session, three times a week, for 16 weeks. The Test of Visual Perceptual Skill–third edition (TVPS-3) was used to evaluate visual perception, and executive functions were assessed by the Wisconsin Card Sorting Test 64-card version (WCST-64) and the Stroop test. Results: At postintervention, the two intervention groups significantly outperformed the control group on all measures of visual perception and executive functions. Participants in the TTT group had significantly greater before–after changes on all measures of the TVPS-3, WCST-64, and the Stroop test compared to the SOT and controls. Conclusion: Table tennis could be considered a therapy option while treating cognitive/perceptual problems in children with mild intellectual disabilities and borderline intellectual functioning. Implications for clinical professionals and recommendations for further research are discussed. Keywords: visual perception, executive function, table tennis, intellectual disabilities

Yu-Feng Wei,1 Ping-Hung Kuo,2 Ying-Huang Tsai,3 Chi-Wei Tao,4 Shih-Lung Cheng,5,13 Chao-Hsien Lee,6 Yao-Kuang Wu,7 Ning-Hung Chen,8 Wu-Huei Hsu,9 Jeng-Yuan Hsu,10 Ming-Shian Lin,11 Chin-Chou Wang12 1Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan; 2Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Internal Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan; 4Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan; 5Division of Thoracic Medicine, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 7Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Taipei, Taiwan; 8Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan; 9Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University and China Medical University Hospital, Taichung, Taiwan; 10Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 11Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, Chiayi, Taiwan; 12Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 13Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan Background and objective: The overprescription of inhaled corticosteroids (ICS) in the current Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A and B patients with chronic obstructive pulmonary disease (COPD) is not uncommon in clinical practice. The aim of this study was to explore the factors associated with the use of ICS in these patients. Methods: The Taiwan obstructive lung disease (TOLD) study was a retrospective, observational nationwide survey of COPD patients conducted at 12 hospitals (n=1,096) in Taiwan. Multivariate logistic regression models were used to explore the predictors of ICS prescription in GOLD group A and B patients. Results: Among the group A (n=179) and group B (n=398) patients, 198 (34.3%) were prescribed ICS (30.2% in group A and 36.2% in group B, respectively). The wheezing phenotype was present in 28.5% of group A and 34.2% of group B patients. Wheezing was the most significant factor for an ICS prescription in group A (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.14–4.75; P=0.020), group B (OR, 1.93; 95% CI, 1.24–2.99; P=0.004), and overall (OR, 2.04; 95% CI, 1.40–2.96; P

Tih-Shih Lee,1 Shin Yi Quek,1 Siau Juinn Alexa Goh,1 Rachel Phillips,2 Cuntai Guan,3 Yin Bun Cheung,4 Lei Feng,5 Chuan Chu Wang,3 Zheng Yang Chin,3 Haihong Zhang,3 Jimmy Lee,6 Tze Pin Ng,5 K Ranga Rama Krishnan1 1Department of Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore; 2Singapore Clinical Research Institute, Singapore; 3Institute for Infocomm Research, Agency for Science, Technology and Research, Singapore; 4Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore; 5Department of Psychological Medicine, National University of Singapore, Singapore; 6Department of General Psychiatry/Department of Research, Institute of Mental Health, Singapore Background: There is growing evidence that cognitive training (CT) can improve the cognitive functioning of the elderly. CT may be influenced by cultural and linguistic factors, but research examining CT programs has mostly been conducted on Western populations. We have developed an innovative electroencephalography (EEG)-based brain–computer interface (BCI) CT program that has shown preliminary efficacy in improving cognition in 32 healthy English-speaking elderly adults in Singapore. In this second pilot trial, we examine the acceptability, safety, and preliminary efficacy of our BCI CT program in healthy Chinese-speaking Singaporean elderly.Methods: Thirty-nine elderly participants were randomized into intervention (n=21) and waitlist control (n=18) arms. Intervention consisted of 24 half-hour sessions with our BCI-based CT training system to be completed in 8 weeks; the control arm received the same intervention after an initial 8-week waiting period. At the end of the training, a usability and acceptability questionnaire was administered. Efficacy was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which was translated and culturally adapted for the Chinese-speaking local population. Users were asked about any adverse events experienced after each session as a safety measure.Results: The training was deemed easily usable and acceptable by senior users. The median difference in the change scores pre- and post-training of the modified RBANS total score was 8.0 (95% confidence interval [CI]: 0.0–16.0, P=0.042) higher in the intervention arm than waitlist control, while the mean difference was 9.0 (95% CI: 1.7–16.2, P=0.017). Ten (30.3%) participants reported a total of 16 adverse events – all of which were graded “mild” except for one graded “moderate”.Conclusion: Our BCI training system shows potential in improving cognition in both English- and Chinese-speaking elderly, and deserves further evaluation in a Phase III trial. Overall, participants responded positively on the usability and acceptability questionnaire. Keywords: cognitive training, neuro-feedback, memory, attention

Chien-Chang Shen,1,* Hong-Jen Liang,2,* Chia-Chi Wang,3 Mei-Hsiu Liao,4 Tong-Rong Jan11Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, 2Innovation and Incubation Center, Yuanpei University, Hsinchu, 3School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 4Division of Isotope Application, Institute of Energy Research, Taoyuan, Taiwan*These authors contributed equally to this workBackground: It was recently reported that iron oxide nanoparticles attenuated antigen-specific humoral responses and T cell cytokine expression in ovalbumin-sensitized mice. It is presently unclear whether iron oxide nanoparticles influence T helper 1 cell-mediated immunity. The present study aimed to investigate the effect of iron oxide nanoparticles on delayed-type hypersensitivity (DTH), whose pathophysiology requires the participation of T helper 1 cells and macrophages.Methods: DTH was elicited by a subcutaneous challenge with ovalbumin to the footpads of mice sensitized with ovalbumin. Iron oxide nanoparticles (0.2–10 mg iron/kg) were administered intravenously 1 hour prior to ovalbumin sensitization. Local inflammatory responses were examined by footpad swelling and histological analysis. The expression of cytokines by splenocytes was measured by enzyme-linked immunosorbent assay.Results: Administration of iron oxide nanoparticles, in a dose-dependent fashion, significantly attenuated inflammatory reactions associated with DTH, including the footpad swelling, the infiltration of T cells and macrophages, and the expression of interferon-γ, interleukin-6, and tumor necrosis factor-α in the inflammatory site. Iron oxide nanoparticles also demonstrated a suppressive effect on ovalbumin-stimulated production of interferon-γ by splenocytes and the phagocytic activity of splenic CD11b+ cells.Conclusion: These results demonstrated that a single dose of iron oxide nanoparticles attenuated DTH reactions by suppressing the infiltration and functional activity of T helper 1 cells and macrophages in response to antigen stimulation.Keywords: iron oxide nanoparticle, T cell, macrophage, delayed-type hypersensitivity

Chien-Chang Shen1, Hong-Jen Liang2, Chia-Chi Wang3, Mei-Hsiu Liao4, Tong-Rong Jan1 1Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, 2Innovation and Incubation Center, Yuanpei University, Hsinchu, 3School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 4Division of Isotope Application, Institute of Energy Research, Taoyuan, Taiwan Background: Accumulating evidence indicates that iron oxide nanoparticles modulate immune responses, and induce oxidative stress in macrophages. It was recently reported that iron oxide nanoparticles attenuated antigen-specific immunity in vivo, though the underlying mechanism remains elusive. The present study investigates the direct effect of iron oxide nanoparticles on antigen-specific cytokine expression by T cells, and potential underlying mechanisms. Methods: Ovalbumin-primed splenocytes were exposed to iron oxide nanoparticles, followed by restimulation with ovalbumin. Cell viability, cytokine production, and cellular levels of glutathione and reactive oxygen species were measured. Results: The splenocyte viability and the production of interleukin-2 and interleukin-4 were unaffected, whereas interferon-γ production was markedly attenuated by iron oxide nanoparticles (10–100 µg iron/mL) in a concentration-dependent manner. Iron oxide nanoparticles also transiently diminished the intracellular level of glutathione, with a peak response at 6 hours posttreatment. The effects of iron oxide nanoparticles on interferon-γ and glutathione were attenuated by the presence of N-acetyl-L-cysteine, a precursor of glutathione. However, iron oxide nanoparticles did not influence the generation of reactive oxygen species. Conclusion: Iron oxide nanoparticles induced a differential effect on antigen-specific cytokine expression by T cells, in which the T helper 1 cytokine IFN-γ was sensitive, whereas the T helper 2 cytokine interleukin-4 was refractory. In addition, the suppressive effect of iron oxide nanoparticles on interferon-γ was closely associated with the diminishment of glutathione. Keywords: iron oxide nanoparticle, T cell, antigen-specific, glutathione, cytokine

Chien-Chang Shen1, Chia-Chi Wang1, Mei-Hsiu Liao2, Tong-Rong Jan11Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan; 2Division of Isotope Application, Institute of Energy Research, Taoyuan, TaiwanBackground: Superparamagnetic iron oxide nanoparticles have been used in clinical applications as a diagnostic contrasting agent. Previous studies showed that iron oxide nanoparticles deposited in the liver and spleen after systemic administration. The present study investigated the effect of iron oxide nanoparticles on antigen-specific immune responses in mice sensitized with the T cell-dependent antigen ovalbumin (OVA).Methods: BALB/c mice were intravenously administered with a single dose of iron oxide nanoparticles (10-60 mg Fe/kg) 1 hour prior to OVA sensitization, and the serum antibody production and splenocyte reactivity were examined 7 days later.Results: The serum levels of OVA-specific IgG1 and IgG2a were significantly attenuated by treatment with iron oxide nanoparticles. The production of interferon-γ and interleukin-4 by splenocytes re-stimulated with OVA in culture was robustly suppressed in mice administered with iron oxide nanoparticles. The viability of OVA-stimulated splenocytes was also attenuated. In contrast, treatment with iron oxide nanoparticles did not affect the viability of splenocytes stimulated with concanavalin A, a T-cell mitogen.Conclusion: Collectively, these data indicate that systemic exposure to a single dose of iron oxide nanoparticles compromises subsequent antigen-specific immune reactions, including the serum production of antigen-specific antibodies, and the functionality of T cells.Keywords: iron oxide nanoparticle, antigen-specific, immune, ovalbumin

Objective: To assess the association of baseline anti‐Müllerian hormone (AMH) levels with ovulation, time to ovulation and fertility outcomes in women with polycystic ovary syndrome (PCOS) receiving clomiphene citrate (CC) and compare this with placebo. Design: Secondary analysis of the PCOSAct trial (NCT01573858). Setting: 27 trial centres in mainland China. Population or sample: 1000 infertile women with PCOS receiving either CC or placebo. Methods: Baseline serum AMH was measured and analysed as a continuous and as a categorical variable. Interaction between AMH and CC was tested. Predictive values of AMH for ovulation, time to ovulation and fertility outcomes were assessed. Main outcome measures: Ovulation and time to ovulation. Results: 900 baseline AMH data were available for analysis. There were no significant interactions with ovulation or conception for AMH and CC treatment (P = 0.782 and 0.419, respectively). Women in the upper quartile of AMH >15.88 ng/ml had significant lower ovulation (odds ratio [OR] 0.34, 95% CI 0.20–0.58) and conception rates (OR 0.65, 95% CI 0.42–1.00) compared with women in the lower quartile. Associations of AMH with clinical pregnancy (OR 0.98, 95% CI 0.95–1.01) and live birth (OR 0.98, 95% CI 0.96–1.01) were not significant. Ovulation rate increased until baseline AMH levels ≥7.0 ng/ml in women treated with CC but decreased when AMH increased in women with placebo. When AMH <7.0 ng/ml, an AMH threshold at 4.11 ng/ml predicted ovulation in women receiving CC (area under the curve [AUC] 0.64, 95% CI 0.42–0.86), with a sensitivity of 64% and a specificity of 62%, whereas prediction was poor for AMH ≥7.0 ng/ml (AUC 0.38, 95% CI 0.28–0.47). Median time to ovulation was 35 days in the lower quartile for women with placebo but this was significantly prolonged up to 98 days in the upper quartile. CC significantly shortened the time to ovulation up to 56 days. Conclusions: Among women with PCOS, high baseline AMH levels were associated with a 20.1% lower chance of ovulation with a 63‐day longer time to ovulation. AMH can predict ovulation only when the baseline AMH level was <7.0 ng/ml in women with PCOS undergoing ovulation induction with CC. Ovulation rate increased until baseline AMH levels ≥7.0 ng/ml in women treated with CC; a successful ovulation and time to ovulation was highly associated with baseline AMH level in these women. Ovulation rate increased until baseline AMH levels ≥7.0 ng/ml in women treated with CC; a successful ovulation and time to ovulation was highly associated with baseline AMH level in these women. [ABSTRACT FROM AUTHOR]

The present research attempts to evaluate the dose-response relationship between acute resistance exercise and planning. Seventeen participants performed the Tower of London (TOL) in control condition and three different exercise intensity conditions (40%, 70%, and 100% 10-repetition maximal) in a counterbalanced order. The results revealed positive effects of an acute bout of resistance exercise on the TOL. Specifically, a curvilinear trend was observed between exercise intensity and TOL scores that measured performances of "correct" and "move," where moderate intensity demonstrated the most optimal performance compared with the other conditions. None of these differences were found in TOL scores that measure performances of "violation" and "planning speed." These results suggest that acute moderate intensity resistance exercise could facilitate planning-related executive functions in middle-aged adults. [ABSTRACT FROM AUTHOR]

Victor C Kok,1,2 Charles CN Wang,2,3 Szu-Han Liao,2 De-Lun Chen2 1Division of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, 43303, Taiwan; 2Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan; 3Center for Artificial Intelligence and Precision Medicine Research, Asia University, Taichung, 41354, TaiwanCorrespondence: Victor C Kok; Charles CN Wang, Email vkok@alumni.harvard.edu; cnwang@asia.edu.twIntroduction: Only a proportion of triple-negative breast cancer (TNBC) is immunotherapy-responsive. We hypothesized that the tumor microenvironment (TME) influences the outcomes of TNBC and investigated the relevant signaling pathways.Materials and Methods: Immune score (IS) and stromal score (SS) were calculated using the ESTIMATE and correlated with the overall survival (OS) in TNBC. RNA-seq data from 115 TNBC samples and 112 normal adjacent tissues were retrieved. Validations in the methylation levels in 10 TNBC and five non-TNBC cell lines were obtained. Cox model overall survival (OS) validated the derived transcription factor (TF) genes in cBioPortal breast cancer patients.Results: SS-low predicts a higher OS compared with SS-high patients (P = 0.0081 IS-high/SS-low patients had better OS (P = 0.045) than IS-low/SS-high patients. More macrophages were polarized to the M2 state in patients with IS-low/SS-high patients (P < 0.001). Moreover, CIBERSORTx showed more CD8+ cytotoxic T-cells in IS-high/SS-low patients (p = 0.0286) and more resting NK cells in the IS-low/SS-high TME (P = 0.0108). KEGG pathway analysis revealed that overexpressed genes were enriched in the IL-17 and cytokine-cytokine receptor interaction pathways. The lncRNA DRAIC, a tumor suppressor, was consistently deactivated in the 10 TNBC cell lines. On the cBioPortal platform, we validated that 13% of ER-negative, HER2-unamplified BC harbored IL17RA deep deletion and 25% harbored TRAF3IP2 amplification. On cBioPortal datasets, the nine altered TF genes derived from the X2K analysis showed significantly worse relapse-free survival in 2377 patients and OS in 4819 invasive BC patients than in the unaltered cohort.Conclusion: Of note, the results of this integrated in silico study can only be generalized to approximately 17% of patients with TNBC, in which infiltrating stromal cells and immune cells play a determinant prognostic role.Keywords: triple-negative breast cancer, immune cells, tumor microenvironment, IL-17 signaling pathway, immune evasion, in silico study

Objective: To ascertain whether stress biomarkers and psychological indices of stress may predict both conception and miscarriage rates in women undergoing in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI).Design: Prospective observational study.Setting: A university-affiliated tertiary hospital.Population: Infertile women who were undergoing fresh or frozen IVF/ICSI cycles.Methods: Women were recruited to (1) complete validated psychological questionnaires (visual analogue scale of stress, state-trait anxiety inventory, perceived stress scale, fertility problem inventory, Beck depression inventory, and general health questionnaire), at the time of embryo transfer (ET) and pregnancy testing (PT), and (2) provide saliva samples for α-amylase (sAA) measurement before and after ET and at PT.Main Outcome Measures: Women were grouped according to subsequent reproductive outcome; scores/levels of all tests were then compared between groups at each time-point.Results: In all, 197 women completed the study, of which 92 conceived and 28 miscarried. The level of psychological stress, as measured by questionnaires, was highest at the time of PT, whereas the level of biological stress as measured by sAA level (IU/l) post-ET (1.8 × 105  ± 1.5 × 105 ) was significantly (P < 0.001) higher than pre-ET (1.2 × 105  ± 1.0 × 105 ) and at PT (1.0 × 105  ± 1.1 × 105 ). However, there was no difference in psychological scoring and in sAA levels between women who did or did not conceive and who had miscarried or had an ongoing pregnancy.Conclusions: The level of sAA is highest following ET, whereas psychological stress is highest at PT. However, neither stress level appeared to be of prognostic value in predicting conception or miscarriage.Tweetable Abstract: Stress level fluctuated at different time-points, but it did not predict conception or miscarriage. [ABSTRACT FROM AUTHOR]

Human papillomavirus ( HPV) is a common sexually transmitted virus and an important etiologic factor in head and neck cancers. HIV-infected individuals are at increased risk of developing oropharyngeal cancers ( OPC) compared with the general population. HPV-positive OPC are also increasingly a significant cause of morbidity and mortality for HIV-infected individuals in the era of effective combination antiretroviral therapy. The epidemiology and natural history of oral HPV infection have not been well established, but it appears that oral HPV infection is less common than anal infection, and more common among HIV-infected persons than the general population. Prevention of OPC is therefore increasingly important in HIV-infected individuals. Although not demonstrated in randomized controlled trials, HPV vaccination may prevent oral HPV infection as well. The focus of organized HPV cancer prevention programs should include prophylactic HPV vaccination to reduce the burden of high-risk HPV and low-risk HPV types who have not yet been exposed. [ABSTRACT FROM AUTHOR]

R118 is an experimental compound that completed preclinical development as a potential medical therapy for the exercise limitation in peripheral artery disease. Animal studies established that R118 provided partial and reversible mitochondrial complex I inhibition with consequent increases in adenosine monophosphate (AMP) kinase activation in liver and skeletal muscle. After demonstration of improved exercise performance in a mouse model and safety in rodent and primate models, a phase I trial was performed in 24 subjects randomized to R118 vs. placebo (5:1) in escalating doses. Plasma lactic acid levels were transiently elevated in 20% of subjects at the lowest dose and in 100% of subjects using a different formulation at the highest dose, which was associated with hospitalization in all subjects and severe metabolic acidosis requiring prolonged intubation in two subjects. Thus, inhibition of mitochondrial complex I with R118 resulted in severe lactic acidosis, representing unacceptable toxicity from this mechanism of action. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the diagnostic performance of the BACs-on-Beads(™) (BoBs(™)) assay for prenatal detection of chromosomal abnormalities.Design: Retrospective study.Setting: Tertiary prenatal diagnosis centre.Population: Women referred for prenatal diagnosis.Methods: We retrieved 2153 archived DNA samples collected between January 2010 and August 2011 for the BoBs(™) assay. These samples had previously been tested by quantitative fluorescence polymerase chain reaction (QF-PCR) and karyotyping. In the BoBs(™) assay a sample was defined as normal disomic when the ratio of the fluorescence intensities in a chromosome locus lay within the threshold (mean ratio ± 2SD), and as deleted or duplicated when the ratio was below the lower threshold (0.6-0.8) or above the upper threshold (1.3-1.4), respectively. The BoBs(™) results were further validated by microarray and compared in a blinded manner with the original QF-PCR and karyotyping results.Main Outcome Measures: Concordance of any numerical, structural, and submicroscopic chromosomal abnormalities between the methods.Results: BACs-on-Beads(™) was similar to karyotyping and QF-PCR in detecting trisomy 13, trisomy 18, trisomy 21, and sex chromosomal aneuploidies, and superior to QF-PCR in detecting major structural abnormalities (53.3 versus 13.3%) and mosaicism (28.6 versus 0%) involving chromosomal abnormalities other than the common aneuploidies. BoBs(™) detected six microdeletion syndromes missed by karyotyping and QF-PCR; however, BoBs(™) missed two cases of triploidy identified by QF-PCR. Therefore, the sensitivity of BoBs(™) is 96.7% (95% CI 92.6-98.7%), and its specificity is 100% (95% CI 99.8-100%).Conclusions: BACs-on-Beads(™) can replace QF-PCR for triaging in prenatal diagnosis, and gives a better diagnostic yield than current rapid aneuploidy tests. [ABSTRACT FROM AUTHOR]

Objective To evaluate the diagnostic performance of the BACs-on-Beads™ (BoBs™) assay for prenatal detection of chromosomal abnormalities. Design Retrospective study. Setting Tertiary prenatal diagnosis centre. Population Women referred for prenatal diagnosis. Methods We retrieved 2153 archived DNA samples collected between January 2010 and August 2011 for the BoBs™ assay. These samples had previously been tested by quantitative fluorescence polymerase chain reaction ( QF- PCR) and karyotyping. In the BoBs™ assay a sample was defined as normal disomic when the ratio of the fluorescence intensities in a chromosome locus lay within the threshold (mean ratio ± 2 SD), and as deleted or duplicated when the ratio was below the lower threshold (0.6-0.8) or above the upper threshold (1.3-1.4), respectively. The BoBs™ results were further validated by microarray and compared in a blinded manner with the original QF- PCR and karyotyping results. Main outcome measures Concordance of any numerical, structural, and submicroscopic chromosomal abnormalities between the methods. Results BACs-on-Beads™ was similar to karyotyping and QF- PCR in detecting trisomy 13, trisomy 18, trisomy 21, and sex chromosomal aneuploidies, and superior to QF- PCR in detecting major structural abnormalities (53.3 versus 13.3%) and mosaicism (28.6 versus 0%) involving chromosomal abnormalities other than the common aneuploidies. BoBs™ detected six microdeletion syndromes missed by karyotyping and QF- PCR; however, BoBs™ missed two cases of triploidy identified by QF- PCR. Therefore, the sensitivity of BoBs™ is 96.7% (95% CI 92.6-98.7%), and its specificity is 100% (95% CI 99.8-100%). Conclusions BACs-on-Beads™ can replace QF- PCR for triaging in prenatal diagnosis, and gives a better diagnostic yield than current rapid aneuploidy tests. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The objective of the study was to evaluate the ability of a new prenatal diagnostic platform - prenatal BACs-on-Beads[TM] (BoBs[TM]) in detecting mosaicism by comparison to quantitative fluorescence-polymerase chain reaction (QF-PCR). METHODS: A validation study of prenatal BoBs[TM] was firstly performed using 18 artificially constructing mosaic samples involving various aneuploidies and microdeletion conditions. Additionally, we compared the accuracy between prenatal BoBs[TM] and QF-PCR for 18 archived clinical mosaic cases and nine chromosomally abnormal cell lines with reference to conventional karyotype results. RESULTS: In the validation study, BoBs[TM] allowed the detection of mosaicism at a level of 20-40%. Among the clinical mosaic cases, 14/18 cases were within the detection of BoBs[TM], 8/14 (57.1%) could be identified by BoBs[TM] and 6/9 (66.7%) by QF-PCR, but 6/14 (42.9%) were missed by both tests. Three cases (16.7%) were detected by prenatal BoBs[TM] but missed by QF-PCR, whereas QF-PCR detected one case that was missed by BoBs[TM]. The overall sensitivity of BoBs[TM] in detecting mosaicism is 44.4% (8/18), which is slightly higher than that of QF-PCR (33.3%; 6/18). CONCLUSION: Prenatal BoBs[TM] has a sensitivity of 57.1% in the detection clinical mosaic cases. According to the validation test, mosaicism of 20% or greater is detectable by the BoBs[TM] assay. © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background. It is unclear whether hepatitis B e antigen (HBeAg) seroconversion induced by nucleos(t)ide analogues (NUC) has a prognosis that is similar to that of spontaneous HBeAg seroconversion. Methods. A total of 148 noncirrhotic NUC-induced HBeAg seroconverters were consecutively enrolled. A historical control of 407 noncirrhotic spontaneous HBeAg seroconverters was also recruited. We compared the rates of HBeAg seroreversion and HBV reactivation between these 2 cohorts. Results. There were 1652.8 and 465.2 person-years of follow-up for spontaneous and NUC-induced HBeAg seroconverters, respectively. Compared with NUC-induced seroconverters, spontaneous seroconverters were younger when achieving HBeAg seroconversion. We thus compared these 2 cohorts according to their age at HBeAg seroconversion. In patients achieving HBeAg seroconversion before 30 years of age, NUC-induced seroconverters had a higher 2-year HBeAg seroreversion rate than spontaneous seroconverters (12.0% vs 2.9%; P = .004) and were at a higher risk of HBV reactivation (hazard ratio, 4.6; 95% confidence interval, 1.5-14.4). Using multivariate analysis, NUC-induced HBeAg seroconversion remained a risk factor of both endpoints in young HBeAg seroconverters. Conclusion. NUC-induced HBeAg seroconverters may not have durable response after stopping therapy. For patients achieving HBeAg seroconversion before 30 years of age, the risk of HBeAg seroreversion and HBV reactivation is higher in NUC-induced seroconverters than spontaneous HBeAg seroconverters. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine whether medication refill behavior varies by the number of prescribers of antipsychotic medication a patient has.Methods: A total of 7,868 patients with schizophrenia were identified from North Carolina Medicaid records for the period 2001-2003. Medication switching and adherence outcomes in 2003 were constructed from Medicaid pharmacy claims. Adherence was categorized into four levels (nonadherence, partial adherence, full adherence, or excess filler). Patients were stratified into four groups on the basis of the number of providers who prescribed antipsychotics in 2002 (one prescriber, two prescribers, three prescribers, or four or more prescribers). Medication switching was modeled via logistic regression, and the four-level adherence outcome was modeled via ordered logistic regression, with both regressions controlling for the number of prescribers, age, gender, race, and comorbidity. Medication switching in 2003 was also controlled for in the adherence regression. Predicted probabilities of being in the four adherence groups were estimated to examine the impact of the number of prescribers on adherence.Results: Fifty-seven percent of Medicaid patients with schizophrenia had one prescriber for antipsychotic medication, 29% had two prescribers, 10% had three prescribers, and 4% had four or more prescribers in 2002. Patients with more prescribers were significantly more likely than patients with one prescriber to switch medications (p<.01 for patients with three prescribers) and to be either fully adherent or excess fillers (p<.001).Conclusions: Patients with schizophrenia who received medication from multiple prescribers frequently changed medications and filled prescriptions too soon. Care coordination, such as with medical homes, may be effective in improving medication use in this vulnerable population. [ABSTRACT FROM AUTHOR]

The use of rocker models to understand functional tasks of the human lower limb is attractive because of their simplicity. Recent studies have determined a consistent feature of able-bodied walking termed the roll-over shape (ROS), which is the effective rocker shape that the lower limb system conforms to between initial contact and contralateral initial contact during walking. However, it is unclear what effective rocker shapes are used for fore-aft swaying. A better understanding of these shapes could be used to develop improved prostheses for this task, perhaps improving balance and balance confidence, and reducing the occurrence of falling in lower limb prosthesis users. We measured effective rocker shapes used by 11 able-bodied persons during walking and fore-aft swaying. We hypothesized that the curvature of the swaying shapes would be smaller (radius larger) than that of the walking shapes, providing a more stable interface with the ground during swaying. The radius (measured as the inverse of the curvature of the shape) was found to be about 1/3 of the leg length for walking, but over two times the leg length for swaying. A model examining the effective ankle stiffness necessary to achieve these curvatures suggests that the stiffness of a biomimetic prosthetic ankle would need to be over three times higher for fore-aft swaying than for walking. These results suggest that two separate modes would be needed in an ankle-foot prosthesis to mimic the physiologic system for walking and swaying. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Human herpesviruses, e.g., herpes simplex virus (HSV) type 1, Epstein-Barr virus, and cytomegalovirus, appear in saliva at greater frequency in persons infected with human immunodeficiency virus (HIV) than in healthy individuals. However, it is not known if varicella zoster virus (VZV) and HSV-2 appear simultaneously during HIV infection at greater frequency in saliva in this era of highly active antiretroviral therapy (HAART). The aim of this study was to investigate the prevalence and amounts of VZV and HSV-2 in the saliva of HIV-infected orally asymptomatic patients. STUDY DESIGN: Quantitative polymerase chain reaction was used to investigate the prevalence, quantity, risk, and correlations of salivary VZV and HSV-2 from 59 HIV-seropositive individuals and 53 healthy control subjects in a case-control cross-sectional study. Seventy-eight percent of the HIV-seropositive patients (46 out of 59) were taking HAART. RESULTS: VZV DNA was detected in the saliva of 5.1% (3 out of 59) of the HIV-positive group and in only 1 healthy control 1.9% (1 out of 53; P = .62). The amount of VZV DNA in the expressors was low, generally <1,100 copies/mL, with no observed difference between the HIV-positive group and the control subjects (P = 1.0). HSV-2 DNA was not detected in either group. In the HIV-infected group, VZV shedding occurred in those on HAART, but was not associated with oral lesions, specific CD4(+) or CD8(+) T-cell levels, or demographic factors. CONCLUSIONS: Varicella zoster virus was detected at low prevalence in the saliva of HIV-infected persons, whereas HSV-2 was not detected in the saliva of this cohort. HAART does not appear to diminish the risk for asymptomatic VZV shedding. [ABSTRACT FROM AUTHOR]