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Hye-Rin Kang,1,* So Jeong Kim,2,* Ju Gang Nam,3 Young Sik Park,4 Chang-Hoon Lee4 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Veteran Health Service Medical Center, Seoul, 05368, Republic of Korea; 2Division of Pulmonology and Allergy, Hallym University Dongtan Sacred Heart Hospital, Gyeonggi-do, 18450, Republic of Korea; 3Department of Radiology, Seoul National University Hospital, Seoul, 03080, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea*These authors contributed equally to this workCorrespondence: Chang-Hoon Lee, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro Jongno-Gu, Seoul, 03080, Republic of Korea, Tel +82-2-2072-4743, Fax +82-2-762-9662, Email kauri670@empal.comIntroduction: Mortality differences in chronic obstructive pulmonary disease (COPD) between nonsmokers and smokers remain unclear. We compared the risk of death associated with smoking and COPD on mortality.Methods: The study included participants aged ≥ 40 years who visited pulmonary clinics and were categorised into COPD or non-COPD and smoker or nonsmoker on the basis of spirometry results and cigarette consumption. Mortality rates were compared between groups using statistical analysis for all-cause mortality, respiratory disease-related mortality, and cardiocerebrovascular disease-related mortality.Results: Among 5811 participants, smokers with COPD had a higher risk of all-cause (adjusted hazard ratio (aHR), 1.69; 95% confidence interval (CI), 1.23– 2.33) and respiratory disease-related mortality (aHR, 2.14; 95% CI, 1.20– 3.79) than nonsmokers with COPD. Non-smokers with and without COPD had comparable risks of all-cause mortality (aHR, 1.39; 95% CI, 0.98– 1.97) and respiratory disease-related mortality (aHR, 1.77; 95% CI, 0.85– 3.68). However, nonsmokers with COPD had a higher risk of cardiocerebrovascular disease-related mortality than nonsmokers without COPD (aHR, 2.25; 95% CI, 1.15– 4.40).Conclusion: The study found that smokers with COPD had higher risks of all-cause mortality and respiratory disease-related mortality compared to nonsmokers with and without COPD. Meanwhile, nonsmokers with COPD showed comparable risks of all-cause and respiratory mortality but had a higher risk of cardiocerebrovascular disease-related mortality compared to nonsmokers without COPD.Keywords: pulmonary disease, chronic obstructive, smokers, nonsmokers, cigarette smoking, comorbidity

Yi-Jan Wu,1,2 Shu-Sen Chang,3 Hsien-Yi Chen,4 Kai-Fan Tsai,2,5 Wen-Chin Lee,2,5 I-Kuan Wang,6,7 Chern-Horng Lee,8 Chao-Yu Chen,1,2 Shou-Hsuan Liu,1,2 Cheng-Hao Weng,1,2 Wen-Hung Huang,1,2 Ching-Wei Hsu,1,2 Tzung-Hai Yen1,2 1Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan; 2College of Medicine, Chang Gung University, Taoyuan City, Taiwan; 3Institute of Health Behaviors and Community Sciences, Department of Public Health, College of Public Health, National Taiwan University, Taipei City, Taiwan; 4Department of Emergency Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, Taiwan; 5Division of Nephrology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Branch, Kaohsiung City, Taiwan; 6Department of Nephrology, China Medical University Hospital, Taichung City, Taiwan; 7College of Medicine, China Medical University, Taichung City, Taiwan; 8Division of General Internal Medicine and Geriatrics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan City, TaiwanCorrespondence: Tzung-Hai Yen, Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, 5 Fu-Hsing Street, Kweishan, Taoyuan City, Taiwan, Tel +886 3 3281200 ext 8181, Fax +886 3 3282173, Email m19570@cgmh.org.twBackground and Purpose: There is an overall paucity of data regarding the human toxicity of chlorpyrifos and cypermethrin pesticide mixture. Both organophosphate and pyrethroid insecticides are metabolized by carboxylesterases. Thus, its pesticide combination, organophosphates may boost the toxicity of pyrethroids via inhibited its detoxification by carboxylesterases. This study examined the clinical course, laboratory tests, and outcomes of patients with chlorpyrifos, cypermethrin or their pesticide mixture poisoning, and to determine what association, if any, might exist between these findings.Patients and Methods: Between 2000 and 2021, 121 patients poisoned with chlorpyrifos, cypermethrin, or their pesticide mixture were treated at Chang Gung Memorial Hospital. Patients were categorized as chlorpyrifos (n=82), cypermethrin (n=27) or chlorpyrifos and cypermethrin (n=12) groups. Demographic, clinical, laboratory and mortality data were collected for analysis.Results: The patients experienced a broad range of clinical symptoms, including aspiration pneumonia (44.6%), salivation (42.5%), acute respiratory failure (41.3%), acute kidney injury (13.9%), seizures (7.5%), hypotension (2.6%), etc. Leukocytosis (12,700± 6600 /uL) and elevated serum C-reactive protein level (36.8± 50.4 mg/L) were common. The acute respiratory failure rate was 41.3%, comprising 48.8% in chlorpyrifos, 11.1% in cypermethrin as well as 58.3% in chlorpyrifos and cypermethrin poisoning. Patients with chlorpyrifos and cypermethrin pesticide mixture poisoning suffered higher rates of acute respiratory failure (P=0.001) and salivation (P=0.001), but lower Glasgow Coma Scale score (P=0.011) and serum cholinesterase level (P< 0.001) than other groups. A total of 17 (14.0%) patients expired. The mortality rate was 14.0%, including 17.1% in chlorpyrifos, 3.7% in cypermethrin as well as 16.7% in chlorpyrifos and cypermethrin poisoning. No significant differences in mortality rate were noted (P=0.214).Conclusion: Chlorpyrifos pesticide accounted for the major toxicity of the pesticide mixture. While the data show a higher rate of respiratory failure in the chlorpyrifos and cypermethrin pesticide mixture group than others, other measures of toxicity such as mortality and length of stay were not increased.Keywords: chlorpyrifos, cypermethrin, pesticide mixture, poisoning, acute respiratory failure, mortality

Shun-Hua Chen,1 Po-Jen Chen,2 Chiu-Hsiang Lee,3,4 Yu-Ping Wu,3,4 Daniel Kwasi Ahorsu,5,6 Mark D Griffiths,7 Chung-Ying Lin8 1School of Nursing, Fooyin University, Kaohsiung, 83102, Taiwan; 2Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, 824005, Taiwan; 3Department of Nursing, Chung Shan Medical University, Taichung, Taiwan; 4Department of Nursing, Chung Shan Medical University Hospital, Taichung, Taiwan; 5Mental Health Research Centre, the Hong Kong Polytechnic University, Hung Hom, Hong Kong; 6Department of Special Education and Counselling, the Education University of Hong Kong, Tai Po, Hong Kong; 7International Gaming Research Unit, Psychology Department, Nottingham Trent University, Nottingham, UK; 8Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, TaiwanCorrespondence: Chiu-Hsiang Lee, Department of Nursing, Chung Shan Medical University, Department of Nursing, Chung Shan Medical University Hospital, 1253F, Jengshin Hall, Taichung, 402, Taiwan, Tel +886-4-24730022 ext. 12216, Email csha528@gmail.com Daniel Kwasi Ahorsu, Department of Special Education and Counselling, The Education University of Hong Kong, B4-1/F-13, Tai Po, Hong Kong, Email daniel.ahorsu@connect.polyu.hkPurpose: Resilience continues to be an important concept in the nursing profession due to its significant role in personal healthcare, patients’ healthcare, and leadership. The present study examined the mediating role of perceived stress in the association between mindfulness and resilience among registered nurses in order to understand their importance among those in the Taiwanese nursing profession.Materials and Methods: Between October and November 2021, a total of 816 registered nurses participated in a cross-sectional survey including psychometric measures assessing perceived stress (Chinese Perceived Stress Scale-10), mindfulness (Chinese Mindful Attention Awareness Scale), and resilience (Chinese Questionnaire of Resilience).Results: Results indicated that perceived stress mediated the association between mindfulness and resilience (standardized coefficient = 0.251, p< 0.001), although there was no significant association between mindfulness and resilience (standardized coefficient = 0.042, p=0.16). This suggests that perceived stress may function as both distress and eustress because mindfulness was not directly associated with resilience but indirectly via perceived stress.Conclusion: Nurses and their administrators should focus on different ways of coping with stress so that they become more resilient in facing other stressors. Future studies may be conducted to examine the mediating role of perceived stress in the association between other coping strategies and resilience among registered nurses.Keywords: coping, healthcare, Taiwan, cross-sectional survey, mediation analysis, mindfulness, resilience

Yun-Jeong Jeong,1,&ast; Kyoung-Hee Lee,2,&ast; Jisu Woo,2 Ji Yeon Kim,2 Chang-Hoon Lee,2,3 Chul-Gyu Yoo2,3 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Ilsan Dong-gu, Goyang-si, Gyeonggi-do, Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 3Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea&ast;These authors contributed equally to this workCorrespondence: Chul-Gyu Yoo, 101 Daehakno, Jongno-gu, Seoul, 03080, Korea, Tel +82-2-2072-3760, Fax +82-2-762-9662, Email cgyoo@snu.ac.krBackground: Macroautophagy plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but the role of chaperone-mediated autophagy (CMA) has not been investigated. We investigated if and how CMA is involved in the pathogenesis of COPD.Methods: We measured the level of lysosome-associated membrane protein-2A (LAMP-2A), which is a critical component of CMA that functions as a receptor for cytosolic substrate proteins, in total lung tissues and primary human bronchial epithelial cells (HBECs) from healthy never smokers, smokers, and COPD patients. We assessed the effects of LAMP-2A knock-down on cigarette smoke extract (CSE)-induced aging, cell cycle arrest, and apoptosis in BEAS-2B cells and the expression levels of apoptosis hallmarks in primary HBECs and lung tissue sections.Results: We found that the protein levels of LAMP-2A in lung homogenates and primary HBECs from smokers and COPD patients were lower than those from never smokers. In addition, its level in primary HBECs was negatively correlated with years of smoking. CSE caused degradation of LAMP-2A protein via the lysosomal pathway by activating macroautophagy. Knock-down of LAMP-2A markedly enhanced CSE-induced expression of senescence markers such as p16, p21, p27, and p53. G2/M cell cycle arrest, up-regulation of cyclin B1, and apoptosis in BEAS-2B cells. Apoptosis was increased in CSE-treated primary HBECs and in lung tissues from smokers and COPD patients.Conclusion: Cigarette smoke-induced down-regulation of LAMP-2A is involved in acceleration of aging and apoptosis of lung epithelial cells, which might at least partially contribute to COPD pathogenesis.Keywords: COPD, LAMP-2A, lung epithelial cells, aging, apoptosis

Tommy Tsang Cheung,1,&ast; Tu H Mai,2,&ast; Yen Lin Chia,2 Desmond YH Yap,1 Chi-Ho Lee,1 Cecil Chi-Keung Chen,2 Ying Huang,3 Yuwen Jin,3 James Johnston,4 Viktoria Werkström,5 Yuhui Yao,6 Xiaoyun Ge,7 Wenying Zheng8 1Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China; 2Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA; 3Clinical Pharmacology, R&D China, AstraZeneca, Shanghai, People’s Republic of China; 4Late-stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; 5Late-Stage Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Respiratory & Immunology, R&D China, AstraZeneca, Shanghai, People’s Republic of China; 7Clinical Safety, R&D China, AstraZeneca, Shanghai, People’s Republic of China; 8Biometrics, R&D China, AstraZeneca, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yen Lin Chia, Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, 701 Gateway Blvd, South San Francisco, CA, 9408, USA, Tel +1 425 5272574, Email yenlin@gmail.comPurpose: Biological therapies targeting eosinophils have been shown to be effective in treating patients with severe eosinophilic asthma. Benralizumab (Fasenra®, AstraZeneca) is a humanized monoclonal antibody binding to the alpha subunit of the interleukin-5 receptor, which rapidly depletes eosinophils via antibody-dependent cellular cytotoxicity. The aim of this Phase 1 study was to assess the safety, tolerability, and pharmacokinetics of benralizumab in healthy Chinese individuals.Materials and Methods: In this randomized, single-blind study (NCT03928262), healthy Chinese adult participants aged 18 to 45 years, weighing 50 to 100 kg, were randomized 1:1:1 to receive a single subcutaneous (SC) injection of benralizumab 10 mg, 30 mg, or 100 mg in the upper arms on Day 1. Safety was monitored throughout the study (up to Day 85), and blood samples were taken to determine serum benralizumab concentrations and for detection of anti-drug antibody. A non-compartmental analysis was conducted to estimate the pharmacokinetic parameters.Results: Thirty-six healthy participants were enrolled, 12 in each dose group (mean [SD] age 26 [6] years). Following a single SC injection of benralizumab, 13 adverse events were reported by 10 participants (28%), with one mild injection-site reaction assessed as related. The mean serum benralizumab concentrations increased in a dose proportional manner, followed by exponential decreases. The mean terminal half-lives were 15.1 days for the 10 mg dose, 14.4 days for the 30 mg dose, and 15.4 days for the 100 mg dose. All doses resulted in near-complete depletion of eosinophils on Day 2, which was maintained throughout the study to Day 85.Conclusion: A single SC injection of benralizumab was well tolerated by healthy Chinese participants, with no new or unexpected safety findings. The pharmacokinetics of benralizumab in Chinese participants was dose-proportional and consistent with those of non-Chinese participants observed in previous studies.Clinical Trial Registration: NCT03928262 (https://clinicaltrials.gov/ct2/show/NCT03928262)Keywords: benralizumab, pharmacokinetics, healthy Chinese

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

Zeeshan Ahmad Khan,1– 3 Paul Jung-Soo Hong,4,* Christina Hayoung Lee,5,* Yonggeun Hong1– 3,6,7 1Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University, Gimhae, Gyeong-nam, 50834, Korea; 2Biohealth Products Research Center (BPRC), Inje University, Gimhae, Gyeong-nam, 50834, Korea; 3Ubiquitous Healthcare & Anti-Aging Research Center (u-HARC), Inje University, Gimhae, Gyeong-nam, 50834, Korea; 4Department of Chemistry, Newton South High School, Newton, MA, 02459, USA; 5Department of Biology, College of Arts and Sciences, Vanderbilt University, Nashville, TN, 37212, USA; 6Department of Rehabilitation Science, Graduate School of Inje University, Gimhae, Gyeong-nam, 50834, Korea; 7Department of Medicine, Division of Hematology/Oncology, Harvard Medical School-Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA*These authors contributed equally to this workCorrespondence: Yonggeun HongDepartment of Rehabilitation Science, Graduate School of Inje University, 197 Inje-ro, Gimhae, Gyeong-nam, 50834, KoreaTel +82-55-320-3681Fax +82-55-329-1678Email yonghong@inje.ac.krAbstract: Tryptophan and melatonin are pleiotropic molecules, each capable of influencing several cellular, biochemical, and physiological responses. Therefore, sensitive detection of tryptophan and melatonin in pharmaceutical and human samples is crucial for human well-being. Mass spectrometry, high-performance liquid chromatography, and capillary electrophoresis are common methods for both tryptophan and melatonin analysis; however, these methods require copious amounts of time, money, and manpower. Novel electrochemical and optical detection tools have been subjects of intensive research due to their ability to offer a better signal-to-noise ratio, high specificity, ultra-sensitivity, and wide dynamic range. Recently, researchers have designed sensitive and selective electrochemical and optical platforms by using new surface modifications, microfabrication techniques, and the decoration of diverse nanomaterials with unique properties for the detection of tryptophan and melatonin. However, there is a scarcity of review articles addressing the recent developments in the electrochemical and optical detection of tryptophan and melatonin. Here, we provide a critical and objective review of high-sensitivity tryptophan and melatonin sensors that have been developed over the past six years (2015 onwards). We review the principles, performance, and limitations of these sensors. We also address critical aspects of sensitivity and selectivity, limit and range of detection, fabrication process and time, durability, and biocompatibility. Finally, we discuss challenges related to tryptophan and melatonin detection and present future outlooks.Keywords: tryptophan, melatonin, electrochemical, sensors, voltammetry, optical

Tien-Yu Chen,1– 3,&ast; Vincent Yi-Fong Su,4,5,&ast; Chung-Hsin Lee,6 Chi-Hsiang Chung,7– 9 Chia-Kuang Tsai,3,10 Chung-Kan Peng,3,11 Hsiao-Ching Lai,1 Wu-Chien Chien,7– 9,12 Nian-Sheng Tzeng1,13 1Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 2Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 3Sleep Medicine Center, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 4Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan; 5Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 6Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan; 7Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 8School of Public Health, National Defense Medical Center, Taipei, Taiwan; 9Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 10Department of Neurology, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 11Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 12Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 13Student Counseling Center, National Defense Medical Center, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Wu-Chien ChienDepartment of Medical Research, Tri-Service General Hospital, National Defense Medical Center, 7115R, No. 325, Section 2, Cheng-Kung Road, Neihu District, Taipei, 11490, TaiwanTel +886 2-87923311, Ext. 19189Fax +886 2-87927235Email chienwu@mail.ndmctsgh.edu.twNian-Sheng TzengDepartment of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Kung Road, Neihu District, Taipei City, 11490, TaiwanTel +886 2-87927299Fax +886 2-87927221Email pierrens@mail.ndmctsgh.edu.twPurpose: Asthma, which is caused by inflammation of the airways, affects the sensitivity of nerve endings. Narcolepsy is a chronic sleep disorder that may be caused by autoimmunity. Recent studies have reported a positive association between narcolepsy and asthma. We aimed to examine the association between asthma and narcolepsy and determine the effects of therapeutic corticosteroid or bronchodilator use.Materials and Methods: We conducted a nationwide population-based, nested case-control study using Taiwan’s National Health Insurance Research Database (NHIRD) between 2000 and 2013. Subjects with narcolepsy (ICD-9-CM code 347) were enrolled, with 1:3 estimated propensity score-matched controls based on sex, age, and index year. The association between narcolepsy and asthma was assessed using multiple logistic regression analyses. The covariates included sex, age, monthly insurance premiums, geographical area of residence, urbanization level of residence, level of care, and presence of diseases related to immune response and central nervous system. The effects of corticosteroid and bronchodilator use were also analyzed.Results: Overall, 2008 subjects were identified from the NHIRD (502 patients with narcolepsy and 1506 controls). The participants with narcolepsy had almost three times the level of previous asthma diagnosis than controls. Compared to those without asthma, patients with asthma had an adjusted odds ratio (OR) of 3.181 for narcolepsy comorbidity (95% confidence interval [CI]: 2.048– 4.941, p< 0.001). The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity, with an adjusted OR of 0.465 (95% CI, 0.250– 0.634; p< 0.001), in patients with asthma when compared to those without treatment.Conclusion: This study demonstrated a significantly higher level of previous asthma diagnosis in patients with narcolepsy. The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity in asthma patients, compared to those without treatment.Keywords: asthma, narcolepsy, corticosteroid, bronchodilators

Sung Won Chung,1,* Min Kyung Park,1,* Young Youn Cho,1,2,* Youngsu Park,1 Cheol-Hyung Lee,1 Hyunwoo Oh,1 Heejoon Jang,1 Minseok Albert Kim,1 Sun Woong Kim,1 Joon Yeul Nam,1 Yun Bin Lee,1 Eun Ju Cho,1 Su Jong Yu,1 Hyo-Cheol Kim,3 Yoon Jun Kim,1 Jin Wook Chung,3 Jung-Hwan Yoon,1 Jeong-Hoon Lee1 1Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea; 2Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Korea; 3Department of Radiology, Seoul National University College of Medicine, Seoul, Korea*These authors contributed equally to this workCorrespondence: Jeong-Hoon LeeDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, KoreaTel +82-2-2072-2228Fax +82-2-743-6701Email pindra@empal.comBackground: Still in real-world practice, advanced hepatocellular carcinoma (HCC) patients are treated with transarterial chemoembolization (TACE). This study compared the therapeutic effectiveness of initial TACE treatment and initial sorafenib treatment in advanced HCC patients.Patient and Methods: Advanced HCC patients initially treated with sorafenib or TACE were included in this study. Treatment crossover due to an unfavorable response to initial treatment was allowed. Propensity score (PS) matching was applied for balancing baseline characteristics. The primary outcome was overall survival (OS) and the secondary outcomes included tumor response.Results: A total of 554 patients were included in this study: 85 were initially treated with sorafenib (the sorafenib-first group) and 469 with TACE (the TACE-first group). In the entire cohort, the TACE-first group was associated with lower risk of death [adjusted hazard ratio (HR)=0.75, P=0.04]. In the PS-matched cohort (85 patients per group), the TACE-first group showed longer OS than the sorafenib-first group in both univariable (HR=0.68, P=0.02) and multivariable analyses (adjusted HR=0.58, P=0.002). Specifically, within both the entire and the PS-matched cohorts, the TACE-first group showed longer OS in subgroups with major portal vein tumor thrombosis (HR=0.72, P=0.048; HR=0.52, P=0.003) or infiltrative HCC (HR=0.42, P< 0.001; HR=0.30, P=0.004, respectively). The objective response rate was higher in the TACE-first group (29.3% vs 14.7%, P=0.03) within the PS-matched cohort.Conclusion: For advanced HCC, initial TACE leads to longer OS with a more favorable tumor response than initial sorafenib treatment. Intrahepatic tumor control with initial locoregional therapy may be a potent strategy for advanced HCC.Keywords: liver cancer, transarterial therapy, locoregional therapy, tyrosine kinase inhibitor

Chunrui Zou,1,2 Frank Li,2,3 Jiwoong Choi,1,4 Babak Haghighi,5 Sanghun Choi,6 Prathish K Rajaraman,1,2 Alejandro P Comellas,7 John D Newell Jnr,8 Chang Hyun Lee,8,9 R Graham Barr,10 Eugene Bleecker,11 Christopher B Cooper,12 David Couper,13 Meilan Han,14 Nadia N Hansel,15 Richard E Kanner,16 Ella A Kazerooni,17 Eric C Kleerup,18 Fernando J Martinez,19 Wanda O’Neal,20 Robert Paine III,16 Stephen I Rennard,21 Benjamin M Smith,22,23 Prescott G Woodruff,24 Eirc A Hoffman,3,7,8 Ching-Long Lin1– 3,8 1Department of Mechanical Engineering, University of Iowa, Iowa City, IA, USA; 2IIHR-Hydroscience & Engineering, University of Iowa, Iowa City, IA, USA; 3Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA; 4Department of Internal Medicine, School of Medicine, University of Kansas, Kansas City, KS, USA; 5Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 6School of Mechanical Engineering, Kyungpook National University, Daegu, Republic of Korea; 7Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; 8Department of Radiology, University of Iowa, Iowa City, IA, USA; 9Department of Radiology, College of Medicine, Seoul National University, Seoul, Republic of Korea; 10Mailman School of Public Health, Columbia University, New York, NY, USA; 11Department of Medicine, The University of Arizona, Tucson, AZ, USA; 12Department of Physiology, UCLA, Los Angeles, CA, USA; 13Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA; 14Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; 15School of Medicine, Johns Hopkins, Baltimore, MD, USA; 16School of Medicine, University of Utah, Salt Lake City, UT, USA; 17Department of Radiology, University of Michigan, Ann Arbor, MI, USA; 18Department of Medicine, UCLA, Los Angeles, CA, USA; 19Weill Cornell Medicine, Cornell University, New York, NY, USA; 20School of Medicine, University of North Carolina, Chapel Hill, NC, USA; 21Department of Internal Medicine, University of Nebraska College of Medicine, Omaha, NE, USA; 22Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; 23Department of Medicine, McGill University Health Centre Research Institute, Montreal, Canada; 24Department of Medicine, University of California at San Francisco, San Francisco, CA, USACorrespondence: Ching-Long Lin 2406 Seamans Center for the Engineering Art and Science, Iowa City, IA, 52242, USATel +1 319 335 5673Email ching-long-lin@uiowa.eduPurpose: Quantitative computed tomography (qCT) imaging-based cluster analysis identified clinically meaningful COPD former-smoker subgroups (clusters) based on cross-sectional data. We aimed to identify progression clusters for former smokers using longitudinal data.Patients and Methods: We selected 472 former smokers from SPIROMICS with a baseline visit and a one-year follow-up visit. A total of 150 qCT imaging-based variables, comprising 75 variables at baseline and their corresponding progression rates, were derived from the respective inspiration and expiration scans of the two visits. The COPD progression clusters identified were then associated with subject demography, clinical variables and biomarkers.Results: COPD severities at baseline increased with increasing cluster number. Cluster 1 patients were an obese subgroup with rapid progression of functional small airway disease percentage (fSAD%) and emphysema percentage (Emph%). Cluster 2 exhibited a decrease of fSAD% and Emph%, an increase of tissue fraction at total lung capacity and airway narrowing over one year. Cluster 3 showed rapid expansion of Emph% and an attenuation of fSAD%. Cluster 4 demonstrated severe emphysema and fSAD and significant structural alterations at baseline with rapid progression of fSAD% over one year. Subjects with different progression patterns in the same cross-sectional cluster were identified by longitudinal clustering.Conclusion: qCT imaging-based metrics at two visits for former smokers allow for the derivation of four statistically stable clusters associated with unique progression patterns and clinical characteristics. Use of baseline variables and their progression rates enables identification of longitudinal clusters, resulting in a refinement of cross-sectional clusters.Keywords: computed tomography, emphysema, functional small airway disease, longitudinal clustering

Tsung-Lun Li,1 Tai-Hua Chan,2 Cheng-Hui Wang,3– 5 Ruwen Jou,2,6 Ming-Chih Yu,1,3,7 Denise Utami Putri,3,* Chih-Hsin Lee,1,3,8,* Yi-Hsien Lin3 1Department of Internal Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 2Taiwan Centers for Disease Control, Taipei, Taiwan; 3Pulmonary Research Center, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 4Department of Laboratory Medicine, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 5School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 6Institute of Microbiology and Immunology, National Yang-Ming Chiao Tung University, Taipei, Taiwan; 7Schools of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chih-Hsin Lee; Denise Utami PutriPulmonary Research Center, Wanfang Hospital, Taipei Medical University, 111 Sec. 3, Xinglong Road Wenshan District, Taipei, 116, TaiwanTel +886-2930-7930Email chleetw@tmu.edu.tw; 108336@w.tmu.edu.twAbstract: Appropriate treatment is the key element in eliminating tuberculosis (TB), and requires prompt diagnosis. We presented a case of a household contact of rifampicin-resistant TB revealing reactive IFN-gamma release assay with unsuspicious clinical and radiologic examinations. She was diagnosed with latent tuberculosis infection (LTBI) and treated with isoniazid monotherapy. On the ninth month, she developed a progressive cough and was found to harbor active TB disease with added resistance to isoniazid. An individualized anti-TB regimen consisting of moxifloxacin, kanamycin, prothionamide, ethambutol, and pyrazinamide was prescribed for 20 months, leading to sputum culture conversion and improvement of the reported symptom. No recurrence was observed on one-year follow-up. Assuming high compliance to therapy, we propose that the patient may have been underdiagnosed and received sub-optimal treatment leading to acquired-drug resistance. Conventional diagnosis methods based on immunological assay and radiographical findings may be insufficient to distinguish the incipient and subclinical states of TB from LTBI.Keywords: latent tuberculosis infection, LTBI, treatment, acquired drug resistance, drug-resistant TB, subclinical TB, case report

Kuo-Tung Hung,1 Shih-Cheng Yang,1 Cheng-Kun Wu,1,2 Hsing-Ming Wang,1 Chih-Chien Yao,1 Chih-Ming Liang,1,2 Wei-Chen Tai,1,2 Keng-Liang Wu,1,2 Yuan-Hung Kuo,1,2 Chen-Hsiang Lee,2,3 Seng-Kee Chuah1,2 1Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Chang Gung University, College of Medicine, Taoyuan, Taiwan; 3Division of Infectious Disease, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung, TaiwanCorrespondence: Seng-Kee Chuah; Chih-Ming LiangDivision of Hepatogastroenterology, Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung, 833, TaiwanTel + 886-7-7317123 ext. 8301Fax + 886-7-7322402Email chuahsk@seed.net.tw; gimy54861439@gmail.comPurpose: Non-bismuth concomitant quadruple therapy is commonly administered in Taiwan, achieving an acceptable efficacy as a first-line anti-Helicobacter pylori treatment. This study compared the eradication rates between esomeprazole- and lansoprazole-based non-bismuth concomitant quadruple therapy for first-line anti-H. pylori treatment.Patients and Methods: This study included 206 H. pylori-infected naïve patients between July 2016 and February 2019. The patients were prescribed with either a 7-day non-bismuth containing quadruple therapy (esomeprazole, 40 mg twice daily; amoxicillin, 1 g twice daily; and metronidazole, 500 mg twice daily; and clarithromycin, 500 mg twice daily for 7 days [EACM group]; lansoprazole, 30 mg twice daily; amoxicillin, 1 g twice daily; metronidazole, 500 mg twice daily; and clarithromycin, 500 mg twice daily [LACM group]). Then, the patients were asked to perform urea breath tests 8 weeks later.Results: The eradication rates in the EACM group were 86.1% (95% confidence interval [CI], 77.8%– 92.2%) and 90.6% (95% CI, 82.9%– 95.6%) in the intention-to-treat (ITT) and the per-protocol (PP) analyses, respectively. Moreover, the eradication rates in the LACM group were 90.1% (95% CI, 82.6%– 95.2%) and 92.6% (95% CI, 85.5%– 96.9%) in the ITT and the PP analyses, respectively. Consequently, the LACM group exhibited more diarrhea patients than the EACM group (7.1% versus 1.0%, p = 0.029), but all symptoms were mild. Univariate analysis in this study showed that metronidazole-resistant strains were the clinical factor affecting the eradications (95.3% versus 78.9%, p = 0.044). Moreover, a trend was observed in dual clarithromycin- and metronidazole-resistant strains (91.5% versus 66.7%, p = 0.155).Conclusion: The eradication rates between esomeprazole and lansoprazole-based non-bismuth concomitant quadruple therapy for first-line H. pylori treatment were similar in this study. Both could achieve a > 90% report card in the PP analysis.Keywords: Helicobacter pylori, esomeprazole, lansoprazole, concomitant therapy, antibiotic resistance

Shih-Lung Cheng,1,2 Ming-Lin Ho,3 Yun-Fa Lai,4 Hao-Chien Wang,5 Jeng-Yuan Hsu,6 Shih-Feng Liu,7,8 Ming-Shyang Huang,9 Cheng-Hung Lee,10 Ching-Hsiung Lin,3,11 Liang-Wen Hang,12,13 Yu-Chih Liu,14 Kuang-Yao Yang,15,16,* Jia-Horng Wang14,17,* 1Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan; 2Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan; 3Division of Chest Medicine, Kuang Tien General Hospital, Taichung, Taiwan; 4Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 6Division of Clinical Research, Taichung Veterans General Hospital, Taichung, Taiwan; 7Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 9Department of Internal Medicine, E-DA Cancer Hospital and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 10Division of Chest Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 11Division of Chest Medicine, Changhua Christian Hospital, Changhua, Taiwan; 12School of Nursing & Graduate Institute of Nursing, China Medical University, Taichung, Taiwan; 13Sleep Medicine Center, China Medical University Hospital, Taichung, Taiwan; 14Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan; 15Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 16Institute of Emergency and Critical Care Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 17Hyperbaric Oxygen Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan*These authors contributed equally to this workCorrespondence: Kuang-Yao Yang; Jia-Horng Wang Tel +886-2-28757455Fax +886-2-28757610Email kyyang@vghtpe.gov.tw; jiahorng.wang@gmail.comIntroduction: In the prospective, observational, 16-week REACT study conducted between October 21, 2008 and May 12, 2011, we compared the real-world effectiveness of anti-inflammatory reliever and maintenance therapy with budesonide/formoterol (Symbicort® Turbuhaler) and maintenance therapy with fixed-dose fluticasone/salmeterol (Seretide®) plus as-needed, short-acting β2 agonists (SABAs) in Taiwanese patients with inadequate asthma control.Methods: Asthma control was assessed using the five-item Asthma Control Questionnaire (ACQ-5) and standardized pulmonary function testing. Assessments were performed at baseline and at weeks 4– 5 and 12– 16. Overall, we enrolled 842 patients at 11 clinics, 723 of whom were included in analyses (budesonide/formoterol, 563.3± 1.3 μg/d, n=551; fluticasone/salmeterol, 1013.8± 1.4 μg/d, n=172).Results: At baseline, 72.5% and 27.5% of all patients had “partly” and “uncontrolled” asthma, respectively. Mean±SD ACQ-5 scores were 1.54± 1.06 and 1.46± 1.28 in the budesonide/formoterol and fluticasone/salmeterol groups, respectively. ACQ-5 scores significantly improved from baseline (ie, decreased) in both groups at weeks 4 and 16. ACQ-5 difference scores were significantly lower in the budesonide/formoterol group (− 0.91± 1.11) than the fluticasone/salmeterol group (− 0.69± 1.27) at the end of the study (p=0.027). Peak expiratory flow rate significantly improved from baseline in the budesonide/formoterol but not the fluticasone/salmeterol group at the end of the study. Severe exacerbation rates and medical resource utilization were comparable between the budesonide/formoterol and fluticasone/salmeterol groups.Conclusion: Collectively, results indicate the real-world effectiveness of budesonide/formoterol anti-inflammatory reliever and maintenance therapy is better than fixed-dose fluticasone/salmeterol plus as-needed SABA.Trial Registration: ClinicalTrials.gov registration number: NCT00784953.Keywords: budesonide/formoterol, fluticasone propionate/salmeterol, anti-inflammatory reliever and maintenance, real-world

Menq-Rong Wu,1,2 Chia-Hsun Lee,1 Jong-Kai Hsiao1,3 1Department of Medical Imaging, Taipei Tzuchi Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 23142, Taiwan; 2Institute of Biomedical Engineering, National Taiwan University, Taipei 10617, Taiwan; 3School of Medicine, Tzu Chi University, Hualien 97004, TaiwanCorrespondence: Jong-Kai HsiaoDepartment of Medical Imaging, Taipei Tzu Chi General Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 23142, TaiwanTel +886-2-6628-9779-extension 61114Fax +886-2-86272976Email jongkai@tzuchi.com.twPurpose: Stem cell therapy for ischemic stroke has shown success in experimental settings, but its translation into clinical practice is challenging. The choroid plexus (CP) plays a regulatory role in neural regeneration. Mesenchymal stem cells (MSCs) promote neurogenesis in the ventricular–subventricular zone. However, it is unclear whether MSCs interact with the CP in brain tissue repair.Methods: Rat (r)MSCs were labeled with iron oxide nanoparticles (IONs) and transduced with red fluorescent protein, and then injected into the brain of rats with ischemic stroke and monitored over time by magnetic resonance imaging. The functional recovery of rats was determined by the corner test score, Modified Neurological Severity score, and stroke volume. MSCs and CP were also co-cultured for 14 days, and the medium was analyzed with a cytokine array.Results: In vivo imaging and histologic analysis revealed that ION-labeled MSCs were mainly located at the injection site and migrated to the infarct area and to the CP. Functional recovery was greater in rats treated with MSCs as compared to those that received mock treatment. Bidirectional enhancement of proliferation in MSCs and CP was observed in the co-culture; moreover, MSCs migrated to the CP. Cytokine analysis revealed elevated levels of proliferation- and adhesion-related cytokines and chemokines in the culture medium. Wikipathway predictions indicated that insulin-like growth factor 1/Akt signaling (WP3675), chemokine signaling pathway (WP2292), and spinal cord injury (WP2432) are involved in the increased proliferation and migration of MSCs co-cultured with the CP.Conclusion: Crosstalk with the CP enhances MSC proliferation and migration in a transwell assay. Moreover, MRI reveals MSC migration towards the CP in an ischemic stroke model. The secreted factors resulting from this interaction have therapeutic potential for promoting functional recovery in the brain after ischemic stroke.Keywords: iron oxide nanoparticles, cell therapy, mesenchymal stem cell, choroid plexus, brain stroke

Jung-Ki Yoon,1 Jung-Kyu Lee,2 Chang-Hoon Lee,1 Yong Il Hwang,3 Hyunkuk Kim,4 Dongil Park,5 Ki-Eun Hwang,6 Sang-Heon Kim,7 Ki-Suck Jung,3 Kwang Ha Yoo,8 Seung Won Ra,9 Deog Kyeom Kim2,10 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 3Department of Internal Medicine, College of Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea; 6Department of Internal Medicine, Wonkwang University, School of Medicine, Iksan, Republic of Korea; 7Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea; 9Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 10Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of KoreaTel +82-2-870-2228Fax +82-2-831-0714Email kimdkmd@snu.ac.krIntroduction: Blood eosinophils are a predictive marker for the use of inhaled corticosteroids (ICS). However, there is concern over whether a single measure of blood eosinophils is sufficient for outlining a treatment plan. Here, we evaluated the association between variability in blood eosinophils and the effects of ICS in stable COPD cohorts.Methods: COPD patients in the Korean COPD Subtype Study and the Seoul National University Airway Registry from 2011 to 2018 were analyzed. Based on blood eosinophils at baseline and at 1-year follow-up, the patients were classified into four groups with 250/μL as a cutoff value: consistently high (CH), consistently low (CL), variably increasing (VI), and variably decreasing (VD). We compared rates of acute exacerbations (AEs) according to ICS use in each group after calibration of severity using propensity score matching.Results: Of 2,221 COPD patients, 618 were analyzed and a total of 125 (20%), 355 (57%), 63 (10%), and 75 (12%) patients were classified into the CH, CL, VI, and VD groups, respectively. After calibration, we found that ICS users tended to have a lower AE rate in the CH group (RR 0.41, 95% CI 0.21– 0.74) and VI group (RR 0.45, 95% CI 0.22– 0.88), but not in the CL group (RR 1.42, 95% CI 1.08– 1.89) and VD group (RR 1.71, 95% CI 1.00– 2.96).Conclusion: More than one-fifth of patients had an inconsistent blood eosinophil level after the 1-year follow-up, and the AE-COPD rate according to ICS differed based on variability in eosinophils. Regular follow-up of blood eosinophils is required for COPD patients.Keywords: COPD, eosinophils, inhaled corticosteroids, acute exacerbations of COPD, COPD treatment

Ming-Yuan Hong,1,2 Chih-Chia Hsieh,1,2 Chao-Yung Yang,1 Chung-Hsun Lee,1,2 Wen-Chien Ko,2,3 Ching-Chi Lee1,3– 5 1Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Medicine, National Cheng Kung University Medical College, Tainan, Taiwan; 3Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4Department of Adult Critical Care Medicine, Tainan Sin-Lau Hospital, Tainan, Taiwan; 5Graduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, Tainan, TaiwanCorrespondence: Wen-Chien KoDivision of Infectious Disease, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng Li Road, Tainan 70403, TaiwanTel +886-6-2353535 ext. 3596Fax +886-6-2752038Email winston3415@gmail.comChing-Chi LeeGraduate Institute of Medical Sciences, College of Health Sciences, Chang Jung Christian University, No.1, Changda Rd., Gueiren District., Tainan City 71101, TaiwanTel +886-6-2785123 Ext 3326Fax +886-6-2990586Email chichingbm85@gmail.comIntroduction: Klebsiella pneumoniae is a pathogen commonly found in community-onset bacteremia. It causes an invasive syndrome that is frequently presented by metastatic infections and abscesses elsewhere and that is necessary for surgical or drainage intervention. To achieve a scoring algorithm to identify patients with community-onset K. pneumoniae bacteremia (CoKPB) who are at risk for abscess occurrences, a retrospective cohort study consisting of adults with CoKPB was conducted.Methods: A 6-year cohort study consisting of adults having community-onset monomicrobial K. pneumoniae bacteremia was conducted. In addition to clinical variables collected from medical records, the hypermucoviscosity (HMV)-related gene (rmpA and magA) and an HMV phenotype were integrated into the proposed scoring algorithm.Results: Of the 258 eligible adults, only 79 (30.6%) had abscesses related to bacteremia. Besides the presence of magA (ie, capsular serotype K1) and the HMV-phenotype, five clinical predictors were significantly associated with abscesses in a multivariate analysis: male gender, comorbidities with diabetes mellitus or neurological disorders, recent chemotherapy, and high c-reactive protein levels. Together, these predictors were used to calculate the CoKPB abscess score. Based on the scoring algorithm, a cut-off value of +2 yielded the high sensitivity (93.7%) and the acceptable specificity (50.8%); the area under the ROC curve was 0.83.Conclusion: A simple scoring algorithm that has substantial sensitivity and satisfactory specificity was proposed and the importance of the HMV phenotype or capsular K1 serotype was emphasized. The proposed predictive model needs external validation, but this scoring algorithm might be convenient and useful for clinicians.Keywords: Klebsiella pneumoniae, bacteremia, hepatic abscesses, extrahepatic abscesses

Joon Young Choi,1 Hyoung Kyu Yoon,2 Kyeong-Cheol Shin,3 So-Young Park,4 Chang Youl Lee,5 Seung Won Ra,6 Ki Suck Jung,7 Kwang Ha Yoo,4 Chang-Hoon Lee,8 Chin Kook Rhee9 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, St. Vincent’s Hospital, The Catholic University of Korea, Suwon, Republic of Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 3Division of Pulmonology and Allergy, Regional Center for Respiratory Disease, Yeungnam University Medical Center, Daegu, Republic of Korea; 4Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Republic of Korea; 5Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Chuncheon, Republic of Korea; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea; 7Division of Pulmonary Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 9Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Chin Kook RheeDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpodaero, Seochogu, Seoul 06591, Republic of KoreaTel +82 2 2258 6067Fax +82 2 599 3589Email chinkook77@gmail.comPurpose: Previous studies have used various definitions to classify chronic obstructive pulmonary disease (COPD) patients into chronic bronchitis (CB) and non-CB patients. This study was performed to identify differences among three definitions of CB based on the classical method, St. George’s Respiratory Questionnaire (SGRQ), and the CAT (COPD Assessment Test) score.Patients and methods: We extracted data from the multicenter Korea COPD Subgroup Study (KOCOSS) cohort, for which patients recruited from among 47 medical centers in South Korea beginning in April 2012. Patients were classified according to three different definitions of CB: 1) classical definition; 2) SGRQ (using questions regarding cough and sputum); and 3) CAT score (comprising cough [CAT1] and sputum [CAT2] subscale scores).Results: A total of 2694 patients were enrolled in this study. The proportions of CB were 10.8%, 35.8%, and 24.0% according to the classical, SGRQ, and CAT definitions, respectively. The three definitions yielded consistently significant differences between CB and non-CB patients in modified Medical Research Council dyspnea scale CAT score, SGRQ score, number of moderate-to-severe exacerbations per year and forced expiratory volume in 1 second. By three definitions, CB consistently predicted future risk of exacerbation. The kappa coefficient of agreement between the classical definition and SGRQ definition was 0.29, that of the classical definition and CAT definition was 0.32, and that of the SGRQ definition and CAT definition was 0.44.Conclusion: Patients with CB according to the new definitions based on SGRQ or CAT score showed similar clinical characteristics to those defined according to the classical definition. The new CB definitions may be used as alternatives to the classical definition.Keywords: chronic bronchitis, CAT score, SGRQ score, chronic obstructive pulmonary disease, KOCOSS database

Min-Hwan Kim,1 Ki-Taek Kim,2 Seo-Yeon Sohn,1 Jae-Young Lee,3 Chang Hyung Lee,4 Hee Yang,4 Bo Kyung Lee,5 Ki Won Lee,4,5 Dae-Duk Kim1 1College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; 2College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam, Republic of Korea; 3College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; 4Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea; 5Research & Development Center, BOBSNU Co., Ltd., Suwon, Gyeonggi-Do 16229, Republic of KoreaCorrespondence: Dae-Duk KimCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of KoreaTel +82 2 880 7870Fax +82 2 873 9177Email ddkim@snu.ac.krBackground: 20(S)-Protopanaxadiol (PPD) has a higher anti-wrinkle effect than the other glycone forms of ginsenosides. However, as PPD has low solubility in water and a high molecular weight, it cannot easily penetrate the stratum corneum layer, which is the rate-limiting step of topical skin delivery. Thus, the objective was to enhance the topical skin deposition of PPD using an optimized nanostructured lipid carriers (NLC) formulation. NLC formulations were optimized using a Box-Behnken design.Materials and methods: NLC formulations were optimized using a Box-Behnken design, where the amount of PDD (X1), volume of the liquid lipid (X2), and amount of surfactant (X3) were set as the independent variables, while the particle size (Y1), polydispersity index (PDI) (Y2), and entrapment efficiency (EE) (Y3) were dependent factors. An in vitro deposition study was performed using Strat-M® and human cadaver skin, while in vivo skin irritation effect of the NLC formulation was evaluated in humans.Results: An NLC was successfully prepared based on the optimized formulation determined using the Box-Behnken design. The particle size, PDI, and EE of the NLC showed less than 5% difference from the predicted values. The in vitro deposition of PPD after the application of the NLC formulation on a Strat-M® artificial membrane and human cadaver skin was significantly higher than that of the controls. Moreover, NLC formulations with and without PDD were not skin irritants in a human study.Conclusion: An NLC formulation for the topical delivery of PPD was successfully optimized using the Box-Behnken design, and could be further developed to enhance the topical skin deposition of PPD.Keywords: Box-Behnken design, 20(S)-Protopanaxadiol, nanostructured lipid carrier; NLC, Strat-M™, topical delivery

Chen-Hung Lee,1 Ming-Jer Hsieh,1 Shang-Hung Chang,1 Kuo-Chun Hung,1 Chao-Jan Wang,2 Ming-Yi Hsu,2 Jyuhn-Huarng Juang,3 I-Chang Hsieh,1 Ming-Shien Wen,1 Shih-Jung Liu4,5 1Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Linkou, Taiwan; 2Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan; 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, Tao-Yuan, Taiwan; 4Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, Taiwan; 5Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Tao-Yuan 33305, TaiwanCorrespondence: Shih-Jung LiuBiomaterials Lab, Department of Mechanical Engineering, Chang Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan 333, TaiwanTel +886 3 211 8166Fax +886 3 211 8558Email profsjliu5347@gmail.comBackground: The high lifetime risk of vascular disease is one of the important issues that plague patients with diabetes mellitus. Systemic oral vildagliptin administration favors endothelial recovery and inhibits smooth muscle cell (SMC) proliferation. However, the localized release of vildagliptin in the diabetic vessel damage has seldom been investigated.Research design and methods: In this work, nanofiber-eluting stents that loaded with vildagliptin, a dipeptidyl peptidase-4 enzyme (DPP-4) inhibitor, was fabricated to treat diabetic vascular disease. To prepare nanofibers, the poly (D,L)-lactide-co-glycolide (PLGA) and vildagliptin were mixed using hexafluoroisopropanol and electrospinning process. In vitro and in vivo release rates of the vildagliptin were characterized using high-performance liquid chromatography.Results: Effective vildagliptin concentrations were delivered for more than 28 days from the nanofibrous membranes coating on the surface of the stents in vitro and in vivo. The vildagliptin-eluting PLGA membranes greatly accelerated the recovery of diabetic endothelia and reduced SMC hyperplasia. The type I collagen content of the diabetic vascular intimal area that was treated by vildagliptin-eluting stents was lower than that of the non-vildagliptin-eluting group.Conclusion: The experimental results revealed that stenting with vildagliptin-eluting PLGA membranes could potentially promote healing for diabetic arterial diseases.Keywords: re-endothelialization, neointimal hyperplasia, vildagliptin, biodegradable drug-eluting nanofibers

Wei-Chen Tai,1 Chih-Ming Liang,1 Kuo-Wei Bi,2 Chung-Mou Kuo,1 Lung-Sheng Lu,1 Cheng-Kun Wu,1 Shih-Cheng Yang,1 Yuan-Hung Kuo,1 Chen-Hsiang Lee,3 Chih-Fang Huang,4 Chien-Ning Hsu,5 Pin-I Hsu,6 Deng-Chyang Wu,7 Tsung-Hui Hu,1,8 Keng-Liang Wu,1,8 Seng-Kee Chuah1,8 1Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Division of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Division of Family Physician, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 5Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 6Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, National Yang-Ming University, Kaohsiung, Taiwan; 7Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan; 8Chang Gung University College of Medicine, Taoyuan City, TaiwanCorrespondence: Seng-Kee Chuah; Chung-Mou KuoDivision of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung 833, TaiwanTel +886 7 731 7123 ext. 8301Fax +886 7 732 2402Email chuahsk@seed.net.tw; kuo51116@gmail.comPurpose: Steadily maintaining high intra-gastric PH is the major factor for successful Helicobacter pylori (H.pylori) eradication. It is important to search for a stronger PPI. Dexlansoprazole MR is a dual delayed release formulation PPI taken once daily which is capable of maintaining longer duration of high intra-gastric PH. It is very effective in treating gastroesophageal disease but reports on H, pylori eradication is very rare. This study sought to compare dexlansoprazole MR-based concomitant treatment and lansoprazole-based concomitant treatment in H. pylori infection and to investigate the factors that affect the eradication rates.Methods: Two hundred two participants with H. pylori infection were included and randomly assigned to seven days of dexlansoprazole MR-based concomitant therapy (dexlansoprazole MR 60 mg once daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily; DACM group) or a seven days of lansoprazole-based concomitant therapy (lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily, and metronidazole 500 mg twice daily; LACM group). The participants were asked to perform urea breath tests eight weeks later.Results: The eradication rates in the DACM group were 86.1% [95% confidence interval (CI): 77.8%–92.2%] in the ITT analysis and 90.6% (95% CI: 82.9%–95.6%) in the PP analysis, respectively, as compared with 90.1% (95% CI: 82.6%–95.2%) and 92.6% (95% CI: 85.5%–96.9%) (p=0.384 and p=0.572, respectively) in the LACM group for the same analyses. The adverse event rates were 11.5% in the DACM group and 10.2% in the LACM group (p=0.779).Conclusion: As a first-line H. pylori treatment regimen, dexlansoprazole MR-based concomitant therapy attained a successful eradication rate of 90%, which was non inferior to that of lansoprazole-based concomitant treatment.ClinicalTrials.gov identifier: NCT03829150.Keywords: Helicobacter pylori eradication, strong proton-pump inhibitor, dexlansoprazole MR-based concomitant therapy, lansoprazole-based concomitant therapy, antibiotic resistance

Yu-Min Yeh,1,2 Chun-Hui Lee,2 Shang-Hung Chen,2,3 Chung-Ta Lee,4 Yi-Lin Chen,4 Bo-Wen Lin,5 Shao-Chieh Lin,5 Ren-Hao Chan,5 Jenq-Chang Lee,5 Meng-Ru Shen,6,7 Peng-Chan Lin21Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 3National Institute of Cancer Research, National Health Research Institutes, Hsinchu, Taiwan; 4Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 5Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 6Department of Pharmacology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 7Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, TaiwanCorrespondence: Peng-Chan LinDepartment of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng-Li Road, Tainan 704, TaiwanTel +886 6 235 3535, ext. 4620Email pengchanlin@gmail.comPurpose: Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in colorectal cancer (CRC). Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) have been used to determine HER2-positive CRCs; however, the clinical utility of next-generation sequencing (NGS)-based techniques for determining HER2 status in CRC has been limited. Here, we detail our experience regarding the assessment of HER2 alterations in a CRC cohort.Materials and methods: We prospectively enrolled 73 CRC patients who underwent surgery and received adjuvant oxaliplatin treatment. We then examined HER2 alterations using the Oncomine Comprehensive Assay version 1, as well as clinical outcomes, in this cohort.Results: Using the NGS-based assay, HER2 copy number gains in 12 of 73 CRCs were determined to range from 2.74 to 92.62. Of these 12 tumors, 6 had HER2 high-level copy number gain (92.6, 57.9, 57.0, 52.0, 35.2, and 8.42) and were all defined as HER2-positive CRC using HERACLES Diagnostic Criteria. Nevertheless, other 6 patients with low-level copy number gain (ranging from 2.74 to 3.04) and the remaining 61 patients without increase in HER2 copy number were all HER2-negative. Among the 6 HER2-positive CRCs, KRAS and PIK3CA mutations were detected in 1 (17%; G13D) and 2 (33.3%; 1 Q546R and 1 H1047R) patients, respectively. Moreover, 2 of the 6 (33.3%) HER2-positive patients had recurrent disease, while one patient had a partial response after anti-HER2 therapy.Conclusion: NGS-based tools could assist in the simultaneous detection of HER2 and other genomic alterations in patients with CRC. Only CRCs with HER2 high-level copy number gain were HER2-postive by current diagnostic criteria.Keywords: HER2, colorectal cancer, next generation sequencing, PIK3CA

Hee-Young Yoon,1 So Young Park,1 Chang Hoon Lee,2 Min-Kwang Byun,3 Joo Ock Na,4 Jae Seung Lee,5 Won-Yeon Lee,6 Kwang Ha Yoo,7 Ki-Suck Jung,8 Jin Hwa Lee11Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Ewha Womans Seoul Hospital, Ewha Womans University, Seoul, Korea; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; 3Division of Pulmonary Medicine, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Korea; 4Division of Pulmonology, Department of Internal Medicine, Soonchunhyang University, College of Medicine, Cheonan, Korea; 5Department of Pulmonary and Critical Care Medicine, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea; 6Department of Internal Medicine, Wonju Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea; 7Department of Internal Medicine, Konkuk University College of Medicine, Seoul, Korea; 8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, KoreaPurpose: In patients with COPD, acute exacerbation (AE) is not only an important determinant of prognosis, but also an important factor in choosing therapeutic agents. In this study, we evaluated the usefulness of COPD subtypes identified through cluster analysis to predict the first AE. Patients and methods: Among COPD patients in the Korea COPD Subgroup Study (KOCOSS) cohort, 1,195 who had follow-up data for AE were included in our study. We selected seven variables for cluster analysis – age, body mass index, smoking status, history of asthma, COPD assessment test (CAT) score, post-bronchodilator (BD) FEV1 % predicted, and diffusing capacity of carbon monoxide % predicted. Results: K-means clustering identified four clusters for COPD that we named putative asthma-COPD overlap (ACO), mild COPD, moderate COPD, and severe COPD subtypes. The ACO group (n=196) showed the second-best post-BD FEV1 (75.5% vs 80.9% [mild COPD, n=313] vs 52.4% [moderate COPD, n=345] vs 46.7% [severe COPD, n=341] predicted), the longest 6-min walking distance (424 m vs 405 m vs 389 m vs 365 m), and the lowest CAT score (12.2 vs 13.7 vs 15.6 vs 17.5) among the four groups. ACO group had greater risk for first AE compared to the mild COPD group (HR, 1.683; 95% CI, 1.175–2.410). The moderate COPD and severe COPD group HR values were 1.587 (95% CI, 1.145–2.200) and 1.664 (95% CI, 1.203–2.302), respectively. In addition, St. George’s Respiratory Questionnaire score (HR: 1.019; 95% CI, 1.014–1.024) and gastroesophageal reflux disease were independent factors associated with the first AE (HR: 1.535; 95% CI, 1.116–2.112). Conclusion: Our cluster analysis revealed an exacerbator subtype of COPD independent of FEV1. Since these patients are susceptible to AE, a more aggressive treatment strategy is needed in these patients.Keywords: clustering, prognosis, phenotype, asthma-COPD overlap, exacerbation, comorbidity

Yu-Shuan Chen,1–3 Yu-Han Chiu,3 Yuan-Sheng Li,3 En-Yi Lin,3,4 Dean-Kuo Hsieh,5 Chia-Hung Lee,3 Mao-Hsuan Huang,1 Hong-Meng Chuang,1 Shinn-Zong Lin,1,6 Horng-Jyh Harn,1,7,* Tzyy-Wen Chiou3,*1Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, Republic of China; 2Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, Republic of China; 3Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China; 4Department of Chemistry, National Dong Hwa University, Hualien, Taiwan, Republic of China; 5Department and Graduate Institute of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan, Republic of China; 6Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, Republic of China; 7Department of Pathology, Hualien Tzu Chi Hospital, Tzu Chi University, Hualien, Taiwan, Republic of China*These authors contributed equally to this workIntroduction: Kolliphor® EL (K-EL) is among the most useful surfactants in the preparation of emulsions. However, it is associated with low hydrophobic drug loading in the resulting emulsified formulation.Methods: In this study, a formulation for intranasal administration of butylidenephthalide (Bdph), a candidate drug against glioblastoma (GBM), was prepared. Physical characteristics of the formulation such as particle size, zeta potential, conductivity, and viscosity were assessed, as well as its cytotoxicity and permeability, in order to optimize the formulation and improve its drug loading capacity.Results: The optimized formulation involved the integration of polyethylene glycol 400 (PEG 400) in K-EL to encapsulate Bdph dissolved in dimethyl sulfoxide (DMSO), and it exhibited higher drug loading capacity and drug solubility in water than the old formulation, which did not contain PEG 400. Incorporation of PEG 400 as a co-surfactant increased Bdph loading capacity to up to 50% (v/v), even in formulations using Kolliphor® HS 15 (K-HS15) as a surfactant, which is less compatible with Bdph than K-EL. The optimized Bdph formulation presented 5- and 2.5-fold higher permeability and cytotoxicity, respectively, in human GBM than stock Bdph. This could be attributed to the high drug loading capacity and the high polarity index due to DMSO, which increases the compatibility between the drug and the cell. Rats bearing a brain glioma treated with 160 mg/kg intranasal emulsified Bdph had a mean survival of 37 days, which is the same survival time achieved by treatment with 320 mg/kg stock Bdph. This implies that the optimized emulsified formulation required only half the Bdph dose to achieve an efficacy similar to that of stock Bdph in the treatment of animals with malignant brain tumor.Keywords: glioblastoma, polyethylene glycol 400, butylidenephthalide, loading capacity, permeability, intranasal administration

Chih-Chien Yao,1 Chung-Mou Kuo,1 Chien-Ning Hsu,2 Shih-Cheng Yang,1 Cheng-Kun Wu,1 Wei-Chen Tai,1 Chih-Ming Liang,1 Keng-Liang Wu,1 Chih-Fang Huang,3 Kuo-Wei Bi,4 Chen-Hsiang Lee,5 Seng-Kee Chuah11Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan; 2Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung and School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Division of Family physician, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 5Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, TaiwanPurpose: To assess the difference of the first-line therapy for Helicobacter pylori in patients with or without type 2 diabetes (DM) and to investigate the clinical factors influencing treatment outcomes.Patients and methods: In total, 719 patients with H. pylori infection were treated with 7-day standard first-line triple therapy, of whom 182 did and 537 did not have DM. Propensity score matched at a 1:2 ratio – for age, sex and body mass index was performed for the two groups, yielding a DM group with 147 patients and a non-DM group with 249 matched controls for analysis. Urea breath test was performed 6–8 weeks after treatment. Clinical and laboratory parameters were collected for identifying factors associated with failed eradication.Results: H. Pylori was eradicated in 74.1% (95% confidence interval [CI] =66.2–81.0) of the DM group and 85.3% (95% CI =80.8–89.4) of the non-DM group (p=0.005). Of 51 gastric biopsy samples cultured for H. pylori, 41 were positive. In the DM group, the rates of resistance to amoxicillin, clarithromycin, levofloxacin, and tetracycline were 0%, 50.0%, 50.0% and 0%, respectively. In the non-DM group, the comparable proportions were 2.9%, 17.1%, 22.9%, and 0%, respectively. Univariate analysis revealed that DM (Odds ratio [OR], 1.771, 95% CI, 1.167–2.668, p=0.006), clarithromycin resistance (OR, 15.273; 95% CI, 1.687–138.269; p=0.015), and amoxicillin resistance (OR, 4.672; 95% CI, 2.431–8.979; p90% eradication.Keywords: Helicobacter pylori infection, standard triple therapy

Bharath Kumar Velmurugan,1 Hsin-Kai Wang,2,3 Chia-Min Chung,4,5 Chien-Hsun Lee,6 Lan-Ru Huang,7 Kun-Tu Yeh,6,7* Shu-Hui Lin6,8*1Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam; 2Public Health Bureau, Tainan City Government, Tainan City, Taiwan; 3Jenteh Junior College of Medicine, Nursing and Management, Taiwan; 4Graduate Institute of BioMedical Sciences, China Medical University, Taichung, Taiwan; 5Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan; 6Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan; 7School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 8Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan *These authors contributed equally to this workIntroduction: Oral cancer is a prevalent form of cancer worldwide, particularly in Taiwan, and mechanisms involved in oral squamous cell carcinoma (OSCC) progression remain relatively unknown. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncoprotein, is aberrantly expressed in many human malignant tumors including oral cancer. However, the expression and role played by CIP2A in oral cancer pathogenesis remain obscure.Methods: In this study, immunohistochemistry was used to analyze CIP2A expression between OSCC tissues and their adjacent noncancerous tissues. Furthermore, associations between CIP2A expression and histopathological parameters were investigated.Results: In this study, we showed that CIP2A was overexpressed in most of the OSCC tissues. High CIP2A expression was significantly associated with moderate/poor tumor differentiation (P=0.02). No significant association was found between CIP2A expression and other clinical parameters. Kaplan–Meier analysis revealed that high CIP2A expression showed poorer survival rates than those with low CIP2A expression (P=0.047). Multivariate Cox regression analysis indicated that CIP2A expression, N stage, American Joint Committee on Cancer stage and clinical therapy were independent prognostic factors for survival.Conclusion: Thus, our study suggests that CIP2A is an independent prognostic marker for OSCC and a novel target for OSCC treatment.Keywords: CIP2A, OSCC: prognosis, survival, Taiwan

Kiran Reddy Kanubaddi, Shin-Han Yang, Li-Wei Wu, Chia-Hung Lee, Ching-Feng Weng Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan Abstract: Alzheimer’s disease (AD), an age-related neurodegenerative disease, the most common causes of dementia is a multifactorial pathology categorized by a complex etiology. Numerous nutraceuticals have been clinically evaluated, but some of the trials failed. However, natural compounds have some limitations due to their poor bioavailability, ineffective capability to cross the blood–brain barrier, or less therapeutic effects on AD. To overcome these disadvantages, nanoparticle-conjugated natural products could promote the bioavailability and enhance the therapeutic efficacy of AD when compared with a naked drug. This application generates and implements new prospect for drug discovery in neurodegenerative diseases. In this article, we confer AD pathology, review natural products in clinical trials, and ascertain the importance of nanomedicine coupled with natural compounds for AD. Keywords: Alzheimer’s disease, amyloid beta, bioavailability, natural products, nutraceuticals

Chen-Hsiang Lee,1 I-Ling Chen,2 Chia-Chin Li,3 Chun-Chih Chien31Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, TaiwanBackground: Flomoxef is potentially effective against β-lactamase-producing Enterobacteriaceae because limited clinical data demonstrate its effectiveness against Enterobacteriaceae bloodstream infections (BSIs) based on its minimum inhibitory concentrations (MICs). This study was conducted to determine the optimal breakpoints based on the survival of patients with Enterobacteriaceae BSIs treated with flomoxef.Methods: The 30-day crude mortality rate was analyzed among 224 adults who initiated flomoxef monotherapy for Enterobacteriaceae BSIs at a medical center over a 3-year period, according to the flomoxef MICs of the initial isolates. The outcome was evaluated by classification and regression tree modeling and by logistic regression analysis.Results: The 30-day crude mortality was approximately two fold greater in patients whose isolates had flomoxef MICs of ≥2 mg/L (54.9% [62/113]) than in those with isolates with MICs of ≤1 mg/L (26.1% [29/111]); the differences were significant in bivariate analysis (P

Cheng-Hung Lee,1 Ming-Jer Hsieh,1 Kuo-Sheng Liu,2,3 Che-Wei Cheng,3 Shang-Hung Chang,1 Shih-Jung Liu,3,4 Chao-Jan Wang,5 Ming-Yi Hsu,5 Kuo-Chun Hung,1 Yung-Hsin Yeh,1 Wei-Jan Chen,1 I-Chang Hsieh,1 Jyuhn-Huarng Juang,6 Ming-Shien Wen1 1Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Chang Gung University College of Medicine, Tao-Yuan, Taiwan; 2Department of Cardiovascular Surgery, Chang Gung Memorial Hospital-Linkou, Tao-Yuan, Taiwan; 3Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, Taiwan; 4Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan; 5Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan; 6Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, Tao-Yuan, Taiwan Objective: The current treatment of atherosclerotic coronary heart disease with limus-eluting stents can lead to incomplete endothelialization and substantial impairment of arterial healing relative to treatment with bare-metal stents. The sustained and local delivery of ticagrelor, a reversibly binding P2Y12 receptor inhibitor, using hybrid biodegradable nanofibers/stents, was developed to reduce neointimal formation and endothelial dysfunction.Methods: In this investigation, a solution of ticagrelor, poly(D,L)-lactide-co-glycolide, and hexafluoro isopropanol was electrospun to fabricate ticagrelor-eluting nanofibrous drug-eluting stents. The in vitro and in vivo ticagrelor concentrations were measured using a high-performance liquid chromatography assay. The effectiveness of ticagrelor-eluting stents was examined relative to that of sirolimus-eluting stents. Results: Adequate ticagrelor levels were detected for four weeks in vitro. Less HES5-positive labeling was found near the ticagrelor-eluting stented vessels (0.33±0.12) than close to the sirolimus-eluting stented vessels (0.57±0.15) (p

Ching-Yen Tsai,1 Chen-Hsiang Lee,1,2 I-Ling Chen3 1Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2College of Medicine, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan Background: Recent reports have described decreased effectiveness of teicoplanin in the treatment of bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) with teicoplanin minimal inhibitory concentration (MIC) ≥1.5 mg/L. Consensus guidelines recommend considering use of alternative agents for MRSA infections involving a higher teicoplanin MIC, despite of limited data to support this recommendation. Patients and methods: To compare the clinical outcome among patients with bacteremia due to MRSA with teicoplanin MIC ≥1.5 mg/L, we included patients who received high-dose daptomycin (≥8 mg/kg/day) and those who received standard-dose (6 mg/kg/day) or high-dose (6 mg/kg/12 hours) maintenance teicoplanin. The primary endpoint was a favorable outcome, defined as the resolution of clinical signs and symptoms and a negative culture report at the end of therapy. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. Results: Of 142 patients eligible for inclusion, 28 (19.7%) were treated with high-dose daptomycin, 27 (19.0%) with high-dose teicoplanin, and 87 (61.3%) with standard-dose teicoplanin. In multivariate regression analysis, Pittsburgh bacteremia score ≥4 (OR, 5.3; 95% CI, 1.9–14.5) was independently associated with an unfavorable outcome. After propensity-score matching with age and Pittsburgh bacteremia score ≥4, patients on high-dose daptomycin were more likely to have favorable outcomes than those on standard-dose teicoplanin (74.1% vs 42.6%; P=0.02). However, there was no significant difference in terms of favorable outcomes (P=0.12) between patients receiving high-dose daptomycin and those receiving high-dose teicoplanin after the same propensity-score matching. Conclusion: Treatment with high-dose daptomycin resulted in significantly better outcomes than with standard-dose teicoplanin in the treatment of MRSA bacteremia with teicoplanin MIC ≥1.5 mg/L. However, the clinical outcome of the patients receiving high-dose teicoplanin was similar to that of the patients receiving high-dose daptomycin. Keywords: gram-positive bacteria, antimicrobial susceptibility, pharmacodynamics, glycopeptide, lipopeptide

Jin Hwa Song,1 Chang-Hoon Lee,1 Soo-Jung Um,2 Yong Bum Park,3 Kwang Ha Yoo,4 Ki Suck Jung,5 Sang-Do Lee,6 Yon-Mok Oh,6 Ji Hyun Lee,7 Eun Kyung Kim,7 Deog Kyeom Kim8,9 On behalf of KOLD, KOCOSS, and SNU airway registry investigators 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Division of Respiratory Medicine, Department of Internal Medicine, Dong-A University College of Medicine, Dong-A University Medical Center, Busan, Republic of Korea; 3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Seoul, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea; 5Division of Pulmonary Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical School, Anyang Gyeonggi-do, Republic of Korea; 6Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea; 7Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam Gyeonggi-do, Republic of Korea; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 9Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Purpose: While GOLD classification has been revised, its clinical impacts on outcomes of COPD patients have not been widely evaluated in real-world cohorts.Materials and methods: According to 2007, 2013, and 2017 GOLD classifications, distribution and clinical characteristics of group-shifted patients and the risk of acute exacerbation were analyzed in combined Korean COPD cohorts. Future risk for annual moderate-to-severe exacerbation was estimated as incidence rate ratio (IRR) and compared by groups.Results: Among 1,880 COPD patients, in GOLD 2017 classification, groups B and A were increased to 61.2% and 22.2% of total population, while group C was shrunken to 2.2% and patients with higher risk were decreased (16.6% in GOLD 2017 vs 44.7% in GOLD 2013). The kappa coefficient of agreement of both systems was 0.581 (agreement 71.7%). Groups B and D showed higher IRR of moderate-to-severe exacerbation than group A (IRR 2.4 and 5.3 respectively, P

Chen-Hsiang Lee,1,2 Seng-Kee Chuah,2,3 Wei-Chen Tai,2,3 I-Ling Chen4 1Department of Internal Medicine, Division of Infectious Diseases, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Internal Medicine, Division of Gastroenterology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Department of Pharmacology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan Objective: Platelets catalyze the development of hyperinflammation and microthrombosis and contribute to increases in accumulation of circulating platelet-leukocyte complex, the key event in the development of disseminated infection. Subjects and methods: To determine the relationships of platelet activity in diabetic patients with invasive Klebsiella pneumoniae liver abscess syndrome (IKLAS), a total of 175 diabetic patients with community-acquired Klebsiella pneumoniae (KP) bacteremia were included in this study. We compared the platelet reactivity of 40 patients with IKLAS, 40 patients with non-IKLAS, and eight healthy controls using a whole-blood flow cytometry-based assay. Results: Patients who were infected with strains expressing K1/K2 serotype (adjusted odds ratio [AOR], 8.81; 95% CI, 2.18–35.53) and those with HbA1c ≥9% (AOR, 4.97; 95% CI, 1.73–14.23) were more likely to present with IKLAS, whereas those who had recent therapy with aspirin (AOR, 0.17; 95% CI, 0.04–0.79) were less likely to present with IKLAS. Among patients with IKLAS, patients with a poor glycemic control were more likely to present with hepatic venous thrombophlebitis than those with suboptimal or good glycemic control (P=0.03). Patients with IKLAS had a higher median fluorescence intensity of the platelet membrane expression of P-selectin than those with non-IKLAS (78.0 vs 28.0, P

Hsiang Tso Huang,1 Hsin-Ming Wang,1 Shih-Cheng Yang,1 Wei-Chen Tai,1 Chih-Ming Liang,1 Keng-Liang Wu,1 Chen-Hsiang Lee,2 Seng-Kee Chuah1 1Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niao-Song District, Kaohsiung 833, Taiwan; 2Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Niao-Song District, Kaohsiung 833, Taiwan Purpose: To assess the efficacy of amoxicillin, tetracycline, high-dose metronidazole, and a proton-pump inhibitor for third-line Helicobacter pylori eradication. Methods: We enrolled 70 consecutive patients who had registered, failed to respond to two rounds of H. pylori eradication, and undergone endoscopy for H. pylori culture. Seven patients were lost to follow-up. Patients were treated according to the results of antibiotic-susceptibility testing reports (cultured group, n=39). Those who failed the H. pylori culture were prescribed 14-day quadruple therapy containing esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, tetracycline 500 mg four times daily, and metronidazole 500 mg three times daily (empirical group, n=24). A follow-up urea breath test was performed 8 weeks later. Results: Antibiotic-resistance rates were 79.5% (clarithromycin), 94.9% (levofloxacin), 66.7% (metronidazole), 2.6% (amoxicillin), and 0 (tetracycline). Eradication rates attained by the cultured and empirical group were 89.7% (95% CI 72.7%–97.1%) and 58.3% (95% CI 36.6%–77.9%) in per-protocol analysis (P=0.004) and 81.4% (95% CI 66.6%–91.6%) and 51.8% (95% CI 31.9%–71.3%) in intention-to-treat analysis (P=0.014), respectively. Culture-guided therapy was the only clinical factor influencing the efficacy of H. pylori eradication (OR 0.16, 95% CI 0.04–0.60; P=0.006). Despite the high metronidazole-resistance rate (66.7%) after two treatment failures, the eradication rate in patients with this condition was 84%. Conclusion: Empirical 14-day modified quadruple therapy is not acceptable as an alternative third-line rescue H. pylori treatment. The success rate of third-line susceptibility-guided treatment was near 90%. This report is valuable as a reminder to medical practitioners that rather than a try-and-see approach, susceptibility-guided therapy should always be considered whenever possible for patients who have undergone several treatment failures. Keywords: amoxicillin-resistance, metronidazole-resistance, empirical quadruple therapy, culture-guided therapy

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

Ching-Yen Tsai,1 Chen-Hsiang Lee,1,2 Chun-Chih Chien,3 I-Ling Chen4 1Division of Infectious Diseases, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Department of Pharmacology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan Objectives: Teicoplanin, a glycopeptide, is regarded as among the drug choices for methicillin-resistant Staphylococcus aureus (MRSA) infections. Few studies have evaluated the relationship between teicoplanin minimal inhibitory concentrations (MICs) and outcomes among patients with serious MRSA infections. Subjects and methods: We investigated the relationship between teicoplanin maintenance dose and clinical outcomes, on the completion of teicoplanin therapy, in bacteremia patients with MRSA infection, with different teicoplanin MICs. A total of 146 adult patients with MRSA bacteremia were enrolled at Kaohsiung Chang Gung Memorial Hospital between September 2012 and September 2015. Results: A higher number of patients in the high-dose regimen group (6 mg/kg/12 h) had favorable outcomes than those in the standard-dose regimen group (6 mg/kg/24 h) (84.1% vs 41.2%; p

Shang-Hung Chang,1 Cheng-Hung Lee,1 Yung-Hsin Yeh,1 Shih-Jung Liu,2 Chao-Jan Wang,3 Ming-Yi Hsu,3 Wei-Jan Chen1 1Cardiovascular Department, Chang Gung Memorial Hospital, Chang-Gung University College of Medicine, Tao-Yuan, Taiwan; 2Department of Mechanical Engineering, Chang Gung University, Tao-Yuan, Taiwan; 3Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan Background: The drug-eluting stent is a standard approach for the treatment of coronary artery disease. Propylthiouracil (PTU), an antithyroid drug, has been proven to suppress neointimal formation after balloon injury. Materials and methods: This study used a biodegradable polymer coating with PTU to test its effects on platelet function, re-endothelialization, and neointimal formation after vascular injury. Electrospinning was used to fabricate hybrid stents and generate PTU-loaded nanofibers.Results: PTU-eluting stents maintained a stable release of PTU for 3 weeks. The PTU-coated stent markedly decreased the neointimal formation induced by vascular injury in the descending aorta of rabbits. Moreover, the PTU coating reduced platelet adhesion on the surface of the biodegradable membrane, which was reflected by the decreased expression of adhesion molecule in PTU-treated endothelial cells. The PTU coating enhanced re-endothelialization in injured aortas. In vitro, PTU exerted less suppressive effect on the proliferation and migration of endothelial cells than on those of vascular smooth muscle cells. Furthermore, treatment of endothelial cells with PTU induced phosphorylation (Ser1177) of endothelial nitric oxide synthase as well as its association with heat shock protein 90, supporting the protective role of PTU in endothelial function. The level of thyroid-stimulating hormone remained unchanged during the experimental period. Conclusion: This study indicates that PTU can be released locally and steadily in injured aortas, with some local effects but without systemic effects. Furthermore, PTU-coated stents may have beneficial effects on neointimal formation, endothelial cell, and platelet functions. Keywords: drug-eluting stent, propylthiouracil, neointimal formation, endothelial cell, platelet

I-Ling Chen,1,2 Chen-Hsiang Lee,2–4 Shih-Wen Ting,2,3 Lily Yu-Chin Wang1 1Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Infection Control Team, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4College of Medicine, Chang Gung University, Kaohsiung, Taiwan Objectives: The increasing number of reports on infections due to carbapenem-resistant Gram-negative bacilli (GNB) has raised concerns, because they have complicated empiric or guided antibiotic therapy for critically ill patients. We aimed to develop a scoring system to predict nosocomial imipenem-resistant GNB (IR-GNB) septicemia among the critically ill patients.Materials and methods: The study included critically ill adult patients with nosocomial GNB septicemia at Kaohsiung Chang Gung Memorial Hospital (CGMH) in 2013–2015, and the scoring system for predicting IR-GNB septicemia was developed, followed by prospective validation conducted among patients at Linkou CGMH and Kaohsiung CGMH between January and June, 2016.Results: In the development of the scoring system, 748 patients were included. The independent factors associated with IR-GNB septicemia were prior exposure (days) to carbapenems (adjusted odds ratio [aOR] per 1-day increase, 1.1; 1–3 days: 2 points, 4–6 days: 5 points, 7–9 days: 8 points, and ≥10 days: 13 points), use of mechanical ventilation (aOR 3.7; 5 points), prior colonization with IR-GNB strains (aOR 3.5; 5 points) within 30 days before the onset of GNB septicemia, and comorbid condition with chronic kidney disease (aOR 2.1; 3 points). The internal validation showed an area under the receiver operating characteristic curve (ROC) of 0.75; and an external validation among 314 patients showed similarly good performance (ROC 0.77). Youden’s index indicated the score of ≥6 as the best cutoff value with sensitivity of 75% and specificity of 79%.Conclusion: This scoring system might help clinicians stratify the risk for developing IR-GNB septicemia among critically ill patients and combined antibiotics may be used until antimicrobial de-escalation/adjustment is clearly indicated by the subsequently identified GNB and its susceptibility profile. Keywords: antimicrobial resistance, carbapenem, bacteremia, nosocomial infection, scoring system, outcome

Yong Suk Jo,1 Ho Il Yoon,2 Deog Kyeom Kim,3 Chul-Gyu Yoo,1 Chang-Hoon Lee1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea Background and objective: Guidelines recommend the use of simple but comprehensive tools such as COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ) to assess health status in COPD patients. We aimed to compare the ability of CAT and CCQ to predict exacerbation in COPD patients. Methods: We organized a multicenter prospective cohort study that included COPD patients. The relationships between CAT, CCQ, and other clinical measurements were analyzed by correlation analysis, and the impact of CAT and CCQ scores on exacerbation was analyzed by logistic regression analyses and receiver operating characteristic curve. Results: Among 121 COPD patients, CAT and CCQ score correlated with other symptom measures, lung function and exercise capacity as well. Compared with patients who did not experience exacerbation, those who experienced exacerbation (n=45; 38.2%) exhibited more severe airflow limitation, were more likely to have a history of exacerbation in the year prior to enrollment, and demonstrated higher CAT scores. CCQ scores were not significantly associated with exacerbations. A CAT score of ≥15 was an independent risk factor for exacerbation (adjusted odds ratio [aOR], 2.40; 95% CI, 1.03–6.50; P=0.04). Furthermore, CAT scores of ≥15 demonstrated an increased predictive ability for exacerbation compared with currently accepted guidelines for the use of CAT (≥10) and CCQ (≥1) in the assessment of COPD patients (area under the curve for CAT ≥15, CAT ≥10, and CCQ ≥1 was 0.61±0.04, 0.53±0.03, and 0.50±0.03, respectively; P=0.03). Conclusion: A CAT score of ≥15 indicates increased risk of exacerbation in COPD patients, whereas there is no evidence for increased risk based on CCQ score. Keywords: COPD, exacerbation, questionnaire

Cheng SL, Ho ML, Lai YF, et al. Drug Des Devel Ther. 2020;14:5441–5450.The authors have advised there is an error in the formatting of the paper title on page 5441, the title “Budesonide/Formoterol Anti-Inflammatory Reliever and Maintenance or Fluticasone Propionate/Salmeterol Plus As-Needed, Short-Acting β2 Agonist: Real-World Effectiveness in pAtients without Optimally Controlled asThma (REACT) Study” should read “Budesonide/Formoterol Anti-Inflammatory Reliever and Maintenance or Fluticasone Propionate/Salmeterol Plus As-Needed, Short-Acting β2 Agonist: Real-world Effectiveness in pAtients without optimally Controlled asThma (REACT) Study”.The authors have also advised the affiliation list on page 5441 is incorrect. Read the original article

Chih-Jen Yang,1 Wen-I Liao,1 Zun-Cheng Tang,2 Jen-Chun Wang,1 Chien-Hsing Lee,3 Wei-Chou Chang,4 Chin-Wang Hsu,5,6 Shih-En Tang,7 Shih-Hung Tsai1 1Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, 2Department of Biological Imaging and Radiological Science, National Yang-Ming University, 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, 4Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, 5Department of Emergency Medicine, School of Medicine, College of Medicine, 6Department of Emergency and Critical Medicine, Wan Fang Hospital, Taipei Medical University, 7Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan Abstract: Acute hyperglycemia is a common finding in patients presenting to emergency departments (EDs) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Several studies have argued against the association between hyperglycemia at admission and adverse outcomes in patients with diabetes and an acute illness. Recent studies have shown that glucose-related variables (eg, glycemic gaps and stress hyperglycemia ratios) that are adjusted for glycated hemoglobin levels can indicate the severity of a variety of diseases. The objective of this study was to assess whether these hemoglobin A1c (HbA1c)-based adjusted average glycemic variables were associated with unfavorable outcomes in patients admitted to a hospital with AECOPD. We found that 1) pulmonary infection is a major risk factor for AECOPD; 2) a higher glycemic gap and modified stress hyperglycemia ratio were associated with the development of acute respiratory failure (ARF) in patients with diabetes admitted to an ED because of AECOPD; and 3) the glycemic gap and modified stress hyperglycemia ratio had superior discriminative power over acute hyperglycemia and HbA1c for predicting the development of ARF, although the HbA1c-adjusted glycemic variables alone were not independent risk factors for ARF. Keywords: chronic obstructive pulmonary disease, diabetes mellitus, acute respiratory failure, glycated hemoglobin, hyperglycemia, glycemic gap, stress hyperglycemia ratio

Jimyung Park,1 Chang-Hoon Lee,1 Yeon Joo Lee,2 Jong Sun Park,2 Young-Jae Cho,2 Jae Ho Lee,2 Choon-Taek Lee,2 Ho Il Yoon2 On behalf of the Korean Obstructive Lung Disease (KOLD) Study Group 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-Si, South Korea Purpose: COPD is characterized by an accelerated and progressive decline in forced expiratory volume in 1 second (FEV1) and lung hyperinflation. Although lung hyperinflation is the hallmark of COPD, data on the longitudinal changes in lung hyperinflation and any association with the decline in FEV1 are lacking. The aim of this study was to evaluate the longitudinal changes in lung hyperinflation and to investigate its relationship with FEV1 decline. Patients and methods: We conducted a prospective cohort study and studied 176 COPD patients with annual lung volume measurements over a period of 5 years or more. We used a random coefficient model to calculate the annual changes in lung volumes and to evaluate the factors associated with changes in lung hyperinflation. Additionally, the relationship between the change in lung hyperinflation and FEV1 was assessed. Results: Residual volume (RV), inspiratory capacity (IC), and total lung capacity (TLC) declined at a mean rate of 39.5, 49.6, and 63.8 mL/year, respectively. While IC/TLC declined at 0.70%/year, RV/TLC also declined at 0.35%/year. Changes in both IC/TLC and RV/TLC varied significantly. Frequent exacerbations led to an increase in RV/TLC and faster decline in IC/TLC over time. RV/TLC declined in 59.7% and increased in 40.3% of the patients. A significant negative correlation was found between the rates of change in FEV1 and RV/TLC, and the rate of decline in FEV1 was greater in patients with an increase in RV/TLC than in those with a decline in RV/TLC (54.2 vs 10.7 mL/year, P

Chan Ho Lee, Eun Kyung Goag, Su Hwan Lee, Kyung Soo Chung, Ji Ye Jung, Moo Suk Park, Young Sam Kim, Se Kyu Kim, Joon Chang, Joo Han Song Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea Background: Iron-catalyzed oxidative stress contributes to lung injury after exposure to various toxins, including cigarette smoke. An oxidant/antioxidant imbalance is considered to play a critical role in the pathogenesis of COPD. Ferritin is a key protein in iron homeostasis, and its capacity to oxidize and sequester the metal preventing iron prooxidant activity implicates its possible role in the alteration of antioxidant imbalance. We investigated the relationship among cigarette smoking, lung function, and serum ferritin concentration in a large cohort representative of the Korean adult population. Materials and methods: Among 50,405 participants of the Korean National Health and Nutrition Examination Survey from 2010 to 2014, 15,239 adult subjects older than 40 years with serum ferritin levels and spirometric data were selected for this study. Results: The mean age was 56.5 years for men (43%) and 56.9 years for women (57%). The prevalence of airway obstruction was 13.4%, which was significantly higher in men than in women, and increased in former or current smokers. The median levels of serum ferritin were highest in the airway obstruction group, followed by the restrictive pattern group, and lowest in the normal lung function group. The median ferritin levels were increased by smoking status and amounts in each spirometric subgroup. In multivariable regression analysis, serum ferritin was positively associated with forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity, whereas the smoking amount was negatively associated with the adjustment with age, sex, height, and weight. Conclusion: Serum ferritin levels were increased in former or current smokers and were increased with smoking amount in all subgroups of participants categorized according to spirometric results. The result was also evident in the subgroups divided by obstructive severity. While smoking amount was inversely related to lung function, higher levels of serum ferritin were associated with enhanced spirometric results in a representative sample of the general Korean adult population. Future prospective studies will be needed to clarify the causality between serum ferritin and lung functions and their role in COPD morbidity. Keywords: airway obstruction, ferritin, smoking

Eun Sun Kim,1 Young Tae Kim,2 Chang Hyun Kang,2 In Kyu Park,2 Won Bae,1 Sun Mi Choi,1 Jinwoo Lee,1 Young Sik Park,1 Chang-Hoon Lee,1 Sang-Min Lee,1 Jae-Joon Yim,1 Young Whan Kim,1 Sung Koo Han,1 Chul-Gyu Yoo1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, 2Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea Purpose: This study aimed to investigate whether the prevalence of postoperative pulmonary complications (PPCs) in patients with non-small-cell lung cancer (NSCLC) is even higher in the early stages of COPD than in such patients with normal lung function and to verify the usefulness of symptom- or quality of life (QoL)-based scores in predicting risk for PPCs.Patients and methods: Patients undergoing pulmonary resection for NSCLC between July 2012 and October 2014 were prospectively enrolled. Preoperative measurements of lung function, dyspnea, and QoL, operative characteristics, PPCs, duration of postoperative hospitalization, and in-hospital mortality were assessed.Results: Among 351 consecutive patients with NSCLC, 343 patients with forced expiratory volume in 1 second (FEV1) ≥70% of predicted value were enrolled. At least one PPC occurred in 57 (16.6%) patients. Prevalence of PPC was higher in patients with COPD (30.1%) than in those with normal spirometry (10.0%; P

Jun-jie Zhang,1,2,* Xiao-fei Gao,1,* Zhen Ge,1,2 Xiao-Min Jiang,1 Ping-xi Xiao,1,2 Nai-liang Tian,1,2 Jing Kan,2 Chi-Hang Lee,3 Shao-Liang Chen1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, 2Department of Cardiology, Nanjing Heart Center, Nanjing, People’s Republic of China; 3Department of Cardiology, National University Heart Center, Singapore *These authors contributed equally to this work Background: There is a paucity of evidence regarding the association between obstructive sleep apnea (OSA) and patients undergoing percutaneous coronary intervention (PCI) for coronary artery disease. We sought to investigate whether OSA affects the clinical outcomes of patients undergoing PCI.Patients and methods: All enrolled individuals treated with PCI were evaluated for OSA by polysomnography. The primary end point was defined as major adverse cardiac events (MACEs) at 2 years, including cardiac death, myocardial infarction (MI), and/or target vessel revascularization.Results: A total of 340 consecutive patients undergoing PCI were assigned to the OSA (n=152, apnea–hypopnea index ≥15) and non-OSA (n=188, apnea–hypopnea index

Min Kyung Hyun,1 Na Rae Lee,2 Eun Jin Jang,3 Jae-Joon Yim,4 Chang-Hoon Lee4 1Department of Preventive Medicine, College of Korean Medicine, Dongguk University, Gyeongju, Republic of Korea; 2National Evidence-based Healthcare Collaborating Agency, Seoul, Republic of Korea; 3Department of Information Statistics, College of Natural Science, Andong National University, Andong, Republic of Korea; 4Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Objective: We investigated the effect of treatment with inhaled drugs on changes in mood, focusing on depression and anxiety during treatment in patients with newly diagnosed chronic obstructive pulmonary disease (COPD).Methods: We prospectively selected new COPD patients from three Seoul National Hospitals. Participants underwent face-to-face interviews to evaluate clinical characteristics and drug use, and completed questionnaires using the Hospital Anxiety and Depression Scale (HADS) at the start of the project, the 4th week, and the 12th week. We compared changes in HADS scores both between inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) users and non-ICS/LABA users, as well as between long-acting muscarinic antagonist (LAMA) users and non-LAMA users. The general linear mixed model was applied for multivariate analysis.Results: Ninety new COPD patients participated in the study. Of these 90 patients, 84 completed face-to-face interviews. In the univariate analysis, those who were treated by ICS/LABA or LAMA showed a significant increase in HADS-A at the 4-week evaluation (0.73±2.56, P=0.038), but the statistical significance was lost in the multivariable analysis. No significant difference was found in the change in HADS scores between ICS/LABA users and non-ICS/LABA users, or between LAMA users and non-LAMA users in multivariate general linear mixed model analyses.Conclusion: In this prospective observational study, we found no significant effects of inhaled treatment on mood problems among new COPD patients. Further research should be conducted to identify the association between anxiety and depression and inhaled drugs for COPD treatment.Keywords: Hospital Anxiety and Depression Scale, mood disorders, adverse effects of inhaled drugs, chronic obstructive pulmonary disease

Hyung-Jun Kim,1,2 Jinwoo Lee,1,2 Young Sik Park,1,2 Chang-Hoon Lee,1,2 Sang-Min Lee,1,2 Jae-Joon Yim,1,2 Chul-Gyu Yoo,1,2 Young Whan Kim,1,2 Sung Koo Han,1,2 Sun Mi Choi1,2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Purpose: Chronic obstructive pulmonary disease (COPD) is associated with increased postoperative complications. Recently, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classified COPD patients into four groups based on spirometry results and the severity of symptoms. The objective of this study was to evaluate the impact of GOLD groups on postoperative complications. Patients and methods: We reviewed the medical records of COPD patients who underwent preoperative spirometry between April and August 2013 at a tertiary hospital in Korea. We divided the patients into GOLD groups according to the results of spirometry and self-administered questionnaires that assessed the symptom severity and exacerbation history. GOLD groups, demographic characteristics, and operative conditions were analyzed. Results: Among a total of 405 COPD patients, 70 (17.3%) patients experienced various postoperative complications, including infection, wound, or pulmonary complications. Thoracic surgery, upper abdominal surgery, general anesthesia, large estimated blood loss during surgery, and longer anesthesia time were significant risk factors for postoperative complications. Patients in high-risk group (GOLD groups C or D) had an increased risk of postoperative complications compared to those in low-risk group (GOLD groups A or B). Conclusion: COPD patients in GOLD groups representing a high exacerbation risk have an increased risk of postoperative complications compared to those with low risk. Keywords: chronic obstructive pulmonary disease, dyspnea, postoperative complications, risk assessment, spirometry

Hyeon-Kyoung Koo,1 Kwang Nam Jin,2 Deog Kyeom Kim,3 Hee Soon Chung,3 Chang-Hoon Lee3,4 1Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, College of Medicine, Ilsan Paik Hospital, Inje University, Goyang-si, Gyeonggi-Do, 2Department of Radiology, Seoul Metropolitan Government – Seoul National University Boramae Medical Center, 3Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, 4Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Objectives: Emphysema is one of the prognostic factors for rapid lung function decline in patients with COPD, but the impact of incidentally detected emphysema on population without spirometric abnormalities has not been evaluated. This study aimed to determine whether emphysema detected upon computed tomography (CT) screening would accelerate the rate of lung function decline and influence the possibility of future development of airflow limitation in a population without spirometric abnormalities.Materials and methods: Subjects who participated in a routine screening for health checkup and follow-up pulmonary function tests for at least 3 years between 2004 and 2010 were retrospectively enrolled. The percentage of low-attenuation area below −950 Hounsfield units (%LAA−950) was calculated automatically. A calculated value of %LAA−950 that exceeded 10% was defined as emphysema. Adjusted annual lung function decline was analyzed using random-slope, random-intercept mixed linear regression models.Results: A total of 628 healthy subjects within the normal range of spriometric values were included. Multivariable analysis showed that the emphysema group exhibited a faster decline in forced vital capacity (−33.9 versus −18.8 mL/year; P=0.02). Emphysema was not associated with the development of airflow limitation during follow-up.Conclusion: Incidental emphysema quantified using CT scan was significantly associated with a more rapid decline in forced vital capacity in the population with normative spirometric values. However, an association between emphysema and future development of airflow limitation was not observed. Keywords: annual decline rate, respiratory function tests, pulmonary emphysema, chronic obstructive pulmonary disease

Soo Jung Kim,1,2 Jinwoo Lee,1,2 Young Sik Park,1,2 Chang-Hoon Lee,1,2 Ho Il Yoon,1,3 Sang-Min Lee,1,2 Jae-Joon Yim,1,2 Young Whan Kim,1,2 Sung Koo Han,1,2 Chul-Gyu Yoo1,2 1Department of Internal Medicine, Seoul National University College of Medicine, Seoul, 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea Background: According to the Fletcher–Peto curve, rate of decline in forced expiratory volume in 1-second (FEV1) accelerates as age increases. However, recent studies have not demonstrated that the rate of FEV1 decline accelerates with age among COPD patients. The objective of the study is to evaluate annual rate of FEV1 decline as age increases among COPD patients. Methods: In this retrospective cohort study, we enrolled COPD patients who were followed up at two tertiary care university hospitals from January 2000 to August 2013. COPD was defined as post-bronchodilator (BD) FEV1/forced vital capacity (FVC) of

Min-Sun Kwak,1 Eunyoung Kim,2 Eun Jin Jang,3 Hyun Jung Kim,4 Chang-Hoon Lee5 1Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Statistics, Kyungpook National University, Daegu, Republic of Korea; 3Department of Information Statistics, Andong National University, Andong, Republic of Korea; 4Department of Preventive Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; 5Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea Purpose: Although tiotropium (TIO) and inhaled corticosteroid (ICS)/long-acting β-agonists are frequently prescribed together, the efficacy of “triple therapy” has not been scientifically demonstrated. We conducted a systematic review and meta-analysis using Bayesian methods to compare triple therapy and TIO monotherapy.Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases for randomized controlled trials comparing the efficacy and safety of triple therapy and TIO monotherapy in patients with chronic obstructive pulmonary disease (COPD). We conducted a meta-analysis to compare the effectiveness and safety of triple therapy and TIO monotherapy using Bayesian random effects models.Results: Seven trials were included, and the risk of bias in the majority of the studies was acceptable. There were no statistically significant differences in the incidence of death and acute exacerbation of disease in the triple therapy and TIO monotherapy groups. Triple therapy improved the prebronchodilator forced expiratory volume in 1 second (mean difference [MD], 63.68 mL; 95% credible interval [CrI], 45.29–82.73), and patients receiving triple therapy showed more improvement in St George Respiratory Questionnaire scores (MD, -3.11 points; 95% CrI, -6.00 to -0.80) than patients receiving TIO monotherapy. However, both of these differences were lower than the minimal clinically important difference (MCID). No excessive adverse effects were reported in triple therapy group.Conclusion: Triple therapy with TIO and ICSs/long-acting β-agonists was only slightly more efficacious than TIO monotherapy in treating patients with COPD. Further investigations into the efficacy of new inhaled drugs are needed. Keywords: inhaled long-acting muscarinic antagonists (LAMAs), inhaled corticosteroids (ICSs), inhaled long-acting β2-agonists (LABAs), chronic obstructive pulmonary disease (COPD)

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

Ha Youn Lee,1,2 Sun Mi Choi,1,2 Jinwoo Lee,1,2 Young Sik Park,1,2 Chang-Hoon Lee,1,2 Deog Kyeom Kim,2,3 Sang-Min Lee,1,2 Ho Il Yoon,2,4 Jae-Joon Yim,1,2 Young Whan Kim,1,2 Sung Koo Han,1,2 Chul-Gyu Yoo1,2 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 2Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea; 4Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea Background: Tiotropium failed to slow the annual rate of forced expiratory volume in 1 second (FEV1) decline in chronic obstructive pulmonary disease (COPD) patients with