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Background Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. It has also imposed a substantial economic and social burden on the health care system. In Taiwan, a nationwide COPD pay-for-performance (P4P) program was designed to improve the quality of COPD-related care by introducing financial incentives for health care providers and employing a multidisciplinary team to deliver guideline-based, integrated care for patients with COPD, reducing adverse outcomes, especially COPD exacerbation. However, the results of a survey of the effectiveness of the pay-for-performance program in COPD management were inconclusive. To address this knowledge gap, this study evaluated the effectiveness of the COPD P4P program in Taiwan. Methods This retrospective cohort study used data from Taiwan’s National Health Insurance claims database and nationwide COPD P4P enrollment program records from June 2016 to December 2018. Patients with COPD were classified into P4P and non-P4P groups. Patients in the P4P group were matched at a ratio of 1:1 based on age, gender, region, accreditation level, Charlson Comorbidity Index (CCI), and inhaled medication prescription type to create the non-P4P group. A difference-in-difference analysis was used to evaluate the influence of the P4P program on the likelihood of COPD exacerbation, namely COPD-related emergency department (ED) visit, intensive care unit (ICU) admission, or hospitalization. Results The final sample of 14,288 patients comprised 7144 in each of the P4P and non-P4P groups. The prevalence of COPD-related ED visits, ICU admissions, and hospitalizations was higher in the P4P group than in the non-P4P group 1 year before enrollment. After enrollment, the P4P group exhibited a greater decrease in the prevalence of COPD-related ED visits and hospitalizations than the non-P4P group (ED visit: −2.98%, p, Graphical Abstract

Chronic obstructive pulmonary disease (COPD) has significant contributions to morbidity and mortality world-wide. Early symptoms of COPD are not readily distinguishable, resulting in a low rate of diagnosis and intervention. Different guidelines and recommendatations for the diagnosis and treatment of COPD exist globally. The first edition of clinical practice guidelines for COPD was published in 2016 by the Ministry of Health and Welfare in Taiwan in collaboration with the Taiwan evidence-based medicine association and Cochrane Taiwan, and was revised in 2019 in order to update recent diagnostic and therapeutic modalities for COPD and its acute exacerbation. This revised guideline covered a range of topics highlighted in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, including strategies for the diagnosis, assessment, monitoring, and management of stable COPD and exacerbations, with particular focus on evidence from Taiwan. The recommendations included in the revised guideline were formed based on a comprehensive systematic review or meta-analysis of specific clinical issues identified by an expert panel that surveyed relevant scientific evidence in the literature and guidelines published by the clinical communities and organizations nationally and internationally. The guidelines and recommendations are applicable to the clinical settings in Taiwan. We expect this revised guideline to facilitate the diagnosis, treatment and management of patients with COPD by physicians and health care professionals in Taiwan. Adaptations of the materials included herein for educational and training purposes is encouraged.

This study investigated the prevalence and clinical outcomes of pulmonary bacterial co-infections and secondary bacterial infections in patients with severe influenza pneumonitis.We retrospectively analyzed the data of adult patients with severe influenza pneumonitis admitted to medical ICUs. Bacterial co-infections and secondary bacterial infections were identified. The risk factors of bacterial infection were evaluated. The outcomes of patients regarding co-infection or secondary bacterial infection were analyzed.We identified 117 critically ill patients with laboratory-confirmed influenza pneumonitis admitted to the medical ICUs. Klebsiella pneumoniae (31.4%) and Staphylococcus aureus (22.8%) were the most identified bacteria in patients with bacterial co-infection. A high proportion of methicillin-resistant Staphylococcus aureus (17.1%) was noted. Liver cirrhosis and diabetes mellitus were the independent risk factors for bacterial co-infection. Acinetobacter baumannii (30.7%) and S. aureus (23.1%) were the most often identified bacteria in patients with secondary bacterial pneumonia. Patients with secondary bacterial infections had a longer duration of mechanical ventilation, and longer ICU and hospital stay.High rates of drug-resistant bacterial co-infections and secondary bacterial infections were identified in patients with severe influenza pneumonitis requiring ICU care and were associated with more morbidity in these patients.

Ming-Shian Lu,1 Hung-I Lu,2 Tzu-Ping Chen,3 Che-Chia Chang,1 Tsung-Ming Yang,4 Miao-Fen Chen5,6 1Division of Thoracic and Cardiovascular Surgery, Chiayi Chang Gung Memorial Hospital, Puzi, Chiayi County, Taiwan; 2Division of Thoracic and Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan; 3Division of Thoracic and Cardiovascular Surgery, Keelung Chang Gung Memorial Hospital, Keelung City, Taiwan; 4Division of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Puzi, Chiayi County, Taiwan; 5Department of Radiation Oncology, Chiayi Chang Gung Memorial Hospital, Puzi, Chiayi County, Taiwan; 6College of Medicine, Chang Gung University, Taoyuan City, TaiwanCorrespondence: Miao-Fen ChenDepartment of Radiation Oncology, Chiayi Chang Gung Memorial Hospital, No. 6, Sec. West, Jiapu Road, Puzi City, Chiayi County, 61363, TaiwanTel +886 5 362100 Ext 2011Fax +886 5 3623002Email miaofen@cgmh.org.twPurpose: The survival outcome of lung cancer patients with coexisting liver cirrhosis has thus far received limited attention in the literature. In this study, we evaluated whether liver cirrhosis is an independent risk factor for the survival of patients with lung cancer.Materials and Methods: We conducted a retrospective, multicenter, propensity-matched study of lung cancer patients with and without liver cirrhosis. To determine differences in survival, we sought to identify risk factors associated with poor outcomes using Kaplan–Meier survival analysis and Cox proportional hazards regression.Results: There were no statistically significant differences in the baseline clinical characteristics of patients between the cirrhosis and non-cirrhosis groups. The median overall survival of patients with and without cirrhosis was 13.07 months (95% confidence interval [CI]: 10.56– 16.84) and 13.67 months (95% CI: 10.42– 16.91), respectively (p=0.76). Cox proportional hazards regression analysis revealed that liver cirrhosis was not an independent risk factor for poor outcome (hazard ratio [HR]: 1.057, 95% CI: 0.805– 1.388, p=0.690). In patients with cirrhosis, lower serum albumin levels, higher Charlson Comorbidity Index score, advanced-stage lung cancer, and treatment modality were factors associated with poor outcome. Increase in serum albumin by 1 g was associated with a 30% reduction in the risk of mortality (HR: 0.700, 95% CI: 0.494– 0.993, p=0.045). While every point increase in the Charlson Comorbidity Index score by 1 point was linked to a 9% higher risk of mortality (HR: 1.090, 95% CI: 1.023– 1.161, p=0.007).Conclusion: The survival rates of lung cancer patients with and without cirrhosis did not differ significantly. Higher serum albumin levels and lower Charlson Comorbidity Index scores were associated with improved survival.Keywords: liver cirrhosis, lung neoplasm, outcome, survival

Meng-Jer Hsieh,1 Ning-Hung Chen,2 Shih-Lung Cheng,3,4 Chi-Wei Tao,5 Yu-Feng Wei,6,7 Yao-Kuang Wu,8 Ming-Cheng Chan,9,10 Shih-Feng Liu,11– 13 Wu-Huei Hsu,14 Tsung-Ming Yang,15 Ming-Shian Lin,16,17 Ching-Lung Liu,18 Ping-Hung Kuo,19 Ying-Huang Tsai1,20 1Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung Medical Foundation and Department of Respiratory Therapy, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 2Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital and School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan; 4Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, Taiwan; 5Department of Internal Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan; 6School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 7Department of Internal Medicine, E-Da Cancer Hospital, Kaohsiung, Taiwan; 8Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan; 9Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 10National Chung Hsing University, Taichung, Taiwan; 11Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 12Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 13College of Medicine, Chang Gung University, Taoyuan, Taiwan; 14Critical Medical Center, China Medical University Hospital, Taichung, Taiwan; 15Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan; 16Division of Pulmonary Medicine, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; 17Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan; 18Division of Chest Medicine, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan; 19Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 20Department of Pulmonary and Critical Care Medicine, Xiamen Chang Gung Hospital, Xiamen, 361028, People’s Republic of ChinaCorrespondence: Ying-Huang Tsai, Department of Pulmonary and Critical Care Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung Medical Foundation and Department of Respiratory Therapy, College of Medicine, Chang Gung University, No. 5 Fu-Xin St, Kweishan District, Taoyuan, Taiwan, Email chestmed@cgmh.org.twBackground: Long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) combination therapy improved lung function and health-related quality-of-life and reduced exacerbation rates and dyspnea in symptomatic chronic obstructive pulmonary disease (COPD) patients. We compared the real-world effects of three fixed-dose LABA/LAMA combinations for COPD in Taiwan.Methods: This multicenter, retrospective study evaluated 1-year outcomes after LABA/LAMA combination therapy in patients with symptomatic COPD. Exacerbations and symptoms of COPD, lung functions, and therapy escalation were compared among patients using tiotropium/olodaterol, umeclidinium/vilanterol and indacaterol/glycopyrronium. Propensity score matching (PSM) was applied to balance the baseline characteristics.Results: Data of 1,617 patients were collected. After PSM, time to first moderate-to-severe COPD exacerbation was comparable among three groups, while the annualized rates of the exacerbation (episodes/patient/year) in patients receiving tiotropium/olodaterol (0.19) or umeclidinium/vilanterol (0.17) were significantly lower than those receiving indacaterol/glycopyrronium (0.38). COPD-related symptoms were stable over the treatment period, and there was no significant difference in the changes of symptom scores including CAT and mMRC among three groups at the end of the study period.Conclusion: This study presented valuable real-world outcome in terms of exacerbation and treatment response of COPD patients treated with fixed-dose LABA/LAMA regimens in Taiwan. The annualized rates of moderate-to-severe exacerbation in patients receiving tiotropium/olodaterol or umeclidinium/vilanterol were significantly lower than those receiving indacaterol/glycopyrronium, though the time to first moderate-to-severe exacerbation was similar among different fixed-dose LABA/LAMA combinations.Keywords: tiotropium/olodaterol, umeclidinium/vilanterol, indacaterol/glycopyrronium, LABA/LAMA therapy, Taiwan, cohort study, propensity score matching, chronic obstructive pulmonary disease, moderate-to-severe exacerbation

Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.

Rationale The potential benefits of statins for the prevention of exacerbations in patients with COPD remains controversial. No previous studies have investigated the impact of statins on clinical outcomes in COPD patients with frequent exacerbations. Objective This study aimed to evaluate the association between the use of statins and the risk of subsequent hospitalized exacerbations in COPD frequent exacerbators. Materials and Methods We conducted a population-based cohort study using the Taiwan National Health Insurance Research Database. 139,223 COPD patients with a first hospitalized exacerbation between 2004 and 2012 were analyzed. Among them, 35,482 had a second hospitalized exacerbation within a year after the first exacerbation, and were defined as frequent exacerbators. 1:4 propensity score matching was used to create matched samples of statin users and non-users. The competing risk regression analysis model was used to evaluate the association between statin use and exacerbation risk. Results The use of statins was associated with a significantly reduced risk in subsequent hospitalized exacerbations in COPD patients after their first hospitalized exacerbation (adjusted subdistribution hazard ration [SHR], 0.89; 95% CI, 0.85-0.93, P

Background Studies have indicated that individuals taking aspirin have a reduced risk of cancers and have also established chemo-preventive benefit of aspirin in colorectal cancer. However, research on the association between aspirin use and the survival in patients with lung cancer has revealed inconsistent results. In this study, we investigated the effect of aspirin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients. Methods We identified a cohort of 38,842 patients diagnosed with NSCLC between 2000 and 2012 using the Taiwan’s National Health Insurance Research Database and used propensity score matching to reduce possible confounding factors. In total, 9864 patients (4932 matched pairs) were included in the matched cohort. Aspirin exposure was analyzed to identify a possible association with mortality in patients with inoperable NSCLC. Time-dependent Cox regression models were used to calculate the hazard ratios (HRs) and the 95% confidence intervals (95% CIs) that corresponded with aspirin exposure. Results A total of 4979 patients used aspirin at the time of diagnosis of NSCLC. The median overall survival (OS) of the aspirin users was 1.73 (interquartile range, 0.94–3.53) years compared with the 1.30 (interquartile range, 0.69–2.62) years of the non-aspirin users. The Cox proportional hazard model with the time-dependent covariate revealed that aspirin use was associated with a significantly longer OS (HR: 0.83, 95.0% CI: 0.80–0.86). After controlling the sociodemographic characteristics (age, sex, income, and level of urbanization) and lung cancer treatments by propensity score matching, the aspirin users still had a significantly longer OS than the non-aspirin users (HR: 0.79, 95.0% CI: 0.75–0.83). Conclusion Aspirin use is associated with a longer OS in patients with inoperable NSCLC, suggesting that aspirin has a potential anticancer effect. These results warrant further randomized clinical trials to evaluate the actual role of aspirin in the treatment of NSCLC patients.

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

綜合活動學習領域在歷次課程改革過程中有不同的改變，及至《十二年國民基本教育課程綱要總綱》頒布，更名為綜合活動領域，並在國小階段減少授課節數，綜合活動領域的重要性再度受到質疑。然而，從教育社會學觀點來看綜合活動領域，有其價值及意義。本研究透過文獻探討，探究我國綜合活動領域的理論背景，以及歷年課程標準中與綜合活動領域相關的課程安排。研究方法以教育部課程與教學綜合活動領域中央輔導團輔導員的訪談結果，透過紮根理論的主軸編碼整理訪談資料。從主軸編碼中發現綜合活動設定為領域學科的現象，其因果條件包含時間脈絡、國際趨勢、學生學習及理論等，在領域遭受質疑的脈絡中，從歷史、國際、學習、理論及課程加以解釋，並歸納出理論、政策及教師賦權增能的專業強化行動策略，以達到提升教師熱忱與認同的結果。最後，本研究提出我國發展綜合活動領域國小課程發展之反思。 Integrative activities learning area changed with the process of different stages of curriculum reform. However, the name of this field was altered to integrative activities area and the curriculum periods in elementary schools decreased in 12-year basic education curriculum guidelines in 2018. This brings the questioning of the importance of the integrative activities area. Nevertheless, this field has the value and meaning from the perspective of the sociology of education. Through the literature review, the theory background of this field and the integrative activities area related curriculum throughout the history of curriculum reform are investigated. The research method is grounded theory based on the interview with the Ministry of Education Curriculum and Teaching Central Advisors and axial coding was implemented. The findings of the research are as follow. The phenomenon was the integrative activities area being a subject (field) in schools. The causal conditions include time context, international trends, students’ learning and theory. While the contextual condition is the questioning of the field, the explanation from the points of history, international context, learning and theory is proposed. The strategic action / interaction in this research is the strengthening of the profession, such as theory, policy and teacher empowerment to reach the consequences of the teachers’ enthusiasm and recognition. Finally, reflection on the development of the field is proposed.

Chronic obstructive pulmonary disease (COPD) is preventable and treatable. However, many patients remain undiagnosed and untreated due to the underutilization or unavailability of spirometers. Accordingly, we used Spirobank Smart, an app-based spirometer, for facilitating the early detection of COPD in outpatient clinics. This prospective study recruited individuals who were at risk of COPD (i.e., with age of ≥40 years, ≥10 pack-years of smoking, and at least one respiratory symptoms) but had no previous COPD diagnosis. Eligible participants were examined with Spirobank Smart and then underwent confirmatory spirometry (performed using a diagnostic spirometer), regardless of their Spirobank Smart test results. COPD was defined and confirmed using the postbronchodilator forced expiratory volume in 1 s/forced vital capacity values of &lt, 0.70 as measured by confirmatory spirometry. A total of 767 participants were enrolled and examined using Spirobank Smart, 370 participants (94.3% men, mean age of 60.9 years and mean 42.6 pack-years of smoking) underwent confirmatory spirometry. Confirmatory spirometry identified COPD in 103 participants (27.8%). At the optimal cutoff point of 0.74 that was determined using Spirobank Smart for COPD diagnosis, the area under the receiver operating characteristic was 0.903 (95% confidence interval (CI) = 0.860–0.947). Multivariate logistic regression revealed that participants who have an FEV1/FVC ratio of &lt, 74% that was determined using Spirobank Smart (odds ratio (OR) = 58.58, 95% CI = 27.29–125.75) and old age (OR = 3.23, 95% CI = 1.04–10.07 for 60 ≤ age &lt, 65, OR = 5.82, 95% CI = 2.22–15.27 for age ≥ 65) had a higher risk of COPD. The Spirobank Smart is a simple and adequate tool for early COPD detection in outpatient clinics. Early diagnosis and appropriate therapy based on GOLD guidelines can positively influence respiratory symptoms and quality of life.

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between the Y-adapter and the inspiratory limb of the ventilator circuit during mechanical ventilation. The SMI was actuated at the beginning of inspiration and expiration. In separate experiments, a manual resuscitator with T-adapter was attached to endotracheal tube, collecting filter, and a passive test lung. Drug was eluted from collecting filters with salt-based solvent and analyzed using high-performance liquid chromatography. Results showed the percent of SMI label dose inhaled was 3-fold higher with the commercial in-line adapter with actuation during expiration than when synchronized with inspiration. SMI with T-adapter delivery via ventilator was similar to inhalation (1.20%) or exhalation (1.02%), and both had lower delivery dose than with manual resuscitator (2.80%, p = 0.01). The inhaled dose via endotracheal tube was much lower than inhaled dose with spontaneous breathing (22.08%). In conclusion, the inhaled dose with the commercial adapter was higher with SMI actuated during expiration, but still far less than reported spontaneous inhaled dose.

Yun-Ju Chen,1 Jun-Yu Fan,2 Su-Er Guo,2–4 Su-Lun Hwang,2,3 Tsung-Ming Yang4 1Division of Respiratory Therapy, Chiayi Chang Gung Memorial Hospital,Chang Gung Medical Foundation, Chiayi, Taiwan, Republic of China; 2Graduate Institute of Nursing, College of Nursing, Chang Gung University of Science and Technology, Chiayi, Taiwan, Republic of China; 3Chronic Diseases and Health Promotion Research Centre, Chang Gung University of Science and Technology, Chiayi, Taiwan, Republic of China; 4Division of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chang Gung Medical Foundation, Chiayi, Taiwan,Republic of China Purpose: Pulmonary rehabilitation (PR) is recognized as the chief non-pharmacologic management approach for patients with COPD, but is clinically under-utilized. In Taiwan, respiratory therapists (RTs) are one of the first-line health care providers who spend vast amounts of time with COPD patients in PR programs. To better enhance patients’ knowledge of and participation in PR, it is necessary to understand how PR is viewed by RTs, as well as how these views influence their behavioral intentions toward promoting PR. This study applied the Theory of Planned Behavior (TPB) to investigate both the behavioral intentions and the influential factors surrounding PR in RTs.Patients and methods: This cross-sectional study used structured self-administered questionnaires at a national symposium for RTs to collect data on their knowledge, attitudes, subjective norms, perceived behavioral controls, and behavioral intentions with regard to promoting PR. Multiple linear regression analysis was used to identify significant factors affecting the intended promotion of PR by RTs.Results: The response rate after excluding respondents with incomplete data was 88.1% (n=379). A majority of the participants were college graduates, aged over 30 years, and women. The respective percentage scores derived from questionnaires gauging the knowledge, attitudes, subjective norms, self-efficacy, and behavioral intentions components of total PR scores were 63.12%, 71.33%, 68.96%, 66.46%, and 80.29%. The factors significantly affecting RTs’ intentions to suggest PR participation to COPD patients or encourage it were attitudes, subjective norms, and self-efficacy. The total model explained 22.5% of the variance in behavioral intentions.Conclusion: The results of the study suggest that RTs strongly intend to promote PR, but are hindered by insufficient knowledge, attitudes, and self-efficacy with regard to it. Applying TPB provided insight into which factors can be addressed, and by whom. For example, enhancing RTs’ self-efficacy can be achieved through PR training via school curricula, further regular continuing education and/or courses, and practical experience. Keywords: behavioral intention, theory of planned behavior, exercise program, self-efficacy, respiratory therapist, COPD

Background/purpose Positional obstructive sleep apnea (OSA) is defined as an apnea hypopnea index at least twice as high in the supine position as in the lateral position. Whether a positional OSA patient persistently has positional OSA in the follow-up period is unknown. This study was conducted to investigate the maintenance of the positional effect on OSA patients and the predictors of changing from positional OSA to nonpositional OSA. Methods Patients who were diagnosed to have positional OSA were screened for a follow-up polysomnography (PSG), which evaluated the effect of the same lateral position as baseline PSG on the severity of OSA. Those who met the criteria of positional OSA in both PSGs were classified as the unchanged group, the others were classified as the changed group. Results Seventy-eight positional OSA patients were enrolled in the final analyses. Twenty-seven of the enrolled patients (35%) were changed to nonpositional OSA patients in the second PSG. A higher apnea index in the lateral position was found in the changed group compared with that in the unchanged group ( p = 0.02). Logistic regression also showed that the apnea index in the lateral position was the only independent predictor of changing from positional OSA to nonpositional OSA in the follow-up PSG (odds ratio = 1.13, p = 0.004). Conclusion One-third of positional OSA patients who had a high apnea index in the lateral position tends to become nonpositional OSA patients in the follow-up PSG and must be closely monitored if receiving positional therapy only.

Somatic mutations of MET gene are emerging as important driver mutations for lung cancers. To identify the common clinicopathological features of MET exon 14 skipping mutations and amplification and clarify whether the two MET gene alterations cause protein overexpression were investigated using 196 lung cancer samples of Taiwan through real time-qPCR/sequencing, fluorescence in situ hybridization, and immunohistochemistry. The two MET gene alterations are both present in low frequency, ~1%, in the studied lung cancer population of Taiwan. MET exon 14 skipping mutations were identified from two early-stage patients, who were both relatively advanced in age, and did not carry other driver mutations. One was an adenocarcinoma and the other was a rare carcinosarcoma. Three gene amplifications cases were identified. Neither of the two MET gene alterations would lead to protein overexpression; hence, direct detection in nucleic acid level would be a preferred and straightforward solution for the identification of skipping mutations. The presence of MET exon 14 mutations in minor histological types of lung cancers urge to extend screening scope of this mutation in lung cancer and treatment response evaluation in clinical trials. These would be important next steps for the success of MET target therapy in clinical practice.

Supplemental material, Table_S1 for Metformin Prolongs Survival in Type 2 Diabetes Lung Cancer Patients With EGFR-TKIs by Ming-Szu Hung, Min-Chun Chuang, Yi-Chuan Chen, Chuan-Pin Lee, Tsung-Ming Yang, Pau-Chung Chen, Ying-Huang Tsai and Yao-Hsu Yang in Integrative Cancer Therapies

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

Objective To evaluate the effects of metformin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients with diabetes using the Taiwanese National Health Insurance Research Database. Research design and methods In total, 7,620 patients were eligible in this study, among them, 3,578 patients were metformin users and 4,042 were non-users. Propensity score matching was used to reduce possible confounding factors. In total, 4,182 patients (2,091 matched pairs) were included in the matched cohort. Cox proportional hazard model with time-dependent covariate were also applied to evaluate the association between metformin use and overall survival (OS). Results A total of 3,578 patients were metformin users at the time of diagnosis of NSCLC. Cox proportional hazard model with time-dependent covariate revealed that metformin use was associated with a significantly longer OS (HR: 0.85, 95.0% CI: 0.80–0.90). The survival benefit of metformin use was maintained after propensity score matching at a ratio of 1:1 (HR: 0.90, 95.0% CI: 0.84–0.97). Conclusions Metformin use is associated with longer OS in inoperable NSCLC patients with diabetes, suggesting a potential anti-tumorigenic effect for metformin. Further research is needed to investigate the actual role of metformin in the treatment of NSCLC patients with diabetes.

Ying-Huang Tsai,1,* Tsung-Ming Yang,1–3,* Chieh-Mo Lin,1,2 Shu-yi Huang,1 Yu-Wen Wen4 1Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, 2Graduate Institute of Clinical Medical Sciences, College of Medicine, 3School of Traditional Chinese Medicine, 4Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan, Republic of China *These authors contributed equally tothis work Rationale: COPD has attracted widespread attention worldwide. The prevalence of COPD in Taiwan has been reported, but little is known about trends in health care resource utilization and pharmacologic management in COPD treatment.Objective: The objective of this article was to study trends in health care resource utilization, pharmacologic management, and medical costs of COPD treatment in Taiwan.Materials and methods: Reimbursement claims in the Taiwan National Health Insurance System from 2004 to 2010 were collected. The disease burden of COPD, including health care resource utilization and medical costs, was evaluated.Results: The pharmacy cost of COPD increased from 2004 to 2010 due to the increased utilization of long-acting muscarinic antagonist (LAMA) and fixed-dose combination of long-actingβ2-agonist and inhaled corticosteroid (LABA/ICS), whereas the cost of all other COPD-related medications decreased. The average outpatient department (OPD) cost per patient increased 29.3% from 1,070 USD in 2004 to 1,383 USD in 2010. The highest average total medical cost per patient was 3,434 USD in 2005, and it decreased 12.4% to 3,008 USD in 2010. There was no significant difference in the average number of OPD visits and emergency department visits per patient. The highest average number of hospital admissions was 0.81 in 2005, and it decreased to 0.65 in 2010. The average number of intensive care unit (ICU) admissions decreased from 0.52 in 2005 to 0.31 in 2010.Conclusion: From 2004 to 2010, the average total medical cost per patient of COPD was slightly decreased because of the decreased average number of hospital admissions and ICU admissions. The costs of both LAMA and LABA/ICS increased, while the cost for all other COPD-related medications decreased. These findings suggest that the increased utilization of LAMA and LABA/ICS may have contributed to the decreased average number of hospital admissions and ICU admissions in COPD patients from 2004 to 2010. Keywords: COPD, health care resource utilization, pharmacologic management

Background Few studies have evaluated the size distribution of inhaled and exhaled aerosolized drugs, or the effect of heated humidification on particle size and lung deposition. The present study evaluated these aspects of bronchodilator (salbutamol/ipratropium) delivery using a lung model in the absence and presence of heat and humidification. Methods We positioned filters to collect and measure the initial drug, inhaled drug, and exhaled drug. Particle size distribution was evaluated using an 8-stage Marple personal cascade impactor with 0.2-μm polycarbonate filters. Results A greater inhaled drug mass was delivered using a vibrating mesh nebulizer (VMN) than by using a small volume nebulizer (SVN), when heated humidifiers were not employed. When heated and humidified medical gas was used, there was no significant difference between the inhaled drug mass delivered by the VMN and that delivered by the SVN. A significantly greater mass of inhaled 1.55-μm drug particles was produced by the VMN than with the SVN, under heated and humidified conditions. However, the mass median aerodynamic diameters (MMADs) of the aerosolized drug produced by the SVN and VMN did not differ significantly under the same conditions. Conclusions The VMN produced more fine particles of salbutamol/ipratropium, and the drug particle size clearly increased in the presence of heat and humidification.

The purpose of this study is to establish a turbidity forecasting model as well as an early-warning system for turbidity management using rainfall records as the input variables. The Taipei Water Source Domain was employed as the study area, and ANOVA analysis showed that the accumulative rainfall records of 1-day Ping-lin, 2-day Ping-lin, 2-day Fei-tsui, 2-day Shi-san-gu, 2-day Tai-pin and 2-day Tong-hou were the six most significant parameters for downstream turbidity development. The artificial neural network model was developed and proven capable of predicting the turbidity concentration in the investigated catchment downstream area. The observed and model-calculated turbidity data were applied to developing the turbidity early-warning system. Using a previously determined turbidity as the threshold, the rainfall criterion, above which the downstream turbidity would possibly exceed this respective threshold turbidity, for the investigated rain gauge stations was determined. An exemplary illustration demonstrated the effectiveness of the proposed turbidity early-warning system as a precautionary alarm of possible significant increase of downstream turbidity. This study is the first report of the establishment of the turbidity early-warning system. Hopefully, this system can be applied to source water turbidity forecasting during storm events and provide a useful reference for subsequent adjustment of drinking water treatment operation.

Optimization methods usually obtain the travel direction of the solution by substituting the solutions into the objective function. However, if the solution space is too large, this search method may be time consuming. In order to address this problem, this study incorporated the Taguchi method into the solution space search process of the optimization method, and used the characteristics of the Taguchi method to sequence the effects of the variation of decision variables on the system. Based on the level of effect, this study determined the impact factor of decision variables and the optimal solution for the model. The integration of the Taguchi method and the solution optimization method successfully obtained the optimal solution of the optimization problem, while significantly reducing the solution computing time and enhancing the river water quality. The results suggested that the basin with the greatest water quality improvement effectiveness is the Dahan River. Under the optimal strategy of this study, the severe pollution length was reduced from 18 km to 5 km.

Background: Metformin use reportedly reduces cancer risk and improves survival in lung cancer patients. This study aimed to investigate the effect of metformin use in patients with diabetes mellitus (DM) and lung cancer receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Methods: A nationwide, population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. From January 1, 2004, to December 31, 2012, a total of 373 metformin and 1260 non-metformin lung cancer cohorts with type 2 DM and EGFR-TKI treatment were studied. Results: Metformin use was significantly associated with a reduced risk of death (hazard ratio: 0.73, 95% confidence interval [CI]: 0.62-0.85, P < .001), as well as a significantly longer median progression-free survival (9.2 months, 95% CI: 8.6-11.7, vs 6.4 months, 95% CI: 5.9-7.2 months, P < .001) and median overall survival (33.4 months, 95% CI: 29.4-40.2, vs 25.4 months, 95% CI: 23.7-27.2 months, P < 0.001). Conclusions: In conclusion, metformin may potentially enhance the therapeutic effect and increase survival in type 2 DM patients with lung cancer receiving EGFR-TKI therapy.

The Hoshin Kanri (HK) planning process is widely used in Japanese and Western companies for strategy planning and performance measurement in the manufacturing sector. Human resource management (HRM) plays an important role in business operations; HRM practices have a significant positive effect on implementing total quality management and on employee and customer satisfaction. However, HRM has always been considered reactive, uncoordinated, and unprofessional, delivering poor, slow, and ineffective services. This study presents the envision, identify, diagnose, prioritise, execute, and review (EIDPER) model, an extension of HK. EIDPER translates strategies into achievable actions to fulfil organisational objectives. We introduce a case study to illustrate applying EIDPER to the recruitment process of the HRM department in a high-tech manufacturing firm. The approach was successfully applied in the HRM department of the case company and effectively reduced hiring costs by US$360,000 in 5 years and improved...

A modified Streeter–Phelps equation and the Hydrological Engineering Centers River Analysis System (HEC-RAS) were combined to assess water quality of the Tan-Sui River and its tributaries. The Tan-Sui River is the main source of water supply for northern Taiwan, and the water quality of its stream is significantly affected by tides. In this study, HEC-RAS was employed to assess the impact of tides on water quality and to calculate reoxygenation coefficients. The modified Streeter–Phelps equation was used to calculate water quality in terms of contaminant degradation and reoxygenation. Biochemical oxygen demand (BOD) and ammonia nitrogen (NH3–N), the most important identified sources of water pollution in the rivers investigated, were evaluated. Dissolved oxygen (DO) was also simulated, since it is often used as a staple of water quality. Results showed that employing HEC-RAS for hydraulic calculations improves the modified Streeter–Phelps simulation. In river sections without tidal influence, water quality was sensitive to the BOD and NH3–N degradation constants. Downstream of Chin-Mei Creek, while the BOD degradation constant decreased by 80%, BOD and DO concentrations increased from 7.1 mg/L to 10.7 mg/L and 5.0 mg/L to 7.2 mg/L, respectively, indicating that water quality was not as sensitive to variations of the BOD degradation constant as expected. The concentrations of DO and BOD at the river mouth had a significant impact on water quality for the tidal sections of the investigated rivers due to mixing of tidal and river waters. The BOD and NH3–N degradation constants in the tidal sections had little impact on water quality simulations. This study demonstrated the innovative combination of the modified Streeter–Phelps equation and HEC-RAS to assess the impact of tidal variation and to simulate the water quality of a tidal river when available data is rather limited.

Discharge measurement in a tidal stream is always a difficult task. Owing to the complex flow conditions, discharge measurement in tidal streams has to be finished quickly, and must be highly efficient in order to yield an accurate measurement of real-time discharge. Measuring the discharge of tidal streams is done in three steps: (1) establishing the stage and cross-sectional area relation, (2) estimating the index velocity by using a velocity distribution equation based on the probability concept, (3) establishing the relationship between the index and mean velocities. Then the cross-sectional area and mean velocity can be estimated by the gage height and index velocity, respectively. The discharge of tidal streams is computed as the product of the cross-sectional area and mean velocity. The velocity distribution of the Taipei Bridge and Guan-du Bridge in the Tanshui River were established and analyzed to demonstrate the use of discharge measurement by index velocity for estimating the discharge of this tidal stream. The results reveal no large difference between the discharges measured by the conventional methods and the index velocity. This pilot study proposed a cost-effectiveness and efficient method. It is an easy, quick, and accurate model for measuring the real-time discharge of a tidal stream. It makes automatic, real-time, and continuous monitoring of the discharge in a tidal stream become possible.

When grown as three-dimensional structures, tumor cells can acquire an additional multicellular resistance to apoptosis that may mimic the chemoresistance found in solid tumors. We developed a multicellular spheroid model of malignant mesothelioma to investigate molecular mechanisms of acquired apoptotic resistance. We found that mesothelioma cell lines, when grown as multicellular spheroids, acquired resistance to a variety of apoptotic stimuli, including combinations of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), ribotoxic stressors, histone deacetylase, and proteasome inhibitors, that were highly effective against mesothelioma cells when grown as monolayers. Inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, particularly rapamycin, blocked much of the acquired resistance of the spheroids, suggesting a key role for mTOR. Knockdown by small interference RNA of S6K, a major downstream target of mTOR, reproduced the effect of rapamycin, thereby confirming the role of mTOR and of S6K in the acquired resistance of threedimensional spheroids. Rapamycin or S6K knockdown increased TRAIL-induced caspase-8 cleavage in spheroids, suggesting initially that mTOR inhibited apoptosis by actions at the death receptor pathway; however, isolation of the apoptotic pathways by means of Bid knockdown ablated this effect showing that mTOR actually controls a step distal to Bid, probably at the level of the mitochondria. In sum, mTOR and S6K contribute to the apoptotic resistance of mesothelioma cells in three-dimensional, not in two-dimensional, cultures. The three-dimensional model may reflect a more clinically relevant in vitro setting in which mTOR exhibits anti-apoptotic properties.

PurposeThe planning approach used is issue‐based planning or formal strategic planning, leading to local optimization and duplicated redundancy. An approach is presented in the rapid growth of the business scale which emphasizes both customization and effectiveness, not only operation efficiency. The paper addresses these issues.Design/methodology/approachA two‐phase approach is applied to obtain a smooth implementation. A lean operation concept is executed in the first phase to reduce the engineer's workload, and the business process re‐engineering (BPR) technique is used in phase two to transform the working model.FindingsThis paper presents an extension model of hoshin kanri to translate strategies into achievable policies and actions to fulfil the objectives of the enterprise. This model not only comprises a complete plan and executive structure which is simple and effective, but also conducts complicated communication processes at different levels to achieve the common goals as envisioned by the executive management.Practical implicationsA case study is introduced to show the complete policy deployment process and realize the actual “vital few”. This study has been successfully implemented in the case company, and the labor productivity was improved by 6 percent over a two‐year period.Originality/valueThe paper presents a successful application of hoshin kanri for a semiconductor manufacturing company within a rapid growth environment.

Background/purpose To evaluate the ICU mortality rate of mechanically ventilated hematopoietic stem cell transplantation (HSCT) recipients and to identify the factors that were associated with ICU mortality. The impact of surgical lung biopsy (SLB) in patients with unexplained pulmonary infiltrates was also evaluated. Methods Forty-one mechanically ventilated HSCT recipients admitted to the ICU during the study period were enrolled. The medical records were reviewed and data at ICU admission were analyzed. Data were compared between ICU survivors and nonsurvivors. The pathologic findings of SLB and the resulting impact on treatment were analyzed. Results Eight patients (19.5%) survived the ICU stay, and seven (17%) lived to hospital discharge. The most common etiologies of ICU mortality included bacterial pneumonia, cytomegalovirus pneumonia, diffuse alveolar hemorrhage, sepsis, and aspergillosis. The factors associated with higher mortality were older age when performing HSCT, older age at ICU admission, higher acute physiology and chronic health evaluation (APACHE) II score, shock, higher respiratory rate, and higher heart rate at the time of ICU admission. Ten patients underwent SLB which resulted in treatment changes in five of them. Three patients had complications of SLB and one patient died of complications. Conclusion The ICU mortality rate of mechanically ventilated HSCT recipients was high. Factors associated with ICU mortality were older age, high APACHE II score, presence of shock, and higher respiratory or heart rate at the time of ICU admission. SLB might provide specific diagnosis in HSCT recipients with unexplained pulmonary infiltrates and aid modification of treatment. [ J Formos Med Assoc 2007;106(4):295-301]

Combinatorial therapies using the proteasome inhibitor, bortezomib, have been found to induce synergistic apoptosis in cancer cells grown as monolayers; however, three-dimensional spheroid culture may be a better model for the multicellular resistance found in solid tumors, such as lung cancer. We tested the combinatorial apoptotic strategy of using bortezomib together with TNF-related apoptosis-inducing ligand (TRAIL), both in monolayers and in spheroids of A549 lung cancer cells. Indeed, bortezomib plus TRAIL induced synergistic apoptosis in A549 cells grown as monolayers, but had little effect on A549 cells grown as three-dimensional multicellular spheroids. The acquired resistance of spheroids was not due to a limitation of diffusion, to survival pathways, such as NF-kappaB or PI3K/Akt/mTOR, or to the up-regulation of FLIP(S) (Fas-associated death domain-like IL-1 beta-converting enzyme inhibitory protein, short). We then investigated a role for the Bcl-2 family of anti- and proapoptotic proteins. When cells formed spheroids, antiapoptotic Bcl-2 increased, whereas antiapoptotic Mcl-1 decreased. ABT-737, a small molecule that inhibits Bcl-2, but not Mcl-1, abolished the multicellular resistance of A549 spheroids to bortezomib plus TRAIL. In another lung cancer cell line, H1299, acquisition of multicellular resistance in spheroids was also accompanied by an increase in Bcl-2 and decrease in Mcl-1. In H1299 spheroids compared with those of A549, however, Mcl-1 remained higher, and Mcl-1 knockdown was more effective than ABT-737 in removing multicellular resistance. Our study suggests that the balance of Bcl-2 family proteins contributes to the acquired multicellular resistance of spheroids, and suggests a possible target for improving the response of lung cancer to bortezomib therapies.

Solid tumors such as mesothelioma exhibit a stubborn resistance to apoptosis that may derive from survival pathways, such as PI3K/Akt/mTOR, that are activated in many tumors, including mesothelioma. To address the role of PI3K/Akt/mTOR, we used a novel approach to study mesothelioma ex vivo as tumor fragment spheroids. Freshly resected mesothelioma tissue from 15 different patients was grown in vitro as 1- to 2-mm-diameter fragments, exposed to apoptotic agents for 48 hours with or without PI3K/Akt/mTOR inhibitors, and doubly stained for cytokeratin and cleaved caspase 3 to identify apoptotic mesothelioma cells. Mesothelioma cells within the tumor spheroids exhibited striking resistance to apoptotic agents such as TRAIL plus gemcitabine that were highly effective against monolayers. In a majority of tumors (67%; 10 of 15), apoptotic resistance could be reduced by more than 50% by rapamycin, an mTOR inhibitor, but not by LY294002, a PI3K inhibitor. Responsiveness to rapamycin correlated with staining for the mTOR target, p-S6K, in the original tumor, but not for p-Akt. As confirmation of the role of mTOR, siRNA knockdown of S6K reproduced the effect of rapamycin in three rapamycin-responsive tumors. Finally, in 37 mesotheliomas on tissue microarray, p-S6K correlated only weakly with p-Akt, suggesting the existence of Akt-independent regulation of mTOR. We propose that mTOR mediates survival signals in many mesothelioma tumors. Inhibition of mTOR may provide a nontoxic adjunct to therapy directed against malignant mesothelioma, especially in those with high baseline expression of p-S6K.

Malignant pleural effusion is an important staging criterion in non-small cell lung cancer (NSCLC). Although cytologic examination remains the major diagnostic tool for NSCLC-related malignant pleural effusion, sometimes other invasive methods maybe required. Aberrant activation of Wnt signaling pathway due to Wnt inhibitory factor-1 (WIF-1) promoter region hypermethylation is common in NSCLC, and can be specifically detected by methylation-specific polymerase chain reaction (MSP). We hypothesized that WIF-1 promoter region MSP can be used to improve the diagnostic yield of NSCLC-related malignant pleural effusion. We performed WIF-1 promoter region MSP in 36 definite malignant pleural effusions from consecutive NSCLC patients and 35 pleural effusion specimens of benign origin. Pleural effusion cells were collected for DNA extraction. After bisulfite treatment, DNA was amplified by methylation-specific and unmethylation-specific primers, respectively, to identify the methylation status of WIF-1 promoter region. The results of WIF-1 promoter region MSP were positive in 25 (69.4%) of 36 NSCLC patients with malignant pleural effusion. In addition, the results of WIF-1 promoter region MSP were negative in all 35 patients with pleural effusion of benign origin. The age, gender, and smoking status of patients were not correlated with the methylation status of WIF-1 promoter region in NSCLC-related malignant pleural effusion. WIF-1 promoter region MSP might be used as an adjuvant tool to complement cytologic examination for the diagnosis of NSCLC-related malignant pleural effusion.

There are several methods to avoid optical feedback and reduce laser noise in optical recording systems. However, most of them utilize high cost optical components or electronics or increase the pickup head size. Furthermore, it is difficult to fit these components into in a small package like a holographic laser module. In this paper, a simple method for avoiding feedback noise in a holographic pickup head is proposed. A single wave plate is added to the optical system to rotate the polarization of the laser feedback to be orthogonal to the emitting polarization state. Experimental results show that it is feasible and practically reduces laser noise.