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Chun-Ta Huang,1 Sheng-Yuan Ruan,1 Feipei Lai,2– 4 Jung-Yien Chien,1 Chong-Jen Yu1 1Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 2Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan; 3Department of Computer Science & Information Engineering, National Taiwan University, Taipei, Taiwan; 4Department of Electrical Engineering, National Taiwan University, Taipei, TaiwanCorrespondence: Jung-Yien Chien, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Zhongshan S. Road, Zhongzheng Dist, Taipei, 100, Taiwan, Tel +886-2-23562905, Fax +886-2-23222890, Email jychien@ntu.edu.twPurpose: The 6-minute walk test (6MWT) is often used to evaluate chronic obstructive pulmonary disease (COPD) patients’ functional capacity, with 6-minute walk distance (6MWD) and related measures being linked to mortality and hospitalizations. This study investigates the prognostic value of pace variability, a significant indicator in sports medicine, during the 6MWT for COPD patients.Patients and Methods: We retrospectively screened consecutive COPD patients who had been prospectively enrolled in a pay-for-performance program from January 2019 to May 2020 to determine their eligibility. Patient characteristics, including demographics, exacerbation history, and 6MWT data, were analyzed to investigate their potential associations with prognosis. The primary outcome was a composite of adverse events, including overall mortality or hospitalizations due to exacerbations during a 1-year follow-up period. To analyze the 6MWT data, we divided it into three 2-minute epochs and calculated the average walk speed for each epoch. We defined pace variability as the difference between the maximum and minimum average speed in a single 2-minute epoch, divided by the average speed for the entire 6-minute walk test.Results: A total of 163 patients with COPD were included in the study, and 19 of them (12%) experienced the composite adverse outcome. Multivariable logistic regression analyses revealed that two predictors were independently associated with the composite outcome: % predicted 6MWD < 72 (adjusted odds ratio [aOR] 7.080; 95% confidence interval [CI] 1.481– 33.847) and pace variability ≥ 0.39 (aOR 9.444; 95% CI 2.689– 33.170). Patients with either of these adverse prognostic features had significantly worse composite outcome-free survival, with both log-rank P values less than 0.005. Notably, COPD patients with both adverse features experienced an especially poor outcome after 1 year.Conclusion: Patients with COPD who exhibited greater pace variability during the 6MWT had a significantly higher risk of overall mortality and COPD-related hospitalizations, indicating a worse prognosis.Keywords: 6-minute walk test, chronic obstructive pulmonary disease, outcome, pace, variability

Chien-Feng Lee,1,* Yunn-Jy Chen,2,* Wen-Chi Huang,3 Jen-Wen Hou,4 Yu-Ting Liu,5 Tiffany Ting-Fang Shih,6 Pei-Lin Lee,7– 10 Chong-Jen Yu1,8,9 1Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan; 2Department of Dentistry, School of Dentistry, National Taiwan University Hospital, Taipei, Taiwan; 3Department of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan; 4Graduate Institute of Electronics Engineering, National Taiwan University, Taipei, Taiwan; 5MediaTek Inc., Hsinchu, Taiwan; 6Department of Radiology and Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan; 7Center of Sleep Disorder, National Taiwan University Hospital, Taipei, Taiwan; 8Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 9School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 10Center for Electronics Technology Integration, National Taiwan University, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Pei-Lin Lee, Tel +886-2-2356-2755, Fax +886-2-2358-2867, Email leepeilin@ntu.edu.twObjective: Both continuous positive airway pressure (CPAP) pressure and polysomnographic phenotypes have been associated with mandibular advancement device (MAD) treatment response, but the precise relationship has not been fully elucidated. We hypothesized that utilizing CPAP pressure would predict the MAD response in treatment-naïve patients with moderate-severe obstructive sleep apnea (OSA), and the MAD response would be associated with two polysomnographic phenotypes, including sleep stage dependency and positional dependency.Methods: OSA treatment-naïve patients with an apnea-hypopnea index (AHI) ≥ 15/h who declined CPAP treatment and received MAD treatment for 3– 6 months were enrolled. The MAD treatment response was defined as 1) residual AHI under MAD (AHIMAD) < 5/h and 2) AHIMAD < 10/h. Logistic regression was applied to identify the association between CPAP pressure and MAD treatment responders. The predictability of the MAD responder status utilizing CPAP pressure was assessed with the area under the receiver operating characteristic (AUROC).Results: A total of 128 enrolled patients (AHI ≥ 30/h in 74.2%) were recruited, of whom 119 patients and 80 patients were included for analysis of sleep stage and positional dependency, respectively. REM-predominant OSA had lower AHI than stage-independent OSA, while the supine-predominant phenotype had lower anthropometrics than the nonpositional-dependent phenotype. The response rates for AHIMAD < 5/h and AHIMAD < 10/h were 25.8% and 48.4%, respectively. Lower anthropometrics, baseline AHI, and supine predominance were associated with the responder status, while CPAP pressure was an independent predictor. The AUROCs for the prediction of AHIMAD < 5/h and AHIMAD < 10/h responders were 0.635 and 0.664, respectively. Utilizing a CPAP level > 14 cmH2O as the cutoff to predict criterion 1 and 2 nonresponders, the sensitivity was 93.9% and 95.2%, respectively.Conclusion: In treatment-naïve patients with moderate-severe OSA, the supine-predominant phenotype and lower CPAP pressure were associated with the MAD response, while the sleep stage dependency phenotype was not. Utilization of a CPAP level > 14 cmH2O could be a sensitive measure to identify nonresponders.Keywords: continuous positive airway pressure, mandibular advancement device, polysomnography, phenotype, sleep apnea, obstructive

Shih-Lung Cheng,1,2,&ast; Yi-Rong Li,3,&ast; Nicole Huang,4 Chong-Jen Yu,5 Hao-Chien Wang,5 Meng-Chih Lin,6 Kuo-Chin Chiu,7 Wu-Huei Hsu,8 Chiung-Zuei Chen,9 Chau-Chyun Sheu,10,11 Diahn-Warng Perng,12 Sheng-Hao Lin,13 Tsung-Ming Yang,14 Chih-Bin Lin,15 Chew-Teng Kor,16 Ching-Hsiung Lin13,17,18 1Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, 220, Taiwan; 2Department of Chemical Engineering and Materials Science, Yuan Ze University, Zhongli, Taoyuan, 320, Taiwan; 3Changhua Christian Hospital, Thoracic Medicine Research Center, Changhua, 500, Taiwan; 4Institute of Hospital and Health Care Administration, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 5Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan; 7Division of Chest, Department of Internal Medicine, Poh-Ai Hospital, Luodong, 265, Taiwan; 8Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 9Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University, College of Medicine and Hospital, Tainan, 701, Taiwan; 10Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan; 11Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan; 12Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, 112, Taiwan; 13Department of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, Changhua, 500, Taiwan; 14Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, 613, Taiwan; 15Department of Internal Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; 16Big Data Center, Changhua Christian Hospital, Changhua, Changhua Christian Hospital, Changhua, 500, Taiwan; 17Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, 402, Taiwan; 18Department of Recreation and Holistic Wellness, MingDao University, Changhua, 523, Taiwan&ast;These authors contributed equally to this workCorrespondence: Ching-Hsiung LinDepartment of Internal Medicine, Division of Chest Medicine, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 50006, TaiwanTel +886-4-7238595Fax +886-4-7232942Email 47822@cch.org.twBackground: 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< 0.05, 95% confidence interval [CI]: − 0.277 to − 0.086; hospitalization: − 1.62%, p< 0.05, 95% CI: − 0.232 to − 0.020), whereas no significant difference was observed between the groups in terms of the changes in the prevalence of COPD-related ICU admissions.Conclusion: The COPD P4P program exerted a positive net effect on reducing the likelihood of COPD exacerbation, namely COPD-related ED visits and hospitalizations. Future studies should examine the long-term cost-effectiveness of the COPD P4P program.Keywords: COPD, pay-for-performance program, guideline-based, comprehensive care, exacerbation, financial incentive

Jie-Xin Huang,1 Yi-Cheng Wu,2 Ya-Yun Cheng,1 Chih-Liang Wang,3,4,* Chia-Jung Yu1,4–6,* 1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 2Department of Thoracic Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 3School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 4Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 5Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 6Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Chia-Jung YuDepartment of Cell and Molecular Biology, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Guishan District, Taoyuan City, TaiwanTel +886-3-2118800 ext. 3424Fax +886-3-2118042Email yucj1124@mail.cgu.edu.twChih-Liang WangDivision of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, 5 Fuxing Street, Guishan District, Taoyuan City, TaiwanEmail wang5726@gmail.comPurpose: Karyopherin alpha 2 (KPNA2) has been reported as an oncogenic protein in numerous human cancers and is currently considered a potential therapeutic target. However, the transcriptional regulation and physiological conditions underlying KPNA2 expression remain unclear. The aim of the present study was to investigate the role and regulation of interferon regulatory factor-1 (IRF1) in modulating KPNA2 expression in lung adenocarcinoma (ADC).Materials and methods: Bioinformatics tools and chromatin immunoprecipitation were used to analyze the transcription factor (TF) binding sites in the KPNA2 promoter region. We searched for a potential role of IRF1 in non-small-cell lung cancer (NSCLC) using Oncomine and Kaplan-Meier Plotter datasets. qRT-PCR was applied to examine the role of IRF1 and signaling involved in regulating KPNA2 transcription. Western blotting was used to determine the effects of extracellular stimulation and intracellular signaling on the modulation of KPNA2-related TF expression.Results: IRF1 was identified as a novel TF that suppresses KPNA2 gene expression. We observed that IRF1 expression was lower in cancerous tissues than in normal lung tissues and that its low expression was correlated with poor prognosis in NSCLC. Notably, both ataxia telangiectasia mutated (ATM) and mechanistic target of rapamycin (mTOR) inhibitors reduced KPNA2 expression, which was accompanied by increased expression of IRF1 but decreased expression of E2F1, a TF that promotes KPNA2 expression in lung ADC cells. IRF1 knockdown restored the reduced levels of KPNA2 in ATM inhibitor-treated cells. We further demonstrated that epidermal growth factor (EGF)-activated mTOR and hypoxia-induced ATM suppressed IRF1 expression but promoted E2F1 expression, which in turn upregulated KPNA2 expression in lung ADC cells.Conclusion: IRF1 acts as a potential tumor suppressor in NSCLC. EGF and hypoxia promote KPNA2 expression by simultaneously suppressing IRF1 expression and enhancing E2F1 expression in lung ADC cells. Our study provides new insights into targeted therapy for lung cancer.Keywords: lung adenocarcinoma, KPNA2, IRF1, E2F1, EGF, hypoxia

Chia-Jung Liu,1 Tai-Fen Lee,2 Sheng-Yuan Ruan,1 Chong-Jen Yu,1 Jung-Yien Chien,1 Po-Ren Hsueh1,21Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan; 2Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, TaiwanObjectives: The incidence of Pneumocystis pneumonia (PCP) has been increasing among non-HIV-infected patients. Here, we investigated the clinical characteristics, treatment outcomes, and prognostic factors of PCP in non-HIV-infected patients.Patients and methods: Information on clinical characteristics, treatment outcomes, and prognostic factors of PCP patients who were treated at a medical center in northern Taiwan from October 2015 to October 2016 were retrieved from medical records and evaluated.Results: Among the patients with PCP included in the study, 84 were non-HIV-infected and 25 were HIV-infected. Non-HIV-infected patients with PCP had a longer duration between radiographic findings and treatment (P

Te-Wei Ho,1,2 Sheng-Yuan Ruan,3 Chun-Ta Huang,3,4 Yi-Ju Tsai,5 Feipei Lai,1 Chong-Jen Yu3 1Graduate Institute of Biomedical Electronics and Bioinformatics, College of Electrical Engineering and Computer Science, National Taiwan University, Taipei, Taiwan; 2Department of Surgery, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 4Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan; 5Graduate Institute of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan Purpose: Claim data from Taiwan’s National Health Insurance (NHI) database have previously been utilized in the study of COPD. However, there are limited data on the positive predictive value of claim data for COPD diagnosis. Therefore, this study aimed to characterize and validate the COPD cohort identified from the NHI research database.Methods: This cross-sectional study compared records from claim data with those from a medical center. From 2007 to 2014, a COPD cohort was constructed from claim data using ICD9-CM codes for COPD. The diagnostic positive predictive value of these data was assessed with reference to physician-verified COPD. In addition, a multivariate logistic regression model was built to identify independent factors associated with the positive predictive value of COPD diagnosis by claim data.Results: During the 8-year study period, a total of 12,127 subjects met the criterion of having two or more outpatient codes in 1 year or one or more inpatient COPD codes in their claim data. Of this total, the diagnosis of COPD was verified by physicians in 7,701 (63.5%) subjects. Applying a more stringent criterion – three or more outpatient codes or two or more inpatient codes – improved the diagnostic positive predictive value to 72.2%. Age ≥65 years and a claim for spirometry were the two most important factors associated with the positive predictive value of claim-data-defined COPD. Adding spirometry testing to diagnostic ICD9-CM codes for COPD increased the positive predictive value to 84.6%.Conclusion: This study emphasizes the importance of validation of disease-specific diagnosis prior to applying an administrative database in clinical studies. It also indicates the limitation of ICD9-CM codes alone in recognizing COPD patients within the NHI research database. Keywords: chronic obstructive pulmonary disease, database, International Classification of Diseases code, Taiwan, validity

Chih-Cheng Lai,1 Ya-Hui Wang,2 Cheng-Yi Wang,3 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) on the risk of pneumonia and severe exacerbations in patients with COPD.Patients and methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1) of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death.Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15–1.29) than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16–1.21) than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring hospitalization (aHR, 1.24; 95% CI, 1.21–1.28) or emergency department visits (aHR, 1.16; 95% CI, 1.13–1.18), pneumonia requiring mechanical ventilation (aHR, 1.35; 95% CI, 1.24–1.47), and mortality (aHR, 1.33; 95% CI, 1.26–1.42).Conclusion: ARBs were associated with lower rates of pneumonia, severe pneumonia, and mortality than ACEis in patients with COPD. Keywords: angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, COPD, severe exacerbation, pneumonia, mortality

Yueh Lan Huang,1 Chih-Cheng Lai,2 Ya-Hui Wang,3 Cheng-Yi Wang,1 Jen-Yu Wang,1 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 2Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, 3Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan Background: There is conflicting information regarding the effects of selective and nonselective beta-blocker treatment in patients with COPD.Participants and methods: This nested case–control study used the Taiwan National Health Insurance Research Database. We included COPD patients who used inhalation steroid and beta-blockers between 1998 and 2010. From this cohort, there were 16,067 patients with severe exacerbations included in the analysis and 55,970 controls matched on age, sex, COPD diagnosis year, and beta-blockers treatment duration by risk set sampling.Results: For the selective beta-blocker users, the current users had a lower risk of severe exacerbations than the nonusers (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.85–0.96). In contrast, for the nonselective beta-blocker users, the current users had a higher risk of severe acute exacerbations than the nonusers (OR, 1.21; 95% CI, 1.14–1.27). A higher risk of severe exacerbation during increasing mean daily dose or within about the initial 300 days was found in nonselective beta-blockers, but not in selective beta-blockers. One selective beta-blocker, betaxolol, had a significantly lower risk of severe exacerbations (OR, 0.75; 95% CI, 0.60–0.95). Two nonselective beta-blockers (labetalol and propranolol) were associated with a significantly higher risk of exacerbations (OR, 1.49; 95% CI, 1.32–1.67 for labetalol; OR, 1.16; 95% CI, 1.10–1.23 for propranolol).Conclusion: Selective beta-blockers can be cautiously prescribed for patients with COPD and cardiovascular disease (CVD), however, nonselective beta-blockers should not be prescribed for patients with COPD. Betaxolol may be the preferred choice of suitable selective beta-blocker for patients with COPD, however, labetalol and propranolol should be avoided for patients with COPD. Keywords: beta-blocker, COPD, selective, nonselective

Hsi-Hsing Yang,1,2 Chih-Cheng Lai,3 Ya-Hui Wang,4 Wei-Chih Yang,5 Cheng-Yi Wang,4,* Hao-Chien Wang,6,* Likwang Chen,5 Chong-Jen Yu6 On behalf of Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, 2Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, 3Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, 4Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, 6Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan *These authors contributed equally to this work Background: It remains unclear whether severe exacerbation and pneumonia of COPD differs between patients treated with budesonide/formoterol and those treated with fluticasone/salmeterol. Therefore, we conducted a comparative study of those who used budesonide/formoterol and those treated with fluticasone/salmeterol for COPD.Methods: Subjects in this population-based cohort study comprised patients with COPD who were treated with a fixed combination of budesonide/formoterol or fluticasone/salmeterol. All patients were recruited from the Taiwan National Health Insurance database. The outcomes including severe exacerbations, pneumonia, and pneumonia requiring mechanical ventilation (MV) were measured.Results: During the study period, 11,519 COPD patients receiving fluticasone/salmeterol and 7,437 patients receiving budesonide/formoterol were enrolled in the study. Pairwise matching (1:1) of fluticasone/salmeterol and budesonide/formoterol populations resulted in to two similar subgroups comprising each 7,295 patients. Patients receiving fluticasone/salmeterol had higher annual rate and higher risk of severe exacerbation than patients receiving budesonide/formoterol (1.2219/year vs 1.1237/year, adjusted rate ratio, 1.08; 95% CI, 1.07–1.10). In addition, patients receiving fluticasone/salmeterol had higher incidence rate and higher risk of pneumonia than patients receiving budesonide/formoterol (12.11 per 100 person-years vs 10.65 per 100 person-years, adjusted hazard ratio [aHR], 1.13; 95% CI, 1.08–1.20). Finally, patients receiving fluticasone/salmeterol had higher incidence rate and higher risk of pneumonia requiring MV than patients receiving budesonide/formoterol (3.94 per 100 person-years vs 3.47 per 100 person-years, aHR, 1.14; 95% CI, 1.05–1.24). A similar trend was seen before and after propensity score matching analysis, intention-to-treat, and as-treated analysis with and without competing risk.Conclusions: Based on this retrospective observational study, long-term treatment with fixed combination budesonide/formoterol was associated with fewer severe exacerbations, pneumonia, and pneumonia requiring MV than fluticasone/salmeterol in COPD patients. Keywords: COPD, ICS/LABA, exacerbation, pneumonia

Cheng-Yi Wang,1,2 Chih-Cheng Lai,3 Wei-Chih Yang,4 Chia-Chieh Lin,1,2 Likwang Chen,4 Hao-Chien Wang,5 Chong-Jen Yu5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE) 1Department of Internal Medicine, 2Medical Research Center, Cardinal Tien Hospital, Fu Jen Catholic University College of Medicine, New Taipei City, 3Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, 4Institute of Population Health Sciences, National Health Research Institutes, Zhunan, 5Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan Abstract: To investigate the association between inhaled corticosteroid (ICS) exposure patterns and the risk of pneumonia in chronic obstructive pulmonary disease (COPD) patients, we performed a nested case-control study. Between 1998 and 2010, 51,739 patients, including 19,838 cases of pneumonia, were matched to 74,849 control subjects selected from a cohort of COPD patients using ICSs via risk-set sampling of the database constructed by the National Health Research Institutes of Taiwan. After adjusting for covariates, the current use of ICSs was associated with a 25% increase in the risk of pneumonia (odds ratio [OR] =1.25, 95% confidence interval [CI] =1.20–1.30), and there was an increase in the OR with increase in the average daily dosage. Additionally, users of fluticasone/salmeterol, fluticasone, and either fluticasone/salmeterol or fluticasone were more likely to be at a higher risk of pneumonia (OR =1.35, 95% CI =1.28–1.41; OR =1.22, 95% CI =1.10–1.35; and OR =1.33, 95% CI =1.27–1.39, respectively). In contrast, there were no statistically significant associations between the risk of pneumonia and the use of budesonide/formoterol, budesonide, or either budesonide/formoterol or budesonide. In conclusion, ICSs are significantly associated with an increased risk of pneumonia in COPD patients. The effect is prominent for fluticasone-containing ICSs but not for budesonide-containing ICSs. Keywords: chronic obstructive pulmonary disease, inhaled corticosteroid, pneumonia

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

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

Jeng-Sen Tseng,1,2 Tsung-Ying Yang,2 Kun-Chieh Chen,1,2 Kuo-Hsuan Hsu,1,3 Chong-Jen Yu,4 Wei-Yu Liao,4 Chi-Ren Tsai,5,6 Meen-Hsin Tsai,2,7 Sung-Liang Yu,8–11 Kang-Yi Su,8,12 Jeremy JW Chen,1 Hsuan-Yu Chen,7 Gee-Chen Chang1,2,13–151Institute of Biomedical Sciences, National Chung-Hsing University, 2Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, 3Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 4Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, 5Department of Pediatrics, Taichung Veterans General Hospital, 6Institute of Molecular Biology, National Chung-Hsing University, Taichung, 7Institute of Statistical Science, Academia Sinica, 8Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, 9Center for Optoelectronic Biomedicine, College of Medicine, National Taiwan University, 10Graduate Institute of Pathology, College of Medicine, National Taiwan University, 11Department of Laboratory Medicine, National Taiwan University Hospital, 12Center of Genomic Medicine, National Taiwan University, Taipei, 13School of Medicine, China Medical University, 14Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, 15Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, TaiwanBackground: Tumor cells before and after epidermal growth-factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) therapy might display different characteristics. The aim of this study was to evaluate the influence of prior EGFR TKI therapy on the efficacy of subsequent pemetrexed plus platinum (PP) in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma.Materials and methods: Advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma receiving PP as first-line chemotherapy were enrolled retrospectively in two medical centers of Taiwan. The objective of this study was to compare objective response rate (ORR), disease-control rates (DCR), progression-free survival (PFS), and overall survival (OS) of PP in patients with and without prior EGFR TKI therapy.Results: In total, 105 patients were analyzed. Sixty-one patients (58.1%) had prior EGFR TKI therapy and used PP as second-line treatment. The other 44 patients (41.9%) received PP as first-line therapy. ORRs of PP in patients with and without prior EGFR TKI therapy were 24.6% and 38.6%, respectively (P=0.138). DCRs of the two groups were 62.3% and 65.9%, respectively (P=0.837). The median PFS (6.1 versus 6.1 months, P=0.639) and OS (34.4 versus 32.3 months, P=0.394) were comparable between the groups with and without prior EGFR TKI therapy. In a subgroup analysis of patients with prior EGFR TKI therapy, there was no significant association between the efficacy of first-line EGFR TKI and the outcome of subsequent PP therapy.Conclusion: Our results suggested that prior EGFR TKI therapy would not influence the efficacy of subsequent PP therapy in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma.Keywords: non-small-cell lung cancer, epidermal growth-factor receptor mutation, epidermal growth-factor receptor tyrosine-kinase inhibitor, pemetrexed

Background/purpose: This study evaluated the immune response elicited by two formulations of an AS03(A)-adjuvanted H5N1 A/Indonesia/05/2005 prepandemic influenza vaccine, developed using manufacturing processes with or without thiomersal. In addition, it also evaluated compliance to the Centre for Biologics Evaluation and Research and Committee for Medicinal Products for Human Use (CHMP) immunogenicity guidance criteria for pandemic influenza vaccines in adults.Methods: This phase III, observer-blind, randomized study (NCT00812981) enrolled 320 subjects aged 18-60 years into two groups to receive, 21 days apart, two doses of the formulation manufactured using either the thiomersal-containing process (Group TC) or the thiomersal-free process (Group TF). Blood samples collected before vaccination, 21 days after the second vaccine dose, and 6 months following the first vaccine dose (Days 0, 42, and 180) were analysed using a hemagglutination inhibition (HI) assay. Safety assessments were made for the entire study period.Results: Twenty-one days after the second dose of vaccine, both groups met the CHMP criteria for vaccine-homologous HI response (seroprotection rates/seroconversion rates ≥ 98.7%, seroconversion factor ≥ 121.9) and also for a heterologous HI response against the A/Vietnam/1194/2004 strain (seroprotection rates/seroconversion rates ≥ 81.3%, seroconversion factor ≥ 10.8). Six months after the first dose of vaccine, a marked persistence of the vaccine-homologous HI response was observed that still met one or more CHMP criteria. Pain at the injection site (Group TF 95%, Group TC 91.8%) and myalgia (Group TF 68.8%, Group TC 63.5%) were the most frequently recorded solicited symptoms. Overall, both formulations had a clinically acceptable safety profile.Conclusion: Administration of two doses of the AS03(A)-adjuvanted H5N1 prepandemic influenza vaccine was found to be highly immunogenic in adults with a clinically acceptable safety profile. The ability to confer cross-clade protective immunity makes it a suitable option for mitigation of the morbidity and mortality of outbreaks and pandemics due to H5N1 and drifted strains. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to examine the level of symptoms, psychological distress, and supportive care needs and factors related to five unmet need domains in lung cancer patients.Methods: A cross-sectional study of 152 lung cancer patients at a medical center in Taiwan assessed their symptoms, psychological distress, and unmet supportive needs in five major care domains. Logistic regression was applied to examine the related factors of unmet supportive care needs.Results: In general, patients had mild-to-moderate levels of symptoms and high prevalence of psychological distress. Regardless of their treatment status, they reported high levels of supportive care needs. The top three need domains were: (1) health system and information, (2) psychological, and (3) patient care and support. Levels of symptoms, anxiety, and depression were the most significant factors in unmet supportive care needs.Conclusion: The effect of symptoms and psychological distress on unmet supportive care needs is substantial. Therefore, a systematic assessment of patients' distress and care needs is important for clinical lung cancer care. Further intervention consisting of symptom management, continuing counseling, and preparation for transition from active treatment to the follow-up stages are essential in improving quality of care. [ABSTRACT FROM AUTHOR]

RATIONALE: Gefitinib is effective in treating patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Deletions in exon 19 and L858R in exon 21 are the best-documented EGFR mutations that are associated with effective gefitinib responsiveness. OBJECTIVES: To clarify the influence of gefitinib timing, we conducted a study to compare the outcomes of different lines of gefitinib treatment in patients with exon 19 deletions or L858R. METHODS: We surveyed the clinical data and mutational studies of patients with NSCLC with EGFR mutations in the National Taiwan University Hospital (Taipei, Taiwan). MEASUREMENTS AND MAIN RESULTS: Three hundred and twenty-eight patients, who received gefitinib for stage IIIb or IV NSCLC, were adequately sequenced for EGFR mutations; 192 patients had mutant EGFR, including 77 patients with exon 19 deletions and 75 patients with L858R. The 152 patients with exon 19 deletions or L858R and who were receiving gefitinib were classified into a chemonaive group (91 patients) or a chemotherapy-treated group (61 patients). Chemonaive status before gefitinib and female sex were associated with clinical response to gefitinib (P = 0.006 and 0.053, respectively). Neither overall survival after the start of antitumor therapy nor progression-free survival after gefitinib therapy was significantly different between these two groups (P = 0.207 and 0.804, respectively). Clinical response to gefitinib was the only factor associated with better overall survival (P = 0.001). CONCLUSIONS: This study suggests that gefitinib is effective in patients with EGFR mutations. The gefitinib response rate in chemonaive patients is higher than in chemotherapy-treated patients; however, there is no difference in overall survival. [ABSTRACT FROM AUTHOR]

Primary Klebsiella pneumoniae liver abscess with metastatic complications is a globally emerging infectious disease and is the leading cause of liver abscess in Taiwan. Host immunity and bacterial virulence, especially of the capsular polysaccharide type, are important in determining clinical manifestations. Investigators retrospectively studied the K pneumoniae genotype and capsular serotype from patients with 37 strains of liver abscess; no correlation was noted with genotype, and many genetically different strains caused liver abscess. Although K pneumoniae is prevalent in patients with diabetes, it can attack healthy or alcoholic people as well. Additional studies are needed to explore the mechanisms of bacterial virulence and to optimize treatment strategies. Physicians should be alert to the illness and its complications. [ABSTRACT FROM AUTHOR]

At issue is whether network resources imply some resources available to all members in networks or available only to those occupying structurally central positions in networks. In this article, two conceptual models, the additive and interaction models of the firm, are empirically tested regarding the impact of hospital resources, network resources, and centrality on hospital performance in the Taiwan health care industry. The results demonstrate that: (1) in the additive model, hospital resources and centrality independently affect performance, whereas network resources do not; and (2) no evidence supports the interaction effect of centrality and resources on performance. Based on our findings in Taiwanese practices, the extent to which the resources are acquired externally from networks, we suggest that while adopting interorganizational strategies, hospitals should clearly identify those important resources that reside in-house and those transferred from network partners. How hospitals access resources from central positions is more important than what network resources can hospitals acquire from networks. Hospitals should improve performance by exploiting its in-house resources rather than obtaining network resources externally. In addition, hospitals should not only invest in hospital resources for better performance but should also move to central positions in networks to benefit from collaborations. [ABSTRACT FROM AUTHOR]

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS., (© 2024. The Author(s).)

Automated delivery of therapy in virtual reality (VR) has the potential to be used for smoking cessation. Most obviously, it could be used to practise and establish alternative reactions to smoking cues. The first step in treatment development is to show that VR environments can trigger sufficient cravings in smokers. We evaluated a new VR public house outdoor scenario with 100 individuals who smoked daily. Participants were randomly assigned to the VR scenario with smoking cues or a neutral experience in VR. The VR experiences were presented in a standalone VR headset. Before and after VR, we collected self-reported craving scores for cigarettes and alcohol using the Tobacco Craving Questionnaire (TCQ) and visual analogue scales (VAS). Physiological data were also collected. Compared to the neutral condition, exposure to the smoking cues led to a large increase in craving for a cigarette (TCQ β = 11.44, p < 0.0001, Cohen's d = 1.10) and also a moderate increase in craving for alcohol ( β = 0.7 , p = 0.017 , d = 0.50 ) . There were no significant physiological differences between the two conditions. These results provide good evidence that VR experiences can elicit strong craving for cigarettes. The programming can be part of developing a new VR cognitive therapy to help people reduce smoking., (© 2024. The Author(s).)

Introduction: EGFR tyrosine kinase inhibitors (TKIs) are the standard therapy for non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations in the first-line setting. Despite initial efficacy, resistance to EGFR-TKIs often develops, and platinum-based chemotherapy is the predominant subsequent treatment. For this study, we aimed to identify prognostic factors for overall survival (OS) and progression-free survival (PFS) among advanced EGFR-mutant NSCLC patients receiving platinum-pemetrexed after progression on EGFR-TKIs. Our analysis specifically focuses on 1st-line treatments limited to 1st- or 2nd-generation EGFR-TKIs, while not restricting later-line treatments involving osimertinib prior to chemotherapy., Materials and Methods: From 2012 to 2017, 363 patients who received first-line treatment with first- or second-generation EGFR-TKIs, including gefitinib, erlotinib, and afatinib were enrolled. Some patients received different EGFR-TKIs, including osimertinib, as later-line treatment before platinum-pemetrexed., Results: Median OS from the initiation of platinum-pemetrexed was 22.0 months and median PFS with platinum-pemetrexed was 6.2 months. In the multivariate Cox model, we identified three independent prognostic factors for better OS: postoperative recurrence (HR: 0.34, p = 0.004), first-line EGFR-TKI PFS ≥12 months (HR: 0.54, p = 0.002), and osimertinib treatment after platinum-pemetrexed (HR: 0.56, p = 0.005) while BMI <18.5 indicated poor prognosis (HR:1.76, p = 0.049). No statistically significant independent prognostic factors for PFS were found. Receiving osimertinib before platinum-pemetrexed treatment did not impact PFS with platinum-pemetrexed treatment (HR: 1.11, p = 0.64)., Conclusion: Postoperative recurrence, first-line EGFR-TKI PFS ≥12 months and osimertinib treatment after platinum-pemetrexed predicted better OS, while BMI <18.5 predicted worse OS. Osimertinib treatment before platinum-pemetrexed treatment did not affect the efficacy of platinum-pemetrexed., Competing Interests: Declaration of competing interest Dr. Yao reports personal fees from AstraZeneca, Boehringer Ingelheim, and Pfizer, outside the submitted work. Dr. Liao reports personal fees from AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, MSD Oncology, Novartis, Bristol-Myers Squibb, and Chugai Pharma Taiwan, outside the submitted work. Dr. Ho reports personal fees from Boehringer Ingelheim, Eli Lilly, Amgen, Roche/Genentech/Chugai, MSD, and Pfizer, outside the submitted work; Dr. Shih reports grants from Taipei City Thoracic Disease Academic Research and Education Foundation and personal fees from ACTgenomics, Amgen, Genconn Biotech, AstraZeneca, Roche, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharma, Takeda, CStone Pharmaceuticals, Janssen, TTY Biopharm, Orient EuroPharma, MundiPharma, Ono Pharmaceutical, and Bristol-Myers Squibb, outside the submitted work. Dr. Chen reports personal fees from AstraZeneca, Roche, Novartis, Pfizer, Eli Lilly, Merck Sharp and Dohme, Ono Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. Dr. Yang reports personal fees and other from Amgen, grants, personal fees and other from AstraZeneca, personal fees and other from Bayer, personal fees and other from Boehringer Ingelheim, personal fees and other from Bristol Myers Squibb, personal fees and other from Daiichi Sankyo, other from Eli Lilly, personal fees and other from Merck KGaA, Darmstadt, Germany, personal fees and other from Merck Sharp & Dohme, personal fees and other from Novartis, personal fees from Ono Pharmaceuticals, personal fees from Pfizer, personal fees and other from Roche/Genentech, personal fees and other from Takeda Oncology, personal fees and other from Yuhan Pharmaceuticals, other from JNJ, other from Puma Technology, other from Gilead, other from GSK, outside the submitted work. The other authors declare no conflict of interest., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Airflow obstruction is a hallmark of disease severity and prognosis in bronchiectasis. The relationship between lung microbiota, airway inflammation, and outcomes in bronchiectasis with fixed airflow obstruction (FAO) remains unclear. This study explores these interactions in bronchiectasis patients, with and without FAO, and compares them to those diagnosed with chronic obstructive pulmonary disease (COPD)., Methods: This prospective observational study in Taiwan enrolled patients with either bronchiectasis or COPD. To analyze the lung microbiome and assess inflammatory markers, bronchoalveolar lavage (BAL) samples were collected for 16S rRNA gene sequencing. The study cohort comprised 181 patients: 86 with COPD, 46 with bronchiectasis, and 49 with bronchiectasis and FAO, as confirmed by spirometry., Results: Patients with bronchiectasis, with or without FAO, had similar microbiome profiles characterized by reduced alpha diversity and a predominance of Proteobacteria, distinctly different from COPD patients who exhibited more Firmicutes, greater diversity, and more commensal taxa. Furthermore, compared to COPD and bronchiectasis without FAO, bronchiectasis with FAO showed more severe disease and a higher risk of exacerbations. A significant correlation was found between the presence of Pseudomonas aeruginosa and increased airway neutrophilic inflammation such as Interleukin [IL]-1β, IL-8, and tumor necrosis factor-alpha [TNF]-α, as well as with higher bronchiectasis severity, which might contribute to an increased risk of exacerbations. Moreover, in bronchiectasis patients with FAO, the ROSE (Radiology, Obstruction, Symptoms, and Exposure) criteria were employed to classify individuals as either ROSE (+) or ROSE (-), based on smoking history. This classification highlighted differences in clinical features, inflammatory profiles, and slight microbiome variations between ROSE (-) and ROSE (+) patients, suggesting diverse endotypes within the bronchiectasis with FAO group., Conclusion: Bronchiectasis patients with FAO may exhibit two distinct endotypes, as defined by ROSE criteria, characterized by greater disease severity and a lung microbiome more similar to bronchiectasis without FAO than to COPD. The significant correlation between Pseudomonas aeruginosa colonization and increased airway neutrophilic inflammation, as well as disease severity, underscores the clinical relevance of microbial patterns. This finding reinforces the potential role of these patterns in the progression and exacerbations of bronchiectasis with FAO., (© 2024. The Author(s).)

Background: Secondary pneumonia has a significant clinical impact on critically ill patients with COVID-19., Aim: Considering potential geographic variations, this study explores the clinical implications of secondary pneumonia within East Asian populations., Methods: This multicenter, retrospective cohort study enrolled critical COVID-19 patients requiring intensive care units (ICUs) admission in Taiwan from December 31, 2020, to June 1, 2022., Findings: Among the 187 critical COVID-19 patients, 80 (42.8%) developed secondary pneumonia. The primary causative pathogens were gram-negative bacilli (GNB) (76.8%). Gram-positive cocci and fungi were mainly observed during the initial two weeks of ICU stay. Notably, the incidence of pulmonary aspergillosis was 9.2% during the first week of ICU stay and all Staphylococcus aureus were susceptible to methicillin. Multi-drug resistant organisms (MDROs) were responsible for 28.3% of the cases, exhibiting significantly longer ICU stays compared to the non-MDRO group (median, 27 vs. 14 days, P < 0.001). In the multivariate analysis, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were associated with a significantly increased risk of secondary pneumonia. In-hospital mortality was significantly higher in patients with secondary pneumonia than in those without (37.7% vs. 16.7%, P = 0.02) and survival analysis demonstrated gram-negative bacilli-related secondary pneumonia contributed to a worse prognosis., Conclusions: Secondary pneumonia in critical COVID-19 patients significantly raised in-hospital mortality and extended hospital and ICU stays. Moreover, the presence of GNB notably predicted an unfavorable prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)