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Background: This study aimed to evaluate the effectiveness and safety of fixed-dose combination (FDC) inhaled corticosteroids/long-acting β 2 -agonists (ICS/LABA) in bronchiectasis., Research Design and Methods: A retrospective cohort study analyzed electronic medical records of bronchiectasis patients initiating ICS/LABA FDC or LAMA between 2007 and 2021. All bronchiectasis diagnoses were made by radiologists using high-resolution computed tomography., Results: Of the 1,736 patients, 1,281 took ICS/LABA FDC and 455 LAMA. Among the 694 propensity score matched patients, ICS/LABA FDC had comparable outcomes to LAMA, with HRs of 1.22 (95% CI 0.81-1.83) for hospitalized respiratory infection, 1.06 (95% CI 0.84-1.33) for acute exacerbation, and 1.06 (95% CI 0.66-1.02) for all-cause hospitalization. Beclomethasone/formoterol (BEC/FOR) or budesonide/formoterol (BUD/FOR) led to a lower risk of acute exacerbation compared to fluticasone/salmeterol (FLU/SAL) (BEC/FOR HR 0.59, 95% CI 0.43-0.81; BUD/FOR HR 0.68, 95% CI 0.50-0.93). BEC/FOR resulted in lower risks of hospitalized respiratory infection (HR 0.48, 95% 0.26-0.86) and all-cause hospitalization (HR 0.55, 95% 0.37-0.80) compared to FLU/SAL., Conclusion: Our findings provide important evidence on the effectiveness and safety of ICS/LABA FDC compared with LAMA for bronchiectasis. BEC/FOR and BUD/FOR were associated with better outcomes than FLU/SAL.

Idiopathic pulmonary fibrosis has poor clinical outcomes despite antifibrotic treatment. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome and endothelial-to-mesenchymal transition (EndoMT) were shown to be involved in the pathogenesis of pulmonary fibrosis. However, the detailed mechanism is unknown. Our study aimed to investigate the role of the NLRP3 inflammasome in the regulation of EndoMT in pulmonary fibrosis. The inhibition of the NLRP3 inflammasome via a caspase-1 inhibitor, Ac-YVAD-cmk (YVAD), was intraperitoneally administered to male C57BL/6 mice (8-12 weeks old) one hour before bleomycin intratracheal injection (1.5 U/kg). Immunohistochemical staining, Masson's trichrome staining, enzyme-linked immunosorbent assay, immunofluorescence, and Western blotting were used to assess the activity of the NLRP3 inflammasome and EndoMT in lung samples from mice. Human pulmonary microvascular endothelial cells (HPMECs) were used as a model of EndoMT in vitro with YVAD and bleomycin stimulation. We observed the activation of the NLRP3 inflammasome and EndoMT (decreased vascular endothelial cadherin with increased alpha-smooth muscle actin and vimentin) in the lung samples after bleomycin. However, inhibition of the NLRP3 inflammasome significantly reduces EndoMT via inhibiting focal adhesion kinase (FAK). In vitro studies also confirmed these findings. In conclusion, NLRP3 inflammasome inhibition could reduce lung inflammation and fibrosis via the regulation of EndoMT by the FAK pathway.

We investigated the effects of vegetable glycerin (VG), a main e-cigarette constituent, on endotoxin-induced acute lung injury (ALI). Mice received intratracheal administration of 30% VG in phosphate buffered saline (PBS) vehicle or only PBS (control) for 4 days. On Day 5, mice received an intratracheal instillation of lipopolysaccharide (LPS) (LPS group and VG + LPS group) or PBS (VG group and control group). Lung histopathology, expression of chemokine receptors, and regulatory signaling were analyzed 24 h after the Day 5 treatment. VG significantly increased ALI-associated histopathological and fibrotic changes in both the VG group and LPS-induced ALI mice (VG + LPS group). Immunohistochemistry (IHC) and western blot analyses revealed that VG administration resulted in upregulation of neutrophil markers [lymphocyte antigen 6 complex locus G6D (Ly6G) and myeloperoxidase (MPO)] as well as upregulation of the expression of transforming growth factor-β (TGF-β), a central mediator of fibrogenesis, in the lungs of both VG and VG + LPS groups. VG enhanced the expression of adhesion molecules [very late antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1)] and increased activation of p38 mitogen-activated protein kinase (p38 MAPK) to prompt neutrophil recruitment in the lungs of mice with ALI. Intraperitoneal administration of a p38 inhibitor attenuated these histopathological changes significantly as well as VG-induced upregulation in expression of Ly6G, MPO, VLA-4, VCAM-1, TGF-β, and collagen-1 in mice with ALI. In conclusion, VG enhances neutrophil chemotaxis and fibrosis and it amplifies the inflammatory response associated with LPS-induced ALI in the lungs via enhancement of p38 MAPK activity., (© 2023. The Author(s).)

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD). Pulmonary fibroblasts play an important role in the development of IPF. Emerging evidence indicates that pulmonary endothelial cells could be the source of pulmonary fibroblasts through endothelial mesenchymal transition (EndoMT), which contributes to pulmonary fibrosis. EndoMT is a complex process in which endothelial cells lose their expression of endothelial markers and give rise to the characteristics of mesenchymal cells, including morphological fibroblast-like change and the expression of mesenchymal markers, which result in cardiac, renal, and dermal fibroses. Furthermore, EndoMT inhibition attenuates pulmonary fibrosis. Herein, we demonstrate that nintedanib, a tyrosine kinase receptor inhibitor, ameliorated murine bleomycin (BLM)-induced pulmonary fibrosis and suppressed the in vivo and in vitro models of EndoMT. We demonstrated that the activity of focal adhesion kinase (FAK), a key EndoMT regulator, increased in murine lung tissues and human pulmonary microvascular endothelial cells after BLM stimulation. Nintedanib treatment inhibited BLM-induced FAK activation and thus suppressed both in vivo and in vitro BLM-induced EndoMT. Importantly, we found that the VEGF/FAK signaling pathway was involved in nintedanib regulating EndoMT. These novel findings help us understand the mechanism and signaling pathway of EndoMT to further develop more efficacious drugs for IPF treatment.

Rationale: The association between chronic obstructive pulmonary disease (COPD) and functional gastrointestinal disorders (FGIDs) remains unclear., Methods: Using Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study to explore the relationship of COPD and future FGIDs development. The COPD cohort consisted of 4107 patients with COPD between 2000 and 2005. For a comparison cohort, 12,321 age- and gender-matched patients without COPD were randomly selected. The two cohorts were tracked for 5 year and observed for occurrence of FGIDs. The operational definition of COPD in the Korean Health Insurance Review and Assessment Service database was used to validate the results. The validation study confirmed the accuracy of definitions of COPD (83.5% sensitivity)., Results: The adjusted hazard ratios (aHR) of FGIDs in patients with COPD was higher (aHR: 1.63; 95% confidence interval (CI): 1.45-1.83; P < .001) than that of the comparison patients. In our secondary analysis in which FGIDs was divided into gastroesophageal reflux disease, irritable bowel syndrome and functional dyspepsia. Patients with COPD also had higher risk for all three subtypes of FGIDs: irritable bowel syndrome (aHR: 1.55; 95% confidence interval (CI): 1.27-1.90; P < .001), gastroesophageal reflux disease (aHR: 2.10; 95% confidence interval (CI): 1.76-2.49; P < .001), and functional dyspepsia (aHR: 1.34; 95% confidence interval (CI): 1.11-1.62; P = .003). The results in validated COPD group were consistent with those in unvalidated COPD group., Conclusion: Patients with COPD appeared to be at higher risk for future FGIDs., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: Current clinical guidelines are unclear regarding the association of cardiovascular medication with the risk of acute exacerbation (AE) in patients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO)., Methods: We conducted a retrospective cohort study by interrogating the claims database of Taipei Veterans General Hospital. Patients with coexistent fixed airflow limitation and asthma were enrolled as an ACO cohort between 2009 and 2017. Exposure to cardiovascular medications, including angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), non-selective beta-blockers, cardioselective beta-blockers, dihydropyridine (DHP) calcium channel blockers (CCBs), and non-DHP CCBs, in 3-month period each served as time-dependent covariates. Patients receiving a cardiovascular medication ≥ 28 cumulative daily doses were defined as respective cardiovascular medication users. Patients were followed up until December 31, 2018. The primary endpoint was severe AE, defined as hospitalization or emergency department visit for either asthma, COPD, or respiratory failure. The secondary outcome was moderate AE., Results: The final study cohort consisted of 582 ACO subjects, with a mean follow-up period of 2.98 years. After adjustment, ARB (hazard ratio [HR], 0.64, 95% confidence interval [CI], 0.44-0.93, P = 0.019), cardioselective beta-blocker (HR, 0.29, 95% CI, 0.11-0.72, P = 0.008) and DHP CCB (HR, 0.66, 95% CI, 0.45-0.97, P = 0.035) therapies were associated with lower risks of severe AE. ARB (HR, 0.42, 95% CI, 0.30-0.62, P < 0.001) and DHP CCB (HR, 0.55, 95% CI, 0.38-0.80, P = 0.002) therapies were associated with lower risks of moderate AE. Cardioselective beta-blockers, ARBs, and DHP CCBs were associated with lower risks of severe AE in frequent exacerbators. ACEI, non-selective beta-blocker, or non-DHP CCB use did not change the risk of severe AE., Conclusions: ARB, cardioselective beta-blocker, and DHP CCB therapies may lower the risk of AE in patients with ACO., Competing Interests: There are no financial or other issues that might lead to conflict of interest., (Copyright © 2022 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease.)

Three (60%) of five patients with coronavirus disease 2019 (COVID-19) had olfactory disorder. Two exhibited anosmia at the onset of COVID-19, while one had hyposmia 4 days after the onset of COVID-19. All patients with olfactory disorder were completely recovered with a mean recovery length of 11.3 days., Competing Interests: Declaration of Competing Interest No conflict of interest exists for the author., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Asthma, which is caused by inflammation of the airways, affects the sensitivity of nerve endings. Narcolepsy is a chronic sleep disorder that may be caused by autoimmunity. Recent studies have reported a positive association between narcolepsy and asthma. We aimed to examine the association between asthma and narcolepsy and determine the effects of therapeutic corticosteroid or bronchodilator use., Materials and Methods: We conducted a nationwide population-based, nested case-control study using Taiwan's National Health Insurance Research Database (NHIRD) between 2000 and 2013. Subjects with narcolepsy (ICD-9-CM code 347) were enrolled, with 1:3 estimated propensity score-matched controls based on sex, age, and index year. The association between narcolepsy and asthma was assessed using multiple logistic regression analyses. The covariates included sex, age, monthly insurance premiums, geographical area of residence, urbanization level of residence, level of care, and presence of diseases related to immune response and central nervous system. The effects of corticosteroid and bronchodilator use were also analyzed., Results: Overall, 2008 subjects were identified from the NHIRD (502 patients with narcolepsy and 1506 controls). The participants with narcolepsy had almost three times the level of previous asthma diagnosis than controls. Compared to those without asthma, patients with asthma had an adjusted odds ratio (OR) of 3.181 for narcolepsy comorbidity (95% confidence interval [CI]: 2.048-4.941, p <0.001). The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity, with an adjusted OR of 0.465 (95% CI, 0.250-0.634; p <0.001), in patients with asthma when compared to those without treatment., Conclusion: This study demonstrated a significantly higher level of previous asthma diagnosis in patients with narcolepsy. The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity in asthma patients, compared to those without treatment., Competing Interests: The authors declare no conflicts of interest for this work., (© 2021 Chen et al.)

The role of nintedanib, a multiple tyrosine kinase inhibitor, in the treatment of sepsis-induced acute lung injury (ALI) remains unclear. Lipopolysaccharide (LPS), also known as endotoxin, has been used to induce ALI. The goal of this study was to assess the effect of nintedanib in attenuating the histopathological changes of LPS-induced ALI. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h and 10 min before intratracheal endotoxin instillation. Lung histopathological characteristics, adhesion molecule expression, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed after 24 h. We found that nintedanib significantly reduced histopathological changes and neutrophil recruitment in LPS-induced ALI. The number of neutrophils in bronchoalveolar lavage fluid (BALF) was reduced in nintedanib-treated relative to untreated mice with ALI. Nintedanib mediated the downregulation of the chemotactic response to LPS by reducing the expression of adhesion molecules and the phosphorylated p38:total p38 mitogen-activated protein kinase (MAPK) ratio in the lungs of mice with ALI. Nintedanib also reduced the expression of lymphocyte antigen 6 complex locus G6D (Ly6G) and very late antigen 4 (VLA-4) in BALF neutrophils and mediated the downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in mice with LPS-induced ALI. Nintedanib improved the histopathological changes of LPS-induced ALI by reducing neutrophil chemotaxis. These effects were mediated by the inhibition of adhesion molecules via the activation of GRK2 and the inhibition of p38 MAPK and CXCR2.

Introduction : Tuberculosis, a chronic infection caused by Mycobacterium tuberculosis (MTB), is one of the 10 leading causes of death in the world. The current treatment is a combination antimicrobial therapy administered for 6-9 months. It is important to find therapeutic strategy to shorten the treatment during and strengthen the host immune response against MTB. Areas covered : There is evidence that MTB uses cholesterol in the host macrophage to infect and survive inside the host macrophage. Statins inhibit the synthesis of cholesterol and aid in reducing the levels of cholesterol in human, which have been associated with better outcome in infectious diseases. In this narrative review, we discuss recent studies that investigated the effects of statins on the prevention or treatment of TB infection. Expert opinion : The evaluation of the published evidence suggests that statins may be beneficial in the treatment of patients with TB infections. Future studies may focus not only on the beneficial effects of statins, but also on distinguishing the effects of different statins.

The conditioned medium of induced pluripotent stem cells (iPSC-CM) can attenuate neutrophil recruitment and endothelial leakage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Therefore, we investigated the mechanisms by which iPSC-CM regulate the interaction between neutrophils and the endothelium in ALI. Murine iPSCs (miPSCs) were delivered intravenously to male C57BL/6 mice (8-12 weeks old) 4 h after intratracheal LPS injection. A miPSC-derived conditioned medium (miPSC-CM) was delivered intravenously to mice after intratracheal LPS injection. DMSO-induced HL-60 cells (D-HL-60, neutrophil-like cells) and human umbilical vein endothelial cells (HUVECs) were used as in vitro models to assess the interaction of neutrophils and endothelial cells. miPSC-CM diminished the histopathological changes in the lungs and the neutrophil count in bronchoalveolar lavage fluids of ALI mice. miPSC-CM attenuated the expression of adhesion molecules in the lungs of ALI mice. Human iPSC conditioned medium (hiPSC-CM) reduced the expression of adhesion molecules in a HUVEC and D-HL-60 co-culture after LPS stimulation, which decreased the transendothelial migration (TEM) of D-HL-60. A human angiogenesis factors protein array revealed that leukemia inhibitory factor (LIF) was not detected in the absence of D-HL-60 and hiPSC-CM groups. hiPSC-CM significantly promoted the production of endogenous LIF in in vitro models. Administration of an anti-LIF antibody not only reversed the effect of iPSC-CM in ALI mice, but also blocked the effect of iPSC-CM on neutrophils TEM in in vitro models. However, a controlled IgG had no such effect. Our study demonstrated that iPSC-CM promoted endogenous LIF to inhibit neutrophils TEM and attenuate the severity of sepsis-induced ALI.

Background: Telehealth is a recommended method for monitoring the progression of nonsevere infections in patients with COVID-19. However, telehealth has not been widely implemented to monitor SARS-CoV-2 infection in quarantined individuals. Moreover, studies on the cost-effectiveness of quarantine measures during the COVID-19 pandemic are scarce., Objective: In this cohort study, we aimed to use telehealth to monitor COVID-19 infections in 217 quarantined Taiwanese travelers and to analyze the cost-effectiveness of the quarantine program., Methods: Travelers were quarantined for 14 days at the Taiwan Yangmingshan quarantine center and monitored until they were discharged. The travelers' clinical symptoms were evaluated twice daily. A multidisciplinary medical team used the telehealth system to provide timely assistance for ill travelers. The cost of the mandatory quarantine was calculated according to data from the Ministry of Health and Welfare of Taiwan., Results: All 217 quarantined travelers tested negative for SARS-CoV-2 upon admission to the quarantine center. During the quarantine, 28/217 travelers (12.9%) became ill and were evaluated via telehealth. Three travelers with fever were hospitalized after telehealth assessment, and subsequent tests for COVID-19 were negative for all three patients. The total cost incurred during the quarantine was US $193,938, which equated to US $894 per individual., Conclusions: Telehealth is an effective instrument for monitoring COVID-19 infection in quarantined travelers and could help provide timely disease management for people who are ill. It is imperative to screen and quarantine international travelers for SARS-CoV-2 infection to reduce the nationwide spread of COVID-19., (©Yung-Feng Yen, Yi-Fan Tsai, Vincent Yi-Fong Su, Shang-Yih Chan, Wen-Ruey Yu, Hsuan Ho, Chun-Mei Hou, Chu-Chieh Chen, Lin-Chung Woung, Sheng-Jean Huang. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 11.12.2020.)

Background: Pressure support ventilation (PSV) is the prevalent weaning method. Proportional assist ventilation (PAV) is an assisted ventilation mode, which is recently being applied to wean the patients from mechanical ventilation. Whether PAV or PSV is superior for weaning remains unclear., Methods: Eligible randomized controlled trials published before April 2020 were retrieved from databases. We calculated the risk ratio (RR) and mean difference (MD) with 95% confidence intervals (CIs)., Results: Seven articles, involving 634 patients, met the selection criteria. Compared to PSV, PAV was associated with a significantly higher rate of weaning success (fixed-effect RR 1.16; 95% CI 1.07-1.26; I 2  = 0.0%; trial sequential analysis-adjusted CI 1.03-1.30), and the trial sequential monitoring boundary for benefit was crossed. Compared to PSV, PAV was associated with a lower proportion of patients requiring reintubation (RR 0.49; 95% CI 0.28-0.87; I 2  = 0%), a shorter ICU length of stay (MD - 1.58 (days), 95% CI - 2.68 to - 0.47; I 2  = 0%), and a shorter mechanical ventilation duration (MD - 40.26 (hours); 95% CI - 66.67 to - 13.84; I 2  = 0%). There was no significant difference between PAV and PSV with regard to mortality (RR 0.66; 95% CI 0.42-1.06; I 2  = 0%) or weaning duration (MD - 0.01 (hours); 95% CI - 1.30-1.28; I 2  = 0%)., Conclusion: The results of the meta-analysis suggest that PAV is superior to PSV in terms of weaning success, and the statistical power is confirmed using trial sequential analysis.

The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41-0.71) and erlotinib (HR 0.62, 95% CI 0.46-0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08-2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.

This TB contact cohort study showed that the risk of incident TB, not coprevalent TB, was highest in the diabetes group without metformin use during TB exposure, followed by the nondiabetes population, and was lowest in the diabetes group with metformin use https://bit.ly/3fpJyF0., Competing Interests: Conflict of interest: S-W. Pan has nothing to disclose. Conflict of interest: J-Y. Feng has nothing to disclose. Conflict of interest: Y-F. Yen has nothing to disclose. Conflict of interest: F-Y. Chuang has nothing to disclose. Conflict of interest: H-S. Shen has nothing to disclose. Conflict of interest: V.Y-F. Su has nothing to disclose. Conflict of interest: P-H. Chuang has nothing to disclose. Conflict of interest: Y-J. Chan has nothing to disclose. Conflict of interest: W-J. Su has nothing to disclose., (Copyright ©ERS 2020.)

Neutrophils are involved in the alveolitis of idiopathic pulmonary fibrosis (IPF). However, their pathogenic mechanisms are still poorly understood. Nintedanib has antifibrotic and anti-inflammatory activity in IPF. This study aimed to investigate the regulatory mechanism of nintedanib on neutrophil chemotaxis in bleomycin (BLM)-induced pulmonary fibrosis. Nintedanib was administered via oral gavage to male C57BL/6 mice 24 h after a bleomycin intratracheal injection (1.5 U/kg). Lung histopathological findings, the expression of cytokines, and the regulatory signaling pathways of neutrophil chemotaxis were analyzed. The effect of nintedanib was also investigated in a mouse model with adoptive neutrophil transfer in vivo. Nintedanib significantly decreased the histopathological changes and neutrophil recruitment in BLM-induced pulmonary fibrosis. Nintedanib mediated a downregulation of chemokine (C-X-C motif) receptor 2 (CXCR2) and very late antigen 4 (VLA-4) expression, as well as an upregulation of G protein-coupled receptor kinase 2 (GRK2) activity in peripheral blood neutrophils in BLM-induced pulmonary fibrosis. Nintedanib also decreased the activation of endothelial cells by the decreased expression of vascular cell adhesion molecule 1 (VCAM-1). The effect of nintedanib on regulating neutrophil chemotaxis was also confirmed by a mouse model with adoptive neutrophil transfer in vivo. In conclusion, nintedanib reduces neutrophil chemotaxis and endothelial cell activation to regulate the severity of BLM-induced pulmonary fibrosis. These effects are associated with an enhancement of GRK2 activity and a reduction in CXCR2 and VLA-4 expression on neutrophils and a decrease in VCAM-1 expression on endothelial cells.

It remains uncertain whether statin use is associated with the risks of tuberculosis (TB) and herpes zoster in patients with type 2 diabetes. This study aims to assess the effects of statins vs nonstatin lipid-lowering agents on the risk of these infectious diseases in patients with diabetes., Methods: Participants in the Taiwan National Health Insurance Research Database diagnosed with type 2 diabetes in 2001-2013 were classified as statin users, nonstatin users and lipid-lowering drug-free groups. Participants were observed for incident TB and herpes zoster from diabetes diagnosis until treatment crossover or December 2013. Statin user and nonstatin user were the time-dependent variables in Cox regression analysis., Results: Over 240 782 person-years of observation, statin users (n = 17 696) were associated with a lower TB risk than nonstatin users (n = 5327) and the drug-free group (n = 22 316) (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.44-0.99 and aHR: 0.57; 95% CI: 0.44-0.73). Compared with nonstatin users, statin users showed a dose-dependent association with TB risk (low-potency statin users, aHR: 0.692; 95% CI: 0.455-1.053; high-potency users, aHR: 0.491; 95% CI: 0.241-0.999). Statin users presented with a higher risk of herpes zoster than nonstatin users and the drug-free group (aHR: 1.23; 95% CI: 1.01-1.50 and aHR: 1.20; 95% CI: 1.09-1.33). The risks of TB and herpes zoster were not statistically different between nonstatin users and the drug-free group., Conclusion: Compared with nonstatin drugs, statin use was specifically associated with a decreased risk of TB but a moderately increased risk of herpes zoster in this cohort study., (© 2019 The British Pharmacological Society.)

Induced pluripotent stem cells (iPSCs) can reduce the severity of endotoxin-induced acute lung injury (ALI). However, the interaction between iPSCs and vascular endothelium remains unclear. In this study, we investigated the effects of iPSCs in moderating pulmonary endothelial leakage in endotoxin-induced ALI. Murine iPSCs were delivered intravenously to male C57BL/6 mice (8-12 weeks old) 4 hours after intratracheal lipopolysaccharide (LPS) delivery. Histology, blood and bronchoalveolar lavage fluid (BALF) cytokine and junctional protein assays, and regulatory signaling pathway assays were performed 24 hours later. Human umbilical vein endothelial cells (HUVECs) were used as a model of junctional protein-expressing cells and stimulated with LPS. Our results showed that iPSC treatment alleviated histological signs of ALI, protein leakage, and proinflammatory cytokines. iPSC therapy restored vascular endothelial cadherin (VE-cadherin) expression in ALI mouse lungs. In HUVECs, human iPSCs (hiPSCs) restored disrupted VE-cadherin expression and reduced the activity of Snail and focal adhesion kinase (FAK) phosphorylation in Tyr397 in response to LPS. iPSC-conditioned medium contained extra antiangiogenic factor of tissue inhibitor of metalloproteinases-1 (TIMP-1) compared with control medium. TIMP-1 inhibition diminished the beneficial effects of iPSC-conditioned medium in ALI mice. Our study suggested that iPSCs attenuate endothelial cell leakage in endotoxin-induced ALI via a mechanism involving TIMP-1 and the FAK/Snail pathway. Stem Cells 2019;37:1516-1527., (©AlphaMed Press 2019.)

The appropriate treatment for patients with coexistent chronic obstructive pulmonary disease (COPD) and heart failure (HF) remains unclear. Data from the Taiwan National Health Insurance Research Database was used for this retrospective cohort study. Patients diagnosed with both diseases between 1997 and 2012 were enrolled as the COPD-heart failure overlap cohort. Patients were categorized as non-users and users of specific COPD and HF medications. Medication prescriptions in each 3-month and 1-year period served as time-dependent covariates. The primary endpoint was cumulative survival. The validation study confirmed the accuracy of definitions of COPD (94.0% sensitivity) and HF (96.3% sensitivity).The study included 275,436 patients with COPD-heart failure overlap, with a mean follow-up period of 9.32 years. The COPD-heart failure overlap cohort had more medical service use and higher mortality than did the COPD alone cohort. Use of inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations, long-acting muscarinic antagonist (LAMA), angiotensin receptor blockers (ARBs), β blockers, aldosterone antagonists, and statins reduced mortality risk compared with non-use. Sensitivity and subgroup analyses confirmed the consistency and robustness of results.ICS/LABA combinations, LAMA, ARBs, β blockers, aldosterone antagonists, and statins use was associated with a lower mortality risk in patients with COPD-heart failure overlap.

Underuse or unavailability of spirometry is one of the most important factors causing underdiagnosis of COPD. We reported the development of a COPD prediction model to identify at-risk, undiagnosed COPD patients when spirometry was unavailable. This cross-sectional study enrolled subjects aged ≥40 years with respiratory symptoms and a smoking history (≥20 pack-years) in a medical center in two separate periods (development and validation cohorts). All subjects completed COPD assessment test (CAT), peak expiratory flow rate (PEFR) measurement, and confirmatory spirometry. A binary logistic model with calibration (Hosmer-Lemeshow test) and discrimination (area under receiver operating characteristic curve [AUROC]) was implemented. Three hundred and one subjects (development cohort) completed the study, including non-COPD (154, 51.2%) and COPD cases (147; stage I, 27.2%; II, 55.8%; III-IV, 17%). Compared with non-COPD and GOLD I cases, GOLD II-IV patients exhibited significantly higher CAT scores and lower lung function, and were considered clinically significant for COPD. Four independent variables (age, smoking pack-years, CAT score, and percent predicted PEFR) were incorporated developing the prediction model, which estimated the COPD probability (P COPD ). This model demonstrated favorable discrimination (AUROC: 0.866/0.828; 95% CI 0.825-0.906/0.751-0.904) and calibration (Hosmer-Lemeshow P = 0.332/0.668) for the development and validation cohorts, respectively. Bootstrap validation with 1000 replicates yielded an AUROC of 0.866 (95% CI 0.821-0.905). A P COPD of ≥0.65 identified COPD patients with high specificity (90%) and a large proportion (91.4%) of patients with clinically significant COPD (development cohort). Our prediction model can help physicians effectively identify at-risk, undiagnosed COPD patients for further diagnostic evaluation and timely treatment when spirometry is unavailable.

The immunomodulatory effects of mesenchymal stem cells (MSCs) are established. However, the effects of MSCs on neutrophil survival in acute lung injury (ALI) remain unclear. The goal of this study was to investigate the effect of an MSC-conditioned medium (MSC-CM) on neutrophil apoptosis in endotoxin-induced ALI. In this study, an MSC-CM was delivered via tail vein injection to wild-type male C57BL/6 mice 4 h after an intratracheal injection of lipopolysaccharide (LPS). Twenty-four hours later, bronchoalveolar lavage fluid (BALF) and lung tissue were collected to perform histology, immunohistochemistry, apoptosis assay of neutrophil, enzyme-linked immunosorbent assays, and an electrophoretic mobility shift assay. Human neutrophils were also collected from patients with sepsis-induced acute respiratory distress syndrome (ARDS). Human neutrophils were treated in vitro with LPS, with or without subsequent MSC-CM co-treatment, and were then analyzed. Administration of the MSC-CM resulted in a significant attenuation of histopathological changes, the levels of interleukin-6 and macrophage inflammatory protein 2, and neutrophil accumulation in mouse lung tissues of LPS-induced ALI. Additionally, MSC-CM therapy enhanced the apoptosis of BALF neutrophils and reduced the expression of the anti-apoptotic molecules, Bcl-xL and Mcl-1, both in vivo and in vitro experiments. Furthermore, phosphorylated and total levels of nuclear factor (NF)-κB p65 were reduced in lung tissues from LPS + MSC-CM mice. Human MSC-CM also reduced the activity levels of NF-κB and matrix metalloproteinase-9 in the human neutrophils from ARDS patients. Thus, the results of this study suggest that the MSC-CM attenuated LPS-induced ALI by inducing neutrophil apoptosis, associated with inhibition of the NF-κB pathway., Competing Interests: The authors declare no conflict of interest.

Induced pluripotent stem cells (iPSCs) can attenuate the pathological severity and neutrophil migration of lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, interactions that may occur between iPSCs and the triggering receptor expressed on myeloid cells (TREM) family of proteins remain unclear. In this study, murine iPSCs (miPSCs) were delivered via tail vein injection to wild type, TREM-1 knockout (KO), and TREM-2 KO C57BL/6 mice 4 hours after an intratracheal delivery of LPS. Twenty-four hours later, the bronchoalveolar lavage fluid and lung tissue were collected to perform histology, immunohistochemistry, neutrophil counts, Western blot assays, and enzyme-linked immunosorbent assays. Neutrophils were also isolated from the bone marrow to perform in vitro migration assays. In the lung tissues collected, LPS increased the expression of TREM-1 and TREM-2, with the TREM-2 KO mice expressing more TREM-1 than the wild-type mice. The TREM-2 KO mice also exhibited greater severity of LPS-induced ALI, enhanced neutrophil infiltration in the lung tissues, and a higher ratio of phosphorylated p38 to total p38 (p-p38/p38) in neutrophils. The p-p38/p38 ratio and the expression of vascular cell adhesion molecule-1 and certain proinflammatory cytokines (macrophage inflammatory protein-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β) were increased in whole lung extracts following LPS-induced ALI, and these levels were even more in LPS-treated TREM-2 KO mice. These effects were reduced when miPSCs were administered. Thus, the results of this study suggest that miPSCs attenuate the role of neutrophils in lung inflammation and injury induced by LPS by reducing their expression of TREM-1 and p38 mitogen-activated protein kinase signaling. Stem Cells 2019;37:631-639., (© AlphaMed Press 2019.)

Background: Bronchiectasis-chronic obstructive pulmonary disease (COPD) overlap (BCO) is a neglected area of trials, and it is not covered by guidelines for clinical practice., Methods: Using the National Health Insurance Research Database of Taiwan, COPD patients with or without bronchiectasis from 2000 to 2009 were enrolled as the BCO and COPD alone cohorts, respectively. Patients followed for <28 days, diagnosed with COPD who were not prescribed with COPD medications, and those diagnosed with bronchiectasis who did not receive a chest X-ray or computed tomography were excluded. The primary endpoints were acute exacerbations and mortality., Results: There were 831 patients in the BCO cohort and 3321 patients in the COPD alone cohort, covering 3763.08 and 17,348.95 person-years, respectively, from 2000 to 2011. The BCO cohort had higher risk for exacerbations (adjusted hazard ratio (HR) 2.26, 95% confidence interval (CI) 1.94⁻2.63) and mortality (HR 1.46, 95% CI 1.24⁻1.73) than the COPD alone cohort. In the patients overall, the use of statins, macrolides, and mucolytic agents was associated with significantly lower risks of acute exacerbations (statins, HR 0.37, 95% CI 0.29⁻0.46; macrolides, HR 0.65, 95% CI 0.45⁻0.93; mucolytic agents, HR 0.68, 95% CI 0.59⁻0.78). Statins were associated with a significantly lower risk of mortality (HR 0.32, 95% CI 0.25⁻0.41). In the BCO group, statins and mucolytic agents use was associated with significantly lower risks of acute exacerbations (statins, HR 0.44, 95% CI 0.29⁻0.65; mucolytic agents, HR 0.58, 95% CI 0.45⁻0.75)., Conclusion: Statins and mucolytic agents use may lower risk of acute exacerbation in patients with BCO.

Background: Based on current guidelines, more research is urgently needed to guide appropriate treatment for patients with asthma-chronic obstructive pulmonary disease (COPD) overlap., Objective: The objective of this study was to investigate medication effects on acute exacerbation in patients with coexistent COPD and asthma., Methods: Using Taiwan's National Health Insurance Research Database, we conducted a nationwide population-based study to evaluate medication effects in patients with COPD and asthma. Patients diagnosed with both asthma and COPD between 1997 and 2012 were enrolled as the COPD + asthma cohort. The primary endpoint was acute exacerbation. The definitions of COPD and asthma were validated. The validation study confirmed the accuracy of definitions of COPD (86.2% sensitivity) and asthma (92.0% sensitivity)., Results: The study included 251,398 patients with COPD + asthma and 514,522 patients with COPD alone, with a mean follow-up period of 9.85 years. After adjustment, hazard ratios (HRs) for long-acting muscarinic antagonist (LAMA) and inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) combinations were lower (time-dependent model, 1 year: LAMA, HR 0.51, 95% confidence interval [CI] 0.49-0.54; ICS/LABA combinations, HR 0.61, 95% CI 0.60-0.62; all P < .0001) than were those for LABAs or ICSs in patients with COPD and asthma., Conclusions: The use of LAMA or ICS/LABA combinations was associated with a lower risk of acute exacerbation in patients with COPD and asthma in this study., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: The effect of antacid therapy for patients with COPD and gastroesophageal reflux disease (GERD) remains unclear., Patients and Methods: This nationwide population-based study was conducted using data from Taiwan's National Health Insurance Research Database, and enrolled COPD patients with or without GERD. Patients with COPD who were not prescribed COPD medications were excluded. Patients with GERD who underwent upper gastrointestinal endoscopy or 24-hour pH monitoring and received at least 1 antacid were enrolled as symptomatic GERD group. The primary endpoint was acute exacerbation and mortality., Results: This study included 3,485 patients with COPD and symptomatic GERD, and 13,938 patients with COPD alone and covered 12,806.57 and 56,809.78 person-years, respectively, from 2000 to 2011. After multivariate adjustment, symptomatic GERD was associated with acute exacerbation (adjusted hazard ratio [HR]: 1.35, 95% CI: 1.23-1.48, p <0.0001) and mortality (HR: 1.42, 95% CI: 1.25-1.61, p <0.0001). In the COPD with symptomatic GERD group, use of proton pump inhibitors was associated with a lower risk of acute exacerbation and mortality (acute exacerbation, HR 0.31, 95% CI: 0.20-0.50, p <0.0001; mortality, HR 0.36, 95% CI: 0.20-0.65, p =0.0007), whereas no significant benefit was observed for histamine2-receptor antagonists., Conclusion: Use of proton pump inhibitors was associated with a lower risk of acute exacerbation and mortality in the patients with COPD and symptomatic GERD., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Metformin and the sulfonylureas are common initial antidiabetic agents; the former has demonstrated anti-TB action in in vitro and animal studies. The comparative effect of metformin vs the sulfonylureas on TB risk in patients with type 2 diabetes mellitus (T2DM) remains unclear., Methods: In this retrospective cohort study, patients without chronic kidney disease who received a T2DM diagnosis during 2003 to 2013 were identified from the Taiwan National Health Insurance Research Database. Participants with ≥ 2 years of follow-up were reviewed and observed for TB until December 2013. Patients receiving metformin ≥ 60 cumulative defined daily dose (cDDD) and sulfonylureas < 15 cDDD in the initial 2 years were defined as metformin majors; it was the inverse for sulfonylurea majors. The two groups were matched 1:1 by propensity score and compared for TB risk by multivariate Cox regression analysis., Results: Among 40,179 patients with T2DM, 263 acquired TB (0.65%) over a mean follow-up of 6.1 years. In multivariate analysis, the initial 2-year dosage of metformin, but not that of the sulfonylureas, was an independent predictor of TB (60-cDDD increase (adjusted hazard ratio [HR], 0.931; 95% CI, 0.877-0.990) after adjustment by cofactors, including adapted diabetes complication severity index. Metformin majors had a significantly lower TB risk than that of sulfonylurea majors before and after matching (HR, 0.477; 95% CI, 0.268-0.850 and HR, 0.337; 95% CI, 0.169-0.673; matched pairs, n = 3,161). Compared with the reference group (initial 2-year metformin < 60 cDDD), metformin treatment showed a dose-dependent association with TB risk (60-219 cDDD; HR, 0.860; 95% CI, 0.637-1.161; 220-479 cDDD, HR, 0.706; 95% CI, 0.485-1.028; ≥ 480 cDDD, HR, 0.319; 95% CI, 0.118-0.863)., Conclusions: Metformin use in the initial 2 years was associated with a decreased risk of TB, and metformin users had a reduced risk compared with their sulfonylurea comparators., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Experimental studies have demonstrated that influenza vaccination may protect against tuberculosis (TB) through a Th17 response. This nationwide cohort study aimed to evaluate the association of influenza vaccination with incident TB among elderly persons in Taiwan. This 2005-2012 study included 99,982 elderly persons (64,290 vaccinated and 35,692 unvaccinated) from the Taiwan National Health Insurance Research Database. During the 738,367 person-years of follow-up, 1,141 (1.14%) persons had incident TB. The cumulative incidences of TB were 145.2 cases/100,000 person-years among vaccinated elderly persons and 175.5 cases/100,000 person-years among unvaccinated elderly persons (p = 0.002). The time-dependent Cox proportional hazards model revealed that influenza vaccination was an independent protective factor for incident TB. Our results suggest that influenza vaccination is associated with a lower risk of incident TB among elderly persons in Taiwan. Further investigation of biologic mechanisms is warranted.

Introduction: Few studies have reported outcomes of lung cancer patients with acute respiratory failure (RF) using noninvasive positive pressure ventilation (NIPPV). The aim of this study was to investigate the prognostic factors in these patients., Materials and Methods: This retrospective observational study included all hospitalized lung cancer patients who received NIPPV for acute RF. It was conducted at a tertiary medical center in Taiwan from 2005 to 2010. The primary outcome was all cause mortality at 28 days after the initiation of NIPPV. Secondary outcomes included all-cause in-hospital mortality, weaning from NIPPV, intubation rate, tracheostomy rate, duration of NIPPV, hospital stay and intensive care unit stay., Results: The all-cause mortality rate at day 28 of the enrolled 58 patients was 39.66%. The 90-day and 1-year mortality rates were 63.79% and 86.21%, respectively. NIPPV as the first line therapy for RF had higher 28-day mortality rate than it used for post-extubation RF (57.6% versus 16.0%, p<0.05). Independent predictors of mortality at 28 days were progressive disease or newly diagnosed lung cancer (OR 14.02 95% CI 1.03-191.59, p = 0.048), combined with other organ failure (OR 18.07 95% CI 1.87-172.7, p = 0.012), and NIPPV as the first line therapy for RF (OR 35.37 95% CI 3.30-378.68, p = 0.003)., Conclusion: Lung cancer patients using NIPPV with progressive or newly diagnosed cancer disease, combined with other organ failure, or NIPPV as the first line therapy for respiratory failure have a poor outcome.

Introduction: The relationship between bronchodilator responsiveness and eosinophilic airway inflammation has not been well documented in COPD. It has been investigated in this retrospective study. This issue has grown in importance due to increasing interest in the asthma-COPD overlap syndrome., Methods: 264 stable COPD patients with no past history of asthma were retrospectively analyzed. Correlation analyses between FEV 1 reversibility and sputum eosinophil levels were conducted. Sputum eosinophil levels were dichotomized using FEV 1 reversibility cut-off points (>0.4L and >15% vs. >0.2L and >12%) and compared. The effectiveness of FEV 1 reversibility to predict sputum eosinophilia (>3%) was analyzed with a logistic regression and a ROC analysis., Results: 82 (31.1%) patients with higher FEV 1 reversibility values (0.14 vs. 0.11L, P=.01) presented sputum eosinophilia. FEV 1 reversibility was weakly correlated with the sputum eosinophil level (r=0.162, P=.008). Patients with FEV 1 >0.4L and >15% increment had higher sputum eosinophil levels (6.11 vs. 1.02%, P=.049) whereas the level did not differ when dichotomized by FEV 1 increment >0.2L and >12%. Very positive FEV 1 reversibility (>0.4L and >15%) predicted sputum eosinophilia after adjustment forage, baseline FEV 1 and FVC (OR: 4.262, P=.029). In the ROC analysis, the AUC was 0.58 (P=.034), and FEV 1 increment>0.4L and >15% had a positive predictive value of 63.6% and an overall accuracy of 70.1%., Conclusions: FEV 1 reversibility was weakly correlated with sputum eosinophil levels in COPD. Positive FEV 1 reversibility (>0.4L and >15%) is moderately successful in predicting sputum eosinophilia (>3%)., (Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Statins are widely used to lower cholesterol levels and cardiovascular risk. Further, studies have shown that statins may decrease the risks of infectious diseases and infection-related mortality; however, the association between statin use and active TB disease remains unclear., Methods: Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. Patients taking statins between 2000 and 2013, without antecedent TB disease, were included. Data from 102,424 statin users and 202,718 age-, sex-, and enrollment date-matched subjects were analyzed. The two cohorts were monitored until December 31, 2013, for incident TB disease. The definition of TB disease was validated using the claims database of Taipei Veterans General Hospital., Results: The statin and matched cohorts were observed for 571,568 and 1,027,385 person-years, respectively. Of the total 305,142 subjects, 1,264 (0.41%) developed subsequent TB disease. Validation study confirmed the accuracy of the definition of TB disease (sensitivity, 96.3%), with excellent interobserver agreement (κ = 1.00). Multivariate analysis revealed a reduced risk of TB disease among the statin cohort (hazard ratio [HR], 0.53; 95% CI, 0.47-0.61; P < .001). Compared with the matched group, statin use showed a dose-response relationship with the incident TB disease risk (<180 cumulative defined daily doses [cDDDs]: HR, 1.06; 95% CI, 0.91-1.24; P = .477; 180 to 365 cDDDs: HR, 0.57; 95% CI, 0.45-0.72; P < .001; >365 cDDDs: HR, 0.27; 95% CI, 0.22-0.33; P < .001)., Conclusions: Statin use associates with a lower risk of incident TB disease., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Troponin I is one of the most commonly tested biochemical markers in the emergency room (ER) and in the hospital setting. Besides coronary artery disease (CAD), demand ischemia with underlying tachycardia, anemia, hypertensive emergency, congestive heart failure, kidney disease, sepsis, and pulmonary embolism have also been reported to cause troponin I elevations. Few reports have excluded patients with CAD, and no study has summarized the proportion of these factors relative to an increased troponin I level., Methods: The aim of this retrospective study was to investigate the level of contribution of causative factors in troponin I elevation. Charts of patients tested for troponin I during an ER visit or during hospitalization were collected. Patients with known CAD, abnormal stress tests, cardiac catheterizations, or discharge without an adequate cardiac evaluation were excluded. Logistic regression was used to identify predictors of elevated troponin I levels., Results: A total of 586 patients were investigated in this study. Age, hemoglobin (Hb), heart rate (HR), glomerularfiltration rate, atrial fibrillation, congestive heart failure (CHF), and sepsis were significant predictors of elevated troponin I by analysis in univariate logistic regression (all P < .001). In multivariate logistic regression, sepsis, CHF, age, Hb, and HR were independent predictors of troponin I (all P < .01). A simple clinical scoring system was generated with 1 score on patients with age ≥ 60, Hb < 10 g/dL, and HR ≥ 100 beats per minute (bpm). The prevalence of elevated troponin I was 4%, 16%, 38%, and 50% for patients with scores of 0, 1, 2, and 3, respectively. In patients without sepsis and CHF, the chances of elevated troponin I were 2%, 11%, 28%, and 43%., Conclusions: Sepsis was found to be the strongest independent cause of elevated troponin I levels in non-CAD patients. The scoring system composed of age, hemoglobin (Hb), and heart rate (HR) can assist clinical evaluation of elevated troponin I test in non-CAD patients.

Background and Objective: We investigated the effect of induced pluripotent stem cells (iPSCs) in moderating neutrophil chemotaxis in endotoxin-induced acute lung injury (ALI)., Methods: Male C57BL/6 mice at 8-12 weeks of age were studied. Murine iPSCs were delivered through the tail veins of mice 4 h after intratracheal instillation of endotoxin. Lung histopathological findings, neutrophil counts in peripheral blood and bronchoalveolar lavage fluid (BALF), bone marrow (BM) cell distribution, expression of chemokine receptors and regulatory signalling pathways were analysed after 24 h. Human neutrophils isolated from acute respiratory distress syndrome patients were used in a cell migration assay., Results: iPSCs significantly decreased the histopathological changes of ALI in mice compared to treatment with control cells. Numbers and activity levels of neutrophils in BALF were reduced in iPSC-treated ALI mice. The iPSC therapy restored neutrophil counts in the peripheral blood of ALI mice, but the percentages of mature neutrophils in BM were similar between iPSC-treated and -untreated groups. The iPSCs mediated a downregulation of the chemotactic response to endotoxin by reducing chemokine (C-X-C motif) receptor 2 (CXCR2) expression on mouse peripheral blood neutrophils. This result was confirmed by an in vitro human neutrophil migration assay. In addition, iPSCs or conditioned medium from iPSCs enhanced expression of G protein-coupled receptor kinase 2 (GRK2) on the surface of blood neutrophils in ALI mice., Conclusion: iPSCs reduce neutrophil chemotaxis in endotoxin-induced ALI. These effects are associated with an enhancement of GRK2 activity and reduction of CXCR2 expression., (© 2017 Asian Pacific Society of Respirology.)

Background: A variety of disorders, most notably cardiovascular diseases, was linked to sleep apnea (SA), but their impact on mortality of SA patients had not been systematically investigated. We aimed to develop a composite index based on the comorbidity burden to predict mortality risk., Methods: Using Taiwan National Health Insurance Research Database, 9853 adult SA patients were enrolled and their comorbidity profile at baseline was recorded. The subjects were followed from 1995 till death or the end of 2011. A Cox regression model was used for multivariable adjustment to identify independent predictors for mortality., Results: During an average follow-up period of 5.3 ± 3.1 years, 311 (3.2%) subjects died. SA patients with any comorbidity had a higher risk for death compared to those without comorbidity (HR: 11.01, 95% CI 4.00-30.33, p < 0.001). Age and 10 comorbidities related to increased overall mortality were identified, from which the CoSA (Comorbidities of Sleep Apnea) index was devised. The corresponding hazard ratios for patients with CoSA index scores of 0, 1-3, 4-6, and >6 were 1 (reference), 3.29 (95% CI, 2.04-5.28, p < 0.001), 13.56 (95% CI, 8.63-21.33, p < 0.001), and 38.47 (95% CI, 24.92-59.38, p < 0.001), respectively., Conclusions: Based on the comorbidity burden, we developed an easy-to-use tool to evaluate mortality risk in SA. Key messages: Sleep apnea (SA) is linked to a variety of disorders, particularly cardiovascular diseases. SA patients with any comorbidity may experience a higher risk of death in comparison to those without comorbidity. Comorbidities related to increased mortality are identified and converted into a simple risk indicator, the CoSA (Comorbidities of Sleep Apnea) index scores, which may help to stratify risk of death in daily practice.

Epidemiological studies have identified a trend in the development of depressive and anxiety disorders following a diagnosis of chronic obstructive pulmonary disease (COPD). However, the relationship between COPD and subsequent bipolar disorder remains unclear. From January 1, 2000, we identified adult patients with COPD from the Taiwan National Health Insurance Research Database. A nationwide population-based study was conducted; 46,778 COPD patients and 46,778 age-, sex-, and comorbidity-matched subjects between 2000 and 2011 were enrolled. The two cohorts were followed up till December 31, 2011 and observed for occurrence of bipolar disorder. We observed the COPD and comparison cohorts for 263,020 and 267,895 person-years, respectively, from 2000 to 2011. The incidence rate for bipolar disorder was 1.6/1000 person-years in the COPD cohort and 1.2/1000 person-years in the comparison cohort ( p < 0.001). After multivariate adjustment, the hazard ratio (HR) for subsequent bipolar disorder among the COPD patients was 1.42 (95% confidence interval [CI], 1.22-1.64; p < 0.001). In the COPD patients, short-acting beta-agonists (SABAs) was associated with a significantly increased risk of bipolar disorder development (HR = 1.83, 95% CI = 1.25-2.69, p = 0.002). Other COPD medications were not associated with the risk of bipolar disorder development. The study results indicate that COPD may be an independent risk factor for the development of bipolar disorder. The regular use of SABAs might increase the risk of bipolar disorder in COPD patients.

Background: While Candida pneumonia is life-threatening, biomarker measurements to early detect suspected Candida pneumonia are lacking. This study compared the diagnostic values of measuring levels of (1, 3)-β-D-glucan in endotracheal aspirate, bronchoalveolar lavage fluid, and serum to detect suspected Candida pneumonia in immunocompromised and critically ill patients., Methods: This prospective, observational study enrolled immunocompromised, critically ill, and ventilated patients with suspected fungal pneumonia in mixed intensive care units from November 2010 to October 2011. Patients with D-glucan confounding factors or other fungal infection were excluded. Endotracheal aspirate, bronchoalveolar lavage fluid and serum were collected from each patient to perform a fungal smear, culture, and D-glucan assay., Results: After screening 166 patients, 31 patients completed the study and were categorized into non-Candida pneumonia/non-candidemia (n = 18), suspected Candida pneumonia (n = 9), and non-Candida pneumonia/candidemia groups (n = 4). D-glucan levels in endotracheal aspirate or bronchoalveolar lavage were highest in suspected Candida pneumonia, while the serum D-glucan level was highest in non-Candida pneumonia/candidemia. In all patients, the D-glucan value in endotracheal aspirate was positively correlated with that in bronchoalveolar lavage fluid. For the detection of suspected Candida pneumonia, the predictive performance (sensitivity/specificity/D-glucan cutoff [pg/ml]) of D-glucan in endotracheal aspirate and bronchoalveolar lavage fluid was 67%/82%/120 and 89%/86%/130, respectively, accounting for areas under the receiver operating characteristic curve of 0.833 and 0.939 (both P < 0.05), respectively. Measuring serum D-glucan was of no diagnostic value (area under curve =0.510, P = 0.931) for the detection of suspected Candida pneumonia in the absence of concurrent candidemia., Conclusions: D-glucan levels in both endotracheal aspirate and bronchoalveolar lavage, but not in serum, provide good diagnostic values to detect suspected Candida pneumonia and to serve as potential biomarkers for early detection in this patient population.

Background: Currently, no large study addressing the relationship between lung cancer patients with different therapies and second primary malignancies (SPMs) is available., Methods: Using the Taiwan National Health Insurance Research Database, we conducted a population-based cohort study. Patients with newly diagnosed lung cancer between 1997 and 2005 were enrolled and followed up until Dec. 31, 2011. The endpoint of the study was SPM occurrence. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort to that of the general population., Results: We identified 52,639 patients with lung cancer and excluded 34,267 patients who had expired within one year after diagnosis. The study included 18,372 subjects with a median follow-up period of 2.24 years. 590 patients developed an SPM. The overall cancer risk was significantly increased (SIR 1.33, 95% confidence interval [CI]: 1.22-1.44, p < 0.001), and there was a significant increase in the incidences of head and neck (SIR 1.60, 95% CI 1.21-2.07, p = 0.001), bone and soft tissue (SIR 2.65, 95% CI 1.27-4.87, p = 0.011), genitourinary (SIR 1.50, 95% CI 1.27-1.76, p < 0.001), and thyroid (SIR 3.85, 95% CI 2.28-6.08, p < 0.001) cancers. Importantly, after multivariate adjustment, the use of tyrosine kinase inhibitors (TKIs) statistically significantly reduced SPM incidence (HR, 0.41; 95% CI, 0.21-0.79; p = 0.008)., Conclusions: Our study indicates that lung cancer may be a risk factor for SPM. TKI use was associated with a significantly lower risk of SPM development. However, because patients with epidermal growth factor receptor mutant lung adenocarcinoma (associated with non-smokers) tend to receive TKI treatment, they might have fewer smoking-related SPMs.

Beta (β)-blockers are under-prescribed in patients with heart failure (HF) and concurrent chronic obstructive pulmonary disease (COPD) due to concerns about adverse pulmonary effects and a poor understanding of the effects of these drugs. We aimed to evaluate the survival effects of β-blockers in patients with coexistent HF and COPD. Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. Patients with coexistent HF and COPD diagnosed between 2000 and 2009 were enrolled. Doses of the 3 β-blockers proven to be beneficial to HF (carvedilol, bisoprolol, and metoprolol) during the study period were extracted. The primary endpoint was cumulative survival. Patients were followed until December 31, 2009. The study included 11,558 subjects, with a mean follow-up period of 4.07 years. After adjustment for age, sex, comorbidities, and severity of HF and COPD, bisoprolol use showed a dose-response survival benefit [low dose: adjusted hazard ratio (HR) = 0.76, 95% confidence interval (CI) = 0.59-0.97, P = 0.030; high dose: adjusted HR = 0.40, 95% CI = 0.26-0.63, P < 0.001] compared with nonusers, whereas no survival difference was observed for carvedilol or metoprolol. Compared with patients with HF alone, this special HF + COPD cohort received significantly fewer targeted β-blockers (108.8 vs 137.3 defined daily doses (DDDs)/person-year, P < 0.001) and bisoprolol (57.9 vs 70.8 DDDs/person-year, P < 0.001). In patients with coexisting HF and COPD, this study demonstrated a dose-response survival benefit of bisoprolol use, but not of carvedilol or metoprolol use.

The association of latent tuberculosis infection (LTBI) with subsequent cancer remains unclear. We investigated the risk of future cancer among tuberculosis (TB) contacts with or without subsequent TB activation. Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. TB contacts during 1997 to 2012 were included as the study cohort. Patients with antecedent cancer and TB were excluded. Data from 11,522 TB contacts and 46,088 age-, sex-, and enrollment date-matched subjects during 1997 to 2012 were analyzed. The 2 cohorts were monitored until December 31, 2012 for incidence of cancer and TB infection. LTBI was defined as a TB contact with subsequent TB activation. The primary endpoint was occurrence of newly diagnosed cancer. There was no difference in cancer development between the TB contact cohort and comparison cohort (log-rank test, P = 0.714). After multivariate adjustment, the hazard ratio (HR) for cancer among the LTBI patients was 2.29 [95% confidence interval (CI), 1.26-4.17; P = 0.007]. There was increase in cancer incidences for several specific cancer types, including multiple myeloma (HR 340.28), lung (HR 2.69), kidney and bladder (HR 6.16), hepatobiliary (HR 2.36), and gastrointestinal (HR 2.99) cancers. None of the 136 TB contacts who received isoniazid prophylaxis developed cancer. LTBI patients had a higher risk of future cancer., Competing Interests: The authors have no conflicts of interest to disclose.

Background: The association between amyloidosis and cancer remains unclear., Participants and Methods: Using the Taiwan National Health Insurance Research Database we conducted a population-based cohort study. Patients newly diagnosed with amyloidosis between 1997 and 2009 were enrolled. Patients with antecedent cancer were excluded. Standardized incidence ratios (SIR) of cancers were calculated for the study cohort and compared with cancer incidence among the general population. We used a multivariate Cox regression model to evaluate the predictors of cancer development for patients with amyloidosis., Results: The study included 1,693 subjects with median follow-up of 5.63 years. A total of 68 patients developed cancer. The incidence of kidney cancer (SIR 3.42; 95 % CI 1.11-7.97; p = 0.034) and hematologic malignancies (SIR 3.88; 95 % CI 1.86-7.14; p < 0.001) were significantly higher for patients with amyloidosis., Conclusion: This is currently the largest study to evaluate cancer risk among patients with amyloidosis. The results indicate that amyloidosis may be associated with an increased risk of kidney cancer and hematologic malignancies.

Tuberculosis (TB) disease may be transmitted to close contacts of index cases, causing physical illness. No studies have investigated the risk of developing depressive disorder among TB contacts in a TB-endemic area.Adult participants with a new diagnosis of TB contact (ICD-9-CM codes V01.1 plus chest radiographic order) since January 1, 2008, were identified from the National Health Insurance Research Database in Taiwan. A control cohort matched for age (±5 y), sex, enrolled years, and income level was selected. These 2 cohorts were followed until December 31, 2012, and observed for the development of depressive disorder. The Kaplan-Meier method and the log-rank test were used to examine the difference in cumulative incidences of depressive disorder between groups. Cox proportional-hazard models were used to calculate adjusted hazard ratios (aHRs) for depressive disorder.The TB contact cohort consisted of 9046 patients and matched controls of 36,184 ones. The mean age of TB contacts was 44.7 years, and 56.0% of them were women. During a mean follow-up period of 2.5 years, 127 (1.40%) TB contacts and 521 (1.44%) matched controls developed depressive disorder. TB exposure was found to be an independent risk factor of depressive disorder in women (aHR 1.34, 95% confidence interval [CI] 1.07-1.68), but not in men (aHR 0.71, 95% CI 0.48-1.06) after adjusting for age, comorbidities, and income levels. The risk of depression was significantly higher for female TB contacts than for matched controls in the first and second years (aHR 1.49, 95% CI 1.03-2.14; and aHR 1.53, 95% CI 1.05-2.23, respectively), but not thereafter. Of note, 67 (0.74%) TB contacts and 88 (0.24%) matched controls developed active TB, but none of them had subsequent depressive disorder during follow-up periods.Female TB contacts had an increased risk of depression within the first 2 years after exposure. Clinicians should consider conducting depression evaluations in addition to routine TB contact investigations in this subgroup population.

Purpose: Epidemiological studies have identified a trend in the development of depressive and anxiety disorders following a diagnosis of sleep apnea. The relationship between sleep apnea and subsequent panic disorder, however, remains unclear., Methods: Using a nationwide database, the Taiwan National Health Insurance Research Database, patients with sleep apnea and age-, sex-, income-, and urbanization-matched control patients who did not have sleep apnea were enrolled between 2000 and 2010. Patients with a prior diagnosis of panic disorder before enrollment were excluded. The 2 cohorts were observed until December 31, 2010. The primary endpoint was occurrence of newly diagnosed panic disorder., Results: A total of 8,704 sleep apnea patients and 34,792 control patients were enrolled. Of the 43,496 patients, 263 (0.60%) suffered from panic disorder during a mean follow-up period of 3.92 years, including 117 (1.34%) from the sleep apnea cohort and 146 (0.42%) from the control group. The Kaplan-Meier analysis revealed a predisposition of patients with sleep apnea to develop panic disorder (log-rank test, P <.001). After multivariate adjustment, the hazard ratio for subsequent panic disorder among the sleep apnea patients was 2.17 (95% confidence interval, 1.68-2.81; P <.001)., Conclusions: Sleep apnea appears to confer a higher risk for future development of panic disorder., (© 2015 Annals of Family Medicine, Inc.)

Available evidence shows that metabolic syndrome (Mets) has clear adverse effects for middle-aged and pre-elderly adults; however, the effect of Mets on mortality among elderly adults remains unclear. In addition, the comparative utility of Mets and its component for predicting mortality among the elderly has not been clearly established. Using data from a large Taiwanese cohort, we evaluated the effect of Mets and its components on subsequent all-cause and cause-specific mortality overtime among the elderly. A total of 73,547 elders (age ≥65 years) participated in the Taipei Elderly Health Examination Program from 2007 to 2010. Mets was diagnosed using the adult treatment panel III criteria, and mortality was ascertained by using national death records. Time-dependent analysis was used to evaluate associations of Mets and its components with all-cause mortality, cardiovascular disease (CVD) mortality, and expanded CVD mortality. This retrospective cohort study found that 42.6% of elders had Mets. During 194,057 person-years of follow-up, 2944 deaths were observed. After adjusting for sociodemographic characteristics and comorbidities, Mets was associated with increased risk of expanded CVD mortality (hazard ratio [HR], 1.27; 95% CI, 1.10-1.46) but not all-cause or CVD mortality. Among Mets components, decreased high-density lipoprotein cholesterol (HDL-C, HR 1.25, 95% CI 1.13-1.37) and hyperglycemia (HR 1.21, 95% CI 1.12-1.31) were associated with a significant increase in all-cause mortality. Hypertension and low HDL-C were predictors of CVD mortality and expanded CVD mortality, and, as compared with Mets, were associated with a higher risk of expanded CVD mortality. The present findings indicate that, in elderly adults, individual components of Mets are better predictors of all-cause and cause-specific mortality than is Mets as a whole. Our results suggest that future efforts should focus on preventing and managing individual risk factors (particularly hypertension, low HDL-C, and hyperglycemia) rather than on "diagnosing" Mets in elders.

Study Objectives: To explore the association between the non-apnea sleep disorder (NSD) and autoimmune diseases., Design: Cohort study., Setting: Nationwide database research., Participants: 84,996 adult patients with NSD diagnoses recorded in the Taiwan National Health Insurance Research Database between 2000 and 2003, after excluding those with antecedent autoimmune diseases. A comparison cohort of 84,996 participants was formed by age-, gender-, income-, and urbanization-matched controls., Interventions: None., Measurements and Results: The two cohorts were followed up for occurrence of autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and systemic sclerosis (SSc). A Cox proportional hazards regression model was used for muti-variate adjustment. In patients with NSD, the overall risk for incident autoimmune diseases was significantly higher than in controls (adjusted hazard ratio [HR] = 1.47, 95% confidence interval [CI] = 1.41-1.53). With regard to individual diseases, the risks for SLE, RA, AS and SS among NSD patients were also significantly higher than in controls (HR [95% CI] for SLE, RA, AS, and SS were 1.81 [1.50-2.18], 1.45 [1.36-1.54], 1.53 [1.38-1.70], and 1.51 [1.43-1.60], respectively), whereas the increased risk for SSc did not reach statistical significance (HR: 1.36 [0.82-2.26])., Conclusion: Patients with non-apnea sleep disorder were associated with a higher risk for developing autoimmune diseases., (© 2015 Associated Professional Sleep Societies, LLC.)

Background and Objective: The efficacy of budesonide/formoterol maintenance and reliever therapy (BFMRT) in asthma control is well documented in large randomized controlled trials. However, the acute reliever effects and real-life effectiveness are seldom reported., Methods: This multicenter trial enrolled steroid-naïve, symptomatic asthmatics with baseline exhaled nitric oxide (eNO) of ≥ 40 ppb. There were 120 eligible patients who were randomized and received a dose of inhaled budesonide/formoterol 320/9 μg (lower dose budesonide/formoterol), 640/18 μg (higher dose budesonide/formoterol (HDBF)), or terbutaline (TERB) 1 mg. Inflammatory cells and mediators in induced sputum, eNO and lung function were measured at baseline and 6 h (acute phase). Subsequently, all patients used BFMRT as real-life practice for 24 weeks (maintenance phase)., Results: In the acute phase, the degree of post-treatment reduction in total eosinophil counts, interleukin-8 and matrix metalloproteinase-9 in induced sputum were significantly greater in group HDBF (vs TERB, P < 0.05). The increase in forced expiratory volume in first second (FEV1 ) in group HDBF was significantly higher (vs LDBF and TERB, P < 0.05) 3 h after dosing. In the maintenance phase, significant improvement of asthma control (presented by eNO, FEV1 and a five-item asthma control questionnaire) in real-life settings was observed at 4 weeks and sustained to the end of study. The rate of patients who followed scheduled visits declined over time (87% at week 4 and 42% at week 24)., Conclusions: Budesonide/formoterol as reliever exerts acute, dose-related anti-inflammatory effects and FEV1 improvement in symptomatic asthmatics. BFMRT is effective in asthma control. However, the decrease in long-term follow-up rate remains an issue to overcome in real-life settings., (© 2014 Asian Pacific Society of Respirology.)

Purpose: Chronic obstructive pulmonary disease (COPD) with eosinophilic airway inflammation may represent a unique phenotype, possibly with shared features of COPD and asthma. The role of exhaled nitric oxide (eNO) in identifying COPD patients with sputum eosinophilia was examined in this study., Methods: Ninety COPD patients without past medical history of asthma or allergic diseases were prospectively enrolled, and their eNO, lung function, and cellular profile of induced sputum were measured. Eosinophil cationic protein and IgE in sputum and venous blood also were determined. Subjects with and without sputum eosinophilia (>3 %) were compared. The role of eNO in the prediction of sputum eosinophilia was assessed in a logistic regression model., Results: Patients with sputum eosinophilia had significantly higher levels of eNO (29 vs. 18 ppb, p = 0.01) than those without. The difference in serum total IgE (168 vs. 84.9 IU/ml, p = 0.057) and percentages of positive allergen test results (48.3 vs. 29.5 %, p = 0.082) showed a trend toward significance. The sputum eosinophil level was significantly correlated to the eNO level (r = 0.485, p < 0.001). The eNO level at the cutoff of 23.5 ppb had the maximum sum of sensitivity (62.1 %) and specificity (70.5 %). The unadjusted and adjusted odds ratios of a higher eNO level (>23.5 ppb) in the prediction of sputum eosinophilia were 3.909 (confidence interval (CI) 1.542-9.91, p = 0.004) and 4.329 (CI 1.306-14.356, p = 0.017), respectively., Conclusions: eNO is a good marker to identify COPD patients with eosinophilic airway inflammation.