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Dario Kohlbrenner,1 Noriane A Sievi,1 Oliver Senn,2 Malcolm Kohler,1 Christian F Clarenbach1 1Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland; 2Institute of Primary Care, University of Zurich, Zurich, SwitzerlandCorrespondence: Christian F ClarenbachDepartment of Pulmonology, University Hospital Zurich, Raemistrasse 100, Zurich 8091, SwitzerlandTel +41 44 255 17 12Email christian.clarenbach@usz.chBackground and Objective: Limited evidence on long-term effects of physical activity programs in COPD is available. The aim of the study was to investigate the effects of a three-month program combining physical activity counselling and pedometer-based feedback in addition to usual care, followed by a nine-month unsupervised observation period as compared to usual care in participants with severe to very severe COPD.Methods: Participants were randomized to either a control group receiving usual care or an intervention group receiving motivational support, an activity diary with an individual step count goal (ie, an increase of ≥ 15% from baseline) and a pedometer in addition to usual care. The intervention ended after three months and an unsupervised observational period followed until twelve months. Primary outcome was daily step count after one year.Results: Seventy-four participants were included, 61 (82%) completed the study. Linear regression modelling, adjusted for baseline step count, showed no significant difference in change in step count after 12 months between the groups (&Bgr; = 547.33, 95% CI = − 243.55/1338.20).Conclusion: A three-month program combining physical activity counselling and pedometer-based feedback in addition to usual care does not attenuate the declining course of physical activity in participants with severe and very severe COPD during a long term follow-up of one year as compared to usual care. This result was primarily determined by the low intervention response rates to the combined program.Clinical Trial Registration: www.ClinicalTrials.gov, NCT03114241.Keywords: physical activity, COPD, counselling program, randomized controlled trial, long-term follow-up

Thomas P Lodise,1 Jingyi Li,2 Hitesh N Gandhi,3 Gerald O’Brien,3 Sanjay Sethi4 1Department of Pharmacy Practice, Albany College Pharmacy and Health Sciences, Albany, NY, USA; 2Global Medical Affairs, AstraZeneca, Gaithersburg, MD, USA; 3US Respiratory Medical, AstraZeneca, Wilmington, DE, USA; 4Department of Medicine, University of Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USACorrespondence: Sanjay SethiClinical and Translational Research Center, 875 Ellicott St., Room 6045A, Buffalo, NY 14215, USAEmail ssethi@buffalo.eduBackground: Inhaled corticosteroids (ICS) are widely used and recommended to treat chronic obstructive pulmonary disease (COPD). While generally considered safe, several studies demonstrated an increased risk of pneumonia with the use of ICS in COPD patients. Although all ICS indicated for COPD carry the class labeling warning of increased pneumonia risk, evidence suggests an intraclass difference in the risk of pneumonia between inhaled budesonide and fluticasone. To date, systematic reviews of direct-comparison studies have not been performed to assess if an intraclass difference exists.Research Question: This review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most commonly used ICS in COPD.Study Design and Methods: A search of the medical literature was conducted in PubMed and Embase for the time period of 01/01/69– 05/31/19. The search strategy combined terms that defined the patient/disease type, exposures, outcome, and the study/publication type. Descriptive and comparative statistics reported for fluticasone- and budesonide-containing products in each study, including data for pneumonia event subgroups, were extracted and reported by dose, seriousness, or practice setting. Controlled clinical trials and observational studies meeting the inclusion criteria were assessed for methodologic quality by using the appropriate tool from the list of study quality assessment tools developed by the National Institutes of Health.Results: The summary relative risk (RR) ratio across 5 included studies (57,199 patients) was 1.13 (95% CI: 1.09– 1.19), representing a 13.5% increased risk of pneumonia among fluticasone users compared to budesonide users. Similarly, summary RR ratio for serious pneumonia implied a 14.4% increased risk of serious pneumonia among fluticasone users compared to budesonide users (pooled RR: 1.14; 95% CI: 1.09– 1.20).Interpretation: There is likely a clinically important intraclass difference in the risk of pneumonia between fluticasone- and budesonide-containing inhaled medications in COPD.Keywords: inhaled corticosteroids, pneumonia, COPD

Background Paediatric cases of pleomorphic adenoma of the bronchus are rare in clinical practice, despite pleomorphic adenoma being the most common histological form of salivary gland neoplasm. To date, no such cases have been reported in China. Case presentation We report a case of pleomorphic adenoma of the bronchus in a 10-year-old child with no obvious positive signs on examination. Chest-enhanced computed tomography and bronchoscopy showed a large white mass in the right principal bronchus. The patient was treated by bronchial mass resection. Biopsy confirmed the diagnosis of pleomorphic adenoma. Conclusions We not only describe a rare benign bronchial tumour in children but also demonstrate the successful use of surgery as a radical cure for pleomorphic adenoma.

Jian-lan Hua, Wei-ping Hu, Yi-hui Zuo, Jing Zhang Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of ChinaCorrespondence: Jing ZhangDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan University, 180 Feng Lin Road, Shanghai 200032, People’s Republic of ChinaEmail jingatlas@hotmail.comBackground: COPD is a global respiratory disease that has produced a worldwide health care burden. Acute exacerbation of COPD (AECOPD) is the leading cause of death in patients with COPD and accounts for the majority of expenditure of COPD management. The colonization of potential pathogenic bacteria in the lower respiratory tract is an important cause of the acute exacerbation especially in patients with moderate and severe COPD. Some clinical studies have shown the potential of oral probiotics, aerosol-inhaled amikacin and combined vaccination to prevent AECOPD.Methods and Analysis: We hypothesize that patients with stable COPD will benefit from aerosol-inhaled amikacin, oral probiotics or combined vaccination in terms of preventing acute exacerbation of COPD, slowing the progression of the disease and improving their quality of life. The trial aimsto investigate the efficacy and safety of the above interventions to decolonize bacteria in the lower respiratory tract and prevent acute exacerbation of COPD. In the study, 144 patients with stable phase of moderate-to-very severe COPD will be recruited and randomized into aerosol-inhaled amikacin group, oral probiotics group, combined vaccination group and the control group at a 1:1:1:1 ratio. The primary outcome is time to the first COPD exacerbation. Other endpoints include colonization of potential pathogenic bacteria in induced sputum, microbiome in induced sputum, pulmonary function and symptoms of patients, inflammation level and adverse events, serious adverse events, and death.Keywords: chronic obstructive pulmonary disease, probiotics, amikacin, vaccination

Jie Xia,1– 4,* Lina Sun,5,* Suqin Xu,1– 4 Qiu Xiang,1– 4 Jianping Zhao,1– 4 Weining Xiong,1– 4 Yongjian Xu,1– 4 Shuyuan Chu1– 4,6 1Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 2Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 3Key Laboratory of Pulmonary Diseases of Health Ministry, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 4Key Site of National Clinical Research Center for Respiratory Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, People’s Republic of China; 6Laboratory of Respiratory Disease, Affiliated Hospital of Guilin Medical University, Guilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuyuan Chu; Jie XiaDepartment of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences & Technology, Wuhan, People’s Republic of ChinaTel +8613978345180; +8627-83665520Email emilyyuanchu@163.com; xiajhzu1215@126.comPurpose: Patients with chronic obstructive pulmonary disease (COPD) would have a poor prognosis if they were not continuously managed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. We aim to develop a model to classify whether COPD patients have been continuously managed according to GOLD in the previous year.Methods: The Managed group were COPD patients from a prospectivecohort from November 2017 to November 2019, who have been continuously managed according to GOLD for 1 year. The Control group were COPD patients who were not continuously managed according to GOLD. They were from a retrospective cohort from October 2016 to October 2017 in the same hospitals as the Managed group. A synthetic minority over-sampling technique (SMOTE) algorithm was used to up-sample the Managed group in a training dataset. Features for classification were selected using a support vector machine recursive feature elimination (SVM-RFE) algorithm. The classification model was developed using LibSVM, and its performance was assessed on the testing dataset.Results: The final analysis included 15 subjects in the Managed group and 191 in the Control group. SVM-RFE selects nine features including smoking history, post-bronchodilator (post-)FVC before management, and those after 1-year follow-up (BMI, moderate and severe AECOPD frequency in previous 12 months, mMRC score, post-FEV1, post-FEV1%pred, post-FVC, and post-FEV1/FVC). For our model, positive predictive value is 66.7%, F1 score is 0.978, and AUC is 0.987.Conclusion: SVM classifier combined with SVM-REF feature selection algorithm could achieve good classification between COPD patients who are or are not continuously managed. This model could be applied in clinical practice to help doctors make decisions and enhance COPD patients’ compliance with standard treatment.Keywords: COPD, GOLD, continuous management, support vector machine

Background Oxygen therapy is essential in the management of patients with respiratory problem, including after endotracheal extubation. Conventional oxygen devices may be inadequate in patients requiring high inspiratory flow. HFNC has a growing place in the repertoire of respiratory therapies. The purpose of this study was to compare the efficiency, tolerability, and outcome of HFNC in patients with respiratory failure and post-mechanical ventilation patients in comparison to NIV and conventional oxygen devices. Results In case of respiratory failure patients, there was non-significant statistical difference between HFNC, conventional oxygen therapy and NIV, regarding the difference in ABGs, vital data, and dyspnea scores, at successive time points, except for PO2 after 30 min in patients received NIV, which was significantly higher. There was non-significant statistical difference between the three mentioned modalities of oxygen therapy regarding comfort and clinical outcome. In case of post-extubation patients, there was non-significant statistical difference between the HFNC and conventional oxygen therapy regarding clinical parameters, comfort and outcome. Conclusions HFNC is comparable to conventional oxygen therapy in respiratory failure and post-extubation patients. HFNC is comparable to NIV in respiratory failure patients.

Ellen Tufvesson,1 Finn Radner,1 Georgia Papapostolou,1 Linnea Jarenbäck,1 Saga Jönsson,1 Ulf Nihlén,1 Jaro Ankerst,1 Alf Tunsäter,1 Stefan Peterson,2 Leif Bjermer,1 Göran Eriksson1 1Department of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund University, Skane University Hospital, Lund, Sweden; 2Regional Cancer Centre South, Region Skane, Lund, SwedenCorrespondence: Ellen TufvessonDepartment of Clinical Sciences Lund, Respiratory Medicine and Allergology, Lund University, Skane University Hospital, Lund 22185, SwedenTel +46 73 640 19 16Email ellen.tufvesson@med.lu.sePurpose: For exercise testing of COPD patients, a standard endurance test (ET) with constant workload is recommended. The test suffers from large inter-individual variability and need for large sample sizes in order to evaluate treatment effects.Methods: A new protocol for ET in COPD was designed. In contrast to the standard ET, the new ET involved an increasing workload in order to reduce the standard deviation of endurance time. Two new ETs were compared with the standard ET. In Study A, the new ET started at 75% of the patient’s maximum workload (WMAX) and increased stepwise with 3%/2 min until exhaustion. Study B started at 70% of WMAX and increased linearly with 1%/min.Results: In Study A, that included 15 patients, the standard deviation and range for endurance time and work capacity were narrower for the new versus the standard ET. However, the higher mean workload at end and the low mean work capacity relative to the standard ET indicated that the stepwise increase was too aggressive. In Study B, that included 18 patients, with a modified protocol, the averages for endurance time, workload at end and work capacity were similar for new and standard ET, while the standard deviations and ranges for endurance time and work capacity were kept more narrow in the new ET. The variances for endurance time were not equal between the standard ET and the two new ETs (p< 0.05 for both according to Levene’s test).Conclusion: The new ET reduced the number of patients with extreme endurance times (short and long) compared to the standard test. The new test showed a significant lower variance for endurance time, which potentially can lead to fewer patients needed in comparative studies. The overall best results were observed with a low linear increase during endurance.Keywords: COPD, exercise testing, constant endurance test, endurance time

Simon Wan Yau Ming,1 John Haughney,2 Dermot Ryan,3 Iain Small,4 Federico Lavorini,5 Alberto Papi,6 Dave Singh,7 David MG Halpin,8 John R Hurst,9 Shishir Patel,10 Matthias Ochel,10 Janwillem Kocks,1,11,12 Victoria Carter,1 Antony Hardjojo,1 David B Price1,2 1Observational and Pragmatic Research Institute, Singapore, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Optimum Patient Care, Cambridge, UK; 4Peterhead Health Centre, Aberdeen, UK; 5Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy; 6University of Ferrara, Ferrara, Italy; 7University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 8Royal Devon and Exeter Hospital, Exeter, UK; 9UCL Respiratory, University College London, London, UK; 10Chiesi Limited, Manchester, UK; 11General Practitioners Research Institute, Groningen, the Netherlands; 12University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the NetherlandsCorrespondence: David B PriceCentre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UKTel +65 6802 9724Email dprice@opri.sgIntroduction: The Fostair® 100/6 (BDP/FF) pressurized metered-dose inhaler, delivering an extrafine formulation, is licensed for asthma and COPD in the UK. However, its real-life effectiveness for COPD has not been evaluated. This study compared the clinical effectiveness of BDP/FF against other licensed ICS/LABA combination inhalers: the Seretide® Accuhaler® (FP/SAL) and the Symbicort® Turbohaler® (BUD/FF).Methods: A matched historical cohort study was conducted using records of patients with diagnostic codes for COPD from the Optimum Patient Care Research Database (OPCRD). Patients who had received BDP/FF as their first ICS/LABA were matched 1:1 with patients who had received FP/SAL or BUD/FF, resulting in two matched comparisons. Additional analysis was conducted on patients who had never had diagnostic codes for asthma. Noninferiority in terms of the proportion of patients with moderate/severe COPD exacerbations on the different inhalers in the following year was assessed. Noninferiority was achieved if the upper CI limit were ≤ 1.2.Results: This study included 537 and 540 patient pairs in the BDP/FF vs FP/SALcohort and the BDP/FF vs BUD/FF cohort, respectively. The proportion of patients with COPD exacerbations in the BDP/FF group was not significantly different from either the FP/SAL (68.7% vs 70.2%, AOR 0.89, 95% CI 0.67– 1.19) or BUD/FF group (68.5% vs 69.4%, AOR 0.79, 95% CI 0.58– 1.08). Noninferiority of BDP/FF in preventing COPD exacerbations was fulfilled in both comparisons. In patients without asthma, BDP/FF was also noninferior to BUD/FF (proportion with COPD exacerbations, 67.8% vs 64.7%, AOR 0.79, 95% CI 0.51– 1.1997). Additionally, a significantly lower proportion of patients prescribed BDP/FF had COPD exacerbations than FP/SAL (64.8% vs 73.7%, AOR 0.64 95% CI 0.43– 0.96).Conclusion: Initiating ICS/LABA treatment of COPD with extrafine-formulation BDP/FF was noninferior in preventing moderate/severe exacerbations compared to FP/SAL and BUD/FF.Keywords: metered-dose inhaler, dry-powder inhaler, chronic obstructive pulmonary disease, treatment efficacy, cost-effectiveness

Jia-xi Duan,1,2 Wei Cheng,1,2 Yu-qin Zeng,1,2 Yan Chen,1,2 Shan Cai,1,2 Xin Li,3 Ying-qun Zhu,4 Ming Chen,5 Mei-ling Zhou,6 Li-bing Ma,7 Qi-mi Liu,8 Ping Chen1,2 1Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan 410011, People’s Republic of China; 3Division 4 of Occupational Diseases, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, Hunan 410000, People’s Republic of China; 4Department of Respiratory Medicine, The Third Hospital of Changsha, Changsha, Hunan 410011, People’s Republic of China; 5Department of Respiratory Medicine, The No.1 Traditional Chinese Medicine Hospital in Changde, Changde, Hunan 415000, People’s Republic of China; 6Department of Respiratory Medicine, The First People’s Hospital of Huaihua, Huaihua, Hunan 418000, People’s Republic of China; 7Department of Respiratory Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541000, People’s Republic of China; 8Department of Respiratory and Critical Care Medicine, The Second People’s Hospital of Guilin, Guilin, Guangxi 541000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, People’s Republic of ChinaTel +86 731 8529 5248Email pingchen0731@csu.edu.cnPurpose: Tobacco smoking, biomass smoke, and occupational exposure are the main risk factors for chronic obstructive pulmonary disease (COPD). The present study analyzes data on exposure to these factors in a cohort of patients with COPD and assesses their differences in demographic and clinical characteristics.Patients and Methods: The cross-sectional observational study was conducted from November 2016 to December 2019. Inclusion criteria were patients aged over 40 years old with post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) < 0.7. At baseline, demographic features and exposure history were recorded. Moreover, respiratory symptoms were assessed by the COPD Assessment Test (CAT) and modified Medical Research Council scale (mMRC). A generalized linear mixed model was used to adjust for potential confounders.Results: A total of 5183 patients with COPD were included in the final analysis. The results demonstrate that exposure to tobacco combined with other risk factors resulted in significantly higher CAT scores (16.0 ± 6.7 vs 15.3 ± 6.3, P = 0.003) and more severe dyspnea (patients with mMRC ≥ 2, 71.5% vs 61.6%, P < 0.001) than exposure to tobacco alone. In addition, COPD patients with biomass smoke exposure alone had higher CAT scores than patients with only tobacco or occupational exposure (17.5 ± 6.3 vs 15.3 ± 6.3, and 15.2 ± 6.3, respectively, P < 0.05 for each comparison) and were more likely to be female and older. In addition, COPD patients who suffered from occupational exposure developed more severe dyspnea than those exposed to tobacco alone (70.8% vs 61.6%, P < 0.05), as did those exposed to biomass smoke alone (74.2% vs 61.6%, P < 0.05). This difference remained strong even after adjustment for potential confounders.Conclusion: There are significant demographic and clinical differences among COPD patients with tobacco smoking, biomass smoke, and occupational exposures.Keywords: chronic obstructive pulmonary disease, tobacco, biomass smoke, occupational exposure

Philip W Stone,1 Katherine Hickman,2 Michael C Steiner,3 C Michael Roberts,4,5 Jennifer K Quint,1,* Sally J Singh3,* 1National Heart and Lung Institute, Imperial College London, London, UK; 2West Yorkshire and Harrogate Health and Care Partnership, Bradford, Yorkshire, UK; 3NIHR Leicester Respiratory Biomedical Research Centre, Department of Respiratory Sciences, University of Leicester, Leicester, UK; 4Royal College of Physicians, London, UK; 5QMUL, London, UK*These authors contributed equally to this workCorrespondence: Philip W Stone Email p.stone@imperial.ac.ukBackground: A large proportion of people with COPD are not referred to pulmonary rehabilitation (PR) despite its proven benefits. No previous studies have examined predictors of referral to PR.Objective: To determine the characteristics of people with COPD associated with referral to PR.Methods: Cross-sectional analysis of a primary care cohort of 82,696 Welsh people with COPD generated as part of a UK national audit of COPD care. Data represent care received by patients as of 31/03/2017. Referral to PR was defined as any code in the patient record indicating referral to PR in the last 3 years. Potential predictors of referral to PR were chosen based on clinical judgement and data availability. Independent predictors of PR referral were determined using backward stepwise mixed-effects logistic regression with a random effect for practice. Variables assessed were: age, gender, deprivation, MRC recorded in past year, MRC grade, smoking status recorded in past year, smoking status, number of exacerbations in past year, inhaled therapy prescription, influenza vaccination, and comorbidities of diabetes, hypertension, coronary heart disease, stroke, heart failure, lung cancer, asthma, bronchiectasis, depression, anxiety, severe mental illness, osteoporosis, and painful condition.Results: A total of 13,297 people (16%) with COPD were referred from primary care for PR. Patients with a comorbidity of bronchiectasis or depression, MRC recorded in the last year, higher MRC grade, more exacerbations in the last year, a greater level of inhaled therapy, an influenza vaccination, or were an ex-smoker had significantly higher odds of referral to PR. Patients that were older, female, more deprived, or had a comorbidity of diabetes, asthma, or painful condition had significantly lower odds of referral to PR.Conclusion: Generally appropriate patients are being prioritised for PR referral; however, it is concerning that women, current smokers, and more deprived patients appear to have lower odds of referral.Keywords: COPD, chronic obstructive pulmonary disease, GP, general practitioner, observational study

Introduction Calcium is an important coagulation factor and hypocalcemia is related to progression and poor prognosis of many cardiopulmonary diseases. However, influence of hypocalcemia on pulmonary thromboembolism (PTE) prognosis has never been reported. This study aimed to explore its prognostic value and optimize the pulmonary embolism severity index (PESI), the widely used prognosis assessment model, based on the value. Methods PTE patients’ variables in PESI and other related clinical characteristics including admission serum calcium were collected. Associations between these variables and PTE mortality were assessed by logistic regression and cox analysis. Variables significantly associated with 30-day PTE mortality were included to develop a new prognosis prediction rule and then its validity was compared with PESI and simplified PESI (sPESI). Results 496 PTE patients were included and 49.48% patients had hypocalcemia (serum calcium ≤ 2.13 mmol/L) in admission, showing higher 7-day (P = 0.021), 14-day (P = 0.002), 30-day (13.03% vs 4.98%, P = 0.002) mortalities than patients without hypocalcemia. Adjusting for variables in PESI, hypocalcemia was further revealed to be an independent predictor of 30-day mortality (P = 0.014). The optimal prediction rule contained hypocalcemia and 5 variables in PESI and sPESI, showing higher predictive validity [sensitivity (Sen): 0.930, specificity (Spec): 0.390, area under curve (AUC): 0.800] than PESI (Sen: 0.814, Spec: 0.367, AUC: 0.716) and sPESI (Sen: 0.907, Spec: 0.216, AUC: 0.703). Conclusions Hypocalcemia is an independent predictor of the mortality following acute PTE. Based on hypocalcemia, the optimal prediction rule showed higher validity than PESI and sPESI.

Eisuke Mochizuki,1 Yoshiihiro Kawai,2 Keisuke Morikawa,1 Yutaro Ito,1 Namio Kagoo,1 Tsutomu Kubota,1 Koshiro Ichijyo,1 Masahiro Uehara,1 Masanori Harada,1 Shun Matsuura,1 Masaru Tsukui,1 Naoki Koshimizu1 1Department of Respiratory Medicine, Fujieda Municipal Hospital, Fujieda 426-8677, Japan; 2Department of Radiology, Fujieda Municipal Hospital, Fujieda 426-8677, JapanCorrespondence: Eisuke Mochizuki Tel +81-54-646-1111Fax +81-54-646-1122Email eisukefukui@gmail.comBackground: The validity of four-dimensional dynamic-ventilation CT scan for distinguishing COPD from asthma has not been established.Purpose: To assess whether four-dimensional dynamic-ventilation CT scan can aid in the diagnosis of COPD by comparing local lung movement during tidal breathing between COPD and asthma.Patients and Methods: Thirty-three COPD patients (30 males and three females; median age 74; range 44– 89 years) and 11 asthma patients (five males and six females; median age 55; range: 32– 75 years) underwent whole-lung dynamic-ventilation CT scan. CT data were reconstructed, one respiratory cycle to 10 phases, and in addtion we reconstructed threefold new phase data sets. We then analyzed local lung movement during tidal breathing using unpaired t-tests and chi-squared tests.Results: The local lung movement in COPD patients was significantly smaller than in asthma patients, especially in the ventral part of the lung. This was so even in patients who had mild emphysema (Goddard score < 8).Conclusion: Quantitative evaluation using four-dimensional dynamic-ventilation CT scan demonstrated that local lung movement during tidal breathing, particularly in the ventral lung, was smaller in COPD than in asthma patients, which may help distinguish COPD from asthma.Keywords: COPD, asthma four-dimensional dynamic-ventilation CT

Meng Li,* Tian Yang,* Ruiqing He, Anqi Li, Wenhui Dang, Xinyu Liu, Mingwei Chen Department of Respiratory and Critical Care Medicine of the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi 710061, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingwei ChenDepartment of Respiratory and Critical Care Medicine of the First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi 710061, People’s Republic of ChinaTel/Fax +86-29-85323850Email chenmw36@163.comPurpose: To evaluate the accuracy of inflammatory biomarkers in differentiating patients with asthma–COPD overlap (ACO) from those with COPD alone.Methods: Clinical data of 134 patients with COPD and 48 patients with ACO admitted to the First Affiliated Hospital of Xi’an Jiaotong University from January 2016 to June 2019 were retrospectively analyzed. Receiver operating characteristic (ROC) curve analysis was performed to determine the best cut-off values of fractional exhaled nitric oxide (FeNO), blood eosinophil counts (EOS), and neutrophil to lymphocyte ratio (NLR) for differentiating between ACO and COPD alone. Spearman correlation analysis was conducted to evaluate the relationships between these inflammatory biomarkers and the forced expiratory volume in one second/prediction (FEV1%pred).Results: FeNO and EOS in the ACO patients were significantly higher than those in the COPD patients (FeNO: median 37.50 vs 24.50 ppb, P < 0.001; EOS: median 0.20 vs 0.10 × 109/L, P = 0.004). FeNO was positively correlated with FEV1%pred (r = 0.314, P = 0.030), while NLR was negatively correlated with FEV1%pred (r = − 0.372, P = 0.009) in patients with ACO. In addition, a positive correlation between FeNO and EOS was also found in ACO, especially in patients without history of inhaled corticosteroids (ICS) use (r = 0.682, P < 0.001). The optimal cut-off value of FeNO was 31.5 ppb (AUC = 0.758, 95% CI = 0.631– 0.886) in patients with smoking history, with 70.0% sensitivity and 89.9% specificity for differentiating ACO from COPD. In patients without history of ICS use, the best cut-off value of FeNO was 39.5 ppb (AUC = 0.740, 95% CI = 0.610– 0.870), with 58.3% sensitivity and 84.9% specificity. Among patients without history of ICS use and smoking, 27.5 ppb was optimal cut-off level for FeNO (AUC = 0.744, 95% CI = 0.579– 0.908) to diagnose ACO, with 81.8% sensitivity and 60.7% specificity, and the sensitivity was improved to 91.7% when FeNO was combined with EOS.Conclusion: The inflammatory biomarkers FeNO and EOS can be used as indicators for differentiating between ACO and COPD alone.Keywords: fractional exhaled nitric oxide, blood eosinophil counts, neutrophil to lymphocyte ratio, chronic obstructive pulmonary disease, asthma–COPD overlap

Hannah R Whittaker,1 Jeanne M Pimenta,2 Deborah Jarvis,1 Steven J Kiddle,3 Jennifer K Quint1 1Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UK; 2Epidemiology (Value Evidence and Outcomes), GlaxoSmithKline, R&D, Uxbridge, UK; 3MRC Biostatistics Unit, University of Cambridge, Cambridge, UKCorrespondence: Hannah R WhittakerImperial College, Emmanuel Kaye Building, National Heart and Lung Institute, London, UKEmail h.whittaker@imperial.ac.ukBackground: Estimates for lung function decline in chronic obstructive pulmonary disease (COPD) have differed by study setting and have not been described in a UK primary care population.Purpose: To describe rates of FEV1 and FVC decline in COPD and investigate characteristics associated with accelerated decline.Patients and Methods: Current/ex-smoking COPD patients (35 years+) who had at least 2 FEV1 or FVC measurements ≥ 6 months apart were included using Clinical Practice Research Datalink. Patients were followed up for a maximum of 13 years. Accelerated rate of lung function decline was defined as the fastest quartile of decline using mixed linear regression, and association with baseline characteristics was investigated using logistic regression.Results: A total of 72,683 and 50,649 COPD patients had at least 2 FEV1 or FVC measurements, respectively. Median rates of FEV1 and FVC changes or decline were − 18.1mL/year (IQR: − 31.6 to − 6.0) and − 22.7mL/year (IQR: − 39.9 to − 6.7), respectively. Older age, high socioeconomic status, being underweight, high mMRC dyspnoea and frequent AECOPD or severe AECOPD were associated with an accelerated rate of FEV1 and FVC decline. Current smoking, mild airflow obstruction and inhaled corticosteroid treatment were additionally associated with accelerated FEV1 decline whilst women, sputum production and severe airflow obstruction were associated with accelerated FVC decline.Conclusion: Rate of FEV1 and FVC decline was similar and showed similar heterogeneity. Whilst FEV1 and FVC shared associations with baseline characteristics, a few differences highlighted the importance of both lung function measures in COPD progression. We identified important characteristics that should be monitored for disease progression.Keywords: pulmonary disease, chronic obstructive, spirometry, lung function

Jiansheng Li,1,2,* Hailong Zhang,1,3,* Huanrong Ruan,3 Yimei Si,3 Zikai Sun,4 Hong Liu,5 Jihong Feng,6 Yanqing Wang,7 Lihua Li,8 Li Bai,9 Hui Sun10 1Co-Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 2Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 3The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, People’s Republic of China; 4Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, People’s Republic of China; 5The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People’s Republic of China; 6The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China; 7Haici Hospital of Qingdao, Qingdao, People’s Republic of China; 8Zhengzhou People’s Hospital, Zhengzhou, People’s Republic of China; 9Shanxi Hospital of Integrated Traditional and Western Medicine, Taiyuan, People’s Republic of China; 10Nanyang City Center Hospital, Nanyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiansheng Li No. 156 Jinshui East Road, Zhengdong New District, Zhengzhou, Henan 450046, People’s Republic of ChinaTel +86 371 65676568Fax +86 371 65944307Email li_js8@163.comPurpose: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an essential occurrence in COPD management and is the leading cause of morbidity and mortality. Chinese herbal medicine is widely used in the treatment of AECOPD, but high quality randomized controlled trials are limited. This study aimed to evaluate the efficacy and safety of Chinese herbal medicine as adjuvant therapy for patients with AECOPD.Methods: This was a randomized, double-blind, placebo-controlled study of 378 participants from eight centers in China. Participants were randomly assigned to receive 10 g of Chinese herbal medicine (according to the type of Traditional Chinese medicine syndrome: Sanhanhuayin, Qingrehuatan, or Zaoshihuatan granules) or placebo, two times per day, for 14 days, in addition to conventional medicine. Participants were followed up for 84 days after the treatment. The primary end point was the COPD assessment test (CAT) score. Secondary end points included the Modified British Medical Research Council (mMRC) questionnaire and the COPD patient-reported outcome scale (COPD-PRO). We also assessed treatment failure and treatment success rate, length of hospitalization, number of patients with acute exacerbations, number of patients readmitted due to AECOPD, and number of deaths and intubation.Results: The between-group difference in the change from baseline for CAT on day 14 (end of treatment) was − 2.11 (95% confidence interval [CI], − 3.198 to − 1.050; P< 0.001), exceeding the minimal clinically important difference. The mMRC and COPD-PRO scores were lower in the intervention group compared to the control group (between-group difference in the change from baseline, − 0.28; 95% CI, − 0.48 to − 0.08; P=0.007 and − 2.51; 95% CI, − 4.087 to − 0.929; P=0.002, respectively) on day 14. The intervention group had a significantly shorter duration of hospital stay than the control group (mean difference, − 1.21days; 95% CI, − 2.041 to − 0.419; P=0.003), significantly lower of number of exacerbations (risk ratio [RR], 0.60; 95% CI, 0.409 to 0.892; P=0.010), and significantly lower number of readmissions due to AECOPD (RR, 0.41; 95% CI, 0.193 to 0.865; P=0.015). Significant differences in the number of treatment failures or successes, deaths, and intubation were not observed. The difference in safety variables and adverse events between the two groups was not observed.Conclusion: Chinese herbal medicine appears to be safe and beneficial for AECOPD and can be considered a complementary treatment for patients with AECOPD.Keywords: acute exacerbations, chronic obstructive pulmonary disease, randomized controlled trial, Chinese herbal medicine

Ye-Jin Lee,1 SeungHo Choi,2 Sung-Youn Kwon,2 Yunhwan Lee,2 Jung Kyu Lee,3 Eun Young Heo,3 Hee Soon Chung,3,4 Deog Kyeom Kim3,4 1Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea; 2Department of Internal Medicine, Healthcare Research Institute, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul 135-984 Korea; 3Division of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul, KoreaCorrespondence: Deog Kyeom KimDivision of Pulmonary and Critical Care Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Boramae-Gil 41, Dongjak-gu, Seoul 156-707, Republic of KoreaTel +82-2-870-3207Fax +82-2-831-0714Email kimdkmd@gmail.comBackground: Identifying the genetic basis of airflow limitation is one of the most interesting issues for understanding chronic obstructive pulmonary disease (COPD) pathophysiology. Several studies have shown that some genetic variants associated with COPD have been identified in genome-wide association study (GWAS), especially in patients with moderate to severe COPD; genetic susceptibility for airflow limitation in the early COPD phase has not been widely studied.Objective: We investigated the genetic variants in early COPD.Methods: The present study analyzed Gene-environment interaction and phenotype (GENIE) cohort that included participants who received health screening examination. The association between single nucleotide polymorphism (SNP) and susceptibility to early COPD (FEV1 predicted ≥ 50% and FEV1/FVC < 0.7) was tested.Results: A total of 130 patients with early COPD and 3478 controls (1700 ever smokers and 1778 never smokers) were recruited. When compared with the total controls, certain SNPs (rs2818103, rs875033, rs9354627, rs34552148) on chromosome 6 were included at the top of our list (p= 5.6 × 10– 7 ∼ 9.6 × 10– 6) although they did not reach genome-wide significance. When compared with the never smoker controls, two SNPs (rs2857210, rs2621419) of the HLA-DQB2 gene class were persistently associated with susceptibility to early COPD.Conclusion: Certain SNPs located on chromosome 6 or the HLA-DQB2 gene were the top-scoring SNPs for the association with susceptibility to early COPD in the Korean GENIE cohort.Keywords: early chronic obstructive pulmonary disease, genome-wide association study, single nucleotide polymorphism, SNP, HLA-DQ gene

Huimin Zhao,1 Bei Wu,2 Linglin Kong,1 Junyao Fan,1 Quan Wang,1 Jie Li,1 Jing Mao1 1School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Rory Meyers College of Nursing and NYU Aging Incubator, New York University, New York, NY, USACorrespondence: Jie Li; Jing MaoSchool of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Hangkong Road 13, Qiaokou District, Wuhan 430030, People’s Republic of ChinaTel +86 18971097091; +86 13317135988Fax +86 02783692635; +86 02783692657Email Lijie@hust.edu.cn; maojing@hust.edu.cnPurpose: This cross-sectional study aimed to describe personal growth and to analyze its associated factors among patients with chronic obstructive pulmonary disease (COPD) in China.Patients and Methods: A total of 364 Chinese COPD hospitalized patients were included in the study between November 2016 and April 2018. Participants provided demographic information and completed the Growth Through Uncertainty Scale (GTUS), the Multidimensional Scale of Perceived Social Support (MSPSS), and the modified Medical Research Council dyspnoea scale (mMRC).Results: The mean total score on the GTUS was 142.34 (SD = 7.61). The multiple linear regression analysis showed that factors including educational level, average monthly income, social support, and breathlessness can influence personal growth (R2 = 0.427, F = 44.420, p < 0.001), explaining 42.7% of the variance.Conclusion: COPD patients tend to report a moderate level of personal growth in China. Educational level, average monthly income, social support, and breathlessness were significant factors associated with personal growth. Medical workers should be aware of the level of personal growth among COPD patients and make tailored interventions to facilitate COPD patients’ personal growth, such as increasing social support and decrease breathlessness.Keywords: breathlessness, China, COPD, personal growth, social support

BackgroundExposure to electronic-cigarette (e-cig) aerosols induces potentially fatal e-cig or vaping-associated lung injury (EVALI). The cellular and molecular mechanisms underlying these effects, however, are unknown. We used an air–liquid interface (ALI) in vitro model to determine the influence of two design characteristics of third-generation tank-style e-cig devices—resistance and voltage—on (1) e-cig aerosol composition and (2) cellular toxicity.MethodsHuman bronchial epithelial cells (H292) were exposed to either butter-flavored or cinnamon-flavored e-cig aerosols at the ALI in a Vitrocell exposure system connected to a third-generation e-cig device. Exposures were conducted following a standard vaping topography profile for 2 h per day, for 1 or 3 consecutive days. 24 h after ALI exposures cellular and molecular outcomes were assessed.ResultsWe found that butter-flavored e-cig aerosol produced under ‘sub-ohm’ conditions ( 1 Ω and voltage > 4.5 V), contains lower carbonyl levels (ConclusionThe production of high levels of carbonyls may be flavor specific. Overall, inhaling e-cig aerosols produced under ‘sub-ohm’ conditions is detrimental to lung epithelial cells, potentially via mechanisms associated with OS. This information could help policymakers take the necessary steps to prevent the manufacturing of sub-ohm atomizers for e-cig devices.

Haiyan Sheng,1,2 Yijie Zhang,1,3 Xiaoqian Shi,1,4 Yuhan Hu,1 Baosen Pang,1,4 Jiawei Jin,1,4 Yingmin Ma1 1Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, People’s Republic of China; 3Department of Emergency Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4The Clinical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Yingmin Ma; Jiawei Jin Email ma.yingmin@163.com; jiaweijin@ccmu.edu.cnAims: The aim of the study was to explore the functional and structural changes of the diaphragm and underlying mechanisms in response to 12 or 24 weeks of cigarette smoke (CS) exposure in rats.Materials and Methods: Rats were exposed to CS to develop a COPD model and the rats exposed to room air served as a control group. Rats were randomly divided into four groups: CS12W, CON12W, CS24W, and CON24W. Pulmonary function, lung histopathology, and the contractile properties and ultrastructure of diaphragm muscle were examined in these rats. The changes of transcriptomic profiling of diaphragm muscle were further compared between CS and control rats by the RNA Seq.Results: Both CS groups showed lower FEV0.3/FVC, elevated mean linear intercept (MLI), and reduced mean alveolar numbers (MAN) vs the control groups. The fatigue index (FI) of the diaphragm muscle from the CS12W group, but not CS24W, was significantly increased. Conversely, the force–frequency curves of the diaphragm muscle from the CS24W group, but not CS12W group, were significantly decreased. Consistently, mitochondrial number density (NA) and volume density (Vv) were increased in the CS12W diaphragm muscle, while being decreased in the CS24W group. Furthermore, the diaphragm transcriptomic profiling results showed that genes regulating cell proliferation and energy metabolic activity were un-regulated and genes regulating protein degradation were down-regulated in the CS12W diaphragm, while CS24W diaphragm showed opposite changes.Conclusion: These observations suggested a transition of diaphragm muscle from initial compensatory to decompensatory changes in function, structure, and gene expression during the development of COPD.Keywords: COPD, diaphragm, contractile properties, transcriptional gene expression

Seiichi Kobayashi,1 Masakazu Hanagama,1 Masatsugu Ishida,1 Manabu Ono,1 Hikari Sato,1 Shinsuke Yamanda,1,2 Masaru Yanai1 1Department of Respiratory Medicine, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Miyagi, Japan; 2Department of Pulmonary Medicine, Sendai Kosei Hospital, Sendai, Miyagi, JapanCorrespondence: Seiichi KobayashiDepartment of Respiratory Medicine, Japanese Red Cross Ishinomaki Hospital, 71 Nishimichishita, Hebita, Ishinomaki 986-8522, JapanTel +81 225 21 7220Fax +81 225 96 0122Email skoba-thk@umin.ac.jpPurpose: Asthma–COPD overlap (ACO) has been reported as an association with a lower quality of life, frequent exacerbations, and higher mortality than those with COPD alone. However, clinical characteristics and outcomes of ACO remain controversial.Patients and Methods: We conducted a prospective observational study analyzing data of patients with stable COPD enrolled from the Ishinomaki COPD Network Registry. Patients with features of asthma who had a history of respiratory symptoms that vary over time and intensity, together with documented variable expiratory airflow limitation, were identified, and then defined as having ACO. The characteristics, frequency of exacerbations, and mortality during the 3-year follow-up were compared between patients with ACO and patients with COPD alone.Results: Among 387 patients with COPD, 41 (10.6%) were identified as having ACO. Patients with ACO tended to be younger, have higher BMI, have a shorter smoking history, and use more respiratory medications, especially inhaled corticosteroids. Inflammatory biomarkers including fractional exhaled nitric oxide, blood eosinophil count, total immunoglobulin E (IgE) level, and presence of antigen-specific IgE were significantly higher in patients with ACO than in those with COPD alone. Lung function, mMRC score, CAT score, and comorbidity index were not different between the groups. The annual rate of all exacerbations and severe exacerbations required hospital admission were not different between ACO and COPD alone (0.20 vs 0.14, 0.12 vs 0.10, events per person, respectively). Mortality was significantly higher in patients with COPD alone compared with those with ACO during the study period (P=0.037).Conclusion: The results of our study indicate that ACO is not associated with poor clinical features nor outcomes in an outpatient COPD cohort receiving appropriate treatment.Keywords: asthma, asthma–COPD overlap, COPD, exacerbations, mortality

Background Patient–ventilator asynchrony is associated with increased morbidity and mortality. A direct causative relationship between Patient–ventilator asynchrony and adverse clinical outcome have yet to be demonstrated. It is hypothesized that during trigger errors excessive pleural pressure swings are generated, contributing to increased work-of-breathing and self-inflicted lung injury. The objective of this study was to determine the additional work-of-breathing and pleural pressure swings caused by trigger errors in mechanically ventilated children. Methods Prospective observational study in a tertiary paediatric intensive care unit in an university hospital. Patients ventilated > 24 h and Results Nine-hundred-and-fifty-nine trigger errors in 28 patients were identified. The additional work-of-breathing caused by trigger errors showed great variability among patients. The more asynchronous breaths were present the higher the work-of-breathing of these breaths. A higher spontaneous breath rate led to a lower amount of trigger errors. Patient–ventilator asynchrony was not associated with prolonged duration of mechanical ventilation or paediatric intensive care stay. Conclusions The additional work-of-breathing caused by trigger errors in ventilated children can take up to 30–40% of the total work-of-breathing. Trigger errors were less common in patients breathing spontaneously and those able to generate higher pressure–time–product and pressure swings. Trial registration Not applicable.

Rationale: Use of noninvasive ventilation (NIV) has increased in intensive care units, but sleep during NIV has received little attention. The authors surmised that due to frequent air leaks and mask discomfort, patients receiving NIV would manifest poorer sleep quality than those receiving invasive mechanical ventilation (INV). Methods: A prospective observational study on patients receiving NIV or INV for respiratory failure in a medical intensive care unit or coronary care unit. Patients were monitored by polysomnography for 24 hours with simultaneous collection of data on ventilator and environmental parameters. Results: Eight subjects in each group were studied. Mean total sleep time was 7.29 +1.78 hours (range: 0.57–13.82) in the NIV versus 11.74 +0.65 hours (8.95–15.19) in the INV group (p=0.034). Sleep efficiency was lower in NIV than INV group (30.4% versus 53.3%, respectively; p=0.013). The NIV group had lighter sleep than the INV group (mean % of Stage 1: 36.9% versus 17.2% of total sleep time, respectively; p=0.000), whereas no significant differences were found for other stages. Median total arousal and awakening indexes were higher in the NIV group (16.8/hour versus 4.4/hour and 5.3/hour versus 2.1/hour, respectively; p=0.005), as well as spontaneous arousals and awakenings (p=0.006 and p=0.005, respectively). Sedation was provided mostly by intermittent bolus in the NIV group whereas often by infusion in the INV group. Conclusion: Compared to INV, NIV in critically ill patients was associated with poorer quality and quantity of sleep. Future studies should determine whether adjustments in ventilator settings, mask type or fit, or use of sedation/analgaesia can improve sleep in patients receiving NIV.

Introduction While electronic cigarette (EC) use is rapidly increasing among asthmatic adolescents, little is known about the links between EC use and depression or suicidality. We assessed associated factors for depression and suicidality in asthmatic adolescents with experience of EC use. Methods We analyzed the data from the 11th to 13th Korea Youth Risk Behavior Web-based Surveys, which were completed from 2015 to 2017. Data were obtained from a stratified, multistage, clustered sample. Students supplied 'yes or no' answers to questions about previous asthma diagnosis by a doctor. Associated factors for depression and suicidality were evaluated by logistic regression models after controlling for potential confounding factors. We targeted 203336 adolescents, and 195847 completed the survey. Results The proportion of asthma among the respondents was 8.9%. The rate of experience of EC use was higher among asthmatic respondents than non-asthmatic respondents (10.3% vs 8.6%). Asthmatic respondents with experience of EC use had a much higher proportion of negative mental health states including depression and suicidality than subjects without EC experience. In our adjusted models, perception of stress was most strongly associated with depression (adjusted odds ratio, AOR=4.79; 95% CI: 4.12-5.58), and perception of unhappiness was most strongly associated with suicidal ideation (AOR=5.24; 95% CI: 4.51-6.09) and suicide attempt (AOR=4.37; 95% CI: 3.36-5.69). Conclusions Many Korean asthmatic adolescents with experience of EC use report relatively high depression and suicidal behaviors. A multidisciplinary approach, including psychological help, may be required to prevent suicide among this population, especially those who report associated factors.

Introduction Smoking status based solely on self-reporting is unreliable and might be inaccurate, particularly among women. This study investigated the association between urinary cotinine-verified smoking status and hyperuricemia in a nationwide Korean population. Methods This study included 5,329 participants aged ≥19 years with information on smoking status, urine cotinine levels and serum uric acid. We determined smoking status according to self-reports and urinary cotinine levels. Multivariate linear regression analysis was used to measure the association between smoking exposure and serum uric acid levels. The effects of smoking on hyperuricemia were evaluated by multivariate logistic regression analysis. Results Biochemically-verified active and passive smokers comprised 22% (38.7% of men and 8.8% of women) and 12.3% (11.9% of men and 12.6% of women) of the study population, respectively. While reclassification rate of active smokers was 1.4% in men, 31.8% of cotinine-verified female active smokers were self-reported never smokers. Higher uric acid levels were observed with increased tobacco exposure among women (P trend = 0.007) but not among men. After adjusting for confounders, the risk of hyperuricemia increased with tobacco exposure only in women (P trend = 0.016). Conclusions Cotinine-verified smoking status was associated with increased serum uric acid and hyperuricemia in a dose-response manner only in women. This study might provide evidence to support the importance of smoking cessation in women with gout and further studies are necessary to elucidate the underlying mechanism of the observed association.

Background: It is not evident that the attributable risk of smoking on mortality in Korea has decreased. We investigated the impact of smoking on all-cause mortality and estimated the attributable risk of smoking in Korean adults. Methods: Those aged ≥20 years with smoking history in the Korean National Health and Nutrition Examination Surveys (KNHANES) 2007-2015 were enrolled. We categorized the participants into three groups as follows: never smoker

Silvia Uccelli,1 Laura Pini,1 Damiano Bottone,1 Piera Ranieri,2 Nicla Orzes,1 Claudio Tantucci1 1Respiratory Medicine Unit, Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy; 2Department of Internal Medicine and Rehabilitation, Istituto Clinico Sant’Anna, Brescia, ItalyCorrespondence: Laura Pini Email laura.pini@unibs.itRationale: Patients with chronic obstructive pulmonary disorder (COPD) complain of various COPD-related symptoms with different daily frequencies. During the night-time and at early morning, dyspnea is often reported and may predict an increased risk of COPD exacerbation and hospitalization and all-cause mortality. The aim of the study was to assess the underlying mechanisms of this symptom, seeking functional biomarkers of its occurrence.Methods: Stable COPD patients with moderate-to-severe airflow obstruction and without confounding comorbidities underwent extensive baseline function respiratory tests. Spirometry, maximal flow-volume curves, lung volumes, and lung diffusion capacity parameters were obtained. Inspiratory capacity was also measured both in seated and supine positions. Forced oscillation technique (FOT) and negative expiratory pressure (NEP) method were used to establish the presence of tidal expiratory flow limitation (EFL) during recumbency. Questionnaires for recording COPD-related symptoms were administered. Sleep-related disturbances reported by the patients were also registered.Results: Forty-two consecutive COPD patients aged 65± 9 completed the protocol. They were divided, according to the absence (NFL) or presence (FL) of supine EFL, in NFL group (n=17) and FL group (n=25). FL COPD patients had more severe airflow obstruction (FEV1= 46.4± 19.4 vs 65.1± 12.5% pred., p< 0.01) and they showed no increase of supine IC in contrast with NFL COPD patients (ΔIC= 0.080± 0.18 vs 0.390± 0.28 L, p< 0.01). Dyspnea either during night-time and at early morning was significantly more reported in FL COPD patients than in NFL COPD patients (p< 0.05) and in those with less than 10% increase in supine IC (p< 0.05).Conclusion: Supine EFL is frequently associated with both night-time and early morning dyspnea, suggesting that the development of recumbent dynamic pulmonary hyperinflation, heralded by the lack of increment of IC in supine position, is a pivotal mechanism of this symptom. No or trivial increase in supine IC may indicate the occurrence of dyspnea under these conditions.Keywords: COPD, expiratory flow limitation, pulmonary hyperinflation, dyspnea, nocturnal symptoms, symptoms in the early morning, inspiratory capacity

Introduction: The management of empyema thoracis has evolved over the years. After all lung surgeries chest drain is required, however they suffer from inter observer variability and impair mobility of the patient. However, the newer digital thoracic drain system are portable and have alarms for various situations, furthermore they eliminate inter-observer variability. One such device is Thopaz™ (Medela inc, Switzerland). We wanted to compare efficacy of Thopaz™ with our conventional intercostal chest tube drain in patients undergoing decortications for empyema thoracis. Materials and Methods: One hundred patients were enrolled in study and were randomized into conventional and thopaz group with 50 patients in each group with help of opaque envelopes. Results: Both the groups were comparable in demographic parameters. Majority of the patients in our study were children and young adults. Majority of empyema thoracis involved right side with nontubercular empyema thoracis being the most common cause of decorticartion. Patients managed with Thopaz had a significantly shorter air leak duration, shorter duration of postdecortication chest tube placement and shorter postoperative hospital stay. All postoperative complications were less in Thopaz group. Conclusions: Patients with empyema thoracis undergoing open decortications when managed with digital chest drainage system (Thopaz) experienced faster reduction in air leak, a shorter duration of chest tube placement and in hospital stay. Thopaz usage is also associated with reduction in rate of postoperative complications. We recommend that this digital chest tube drainage system is a very useful tool in armamentarium of thoracic surgeon after lung surgeries.

Marina Hlavati,1,2 Svetlana Tomić,2 Krunoslav Buljan,2 Vikica Buljanović,3 Ivan Feldi,4 Silva Butković-Soldo2 1Department of Diagnostic and Therapeutical Procedures, General Hospital Našice, Našice 31500, Croatia; 2Faculty of Medicine Osijek, University Josip Juraj Strossmayer Osijek, Osijek 31000, Croatia; 3Department for Biochemical Analysis, General Hospital Našice, Našice 31500, Croatia; 4Department of Internal Medicine, General Hospital Našice, Našice 31500, CroatiaCorrespondence: Marina Hlavati Department of Diagnostic and Therapeutical ProceduresGeneral Hospital Našice, Bana Jelačića 10, Našice 31500, CroatiaTel +385915810485Fax +38531613826Email marinahlavati@yahoo.comObjective: This study evaluates the total antioxidant status (TAS) in plasma of stable chronic obstructive pulmonary disease (COPD) patients. Earlier studies of their relationship showed inconsistent findings.Patients and Methods: We compared TAS between 90 COPD patients and 30 age- and sex-matched controls (mean age 67 ± 7.9, 87 males and 33 females) according to airway obstruction severity, gender, smoking status (current/ former/ non-smoker), smoking-dose, the number of exacerbations in the previous year, nutritional status and hypercapnia.Results: There were no differences in pack-years between COPD and controls, neither in COPD groups. The median time from the last exacerbation was 5 months (interquartile range 3− 8.3). TAS was significant higher in COPD than controls (1.68 [1.55− 1.80] versus 1.59 [1.54− 1.68], respectively; P = 0.03). TAS was significantly higher in COPD men than women (1.7 [1.6− 1.8] versus 1.57 [1.5− 1.7], respectively; P = 0.001). In COPD groups, there were no significant differences between the severity of airway obstruction and TAS. We found significant positive correlation between pack-years and TAS in all participants (Rho = 0.429, P = 0.004) and COPD patients (Rho = 0.359, P = 0.02), but not in controls. TAS was a significant predictor of COPD (β = 3.26; P = 0.04; OR = 26.01; 95% CI: 1.20 to 570.8). We failed to find significant differences between TAS and smoking status, frequency of exacerbations in the previous year, nutritional status and hypercapnia.Conclusion: TAS was a significant predictor of COPD. TAS was a significantly higher in stable COPD than controls, higher in COPD men than women, but there was no significant correlation between TAS and the airway obstruction severity. Our results suggest that it could be appropriate to include the time from the last exacerbation in the oxidant–antioxidant balance analysis of COPD patients.Keywords: chronic obstructive pulmonary disease, antioxidants, airway obstruction severity, exacerbation, smoking

Introduction Flavors other than tobacco flavor have been identified as a major reason for electronic nicotine delivery system (ENDS) initiation in youth and are thought to contribute to the continued use of ENDS in users of all ages. Our previous research showed a significant association between overall ENDS use and COPD. This study aims to identify the association of ENDS flavor categories with self-reported COPD. Methods The data analysis included 4909 adults from Population Assessment of Tobacco and Health (PATH) Wave 4 data who were ever established ENDS users and responded to an item about diagnosis of COPD. Weighted multivariable logistic regression models were used to examine the association between different ENDS flavors and self-reported COPD considering complex sampling design. Results Among 4909 ever established ENDS users, 418 adults (weighted percentage 9.8%) had self-reported COPD. Self-reported COPD prevalence differed between different ENDS flavor categories, with the highest (weighted percentage 19.9%) occurring among tobacco flavor users. Compared to non-tobacco flavor categories, tobacco flavor category showed significantly higher association with self-reported COPD (AOR=2.05; 95% CI: 1.20-3.53), after adjusting for potential confounding variables. No significant associations with self-reported COPD were found for other examined ENDS flavor categories including menthol/mint, fruit, candy/ desserts/other-sweets, and other flavors, compared to their corresponding non-users. Conclusions Tobacco flavored ENDS use was significantly associated with self-reported COPD. Future studies are needed to confirm the biological and epidemiological association of flavored ENDS use with COPD.

Irene Belmonte,1 Alexa Nuñez,1,2 Miriam Barrecheguren,1 Cristina Esquinas,1 Mònica Pons,3 Rosa M López-Martínez,4 Gerard Ruiz,4 Albert Blanco-Grau,4 Roser Ferrer,4 Joan Genescà,3,5 Marc Miravitlles,1,6 Francisco Rodríguez-Frías4 1Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 2Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès). Barcelona, Spain; 3Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron; Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 4Department of Clinical Biochemistry, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 5Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain; 6CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, SpainCorrespondence: Marc MiravitllesPneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, P. Vall d’Hebron 119-129, Barcelona 08035, SpainEmail marcm@separ.esBackground: Alpha-1 antitrypsin deficiency (AATD) remains largely underdiagnosed despite recommendations of healthcare institutions and programmes designed to increase awareness. The objective was to analyse the trends in AATD diagnosis during the last 5 years in a Spanish AATD reference laboratory.Methods: This was a retrospective revision of all alpha-1 antitrypsin (AAT) determinations undertaken in our laboratory from 2015 to 2019. We analysed the number of AAT determinations performed and described the characteristics of the individuals tested, as well as the medical specialties and the reasons for requesting AAT determination.Results: A total of 3507 determinations were performed, of which 5.5% corresponded to children. A significant increase in the number of AAT determinations was observed from 349 in 2015 to 872 in 2019. Among the samples, 57.6% carried an intermediate AATD (50– 119 mg/dL) and 2.4% severe deficiency (< 50 mg/dL). The most frequent phenotype in severe AATD individuals was PI*ZZ (78.5%), and aminotransferase levels were above normal in around 43% of children and 30% of adults. Respiratory specialists requested the highest number of AAT determinations (31.5%) followed by digestive diseases and internal medicine (27.5%) and primary care physicians (19.7%). The main reason for AAT determination in severe AATD adults was chronic obstructive pulmonary disease (41.7%), but reasons for requesting AAT determination were not reported in up to 41.7% of adults and 58.3% of children.Conclusion: There is an increase in the frequency of AATD testing despite the rate of AAT determination remaining low. Awareness about AAT is probably increasing, but the reason for testing is not always clear.Keywords: alpha-1 antitrypsin deficiency, diagnosis, screening, lung disease

Background Fibrotic interstitial lung disease (ILD) is often associated with poor outcomes, but has few predictors of progression. Daily home spirometry has been proposed to provide important information about the clinical course of idiopathic pulmonary disease (IPF). However, experience is limited, and home spirometry is not a routine component of patient care in ILD. Using home spirometry, we aimed to investigate the predictive potential of daily measurements of forced vital capacity (FVC) in fibrotic ILD. Methods In this prospective observational study, patients with fibrotic ILD and clinical progression were provided with home spirometers for daily measurements over 6 months. Hospital based spirometry was performed after three and 6 months. Disease progression, defined as death, lung transplantation, acute exacerbation or FVC decline > 10% relative was assessed in the cohort. Results From May 2017 until August 2018, we included 47 patients (IPF n = 20; non-IPF n = 27). Sufficient daily measurements were performed by 85.1% of the study cohort. Among these 40 patients (IPF n = 17; non-IPF n = 23), who had a mean ± SD age of 60.7 ± 11.3 years and FVC 64.7 ± 21.7% predicted (2.4 ± 0.8 L), 12 patients experienced disease progression (death: n = 2; lung transplantation: n = 3; acute exacerbation: n = 1; FVC decline > 10%: n = 6). Within the first 28 days, a group of patients had high daily variability in FVC, with 60.0% having a variation ≥5%. Patients with disease progression had significantly higher FVC variability than those in the stable group (median variability 8.6% vs. 4.8%; p = 0.002). Cox regression identified FVC variability as independently associated with disease progression when controlling for multiple confounding variables (hazard ratio: 1.203; 95% CI:1.050–1.378; p = 0.0076). Conclusions Daily home spirometry is feasible in IPF and non-IPF ILD and facilitates the identification of FVC variability, which was associated with disease progression.

Jenny Tse,1 Keiko Wada,1 Yi Wang,1 Dominic Coppolo,2 Vladimir Kushnarev,3 Jason Suggett3 1IQVIA, Medical and Scientific Services, Real World Solutions, Cambridge, MA, USA; 2Monaghan Medical Corporation, Clinical Strategy and Development, Plattsburgh, NY, USA; 3Trudell Medical International, Science and Technology, London, ON, CanadaCorrespondence: Jenny TseIQVIA, 201 Broadway, 5th Fl, Cambridge, MA 02139, USATel +1 617-583-0627Email Jenny.Tse@iqvia.comPurpose: Managing and preventing disease exacerbations are key goals of COPD care. Oscillating positive expiratory pressure (OPEP) devices have been shown to improve clinical outcomes when added to COPD standard of care. This retrospective database study compared real-world resource use and disease exacerbation among patients with COPD or chronic bronchitis prescribed either of two commonly used OPEP devices.Patients and methods: Patients using the Aerobika® (Trudell Medical International, London, ON, Canada) or Acapella® (Smiths Medical, Wampsville, New York, USA) OPEP device for COPD or chronic bronchitis were identified from hospital claims linked to medical and prescription claims between September 2013 and April 2018; the index date was the first hospital visit with an OPEP device. Severe disease exacerbation, defined as an inpatient visit with a COPD or chronic bronchitis diagnosis, and all-cause healthcare resource utilization over 30 days and 12 months post-discharge were compared in propensity score (PS)-matched Aerobika device and Acapella device users.Results: In total, 619 Aerobika device and 1857 Acapella device users remained after PS matching. After discharge from the index visit, Aerobika device users were less likely to have ≥ 1 severe exacerbation within 30 days (12.0% vs 17.4%, p=0.01) and/or 12 months (39.6% vs 45.3%, p=0.01) and had fewer 12-month severe exacerbations (mean, 0.7 vs 0.9 per patient per year, p=0.01), with significantly longer time to first severe exacerbation than Acapella users (log-rank p=0.01). Aerobika device users were also less likely to have ≥ 1 all-cause inpatient visit within 30 days (13.9% vs 20.3%, p< 0.001) and 12 months (44.9% vs 51.8%, p=0.003) than Acapella users.Conclusion: Patients receiving the Aerobika OPEP device, compared to the Acapella device, had lower rates of subsequent severe disease exacerbation and all-cause inpatient admission. This suggests that Aerobika OPEP device may be a beneficial add-on to usual care and that OPEP devices may vary in clinical effectiveness.Keywords: database, exacerbations, re-hospitalization, sputum clearance, OPEP

Introduction Secondhand smoke (SHS) appears to be an insidious public health issue in Saudi Arabia, with a high percentage of people being reportedly exposed. In an attempt to raise awareness about this issue, we explored medical students’ level of knowledge about SHS risks, as well as their levels of exposure to SHS and the correlation between knowledge and exposure. Methods A cross-sectional study was conducted in February 2020 at the Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. An online, modified version of a validated questionnaire was distributed among 2nd to 6th year medical students. The questionnaire mainly explored the following items: 1) exposure level to SHS; 2) impact of SHS exposure; and 3) knowledge about SHS related health risks, with calculation of a knowledge score (range: 0–8). Adequate knowledge was defined as a score ≥5 (median = 5), and associations with sociodemographic and lifestyle factors and exposure to SHS were analyzed using chi-squared and independent t-test, as appropriate. Results Of a total 416 participants, 65.0% declared having one or more smoking persons among acquaintances, 26.4% being exposed to SHS at home, and 40.1% exposed to parental smoking during childhood. Further, 79.8% reported being regularly exposed to SHS in public places. Majority of participants reported significant discomfort (53.2%) and physical symptoms (98.3%) subsequent to SHS exposure. Among the list of 8 health risks, ear infection in children (28.1%), heart attack in children (37.5%), and cognitive deficit (47.8%) were the least frequently identified. Adequate knowledge was found among 57.5% of the participants, and was higher among females and lower among participants living with their friends, compared to their counterparts (p

BackgroundViral respiratory tract infections, such as influenza A virus (IAV), are common and life-threatening illnesses worldwide. The mechanisms by which viruses are removed from the respiratory tract are indispensable for airway host defense. Mucociliary clearance is an airway defense mechanism that removes pathogens from the respiratory tract. The coordination and modulation of the ciliary beating of airway epithelial cells play key roles in maintaining effective mucociliary clearance. However, the impact of respiratory virus infection on ciliary activity and mucociliary clearance remains unclear.MethodsTracheal samples were taken from wild-type (WT) and Toll-like receptor 3 (TLR3)-knockout (KO) mice. Transient organ culture of murine trachea was performed in the presence or absence of IAV, polyI:C, a synthetic TLR3 ligand, and/or reagents. Subsequently, cilia-driven flow and ciliary motility were analyzed. To evaluate cilia-driven flow, red fluorescent beads were loaded into culture media and movements of the beads onto the tracheal surface were observed using a fluorescence microscope. To evaluate ciliary motility, cilia tips were labeled with Indian ink diluted with culture medium. The motility of ink-labeled cilia tips was recorded by high-speed cameras.ResultsShort-term IAV infection significantly increased cilia-driven flow and ciliary beat frequency (CBF) compared with the control level in WT culture. Whereas IAV infection did not elicit any increases of cilia-driven flow and CBF in TLR3-KO culture, indicating that TLR3 was essential to elicit an increase of cilia-driven flow and CBF in response to IAV infection. TLR3 activation by polyI:C readily induced adenosine triphosphate (ATP) release from the trachea and increases of cilia-driven flow and CBF in WT culture, but not in TLR3-KO culture. Moreover, blockade of purinergic P2 receptors (P2Rs) signaling using P2R antagonist, suramin, suppressed polyI:C-mediated increases of cilia-driven flow and CBF, indicating that TLR3-mediated ciliary activation depended on released extracellular ATP and the autocrine ATP-P2R loop.ConclusionsIAV infection readily increases ciliary activity and cilia-driven flow via TLR3 activation in the airway epithelium, thereby hastening mucociliary clearance and “sweeping” viruses from the airway as an initial host defense response. Mechanically, extracellular ATP release in response to TLR3 activation promotes ciliary activity through autocrine ATP-P2R loop.

Resumen: Introducción: No se ha aclarado suficientemente el papel de la disfunción diafragmática estimada mediante ecografía como predictora del fracaso de la extubación. Métodos: Realizamos una revisión sistemática y metaanálisis de estudios observacionales que incluyeron pacientes intubados sometidos a ventilación mecánica (VM), a los que se realizó una ecografía diafragmática uni- o bilateral para evaluar la disfunción diafragmática antes de la extubación. Se efectuó una búsqueda en las bases de datos Pubmed y Embase entre el primero de enero de 2010 y el 30 de junio de 2019, utilizando los términos diaphragm ultrasound, diaphragm ultrasonography, weaning y extubation. Definimos fracaso del destete como la necesidad de reintubación y soporte con VMI o fracaso de la prueba de respiración espontánea (PRE). Se utilizaron como medidas ecográficas para predecir el fracaso del destete en pacientes intubados sometidos a VM la excursión diafragmática (ED), la fracción de engrosamiento diafragmático (FEG), el tiempo hasta la amplitud del pico inspiratorio del diafragma (TAPI dia), puntuación de ultrasonido pulmonar modificada (PUPm) y el índice de tiempo de excursión diafragmática (ITED). Secundariamente, evaluamos su utilidad para predecir la muerte por cualquier causa, la duración de la estancia hospitalaria y la necesidad de ventilación no invasiva (VMNI) o de oxigenoterapia de alto flujo tras el destete. Para la agregación de datos se utilizó un modelo de efectos aleatorios, la odds ratio (OR) y sus intervalos de confianza (IC) del 95%. La heterogeneidad de los estudios originales se evaluó mediante el estadístico I2. En todos los análisis, los niveles de significación fueron bilaterales y se consideraron significativos los valores de p

Background: Chronic obstructive pulmonary disease (COPD) is associated with a progressive loss of muscle mass and function and a systemic inflammatory process that can cause sarcopenia. Objective: The objective of this study is to estimate the prevalence rate of sarcopenia in COPD patients and to determine the factors associated with sarcopenic patients living in Western Greece. Methods: European Working Group on Sarcopenia in Older People criteria were applied to 69 outpatients with stable COPD. Body composition, exercise capacity, functional performance, physical activity, and health status were also assessed. COPD disease severity (COPD stage) was evaluated with the Global Initiative for chronic obstructive lung disease. The study protocol was approved by the Ethical Committee of the Technological Educational Institute of Western Greece. Results: The sample comprised 69 patients (59 women and 10 men), with a mean age of 71.33 ± 7.48 years. The prevalence of sarcopenia was 24.6% (n = 17). A high percentage (82.6%; n = 57) of the 69 Greek participants did not perform any regular exercise. The findings of this study demonstrated that sarcopenia was positively associated with COPD, age, body mass index, skeletal muscle mass, hand grip strength, and 4 m test. Conclusions: In conclusion, there is a 24.6% prevalence of sarcopenia in patients with COPD. Further research with larger samples would be indicated to clarify the precise association of specific characteristics of patients with sarcopenia and COPD.

Arianne K Baldomero,1,2 Ken M Kunisaki,1,2 John Connett,3 Aprile Pilon,4 Chris H Wendt1,2 1Pulmonary, Allergy, Critical Care, and Sleep Medicine, Minneapolis VA Health Care System, Minneapolis, MN, USA; 2Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Minnesota, Minneapolis, MN, USA; 3Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA; 4APCBio Innovations, Inc., Rockville, MD, USACorrespondence: Arianne K BaldomeroPulmonary, Allergy, Critical Care, and Sleep Medicine, Minneapolis VA Health Care System, 1 Veterans Drive, Post Code: Pulmonary 111N, Minneapolis, MN, USATel +1920-203-5517Email baldo004@umn.edu

Chad Moretz,1 Beth Hahn,1 John White,2 Alyssa Goolsby Hunter,2 Breanna Essoi,2 Caitlin Elliott,2 Riju Ray3 1US Value Evidence & Outcomes, GlaxoSmithKline, Research Triangle Park, NC, USA; 2Optum, Eden Prairie, MN, USA; 3US Medical Affairs, GlaxoSmithKline, Research Triangle Park, NCCorrespondence: Beth HahnGSK, 5 Moore Drive, Research Triangle Park, Durham, NC, USATel +1 919 274 0660Email beth.a.hahn@gsk.comBackground: Long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) provide greater improvements in lung function and symptoms than inhaled corticosteroid (ICS)/LABA in patients with chronic obstructive pulmonary disease (COPD). This study evaluated symptom burden and Global Initiative for Obstructive Lung Disease (GOLD) categorization among patients who recently initiated umeclidinium/vilanterol (UMEC/VI; LAMA/LABA) or fluticasone propionate/salmeterol (FP/SAL; ICS/LABA) single-inhaler dual therapy.Methods: COPD-diagnosed Medicare Advantage enrollees aged ≥ 65 years were identified from the Optum Research Database (ORD). Eligible patients had ≥ 1 pharmacy claim for UMEC/VI or FP/SAL in the 6-month period before sample identification, with no evidence of triple therapy (ICS/LAMA/LABA), asthma, or lung cancer. Symptom burden was assessed via cross-sectional surveys using the COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) dyspnea scale. Patients were classified into GOLD categories using patient-reported symptoms and claims-based exacerbation history. Treatment groups were balanced on potential confounders using inverse probability of treatment weighting (IPTW). CAT and mMRC scores were analyzed with generalized linear regression models using IPTW propensity scores.Results: The final analytic sample included 789 respondents (UMEC/VI: N=392; FP/SAL: N=397). Approximately 66% patients were classified as GOLD B when assessing symptoms with CAT and mMRC together, or CAT alone; more patients were classified as GOLD A (∼ 40%) than GOLD B (∼ 36%) using mMRC alone. Proportions of patients in each GOLD group were similar between treatment cohorts. Post-IPTW multivariable modeling showed similar symptom burden between treatment groups.Conclusion: After controlling for baseline characteristics, symptom burden was similar between patients receiving UMEC/VI or FP/SAL. GOLD classification using mMRC produced more conservative results compared with CAT, potentially underestimating patient symptoms. Many patients receiving FP/SAL were classified as GOLD A or B, despite GOLD recommending non-ICS-containing therapy in these patients. These findings support the need for routine assessment of symptoms in patients with COPD.Keywords: COPD, fluticasone propionate/salmeterol, umeclidinium/vilanterol, CAT, mMRC, GOLD group

Matthew J Hegewald,1,2 Benjamin D Horne,3,4 Frank Trudo,5 James L Kreindler,5 Yen Chung,5 Susan Rea,6 Denitza P Blagev1,2 1Pulmonary and Critical Care Medicine Division, Intermountain Medical Center, Murray, UT, USA; 2Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA; 3Intermountain Heart Institute at Intermountain Healthcare, Salt Lake City, UT, USA; 4Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; 5Health Economics Outcomes Research, AstraZeneca, Wilmington, DE, USA; 6Enterprise Analytics, Intermountain Healthcare, Salt Lake City, UT, USACorrespondence: Matthew J HegewaldPulmonary and Critical Care Medicine Division, Intermountain Medical Center, 5121 S Cottonwood Street, Murray, UT 84107, USATel +1-801-507-4870Fax +1-801-507-4792Email matt.hegewald@imail.orgPurpose: This retrospective, observational cohort study investigated the association of blood eosinophil counts within 1 week of hospitalization for acute exacerbation of COPD (AECOPD) with subsequent risk of all-cause and COPD-related readmission from a large integrated health system.Patients and Methods: Electronic medical records were extracted for index hospitalization for AECOPD at all Intermountain Healthcare hospitals. The primary outcome was the relationship of blood eosinophil count to 30-day all-cause readmission; secondary outcomes were 60-day, 90-day, and 12-month all-cause readmission, COPD-related readmission, and empiric derivation of the eosinophil count with the highest area under the curve (AUC) for predicting 30-day all-cause readmission.Results: Of 2445 included patients, 1935 (79%) had a blood eosinophil count < 300 cells/μL and 510 (21%) had a count ≥ 300 cells/μL. Using a 300-cells/μL threshold, there was no significant difference between high and low eosinophil groups in 30-day (odds ratio [OR]=1.05, 95% confidence interval [CI]=0.75– 1.47) or 60-day (OR=1.15, 95% CI=0.88– 1.51) all-cause readmissions. However, patients with greater (versus lesser) eosinophil counts had increased 90-day and 12-month all-cause readmissions (OR=1.35, 95% CI=1.06– 1.72, and OR=1.32, 95% CI=1.07– 1.62). COPD-related readmission rates were significantly greater for patients with greater (versus lesser) eosinophil counts at 30, 60, and 90 days and 12 months (OR range=1.52– 1.97). A total of 70 cells/μL had the most discriminatory power to predict 30-day all-cause readmission (highest AUC).Conclusion: Eosinophil counts in patients with COPD were not associated with a difference in 30-day all-cause readmissions. However, greater eosinophil counts were associated with increased risk of all-cause readmission at 90 days and 12 months and COPD-related readmission at 30, 60, and 90 days and 12 months. Patients with eosinophils < 70 cells/μL had the lowest risk for 30-day all-cause readmission. Blood eosinophils in patients hospitalized with AECOPD may be a useful biomarker for the risk of hospital readmission.Keywords: AECOPD, phenotype, biomarkers, eosinophils, electronic medical records

Background Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. The aim of the study was to identify a voltage gated potassium channel involved in dysregulated HPV during endotoxemia. Methods Lungs of male C57BL/6 mice with and without endotoxemia (n = 6 ea. group) were analyzed for Kv3.4 gene and protein expression. HPV was examined in isolated perfused lungs of mice with and without endotoxemia and with and without selective Kv3.4 blocker BDS-I (n = 7 ea. group). Pulmonary artery pressure (PAP) and pressure-flow curves were measured during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation. HPV was quantified as the increase in perfusion pressure in response to hypoxia in percent of baseline perfusion pressure (ΔPAP) in the presence and absence of BDS-I. Results Kv3.4 gene (3.2 ± 0.5-fold, p

Background Adiponectin is a polypeptide hormone related to obesity, and a known modulator of pulmonary vascular remodeling. Association between plasma adiponectin levels and pulmonary hypertension (PH) has not been studied in African Americans (AAs) who are disproportionately affected by obesity. The relationship between adiponectin and heart failure (HF) and mortality, outcomes associated with PH, is unclear. Methods We performed cross-sectional and longitudinal analysis to examine if there is an association between plasma adiponectin and PH and associated clinical outcomes, in participants of Jackson Heart Study (JHS). JHS is a prospective observational cohort study of heart disease in AAs from Jackson, Mississippi. Results Of the 3161 participants included in the study, mean age (SD) was 56.38 (12.61) years, 1028 were men (32.5%), and mean (SD) BMI was 31.42 (7.05) kg/m 2 . Median (IQR) adiponectin was 4516.82 (2799.32–7065.85) ng/mL. After adjusting for potential confounders including BMI, higher adiponectin levels were associated with increased odds of PH (adjusted odds ratio per log increment in adiponectin, (1.81; 95% CI, 1.41–2.32). High adiponectin levels were also associated with associated HF admissions (adjusted hazard ratio [HR] per log increment in adiponectin, 1.63, 95% CI, 1.24–2.14) and mortality (adjusted HR per log increment in adiponectin, 1.20; 95% CI 1.02–1.41). Conclusions Elevated plasma adiponectin levels are associated with PH, HF admissions and mortality risk in AAs. High adiponectin levels may help identify an at-risk population that could be evaluated for targeted prevention and management strategies in future studies

Sara Cazorla-Rivero,1,2 Glorian Mura-Escorche,1,2 Francisca Gonzalvo-Hernández,3 Delia Mayato,1 Elizabeth Córdoba-Lanús,1,2,4,* Ciro Casanova1– 3,* 1Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 2University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain; 3Pulmonary Department, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 4Instituto de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), San Cristóbal de La Laguna, Tenerife, Spain*These authors contributed equally to this workCorrespondence: Elizabeth Córdoba-LanúsUniversity of La Laguna- IUETSPC, Av. Astrofísico Francisco Sanchez. Campus Anchieta, Apartado 456, San Cristobal de la Laguna CP 38200, Tenerife, SpainEmail acordoba@ull.edu.esBackground: COPD is characterized by a persistent inflammatory response, especially against cigarette smoke. COPD patients may develop varying degrees of emphysematous destruction of the lungs. A pathophysiological role for miRNAs in COPD has been suggested in several studies. We examined changes in microRNAs expression profile during 10 years follow-up in relation to COPD progression.Methods: Clinical and lung function parameters were registered from every subject included in the study. miRNAs expression was determined in 14 serum samples from 7 patients in two moments (4 smokers with COPD (BODE cohort) and 3 smokers without COPD) by next generation sequencing (NGS) at baseline and after 10 years follow-up. A validation study was performed by qPCR in 20 patients with COPD (13 emphysema-diagnosed by CTscan) and 10 smoker controls at baseline and after 10 years follow-up. hsa-miRNA-20a-5p and hsa-let-7d-5p were used as endogenous controls.Results: A total of 198 miRNAs (≥ 10TPM) were identified by NGS. Between these, hsa-miR-1246 was found significantly downregulated in COPD patients after 10 years when compared to baseline (p< 0.0001, FDR=0.05). Seventy-five percent of these patients had an emphysema diagnose. In the validation analysis, when analyzed longitudinally, hsa-miR-1246 was significantly downregulated in COPD patients with emphysema after 10 years (p= 0.019). However, no association was found between the expression of miR-1246 and any other lung function parameters (FEV1, PaO2, DLCO, IC/TLC) within the follow-up period. GO and KEGG enrichment analysis revealed miR-1246 to be associated with target genes in several pathways involved in COPD/emphysema development.Conclusion: Our findings suggest that hsa-miR-1246 may act as a biomarker of emphysema in COPD. Functional analysis is guaranteed to elucidate its role in COPD.Keywords: COPD progression, miRNAs, emphysema

Enhanced vasoconstriction is increasingly identified as an important contributor to the development of pulmonary hypertension. Chronic hypoxia results in enhanced Rho kinase mediated Ca 2+ sensitization contributing to pressure-dependent pulmonary arterial tone as well as augmented vasoconstriction to endothelin-1 and depolarizing stimuli. We sought to investigate the interaction between these vasoconstrictor stimuli in isolated, pressurized, pulmonary arteries. We used the K + ionophore, valinomycin, to clamp membrane potential (V m ) to investigate the role of membrane depolarization in endothelin-1 and pressure-dependent constriction, and endothelin-1 receptor inhibitors to determine whether membrane depolarization or stretch signal through endothelin-1 receptors. Clamping V m prevented pressure-dependent tone, but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia. Furthermore, endothelin-1 receptor inhibition had no effect on either pressure-dependent tone or vasoconstriction to KCl. As Src kinases contribute to both pressure-dependent tone and enhanced endothelin-1 vasoconstriction following chronic hypoxia, we further investigated their role in depolarization-induced vasoconstriction. Inhibition of Src kinases attenuated enhanced vasoconstriction to KCl. We conclude that membrane depolarization contributes to pressure-dependent tone but not enhanced vasoconstriction to ET-1, and that Src kinases serve as upstream mediators facilitating enhanced Rho kinase-dependent vasoconstriction following chronic hypoxia.

Resumen: A pesar de la aparición de numerosas revisiones sistemáticas y metaanálisis sobre el uso de la doble terapia broncodilatadora para el tratamiento de la enfermedad pulmonar obstructiva crónica, la eficacia comparada de estas combinaciones entre sí no se ha explorado tan exhaustivamente. En la presente revisión narrativa se revisan los primeros estudios de doble terapia broncodilatadora y se evalúan los estudios que comparan dobles terapias broncodilatadoras en dispositivos por separado y en un único dispositivo. Los primeros ensayos de doble terapia en dispositivos separados se realizaron como una prueba de concepto sobre la función pulmonar con escaso tiempo de seguimiento o un número de pacientes reducido. Estos estudios mostraban mejorías no consistentes en función pulmonar, con escasa repercusión en síntomas u otros resultados clínicos. Los estudios que han comparado de forma directa la combinación de dos broncodilatadores de acción prolongada a dosis fijas en un único dispositivo han explorado principalmente las diferencias entre umeclidinio-vilanterol y diversas asociaciones. Estos trabajos muestran una mayor capacidad broncodilatadora de umeclidinio-vilanterol, con una reducción del uso de medicación de rescate. Por otro lado, no se observan diferencias aparentes en el control sintomático que ofrecen estas combinaciones entre sí y existen dudas sobre su impacto en la prevención de agudizaciones moderadas o graves. En el futuro sería interesante poder disponer de estudios que indiquen el efecto a largo plazo de estas combinaciones en el curso de la enfermedad, así como estudios encaminados a investigar los determinantes de las respuestas a estos fármacos tanto en función pulmonar como en síntomas, calidad de vida y exacerbaciones. Abstract: Despite the publication of numerous systematic reviews and meta-analyses on the use of dual bronchodilator therapy in the treatment of chronic obstructive pulmonary disease, the comparative efficacy of the different combinations has not been explored in depth. In this narrative review, we revisit the initial dual bronchodilator therapy studies and evaluate studies that compare dual bronchodilator therapies administered in separate devices and in a single device. The first trials on dual therapy delivered in separate devices were conducted as proof of concept studies, exploring lung function in limited patient numbers with short follow-up periods. These studies showed inconsistent improvements in lung function with little impact on symptoms or other clinical outcomes. Studies that directly compared fixed doses of long-acting bronchodilators in a single device investigated differences between umeclidinium/vilanterol and other combinations. These studies show increased bronchodilator capacity of umeclidinium/vilanterol with reduced use of rescue medication. However, no apparent differences were observed in the symptomatic control achieved by these different combinations, raising doubts about their impact on prevention in moderate or severe exacerbations. In the future, it would be interesting to see studies that analyze the long-term effect of these combinations on the disease course, as well as studies aimed at investigating the determinants of responses to these drugs in terms of lung function, symptoms, quality of life and exacerbations.

Ling Peng,1,2 Li Han,2 Xiao-Ning Li,2 Ya-Fang Miao,2 Fei Xue,2 Chao Zhou1,3 1School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Department of Respiratory Medicine, Zhoupu Hospital Affiliated to Shanghai University of Medicine and Health Sciences, Shanghai, People’s Republic of China; 3Department of Respiratory Medicine, Guangming Traditional Chinese Medicine Hospital of Pudong New Area, Shanghai, People’s Republic of ChinaCorrespondence: Chao ZhouDepartment of Respiratory Medicine, Guangming Traditional Chinese Medicine Hospital of Pudong New Area, No. 339 DongMen Street. Pudong New District, Shanghai 201399, People’s Republic of ChinaTel +86-21-68019069Email zhou2000sh@163.comBackground: The differential diagnosis of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with acute pulmonary embolism (APE) complications are difficult because of the variability of clinical presentations and the shortage of an unfailing screening biomarkers or instruments.Objective: Aimed to detect and compare the expression of serum microRNAs (miR-1233, miR-134) in AECOPD patients complicated with APE.Patients/Methods: Blood samples were collected from 52 AECOPD patients (13 patients with APE complications, 39 patients without APE) and 10 patients with stable COPD. Serum miRNAs expression was detected with real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The levels of plasma D-dimers were determined by detection with an enzyme-linked immunosorbent assay (ELISA). The receiver-operator characteristic (ROC) curve was used for evaluating the diagnostic accuracy of the studied miRNAs.Results: According to the Wells score, 42 of the 52 AECOPD patients were unlikely to have APE (≤ 4 points), whereas the remaining 10 (> 4 points) were likely to have APE. There were 4 cases (4/13 30.8%) in the AECOPD combined with APE group with a Wells score of > 4 points. The expression levels of miR-1233 and miR-134 in the serum were considerably upregulated in the AECOPD+APE group compared with the AECOPD group and the stable COPD group (P< 0.05). The areas under the curve (AUCs) for miR-134 and miR-1233 were, respectively, 0.931 (95% CI 0.863– 0.999) (P< 0.05) and 0.884 (95% CI 0.79– 0.978) (P< 0.05) and were higher compared with the AUC for D-dimer of 0.628 (95% CI 0.447– 0.809), the AUC for age-adjusted D-dimer of 0.705 (95% CI 0.525– 0.885) and the AUC for Wells score of 0.577 (95% CI 0.389– 0.765).Conclusion: Our study indicated that serum miR-1233 and miR-134 have high clinical value in the early diagnosis of AECOPD patients combined with APE, or could be used as potential biomarkers for clinical identification of AECOPD with or without APE complication.Keywords: acute exacerbation of chronic obstructive pulmonary disease, acute pulmonary embolism, D-dimer, microRNA, biomarker

Background Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. Methods Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. Results Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (2 peak, arterial [HCO3−] at rest, and VE/VCO2 slope. In a subgroup analysis, muscle pain was the limiting symptom in LTx recipients with a lower VO2 peak (E/VCO2 slope (≥ 32). Conclusions The majority of our LTx recipients reported peripheral limitation as the prevalent reason for exercise termination. Muscle pain at peak exercise was strictly associated with basal and exercise-induced metabolic altered pathways. The onset of dyspnea (breathing effort) was associated with the intensity of ventilatory response to meet metabolic demands for increasing WR. Our study suggests that only an accurate assessment of symptoms combined with cardio-pulmonary parameters allows a correct interpretation of exercise limitation and a tailored exercise prescription. The role and mechanisms of muscle pain during exercise in LTx recipients requires further investigations.

Nebulized medications are frequently administered in both acute and chronic conditions-viz., management of acute asthma and COPD exacerbations, home maintenance treatment for chronic respiratory diseases like COPD, bronchiectasis, and cystic fibrosis, etc. However, the viral pandemic of COVID-19 has raised concerns on the use of nebulization. This document is intended to provide guidance to physicians on the role and use of nebulization in the current pandemic, based on current evidence and understanding.

Jing Zhu,1,2,* Zhiling Zhao,3,* Bin Wu,4 Zhihong Shi,5 Qingrong Nie,6 Zhen Fu,7 Zhaofu Zeng,1 Weihua Hu,1 Minglin Dong,1 Mengqing Xiong,1 Ke Hu1 1Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The People’s Hospital of China Three Gorges University, Yichang, Hubei, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Institute of Respiratory Diseases, Department of Respiratory, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, People’s Republic of China; 5Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xian Jiaotong University, Xian, Shanxi, People’s Republic of China; 6Division of Respiratory Disease, Liangxiang Hospital of Yanjing Medical College, Capital Medical University, Beijing, People’s Republic of China; 7Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ke Hu Email huke-rmhospital@163.comObjective: The aim of this study was to explain “obesity paradox” in chronic obstructive pulmonary disease (COPD) by evaluating the effect of body mass index (BMI) on lung function in Chinese patients with COPD.Methods: A total of 1644 patients diagnosed with COPD were recruited from four Chinese tertiary hospitals and were divided into four groups including underweight, normal weight, overweight and obese according to BMI classification standard. The medical data of these patients were collected and used for the multiple linear regression analyses.Results: After adjustment for age, sex, educational level, economic status, smoking status, alcohol consumption, duration of COPD history, events of acute exacerbation in previous year, hypertension, diabetes mellitus, cardiovascular disease, cerebrovascular disease and osteoporosis, BMI had a curvilinear correlation with the forced expiratory volume in the first second (FEV1) in patients with Global Initiative for Obstructive Lung Disease (GOLD) 1– 2 grade (first-order coefficient β, 0.09; 95% CI, 0.03– 0.16; second-order coefficient β, − 0.002; 95% CI, − 0.003–-0.001; P< 0.01). However, BMI had a positive correlation with FEV1 in patients with GOLD 3– 4 grade (β, 0.01; 95% CI, 0.008– 0.017; P< 0.01) when BMI was used as a quantitative variable. When BMI was used as a qualitative variable, only FEV1 in overweight group with GOLD 1– 2 grade was significantly higher than that of normal weight group (P< 0.01). Interestingly, both overweight and obese groups had higher FEV1 in GOLD 3– 4 grade compared with normal weight group (β, 0.06; 95% CI, 0.02– 0.11; β, 0.11; 95% CI, 0.04– 0.18; P< 0.01). The effect of BMI on predicted percentage of FEV1 (FEV1%) was similar to that of FEV1 in different GOLD grades.Conclusion: Obesity only had a protective effect on lung function in COPD patients with GOLD 3– 4 grade rather than GOLD 1– 2 grade.Trial Registry: ClinicalTrials.gov, No.: NCT 03182309, URL: www.clinicaltrials.gov.Keywords: overweight, obesity

Introduction The study aimed to establish and internally validate a nomogram to predict successful smoking cessation in a Chinese outpatient population. Methods A total of 278 participants were included, and data were collected from March 2016 to December 2018. Predictors for successful smoking cessation were evaluated by 3-month sustained abstinence rates. Least absolute shrinkage and selection operator (LASSO) regression was used to select variables for the model to predict successful smoking cessation, and multivariable logistic regression analysis was performed to establish a novel predictive model. The discriminatory ability, calibration, and clinical usefulness of the nomogram were determined by the concordance index (C-index), calibration plot, and decision curve analysis, respectively. Internal validation with bootstrapping was performed. Results The nomogram included living with a smoker or experiencing workplace smoking, number of outpatient department visits, reason for quitting tobacco, and varenicline use. The nomogram demonstrated valuable predictive performance, with a C-index of 0.816 and good calibration. A high C-index of 0.804 was reached with interval validation. Decision curve analysis revealed that the nomogram for predicting successful smoking cessation was clinically significant when intervention was conducted at a successful cessation of smoking possibility threshold of 19%. Conclusions This novel nomogram for successful smoking cessation can be conveniently used to predict successful cessation of smoking in outpatients.

Obstructive sleep apnea (OSA), a breathing disorder featured by chronic intermittent hypoxia (CIH) is associated with pulmonary hypertension (PH). Rodents exposed to CIH develop pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. Overexpression of Stim-activated Transient Receptor Potential Channels (TRPC) and Calcium Release-Activated Calcium Channel Protein (ORAI) TRPC-ORAI Ca 2+ channels (STOC) has been involved in pulmonary vascular remodeling and PH in sustained hypoxia. However, it is not known if CIH may change STOC levels. Accordingly, we studied the effects of CIH on the expression of STOC subunits in the lung and if these changes paralleled the progression of the vascular pulmonary remodeling and PH in a preclinical model of OSA. Male Sprague-Dawley rats (∼200 g) were exposed to CIH (5%O 2 , 12 times/h for 8 h) for 14, 21, and 28 days. We measured right ventricular systolic pressure (RVSP), cardiac morphometry with MRI, pulmonary vascular remodeling, and wire-myographic arterial responses to KCl and endothelin-1 (ET-1). Pulmonary RNA and protein STOC levels of TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2, and STIM1 subunits were measured by qPCR and western blot, and results were compared with age-matched controls. CIH elicited a progressive increase of RVSP and vascular contractile responses to KCl and ET-1, leading to vascular remodeling and augmented right ventricular ejection fraction, which was significant at 28 days of CIH. The levels of TRPC1, TRPC4, TRPC 6, ORAI 1, and STIM 1 channels increased following CIH, and some of them paralleled morphologic and functional changes. Our findings show that CIH increased pulmonary STOC expression, paralleling vascular remodeling and PH.