Abstract P073: Co-morbidities and Cardiac Associated Mortality in Smokers

Circulation ◽  
2017 ◽  
Vol 135 (suppl_1) ◽  
Author(s):  
Gregory L Kinney ◽  
Kendra A Young ◽  
Katherine Pratte ◽  
Elizabeth A Regan ◽  
Lindsey Duca ◽  
...  
Keyword(s):  
Pulmonary Disease ◽  
Latent Class ◽  
Proportional Hazards ◽  
Airway Disease ◽  
Cox Proportional Hazards ◽  
Chronic Obstructive ◽  
Longitudinal Assessment ◽  
Vascular Effects ◽  
Obstructive Pulmonary Disease ◽  
Cvd Mortality

Background: Chronic Obstructive Pulmonary Disease (COPD) is a complex syndrome involving all aspects of the lungs which is strongly associated with cigarette smoking. Parenchymal destruction and remodeling are disease processes involving inflammatory pathways likely to have systemic vascular effects outside of the lungs. Indeed cardiovascular disease (CVD) is a leading cause of mortality in people affected by COPD and many co-morbid conditions are also associated with the disease. We explored CVD mortality in smokers considering aspects of COPD as well as co-morbidities in the longitudinal follow-up of the COPDGene study. Methods: The COPDGene study includes baseline and longitudinal assessment of mortality for 8,157 participants with (3,604) and without COPD (4,553) all of whom reported >10 pack-years smoking exposure. Aspects of COPD including CT phenotyping and pulmonary function were combined using Principal Components Analysis (PCA), co-morbidities were combined using Latent Class Analysis (LCA) and cause specific mortality was assessed using study center reports, SSRI searches and single clinician adjudication. Cox Proportional Hazards models accounting for the effects of competing risks were used to assess the association between PCA factors and CVD mortality and PCA factors plus LCA classes and CVD mortality. Results: PCA analysis resulted in 5 factors describing emphysema, airway disease, gas trapping, BMI and its effect on CT measurement and hyperinflation and LCA analysis identified 7 classes of co-morbidities. CVD associated mortality occurred in 128 participants and competing causes of mortality occurred in 605. The PCA factor describing airway disease predicted CVD mortality in the PCA only model (HR 1.8, 95%C.I. 1.4-2.3,p<0.0001), as well as in the LCA model (HR 1.7, 95% C.I. 1.3-2.2, p<0.0001). LCA classes associated with CVD mortality include a class describing diabetes, high BP and high Cholesterol (HR 3.5, 95% C.I. 1.8-6.8, p=0.0003) and a class describing known CVD (HR 2.9, 95% C.I. 1.3-6.7, p=0.01). Conclusions: Co-morbidities of COPD represent independent predictors of CVD associated mortality in smokers accounting for pulmonary disease and competing mortality risks. Clustering of comorbidities using LCA is an approach that may be informative in complex diseases.

Glucosamine use, smoking and risk of incident chronic obstructive pulmonary disease: A large prospective cohort study

2021 ◽  
pp. 1-35
Author(s):  
Xi-Ru Zhang ◽  
Pei-Dong Zhang ◽  
Zhi-Hao Li ◽  
Pei Yang ◽  
Xiao-Meng Wang ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Proportional Hazards ◽  
Smoking Status ◽  
Cox Proportional Hazards ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Cox Proportional Hazards Models ◽  
Large Prospective Cohort Study ◽  
The Uk

Abstract Chronic inflammation exerts pleiotropic effects in the etiology and progression of chronic obstructive pulmonary disease (COPD). Glucosamine is widely used in many countries and may have anti-inflammatory properties. We aimed to prospectively evaluate the association of regular glucosamine use with incident COPD risk and explore whether such association could be modified by smoking in the UK Biobank cohort, which recruited more than half a million participants aged 40–69 years from across the UK between 2006 and 2010. Cox proportional hazards models with adjustment for potential confounding factors were used to calculate hazard ratios (HRs) as well as 95% confidence intervals (95% CIs) for the risk of incident COPD. During a median follow-up of 8.96 years (interquartile range 8.29 to 9.53 years), 9016 new-onset events of COPD were documented. We found that regular use of glucosamine was associated with a significantly lower risk of incident COPD with multivariable adjusted HR of 0.80 (95% CI, 0.75 to 0.85; P<0.001). When subgroup analyses were performed by smoking status, the adjusted HRs for the association of regular glucosamine use with incident COPD were 0.84 (0.73 to 0.96), 0.84 (0.77 to 0.92), and 0.71 (0.62 to 0.80) among never smokers, former smokers and current smokers, respectively. No significant interaction was observed between glucosamine use and smoking status (P for interaction=0.078). Incident COPD could be reduced by 14% to 84% through a combination of regular glucosamine use and smoking cessation

scholarly journals Impact of Pseudomonas aeruginosa Isolation on Mortality and Outcomes in an Outpatient Chronic Obstructive Pulmonary Disease Cohort

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
David M Jacobs ◽  
Heather M Ochs-Balcom ◽  
Katia Noyes ◽  
Jiwei Zhao ◽  
Wai Yin Leung ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pseudomonas Aeruginosa ◽  
Pulmonary Disease ◽  
Proportional Hazards ◽  
Outpatient Setting ◽  
Cox Proportional Hazards ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Hospitalization Rates ◽  
Cox Proportional Hazards Models

Abstract Background Tracheobronchial colonization by Pseudomonas aeruginosa (PA) has been shown to negatively impact outcomes in cystic fibrosis and bronchiectasis. There is uncertainty whether the same association is prevalent in chronic obstructive pulmonary disease (COPD), especially in the outpatient setting. Our objective was to determine (1) whether PA isolation is associated with mortality and (2) changes in exacerbation and hospitalization rates within a longitudinal cohort of COPD outpatients. Methods Pseudomonas aeruginosa colonization was ascertained in monthly sputum cultures in a prospective cohort of COPD patients from 1994 to 2014. All-cause mortality was compared between patients who were colonized during their follow-up period (PA+) and those who remained free of colonization (PA−); Cox proportional hazards models were used. Exacerbation and hospitalization rates were evaluated by 2-rate χ 2 and segmented regression analysis for 12 months before and 24 months after PA isolation. Results Pseudomonas aeruginosa was isolated from sputum in 73 of 181 (40%) patients. Increased mortality was seen with PA isolation: 56 of 73 (77%) PA+ patients died compared with 73 of 108 (68%) PA− patients (P = .004). In adjusted models, PA+ patients had a 47% higher risk of mortality (adjusted hazard ratio = 1.47; 95% confidence interval, 1.03–2.11; P = .04). Exacerbation rates were higher for the PA+ group during preisolation (15.4 vs 9.0 per 100 person-months, P &lt; .001) and postisolation periods (15.7 vs 7.5, P &lt; .001). Hospitalization rates were higher during the postisolation period among PA+ patients (6.25 vs 2.44, P &lt; .001). Conclusions Tracheobronchial colonization by PA in COPD outpatients was associated with higher morbidity and mortality. This suggests that PA likely contributes to adverse clinical outcomes rather than just a marker of worsening disease.

scholarly journals Investigation of the Obesity Paradox in Chronic Obstructive Pulmonary Disease, According to Smoking Status, in the United States

2019 ◽  
Vol 188 (11) ◽  
pp. 1977-1983 ◽  
Author(s):  
Tianshi David Wu ◽  
Chinedu O Ejike ◽  
Robert A Wise ◽  
Meredith C McCormack ◽  
Emily P Brigham
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Proportional Hazards ◽  
Smoking Status ◽  
Obesity Paradox ◽  
The United States ◽  
Cox Proportional Hazards ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Never Smokers

Abstract An obesity paradox in chronic obstructive pulmonary disease (COPD), whereby overweight/obese individuals have improved survival, has been well-described. These studies have generally included smokers. It is unknown whether the paradox exists in individuals with COPD arising from factors other than smoking. Nonsmoking COPD is understudied yet represents some 25%–45% of the disease worldwide. To determine whether the obesity paradox differs between ever- and never-smokers with COPD, 1,723 adult participants with this condition were examined from 2 iterations of the National Health and Nutrition Examination Survey (1988–1994, 2007–2010), with mortality outcomes followed through December 2011. Using Cox proportional hazards models, adjusted for sociodemographic factors, lung function, and survey cycle, ever/never-smoking was found to modify the association between body mass index and hazard of death. Compared with normal-weight participants, overweight/obese participants had lower hazard of death among ever-smokers (for overweight, adjusted hazard ratio (aHR) = 0.56, 95% confidence interval (CI): 0.43, 0.74; for obesity, aHR = 0.66, 95% CI: 0.48, 0.92), but never-smokers did not (overweight, aHR = 1.41, 95% CI: 0.66, 3.03; obesity, aHR = 1.29, 95% CI: 0.48, 3.48). An obesity paradox appeared to be absent among never-smokers with COPD. This, to our knowledge, novel finding might be explained by pathophysiological differences between smoking-related and nonsmoking COPD or by smoking-associated methodological biases.

scholarly journals Predictors of hospitalizations for heart failure decompensation in patients with comorbid occupational chronic obstructive pulmonary disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L.A Shpagina ◽  
O.S Kotova ◽  
I.S Shpagin ◽  
G.V Kuznetsova ◽  
N.V Kamneva ◽  
...  
Keyword(s):  
Heart Failure ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Chronic Obstructive ◽  
Length Of Service ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Patients With Heart Failure ◽  
Occupational Copd ◽  
Heart Failure Decompensation

Abstract Background Heart failure decompensation requiring hospitalization is an important event, associated with mortality and investigating its predictors is topical problem. Chronic obstructive pulmonary disease (COPD) is a common comorbidity for heart failure. Both conditions share common molecular mechanisms such as systemic inflammation. COPD is heterogeneous and subpopulations with different inflammation patterns may interact with heart failure in different manner. Airway inflammation in occupational COPD may differs from COPD in tobacco smokers. Additionally cardiotoxicity of industrial chemicals influence heart failure features. Despite this biological plausibility, heart failure and occupational COPD comorbidity is not studied enough. Purpose To reveal predictors of hospitalizations for heart failure decompensation in patients with heart failure and occupational COPD comorbidity. Methods Occupational COPD patients (n=115) were investigated in a prospective cohort observational study. Comparison group – 115 tobacco smokers with COPD. Control group – 115 healthy persons. Controls were selected by propensity score matching, covariates were COPD duration, age and gender. Then COPD groups were stratified according to heart failure. Working conditions, echocardiography, spirometry, pulsoxymetry, 6-mitute walking test were done. Molecular markers of tissue damage – chemokine ligand 18 (CCL 18), lactate dehydrogenase, cardiac troponin T, N-terminal pro-B-type natriuretic peptide (NT pro-BNP), protein S100 beta, von Willebrand factor were measured in serum by ELISA. Follow up after initial assessment was 12 month. Predictors were determined by Cox proportional hazards regression with ROC analysis. Results Heart failure rate in occupational COPD patients were higher – 54.8% versus 36.5% in tobacco smokers with COPD, p&lt;0.05. Heart failure with preserved ejection fraction was predominant – 40.9%. Prevalence of biventricular heart failure was 38.3%, isolated right heart failure – 13%, left heart failure – 2.6%. Cumulative hospitalization rate in occupational COPD with heart failure group was higher than in comparison group, 17.5% and 9.5% respectively, p=0.01. In Cox proportional hazards regression model predictors of hospitalizations for heart failure decompensation during 12 months in this group were length of service (HR 1.22, 95% CI: 1.03–2.5), aromatic hydrocarbons concentration at workplaces air (HR 1.4, 95% CI: 1.15–1.96), serum protein S100 beta (HR 1.10, 95% CI: 1.02–1.87), SaO2 (HR 1.2, 95% CI: 1.06–2.13). Area under the ROC curve was 0.82. Conclusion Length of service, aromatic hydrocarbons concentration at workplaces air, serum protein S100 beta, SaO2 are considered to be independent risk factors of heart failure decompensation required hospitalization in patients with heart failure and occupational COPD comorbidity. Funding Acknowledgement Type of funding source: None

The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation: Literature review

2021 ◽  
Vol 2 (6) ◽  
Author(s):  
Rodríguez Miguel ◽  
◽  
Chinta Siddharth ◽  
Vittorio Timothy ◽  
◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Airway Disease ◽  
The Other ◽  
Beta Agonist ◽  
Beta Blockade ◽  
Chronic Obstructive ◽  
Agonist Therapy ◽  
Obstructive Pulmonary Disease

Background: New advances have been made in medicine, but the incidence and prevalence of Chronic Obstructive Pulmonary Disease (COPD) are evident, and it is established as the fourth cause of death in the United States representing a high cost for the healthcare system. This condition has been related to atrial fibrillation due to the changes in the lungs and vasculature. Based on this history, we seek to evaluate the outcome of AF in the patients with COPD and its relationship with medical therapy utilized to treat this pulmonary condition with the objective of establishing the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with AF. Discussion: Cell receptors participate in multiple reactions and the sympathetic response is received via the alpha- and beta-receptors are related to the hemodynamic of the vasculature of the lungs and cardiovascular system. The beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but the side effect could be COPD exacerbation; on the other hand, beta-adrenergic or beta-agonist as a therapy for this pulmonary condition could increase the heart rate leading to AF decompensation. There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. The clear benefit in morbidity and mortality of beta-blocker therapy, especially beta1-selective, outweighs the potential for any pulmonary side-effects related to ex-acerbation of COPD or airway disease. Conclusion: There is clear data showing the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, benefits versus risks should be discussed and the medical decision should be made based on them. The deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease. In other words, the benefit should outweigh the risk based on the best outcome for the patient. Keywords: atrial fibrillation; pulmonary disease; obstructive pulmonary disease; chronic obstructive pulmonary disease (COPD); B-Agonist; B-Block (selective; non-selective); digitalis; other antiarrhythmic.

P1666Do beta-blockers increase the risk for hospitalizations in heart failure with preserved ejection fraction? A secondary analysis of beta-blocker use in the TOPCAT trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
D N Silverman ◽  
T B Plante ◽  
M I Infeld ◽  
S P Juraschek ◽  
G Dougherty ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Beta Blocker ◽  
Proportional Hazards ◽  
Beta Blockers ◽  
Secondary Analysis ◽  
Cox Proportional Hazards ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Reduced Ejection Fraction

Abstract Background The use of beta-blockers for treatment of heart failure (HF) with a reduced ejection fraction (EF) is unequivocally beneficial, but their role in the treatment of preserved EF (HFpEF) remains unclear. Purpose In a contemporary HFpEF cohort, we sought to assess the association of HF hospitalizations and the use of beta-blockers in patients with an EF above and below 50%. Methods The TOPCAT trial tested spironolactone vs. placebo among patients with HFpEF, including some with mild reductions in EF between 45–50%. The primary outcome was a composite of cardiovascular (CV) mortality, aborted cardiac arrest, or HF hospitalizations. Medication use, including beta-blockers, was reported at each visit and hospitalization. In the 1,761 participants from the Americas, we compared the association of beta-blocker use (vs. no use) and HF hospitalization or CV mortality using Cox proportional hazards models adjusted for baseline demographics, history of myocardial infarction, atrial fibrillation, chronic obstructive pulmonary disease, asthma, and hypertension. The analyses were repeated in the EF strata ≥50% and <50%. Results Among patients included in the current analysis (mean age 72 years, 50% female, 78% white), 1,496/1,761 (85%) received beta-blockers and 1,566/1,761 (89%) had an EF ≥50%. HF hospitalizations and CV mortality occurred in 399/1,761 (23%) and 223/1,761 (13%) of participants, respectively. Beta-blocker use was associated with an increase in risk of HF hospitalization among patients with preserved EF ≥50% [HR 1.56, (95% CI 1.09–2.24), p=0.01] and was associated with a reduction in risk of hospitalization in patients with an EF <50% [HR 0.42, (95% CI 0.18- 0.99), p<0.05]. We found a significant interaction for EF threshold and beta-blocker use on incident HF hospitalizations (p=0.01). There were no differences in CV mortality. Figure 1. Kaplan Meier incidence plots Conclusions Beta-blocker use was associated with an increase in HF hospitalizations in patients with HFpEF (EF≥50%) but did not affect CV mortality. Further research is needed to confirm these findings and elucidate causality.

scholarly journals Prevalence of asthma chronic obstructive pulmonary disease overlap in patients attending a tertiary health care centre

2021 ◽  
Vol 8 (8) ◽  
pp. 1154
Author(s):  
Suresh Chandravanshi ◽  
Mahesh Kumar Sharma ◽  
D. P. Lakra ◽  
Manisha Khande ◽  
R. K. Panda
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Asthma Management ◽  
Airway Disease ◽  
Chronic Obstructive ◽  
Health Care Centre ◽  
Cross Sectional ◽  
Obstructive Pulmonary Disease ◽  
Chronic Airway Disease ◽  
Chronic Airway

Background: The study aimed to assess the magnitude of asthma chronic obstructive pulmonary disease asthma chronic obstructive (ACO) in patients with chronic airway disease.Methods: The study was conducted as cross-sectional study on patients with chronic airway disease presenting at our institute during the study period of 1 year. Global initiative for asthma management and prevention (GINA) syndromic approach table was used to diagnose patients with chronic airways disease. Syndromic and confirmatory diagnosis of ACO was made based upon clinical features and spirometry respectively.Results: About 73.6% were diagnosed as chronic obstructive pulmonary disease (COPD) and 26.4% cases were diagnosed as asthma. Overall ACO was present in 20% cases. ACO was significantly associated with advancing age, male gender, and longer duration of smoking (p<0.05) in asthma patients whereas in COPD patients ACO was associated with advancing age (p<0.05).Conclusions: Overall one fifth of the patients with chronic airway disease have asthma COPD overlap. The ACO is observed in almost equal proportions in asthma and COPD. ACO prevalence was found to increase with age in patients with asthma and COPD.

scholarly journals Intracellular Secretory Leukoprotease Inhibitor Modulates Inositol 1,4,5-Triphosphate Generation and Exerts an Anti-Inflammatory Effect on Neutrophils of Individuals with Cystic Fibrosis and Chronic Obstructive Pulmonary Disease

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Emer P. Reeves ◽  
Nessa Banville ◽  
Dorothy M. Ryan ◽  
Niamh O’Reilly ◽  
David A. Bergin ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cystic Fibrosis ◽  
Pulmonary Disease ◽  
Proteolytic Enzymes ◽  
Airway Disease ◽  
Cytosolic Calcium ◽  
Neutrophil Function ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Anti Inflammatory

Secretory leukoprotease inhibitor (SLPI) is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca2+) levels which is mediated by production of inositol 1,4,5-triphosphate (IP3) in response to G-protein-coupled receptor (GPCR) stimuli. The aim of this study was to investigate the intracellular function of SLPI and the mechanism-based modulation of neutrophil function by this antiprotease. Neutrophils were isolated from healthy controls (n=10), individuals with cystic fibrosis (CF) (n=5) or chronic obstructive pulmonary disease (COPD) (n=5). Recombinant human SLPI significantly inhibited fMet-Leu-Phe (fMLP) and interleukin(IL)-8 induced neutrophil chemotaxis (P<0.05) and decreased degranulation of matrix metalloprotease-9 (MMP-9), hCAP-18, and myeloperoxidase (MPO) (P<0.05). The mechanism of inhibition involved modulation of cytosolic IP3production and downstream Ca2+flux. The described attenuation of Ca2+flux was overcome by inclusion of exogenous IP3in electropermeabilized cells. Inhibition of IP3generation and Ca2+flux by SLPI may represent a novel anti-inflammatory mechanism, thus strengthening the attractiveness of SLPI as a potential therapeutic molecule in inflammatory airway disease associated with excessive neutrophil influx including CF, non-CF bronchiectasis, and COPD.

scholarly journals The boundaries of mild chronic obstructive pulmonary disease (COPD): design of the searching clinical COPD onset (SOON) study

BMJ Open ◽  
2017 ◽  
Vol 7 (8) ◽  
pp. e015731 ◽  
Author(s):  
Gonzalo Labarca ◽  
Andrea Bustamante ◽  
Gonzalo Valdivia ◽  
Rodrigo Díaz ◽  
Álvaro Huete ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Physical Activity ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Airway Disease ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Peripheral Muscle ◽  
Early Grade

IntroductionClinical onset of chronic obstructive pulmonary disease (COPD) is the point at which the disease is first identifiable by physicians. It is a poorly defined stage which seems to include both mild spirometric and non-spirometric disease, and could be described as early grade COPD, for practical purposes. While dyspnoea; chronic bronchitis and CT imaging evidence of emphysema and airway disease may be present very early, the lone significance of dyspnoea, the most relevant symptom in COPD in identifying these individuals, has been scarcely assessed.The Searching Clinical COPD Onset (SOON) Study was designed primarily to detect clinical, physiological and structural differences between dyspnoeic and non-dyspnoeic individuals with early grade COPD. It is hypothesised that presence of dyspnoea in early disease may identify a subtype of individuals with reduced exercise capacity, notwithstanding of their spirometry results. In addition, dyspnoeic individuals will share worse quality of life, lower physical activity, greater lung hyperinflation greater emphysema and airway thickness and reduced peripheral muscle mass than their non-dyspnoeic counterpart.Methods and analysisSOON is a monocentric study, with a cross sectional design aimed at obtaining representative samples of current or ex-smoker-adults aged ≥45 and ≤80 years. Two hundred and forty participants will be enrolled into four strata, according to normal spirometry or mild spirometric obstruction and presence or not of dyspnoea modified Medical Research Council score ≥1. The primary outcome will be the difference between dyspnoeic and non-dyspnoeic individuals on the 6-min walk test performance, regardless of their spirometry results. To account for the confounding effect of heart failure on dyspnoea, stress echocardiography will be also performed. Secondary outcomes will include clinical (quality of life, physical activity), physiological (exercise testing) and structural characteristics (emphysema, airway disease and peripheral muscle mass by CT imaging).Ethics and disseminationThe Institutional Ethics Committee from Pontificia Universidad Católica de Chile has approved the study protocol and signed informed consent will be obtained from all participants. The findings of the trial will be disseminated through relevant peer-reviewed journals and international conference presentations.Trial registration numberNCT03026439.

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