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1.
Artigo em Inglês | MEDLINE | ID: mdl-33829714

RESUMO

Introduction: Age and vitamin D levels may affect symptom burden in chronic obstructive pulmonary disease (COPD). We used the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) to determine independent associations between vitamin D levels and COPD symptoms in different age strata. Methods: Serum 25-hydroxy(OH)-vitamin D levels were modeled continuously and categorically (<20 ng/ml vs. ≥20 ng/ml). Stratifying by age group (middle-age: 40-64 years old and older: >65 years old), multivariable modeling was performed to identify relationships between 25-OH-vitamin D levels and COPD Assessment Test (CAT), modified Medical Research Council score (mMRC), St. George Respiratory Questionnaire (SGRQ) total and subdomain scores, Veterans' Specific Activity Questionnaire, and six-minute walk test distance. Results: In the middle-aged group, each 5 ng/ml higher 25-OH-vitamin D level was independently associated with more favorable CAT score [-0.35 (-0.67 to -0.03), P=0.03], total SGRQ [-0.91 (-1.65 to -0.17); P=0.02], and the SGRQ subdomains [Symptoms:-1.07 (-1.96 to -0.18), P=0.02; Impact: -0.77 (-1.53 to -0.003), P=0.049; Activity: -1.07 (-1.96 to -0.18), P=0.02]. These associations persisted after addition of comorbidity score, reported vitamin D supplementation, outdoor time, or season of blood draw to models. No associations were observed between 25-OH-vitamin D levels and symptom scores in the older age group. Discussion: When controlled for clinically relevant covariates, higher 25-OH-vitamin D levels are associated with more favorable respiratory-specific symptoms and quality-of-life assessments in middle-age but not older COPD individuals. Study of the role of vitamin D supplementation in the symptom burden of younger COPD patients is needed.

2.
Sci Rep ; 11(1): 4916, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649381

RESUMO

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.

3.
PLoS One ; 16(3): e0245478, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33730034

RESUMO

BACKGROUND: The purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms. METHODS: Subjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom burden, and functional status were administered at annual clinic visits for over a 3 year period. In both cross-sectional and longitudinal analyses, we examined the association of social support as measured by the FACIT-F with COPD outcomes. Cross sectional analyses used multivariable linear or logistic regression, adjusting for covariates. For longitudinal analyses, generalized linear mixed models with random intercepts were used. Models were adjusted with and without depressive symptoms and mediation analyses performed. RESULTS: Of the 1831 subjects with COPD, 1779 completed the FACIT- F questionnaire. In adjusted cross-sectional analysis without depressive symptoms, higher perceived social support was associated with better quality of life, well-being, 6 minute walk distance, and less dyspnea. When also adjusting for depressive symptoms, all associations between social support and COPD outcomes were attenuated and no longer statistically significant. Mediation analysis suggested that depressive symptoms explained the majority (> = 85%) of the association between social support and measured COPD outcomes. Results of the longitudinal analysis were consistent with the cross-sectional analyses. There was no association between social support and odds of exacerbations. CONCLUSION: Higher social support was associated with better COPD outcomes across several measures of morbidity including quality of life, respiratory symptoms, and functional status. In addition, these associations were largely attenuated when accounting for depressive symptoms suggesting that the beneficial association of social support with COPD outcomes may be largely mediated by the association between social support and depression. TRIAL REGISTRATION: SPIROMICS was approved by Institutional Review Boards at each center and all participants provided written informed consent (clinicaltrials.gov: NCT01969344).

4.
NPJ Biofilms Microbiomes ; 7(1): 14, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547327

RESUMO

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25-75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.

5.
Ann Am Thorac Soc ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33631079

RESUMO

RATIONALE: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease that have minimal or no airflow obstruction. OBJECTIVES: Develop a multi-dimensional definition of a lung-related "resilient smoker" that is useful in research studies; then identify a resilient smoker subgroup in the SPIROMICS cohort using this definition. METHODS: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ≥80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD. RESULTS: Consensus was achieved on 6 of 12 diagnostic items which include: cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in FEV1. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of C-reactive protein (CRP) and soluble tumor necrosis receptor factor1A (sTNFRSF1A) was lower in resilient than non-resilient smokers (P=0.02 and P=0.03). CONCLUSIONS: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "non-resilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from non-resilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).

6.
Chest ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33539837

RESUMO

BACKGROUND: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV1 to FVC. RESEARCH QUESTION: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease? STUDY DESIGN AND METHODS: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV1 to FVC ratio of ≥ 0.7 and FEV1 % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV1 to FVC ratio, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV1 to SVC ratio of ≥ 0.7 and 120 with postbronchodilator FEV1 to SVC ratio of < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV1 to SVC ratio of < 0.7 with those characteristics and outcomes. RESULTS: Participants with FEV1 to SVC ratio of < 0.7 were older and had lower FEV1 and more emphysema than those with FEV1 to SVC ratio of ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV1 to SVC ratio of < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV1 to SVC ratio of ≥ 0.7. During a median follow-up time of 1,500 days, an FEV1 to SVC ratio of < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV1 to SVC ratio of < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV1 to SVC ratio of < 0.7 or FEV1 to SVC ratio of less than the lower limit of normal with chest CT scan features and progression to COPD. INTERPRETATION: Low FEV1 to SVC ratio in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.

7.
Eur J Med Chem ; : 112914, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33268145

RESUMO

Previous investigation of the potent antileishmanial properties of antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines with biaryl side chains led to our development of a new clinical candidate for visceral leishmaniasis (DNDI-0690). Within a collaborative backup program, a racemic monoaryl lead (3) possessing comparable activity in mice but a greater hERG liability formed the starting point for our pursuit of efficacious second generation analogues having good solubility and safety. Asymmetric synthesis and appraisal of its enantiomers first established that chiral preferences for in vivo efficacy were species dependent and that neither form afforded a reduced hERG risk. However, in line with our findings in a structurally related series, less lipophilic heteroaryl ethers provided significant solubility enhancements (up to 16-fold) and concomitantly attenuated hERG inhibition. One promising pyridine derivative (49) displayed 100% oral bioavailability in mice and delivered a 96% parasite burden reduction when dosed at 50 mg/kg in a Leishmania donovani mouse model of visceral leishmaniasis.

8.
Sci Rep ; 10(1): 20133, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208859

RESUMO

COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells/mm basement membrane. GCD was divided into tertiles based on log10 transformed values. Log10GCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log10 GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high log10GCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33180550

RESUMO

BACKGROUND: The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain. METHODS: We analyzed computed tomography (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images and imaging software automatically quantified percent emphysema. Unadjusted and adjusted relationships between mucus plug score, percent emphysema, and lung function were determined using regression. RESULTS: Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema and subgroups could be identified with mucus dominant and emphysema dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and percent emphysema were independently associated with lower values for forced expiratory volume in one second and peripheral oxygen saturation (p values < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema (p values <0.001). Compared to smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute walk distance (329 ± 115 vs. 392 ± 117 meters)(p values < 0.001). CONCLUSION: Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting mucus-high/emphysema-low COPD patients in clinical trials of muco-active treatments.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33007162

RESUMO

RATIONALE: Black adults have worse health outcomes compared to white adults in certain chronic diseases, including Chronic Obstructive Pulmonary Disease (COPD). It is unclear if, and to what degree, disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes. METHODS: Individual and neighborhood-scale sociodemographic characteristics were determined in 2649 current or former adult smokers, with and without COPD, at recruitment into the SPIROMICS study. We assessed whether racial differences in symptom, functional and imaging outcomes (St. George's Respiratory Questionnaire [SGRQ], COPD Assessment Test [CAT] score; modified Medical Research Council [mMRC] dyspnea scale; six-minute walk test distance [6MWD], CT scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed models regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES, both separately and sequentially. RESULTS: After adjusting for COPD risk factors, black participants had significantly worse respiratory symptoms and quality of life (mMRC, CAT and SGRQ), higher risk of severe exacerbations and higher percent emphysema, thicker airways (Pi10), and more air trapping on CT metrics compared to whites. Additionally, the association between black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12% to 35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26% to 54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping and airway wall thickness). CONCLUSIONS: Disadvantages by individual and neighborhood-level SES each partly explain disparities in respiratory outcomes between black individuals and whites. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.

11.
Bioorg Med Chem ; 28(22): 115784, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-33007562

RESUMO

A series of 5,8-disubstituted tetrahydroisoquinolines were shown to be effective inhibitors of M. tb in culture and modest inhibitors of M. tb ATP synthase. There was a broad general trend of improved potency with higher lipophilicity. Large substituents (e.g., Bn) at the tetrahydroquinoline 5-position were well-tolerated, while N-methylpiperazine was the preferred 8-substituent. Structure-activity relationships for 7-linked side chains showed that the nature of the 7-linking group was important; -CO- and -COCH2- linkers were less effective than -CH2- or -CONH- ones. This suggests that the positioning of a terminal aromatic ring is important for target binding. Selected compounds showed much faster rates of microsomal clearance than did the clinical ATP synthase inhibitor bedaquiline, and modest inhibition of mycobacterial ATP synthase.

12.
Indoor Air ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037695

RESUMO

Increased outdoor concentrations of fine particulate matter (PM2.5 ) and oxides of nitrogen (NO2 , NOx ) are associated with respiratory and cardiovascular morbidity in adults and children. However, people spend most of their time indoors and this is particularly true for individuals with chronic obstructive pulmonary disease (COPD). Both outdoor and indoor air pollution may accelerate lung function loss in individuals with COPD, but it is not feasible to measure indoor pollutant concentrations in all participants in large cohort studies. We aimed to understand indoor exposures in a cohort of adults (SPIROMICS Air, the SubPopulations and Intermediate Outcome Measures in COPD Study, Air pollution). We developed models for the entire cohort based on monitoring in a subset of homes, to predict mean 2-week measured concentrations of PM2.5 , NO2 , NOx , and nicotine, using home and behavioral questionnaire responses available in the full cohort. Models incorporating socioeconomic, meteorological, behavioral and residential information together explained about 60% of the variation in indoor concentration of each pollutant. Cross validated R2 for best indoor prediction models ranged from 0.43 (NOx ) to 0.51 (NO2 ). Models based on questionnaire responses and estimated outdoor concentrations successfully explained most variation in indoor PM2.5 , NOx , NO2 , and nicotine concentrations.

13.
Int J Chron Obstruct Pulmon Dis ; 15: 2005-2013, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061338

RESUMO

Background: COPD exacerbations occur more frequently with disease progression and are associated with worse prognosis and higher healthcare expenditure. Purpose: To utilize a networked system, optimized with statistical process control (SPC), for remote patient monitoring (RPM) and to identify potential predictors of COPD exacerbations. Methods: Seventeen subjects, mean (SD) age of 69.7 (7.2) years, with moderate to severe COPD received RPM. Over 2618 patient-days (7.17 patient-years) of monitoring, we obtained daily symptom scores, treatment adherence, self-reported activity levels, daily spirometry (SVC, FEV1, FVC, PEF), inspiratory capacity (IC), and oxygenation (SpO2). These data were used to identify predictors of exacerbations defined using Anthonisen and other criteria. Results: After implementation of SPC, concordance analysis showed substantial agreement between FVC (decrease below the 7-day rolling average minus 1.645 SD) and self-reported healthcare utilization events (κ=0.747, P<0.001) as well as between increased use of inhaled short-acting bronchodilators and exacerbations defined by two Anthonisen criteria (κ=0.611, P<0.001) or modified Anthonisen criteria (κ=0.622, P<0.001). There was a moderate agreement between FEV1 (decrease >1.645 SD below the 7-day rolling average) and self-reported healthcare utilization events (κ=0.475, P<0.001) and between SpO2 less than 90% and exacerbations defined by two Anthonisen criteria (κ=0.474, P<0.001) or modified Anthonisen criteria (κ=0.564, P<0.001). Conclusion: Exacerbations were best predicted by FVC and FEV1 below the one-sided 95% confidence interval derived from SPC but also by increased use of inhaled short-acting bronchodilators and fall in oxygen saturation. An RPM program that captures these parameters may be used to guide appropriate interventions aimed at reducing healthcare utilization in COPD patients.

14.
Int J Chron Obstruct Pulmon Dis ; 15: 2467-2476, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116463

RESUMO

Background: Chronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions. Methods: We identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status. Results: In a population of 1431 participants (57% male; mean FEV1% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status. Conclusion: Items from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.

15.
Chronic Obstr Pulm Dis ; 7(4): 370-381, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33108110

RESUMO

Ratrionale: The antimicrobial peptide cathelicidin, also known in humans as LL-37, is a defensin secreted by immune and airway epithelial cells. Deficiencies in this peptide may contribute to adverse pulmonary outcomes in chronic obstructive pulmonary disease (COPD). Objectives: Using clinical and biological samples from the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we assessed the associations of plasma cathelicidin levels with cross-sectional and longitudinal COPD outcomes. Methods: A total of 1609 SPIROMICS participants with COPD and available plasma samples were analyzed. Cathelicidin was modeled dichotomously (lowest quartile [< 50 ng/ml] versus highest 75% [≥ 50 ng/ml]) and continuously per 10 ng/ml. Fixed-effect multilevel regression analyses were used to assess associations between cathelicidin and cross-sectional as well as longitudinal lung function. The associations between cathelicidin and participant-reported retrospective and prospective COPD exacerbations were assessed via logistic regression. Measurements and Main Results: Cathelicidin < 50 ng/ml (N=383) was associated with female sex, black race, and lower body mass index (BMI).At baseline,cathelicidin < 50 ng/ml was independently associated with 3.55% lower % predicted forced expiratory volume in 1 second (FEV1)(95% confidence interval [CI] -6.22% to -0.88% predicted; p=0.01), while every 10 ng/ml lower cathelicidin was independently associated with 0.65% lower % predicted FEV1 (95% CI -1.01% to -0.28% predicted; p< 0.001). No independent associations with longitudinal lung function decline or participant-reported COPD exacerbations were observed. Conclusions: Reduced cathelicidin is associated with lower lung function at baseline. Plasma cathelicidin may potentially identify COPD patients at increased risk for more severe lung disease.

16.
J Am Chem Soc ; 142(39): 16814-16824, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-32901473

RESUMO

Polymeric materials in nature regularly employ ordered, hierarchical structures in order to perform unique and precise functions. Importantly, these structures are often formed and stabilized by the cooperative summation of many weak interactions as opposed to the independent association of a few strong bonds. Here, we show that synthetic, flexible polymer chains with periodically placed and directional dynamic bonds collectively assemble into supramolecular nanofibers when the overall molecular weight is below the polymer's critical entanglement molecular weight. This causes bulk films of long polymer chains to have faster dynamics than films of shorter polymer chains of identical chemical composition. The formation of nanofibers increases the bulk film modulus by over an order of magnitude and delays the onset of terminal flow by more than 100 °C, while still remaining solution processable. Systematic investigation of different polymer chain architectures and dynamic bonding moieties along with coarse-grained molecular dynamics simulations illuminate governing structure-function relationships that determine a polymer's capacity to form supramolecular nanofibers. This report of the cooperative assembly of multivalent polymer chains into hierarchical, supramolecular structures contributes to our fundamental understanding of designing biomimetic functional materials.

17.
Int J Chron Obstruct Pulmon Dis ; 15: 1887-1898, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821092

RESUMO

Rationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype. Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death. Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls). Measurements: We defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George's Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 <20. Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point -1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability. Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.

18.
Tuberc Respir Dis (Seoul) ; 83(4): 257-267, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32773722

RESUMO

Patients with chronic obstructive pulmonary disease receive a range of treatments including but not limited to inhaled bronchodilators, inhaled and systemic corticosteroids, supplemental oxygen, and pulmonary rehabilitation. Pulmonary rehabilitation is a multidisciplinary intervention that seeks to combine patient education, exercise, and lifestyle changes into a comprehensive program. Programs 6 to 8 weeks in length have been shown to improve health, reduce dyspnea, increase exercise capacity, improve psychological well-being, and reduce healthcare utilization and hospitalization. Although the use of pulmonary rehabilitation is widely supported by the literature, controversy still exists regarding what should be included in the programs. The goal of this review was to summarize the evidence for pulmonary rehabilitation and identify the areas that hold promise in improving its utilization and effectiveness.

19.
Sci Rep ; 10(1): 10562, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32601308

RESUMO

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV1 % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV1 % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.

20.
Nat Commun ; 11(1): 3636, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686666

RESUMO

Direct lasing of polymeric membranes to form laser induced graphene (LIG) offers a scalable and potentially cheaper alternative for the fabrication of electrically conductive membranes. However, the high temperatures induced during lasing can deform the substrate polymer, altering existing micro- and nanosized features that are crucial for a membrane's performance. Here, we demonstrate how sequential infiltration synthesis (SIS) of alumina, a simple solvent-free process, stabilizes polyethersulfone (PES) membranes against deformation above the polymers' glass transition temperature, enabling the formation of LIG without any changes to the membrane's underlying pore structure. These membranes are shown to have comparable sheet resistance to carbon-nanotube-composite membranes. They are electrochemically stable and maintain their permeability after lasing, demonstrating their competitive performance as electrically conductive membranes. These results demonstrate the immense versatility of SIS for modifying materials when combined with laser induced graphitization for a variety of applications.

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