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1.
An Acad Bras Cienc ; 92(suppl 2): e20181166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33084754

RESUMO

Knowing about the spatio-temporal patterns in the structure of ichthyoplankton assemblages allows inferring about the spawning behaviour of adult fishes, understanding the recruitment dynamics, and predicting the potential effects of mid- and long-term changes. Here, we studied the ichthyoplankton assemblages from the San José Gulf (Northern Patagonia, Argentina) and investigated their changes in space and time. To do that, we took monthly samples during two consecutive years, in spring and summer. A total of 2088 larvae were caught; they comprised 36 taxa, from which 14 were identified to species, two to genus, one to family and one to order. There were large differences in the structure of the assemblages between years, coincidently with marked changes in the surface water temperature. The structure of the ichthyoplankton assemblages also showed significant differences between the spring and summer: Helcogrammoides cunninghami, Dules auriga and larvae belonging to the family Engraulidae contributed most to these differences. The species diversity was higher in the colder year than in the warmer one. We discuss the potential role of environmental and oceanographic features on the interannual variability in the early stages of coastal fishes within a small gulf.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33052708

RESUMO

RATIONALE: Aberrant lung remodeling in idiopathic pulmonary fibrosis (IPF) is characterized by elevated MMP9 expression but the precise role of this matrix metalloproteinase in this disease has yet to be fully elucidated. METHODS: Quantitative genomic, proteomic, and functional analyses both in vitro and in vivo were used to determine MMP9 expression in IPF cells and the effects of MMP9 inhibition on profibrotic mechanisms. RESULTS: In the present study, we demonstrate that MMP9 expression was increased in airway basal-like cells (ABC-like) from IPF lungs compared with ABC cells from normal lungs. Inhibition of MMP9 activity with an anti-MMP9 antibody, andecaliximab blocked TGF-ß1-induced Smad2 phosphorylation. However, in a subset of IPF patients, TGF-ß1 activation in their ABC-like cells was unaffected or enhanced by MMP9 blockade (i.e. Non-Responders). Further analysis of Non-Responder ABC-like cells treated with andecaliximab revealed an association with the expression of type 1 IFN expression, and the addition of IFNα to these cells modulated both MMP9 expression and TGF-ß1 activation. Finally, inhibition of MMP9 ameliorated pulmonary fibrosis induced by Responder lung cells, but not a Non-Responder in a humanized immunodeficient mouse model of IPF. CONCLUSION: Together, these data demonstrate that MMP9 regulates the activation of ABC-like cells in IPF and targeting this MMP might be beneficial to a subset of IPF patients who show sufficient expression of type 1 IFNs.

3.
An Acad Bras Cienc ; 92(suppl 2): e20191524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33053070

RESUMO

In Patagonia, knowledge about the interaction among tephritids and the native flora is very scarce. In this study we identified for the first time two tephritid species (Cecidochares sp. and Neosphaeniscus m-nigrum) associated with the capitula of Chuquiraga avellanedae. This is the first record of a host plant for the genus Neosphaeniscus. Cecidochares sp. was more abundant and had a shorter development time than N. m-nigrum. Also, two families of parasitoid wasps (Pteromalidae and Eurytomidae) were registered. Further studies are needed to understand the impact of these tephritids on C. avellanedae fitness and their potential to control its populations.

4.
Chest ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031829

RESUMO

BACKGROUND: In the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations, with a similar safety profile. Research Question Does age have an effect on trial outcomes? STUDY DESIGN AND METHODS: IMPACT was a Phase III, double-blind, 52-week trial. Patients ≥40 years of age with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 mcg, FF/VI 100/25 mcg, or UMEC/VI 62.5/25 mcg. Endpoints assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough forced expiratory volume in 1 second (FEV1), proportion of St George's Respiratory Questionnaire (SGRQ) responders (≥4 units decrease from baseline in SGRQ total score) and safety. RESULTS: The intent-to-treat population comprised 10,355 patients; 4724 (46%), 4225 (41%), and 1406 (14%) were ≤64, 65-74, and ≥75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates versus FF/VI (% reduction [95% confidence interval (CI)], ≤64 years: 8% [-1, 16], p=0.070; 65-74 years: 22% [14, 29], p<0.001; ≥75 years 18% [3, 31], p=0.021) and versus UMEC/VI (≤64 years: 16% [7, 25], p=0.002; 65-74 years: 33% [25, 41], p<0.001; ≥75 years 24% [6, 38], p=0.012), with greatest rate reduction seen in the 65-74 and ≥75 years subgroups. Post hoc analyses of CFB in trough FEV1, and proportion of SGRQ responders at Week 52 were significantly greater with FF/UMEC/VI than FF/VI or UMEC/VI in all subgroups. No new safety signals were identified. INTERPRETATION: FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status versus FF/VI and UMEC/VI irrespective of age for most endpoints, with a similar safety profile. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).

5.
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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32966751

RESUMO

BACKGROUND: Whether pharmacological therapy alters decline in forced expiratory volume in 1 second (FEV1) in chronic obstructive pulmonary disease (COPD) remains controversial. Because pharmacotherapy improves health status, exacerbation rate and symptoms, it is unethical to complete placebo-controlled long-term studies aimed at modifying FEV1 decline. OBJECTIVE: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV1 decline. METHODS: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation. RESULTS: There were 33,051 patients in the analysis (active component, n = 21,941; placebo, n = 11,110 in 9 studies). The active treatment arms demonstrated a 5.0 mL/year reduction (95% CI, 0.8-9.1 mL/year, P < 0.001) in the rate of FEV1 decline compared with the placebo arms. The relative FEV1 differences between active and placebo arms were within the range of the differences reported for health status and for the exacerbation rate in those same studies. CONCLUSION: In COPD, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings.

8.
Lancet Respir Med ; 8(9): 925-934, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32890499

RESUMO

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pesquisa Biomédica , Progressão da Doença , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Fibrose Pulmonar/tratamento farmacológico , Pesquisa
10.
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.

12.
Clin Chest Med ; 41(3): 329-337, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32800188

RESUMO

Although smoking results in lung pathology in many, still not all smokers develop chronic obstructive pulmonary disease (COPD). Roughly a quarter of patients with COPD have never smoked. An understanding of both host and environmental factors beyond smoking that contribute to disease development remain critical to understanding disease prevention and ultimately effectively intervene. In this article, we summarize host factors, including genetics and gender, as well as early-life events that contribute to the development of COPD.

13.
Artigo em Inglês | MEDLINE | ID: mdl-32721166

RESUMO

Rationale Usual interstitial pneumonia (UIP) is the defining morphology of idiopathic pulmonary fibrosis (IPF). Guidelines for IPF diagnosis conditionally recommend surgical lung biopsy (SLB) for histopathology diagnosis of UIP when radiology and clinical context are not definitive. A 'molecular diagnosis of UIP' in transbronchial lung biopsy (TBBx), the Envisia Genomic Classifier, accurately predicted histopathologic UIP. Objectives We evaluated the combined accuracy of the Envisia Genomic Classifier and local radiology in the detection of UIP pattern. Methods Ninety-six patients who had diagnostic lung pathology, as well as a TBBx for molecular testing with Envisia Genomic Classier, were included in this analysis. The classifier results were scored against reference pathology. UIP identified on HRCT as documented by features in local radiologists' reports was compared to histopathology. Measurements and Main Results In 96 patients, the Envisia classifier achieved a specificity of 92.1% [CI:78.6%-98.3%] and a sensitivity of 60.3% [CI:46.6%-73.0%] for histology-proven UIP pattern. Local radiologists identified UIP in 18 of 53 patients with UIP histopathology with a sensitivity of 34.0% [CI:21.5%-48.3%], and a specificity of 96.9% [CI:83.8 - 100]). In conjunction with HRCT patterns of UIP, the Envisia classifier results identified 24 additional UIP patients (sensitivity 79.2% specificity 90.6%). Conclusions In 96 patients with suspected ILD, the Envisia Genomic Classifier identified UIP regardless of HRCT pattern. These results suggest that recognition of a UIP pattern by the Envisia Genomic Classifier combined with HRCT and clinical factors in a multidisciplinary discussion may assist clinicians in making an ILD (especially IPF) diagnosis without the need for SLB.

14.
Respir Res ; 21(1): 177, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32646424

RESUMO

BACKGROUND: Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting. METHODS: A composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2-4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 µg or placebo. RESULTS: The composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George's Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6-81.6%) and SGRQ (72.3-78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment. CONCLUSIONS: Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144339 .

16.
Adv Ther ; 37(9): 3775-3790, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32647911

RESUMO

INTRODUCTION: The phase 3 InforMing the PAthway of COPD (chronic obstructive pulmonary disease) Treatment (IMPACT) trial, single-inhaler therapy with fluticasone furoate (FF) 100 µg, umeclidinium (UMEC) 62.5 µg, and vilanterol (VI) 25 µg demonstrated a reduction in the rate of moderate or severe exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This article reports additional evidence of improvements in symptoms and health-related quality of life (HRQoL) with FF/UMEC/VI compared with either FF/VI or UMEC/VI from the IMPACT study. METHODS: Patient-reported HRQoL assessments and symptom measures included as pre-specified IMPACT end points were the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Baseline Dyspnea Index (BDI) as the anchor for the Transitional Dyspnea Index (TDI) focal score (BDI/TDI) in a subset of patients enrolled at study sites in North America and Europe. Change from baseline was assessed at weeks 4, 28, and 52. RESULTS: The intent-to-treat population included 10,355 patients (TDI population: 5058 patients). Clinically meaningful improvements in SGRQ total score between baseline and week 52 favored FF/UMEC/VI over FF/VI (- 1.8 units, p < 0.001) and UMEC/VI (- 1.8 units, p < 0.001). Similar improvements in the CAT and TDI focal score were also observed with FF/UMEC/VI versus FF/VI or UMEC/VI. CONCLUSIONS: This study demonstrates that in patients with symptomatic COPD at risk of exacerbations, once-daily FF/UMEC/VI, compared with FF/VI or UMEC/VI, improves patient-perceived HRQoL and symptoms. TRIAL REGISTRATION NUMBER: NCT02164513.

18.
Sci Rep ; 10(1): 12049, 2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694604

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and heterogeneous interstitial lung disease of unknown origin with a low survival rate. There are few treatment options available due to the fact that mechanisms underlying disease progression are not well understood, likely because they arise from dysregulation of complex signaling networks spanning multiple tissue compartments. To better characterize these networks, we used systems-focused data-driven modeling approaches to identify cross-tissue compartment (blood and bronchoalveolar lavage) and temporal proteomic signatures that differentiated IPF progressors and non-progressors. Partial least squares discriminant analysis identified a signature of 54 baseline (week 0) blood and lung proteins that differentiated IPF progression status by the end of 80 weeks of follow-up with 100% cross-validation accuracy. Overall we observed heterogeneous protein expression patterns in progressors compared to more homogenous signatures in non-progressors, and found that non-progressors were enriched for proteomic processes involving regulation of the immune/defense response. We also identified a temporal signature of blood proteins that was significantly different at early and late progressor time points (p < 0.0001), but not present in non-progressors. Overall, this approach can be used to generate new hypothesis for mechanisms associated with IPF progression and could readily be translated to other complex and heterogeneous diseases.

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.
Thorax ; 75(9): 735-743, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32631932

RESUMO

BACKGROUND: A variety of maintenance inhaler therapies are available to treat asthma and COPD. Patient-centric treatment choices require understanding patient preferences for the alternative therapies. METHODS: A self-completed web-based discrete choice experiment was conducted to elicit patient preferences for inhaler device and medication attributes. Selection of attributes was informed by patient focus groups and literature review. RESULTS: The discrete choice experiment was completed by 810 patients with asthma and 1147 patients with COPD. Patients with asthma most valued decreasing the onset of action from 30 to 5 min, followed by reducing yearly exacerbations from 3 to 1. Patients with COPD most and equally valued decreasing the onset of action from 30 to 5 min and reducing yearly exacerbations from 3 to 1. Both patients with asthma and patients with COPD were willing to accept an additional exacerbation in exchange for a 15 min decrease in onset of action and a longer onset of action in exchange for a lower risk of adverse effects from inhaled corticosteroids. Patients with asthma and COPD valued once-daily over twice-daily dosing, pressurised inhalers over dry powder inhalers and non-capsule priming over single-use capsules, although these attributes were not valued as highly as faster onset of action or reduced exacerbations. CONCLUSIONS: The most important maintenance inhaler attributes for patients with asthma and COPD were fast onset of symptom relief and a lower rate of exacerbations. Concerns about safety of inhaled corticosteroids and device convenience also affected patient preferences but were less important.

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