Propagation of wave packets in randomly stratified media

The propagation of a narrow-band signal radiated by a point source in a randomly layered absorbing medium is studied asymptotically in the weak-scattering limit. It is shown that in a disordered stratified medium that is homogeneous on average a pulse is channelled along the layers in a narrow strip in the vicinity of the source. The space-time distribution of the pulse energy is calculated. Far from the source, the shape of wave packets is universal and independent of the frequency spectrum of the radiated signal. Strong localization effects manifest themselves also as a low-decaying tail of the pulse and a strong time delay in the direction of stratification. The frequency-momentum correlation function in a one-dimensional random medium is calculated.Comment: 11 pages, 3 figures, Revtex-4. Submitted to Phys. Rev.

Superhard Phases of Simple Substances and Binary Compounds of the B-C-N-O System: from Diamond to the Latest Results (a Review)

The basic known and hypothetic one- and two-element phases of the B-C-N-O system (both superhard phases having diamond and boron structures and precursors to synthesize them) are described. The attention has been given to the structure, basic mechanical properties, and methods to identify and characterize the materials. For some phases that have been recently described in the literature the synthesis conditions at high pressures and temperatures are indicated.Comment: Review on superhard B-C-N-O phase

Alveolar eosinophilia in current smokers with chronic obstructive pulmonary disease in the SPIROMICS cohort

To the Editor: Novel therapies for chronic obstructive pulmonary disease (COPD) are urgently needed. Eosinophilic inflammation is an appealing target, because blood or sputum eosinophils in stable COPD may predict responses to systemic or inhaled corticosteroid therapy. Titrating steroid therapy in the stable state on the basis of sputum eosinophils reduced severe exacerbations and has been recommended for clinical practice. However, the prevalence of eosinophilic inflammation in COPD and its uniformity between systemic and lung compartments remain incompletely defined. Controversy exists on whether sputum analysis (reflecting large airway events) is required, or whether blood eosinophilia can suffice, on the basis of strong correlation between the 2 found by 1 group. Thus, better understanding of eosinophils in COPD is needed

Clinical significance of bronchodilator responsiveness evaluated by forced vital capacity in COPD: SPIROMICS cohort analysis

Objective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC)reflecting the change in volume. Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models. Results: A majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1. Conclusion: With advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1,BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD. Clinical trials registration: ClinicalTrials.gov: NCT01969344T4

Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort

Background Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils. Methods We did a multicentre observational study analysing comprehensive baseline data from SPIROMICS in patients with COPD aged 40–80 years who had a smoking history of at least 20 pack-years, recruited from six clinical sites and additional subsites in the USA between Nov 12, 2010, and April 21, 2015. Inclusion criteria for this analysis were SPIROMICS baseline visit data with complete blood cell counts and, in a subset, acceptable sputum counts. We stratified patients on the basis of blood and sputum eosinophil concentrations and compared their demographic characteristics, as well as results from questionnaires, clinical assessments, and quantitative CT (QCT). We also analysed whether blood eosinophil concentrations reliably predicted sputum eosinophil concentrations. This study is registered with ClinicalTrials.gov (NCT01969344). Findings Of the 2737 patients recruited to SPIROMICS, 2499 patients were smokers and had available blood counts, and so were stratified by mean blood eosinophil count: 1262 patients with low (<200 cells per μL) and 1237 with high (≥200 cells per μL) blood eosinophil counts. 827 patients were eligible for stratification by mean sputum eosinophil percentage: 656 with low (<1·25%) and 171 with high (≥1·25%) sputum eosinophil percentages. The high sputum eosinophil group had significantly lower median FEV1 percentage predicted than the low sputum eosinophil group both before (65·7% [IQR 51·8–81·3] vs 75·7% [59·3–90·2], p<0·0001) and after (77·3% [63·1–88·5] vs 82·9% [67·8–95·9], p=0·001) bronchodilation. QCT density measures for emphysema and air trapping were significantly higher in the high sputum eosinophil group than the low sputum eosinophil group. Exacerbations requiring corticosteroids treatment were more common in the high versus low sputum eosinophil group (p=0·002). FEV1 percentage predicted was significantly different between low and high blood eosinophil groups, but differences were less than those observed between the sputum groups. The high blood eosinophil group had slightly increased airway wall thickness (0·02 mm difference, p=0·032), higher St George Respiratory Questionnaire symptom scores (p=0·037), and increased wheezing (p=0·018), but no evidence of an association with COPD exacerbations (p=0·35) or the other indices of COPD severity, such as emphysema measured by CT density, COPD assessment test scores, Body-mass index, airflow Obstruction, Dyspnea, and Exercise index, or Global Initiative for Chronic Obstructive Lung Disease stage. Blood eosinophil counts showed a weak but significant association with sputum eosinophil counts (receiver operating characteristic area under the curve of 0·64, p<0·0001), but with a high false-discovery rate of 72%. Interpretation In a large, well characterised cohort of former and current smoking patients with a broad range of COPD severity, high concentrations of sputum eosinophils were a better biomarker than high concentrations of blood eosinophils to identify a patient subgroup with more severe disease, more frequent exacerbations, and increased emphysema by QCT. Blood eosinophils alone were not a reliable biomarker for COPD severity or exacerbations, or for sputum eosinophils. Clinical trials targeting eosinophilic inflammation in COPD should consider assessing sputum eosinophils. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute

Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort

Background Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. Methods In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40–80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1–4) on the basis of post-bronchodilator FEV1. Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zero-inflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. Findings 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher interleukin-8 concentrations, than were no acute exacerbations. Interpretation Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations. Funding National Institutes of Health, and National Heart, Lung, and Blood Institute

Aspirin Use and Respiratory Morbidity in COPD: A Propensity Score-Matched Analysis in Subpopulations and Intermediate Outcome Measures in COPD Study

Background: Aspirin use in COPD has been associated with reduced all-cause mortality in meta-regression analysis with few equivocal studies. However, the effect of aspirin on COPD morbidity is unknown. Methods: Self-reported daily aspirin use was obtained at baseline from SPIROMICS participants with COPD (FEV 1 /FVC < 70%). Acute exacerbations of COPD (AECOPD) were prospectively ascertained through quarterly structured telephone questionnaires up to 3 years and categorized as moderate (symptoms treated with antibiotics or oral corticosteroids) or severe (requiring ED visit or hospitalization). Aspirin users were matched one-to-one with nonusers, based on propensity score. The association of aspirin use with total, moderate, and severe AECOPD was investigated using zero-inflated negative binomial models. Linear or logistic regression was used to investigate the association with baseline respiratory symptoms, quality of life, and exercise tolerance. Results: Among 1,698 participants, 45% reported daily aspirin use at baseline. Propensity score matching resulted in 503 participant pairs. Aspirin users had a lower incidence rate of total AECOPD (adjusted incidence rate ratio [IRR], 0.78; 95% CI, 0.65-0.94), with similar effect for moderate but not severe AECOPD (IRR, 0.86; 95% CI, 0.63-1.18). Aspirin use was associated with lower total St. George's Respiratory Questionnaire score (β, –2.2; 95% CI, –4.1 to –0.4), reduced odds of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2; adjusted odds ratio, 0.69; 95% CI, 0.51-0.93), and COPD Assessment Test score (β, –1.1; 95% CI, –1.9 to –0.2) but not 6-min walk distance (β, 0.7 m; 95% CI, –14.3 to 15.6). Conclusions: Daily aspirin use is associated with reduced rate of COPD exacerbations, less dyspnea, and better quality of life. Randomized clinical trials of aspirin use in COPD are warranted to account for unmeasured and residual confounding. Trial Registry: ClinicalTrials.gov; No.: NCT01969344; URL: www.clinicaltrials.go

Association of thrombocytosis with COPD morbidity: The SPIROMICS and COPDGene cohorts

Background: Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown. This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity. Methods: Participants with COPD were included from two multi-center observational studies (SPIROMICS and COPDGene). Cross-sectional associations of thrombocytosis (platelet count ≥350×109/L) with AECOPD during prior year (none vs. any), exertional dyspnea (modified Medical Research Council (mMRC) score≥2), COPD Assessment Test (CAT) score≥10, six-minute-walk distance (6MWD), and St. George Respiratory questionnaire (SGRQ) were modeled using multivariable logistic or linear regression. A pooled effect estimate for thrombocytosis was produced using meta-analysis of data from both studies. Results: Thrombocytosis was present in 124/1820 (6.8%) SPIROMICS participants and 111/2185 (5.1%) COPDGene participants. In meta-analysis thrombocytosis was associated with any AECOPD (adjusted odds ratio [aOR] 1.5; 95% confidence interval [95% CI]: 1.1-2.0), severe AECOPD (aOR 1.5; 95% CI: 1.1-2.2), dyspnea (mMRC≥2 aOR 1.4; 95% CI: 1.0-1.9), respiratory symptoms (CAT≥10 aOR 1.6; 95% CI: 1.1-2.4), and higher SGRQ score (β 2.7; 95% CI: 0.5, 5). Thrombocytosis was also associated with classification into Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D (aOR 1.7 95% CI: 1.2-2.4). Conclusions: Thrombocytosis was associated with higher likelihood of prior exacerbation and worse symptoms. Platelet count, a commonly measured clinical assay, may be a biomarker for moderate-severe COPD symptoms, guide disease classification and intensity of treatment. Future longitudinal studies investigating the role of platelets in COPD progression may be warranted. Trial registration: ClinicalTrials.gov: NCT01969344(SPIROMICS) and NCT00608764(COPDGene)

Centrilobular emphysema and coronary artery calcification: Mediation analysis in the SPIROMICS cohort

Background: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established. Methods: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC. Results: FEV 1 /FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV 1 /FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC. Conclusions: The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis. Trial Registration: ClinicalTrials.gov: Identifier: NCT01969344

Alignment of inhaled chronic obstructive pulmonary disease therapies with published strategies :analysis of the Global Initiative for Chronic Obstructive Lung Disease recommendations in SpiroMics

Rationale: Despite awareness of chronic obstructive pulmonary disease (COPD) treatment recommendations, uptake is poor. The Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) spans 2010-2016, providing an opportunity to assess integration of 2011 Global Initiative for Obstructive Lung Disease (GOLD) treatment strategies over time in a large observational cohort study. Objectives: To evaluate how COPD treatment aligns with 2011 GOLD strategies and determine factors associated with failure to align with recommendations. Methods: Information on inhaled medication use collected via questionnaire annually for 4 years was compiled into therapeutic classes (long-acting antimuscarinic agent, long-acting b-agonist, inhaled corticosteroids [ICS], and combinations thereof). Medications were not modified by SPIROMICS investigators. 2011 GOLD COPD categories A, B, C, and D were assigned. Alignment of inhaler regimen with first-/second-line GOLD recommendations was determined, stratifying into recommendation aligned or nonaligned. Recommendation-nonaligned participants were further stratified into overuse and underuse categories. Results: Of 1,721 participants with COPD, at baseline, 52% of regimens aligned with GOLD recommendations. Among participants with nonaligned regimens, 46% reported underuse, predominately owing to lack of long-acting inhalers in GOLD category D. Of the 54% reporting overuse, 95% were treated with nonindicated ICS-containing regimens. Among 431 participants with 4 years of follow-up data, recommendation alignment did not change over time. When we compared 2011 and 2017 recommendations, we found that 47% did not align with either set of recommendations, whereas 35% were in alignment with both recommendations. Conclusions: Among SPIROMICS participants with COPD, nearly 50% reported inhaler regimens that did not align with GOLD recommendations. Nonalignment was driven largely by overuse of ICS regimens in milder disease and lack of long-acting inhalers in severe disease