Epidemiology, genetics, and subtyping of preserved ratio impaired spirometry (PRISm) in COPDGene.

BackgroundPreserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.MethodsData from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45-80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.ResultsThe prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter's syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative "COPD-subtype", "Restrictive-subtype", and a highly symptomatic "Metabolic-subtype".ConclusionsPRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.Trial registrationClinicaltrials.gov Identifier: NCT000608764

Paired inspiratory-expiratory chest CT scans to assess for small airways disease in COPD

Abstract Background Gas trapping quantified on chest CT scans has been proposed as a surrogate for small airway disease in COPD. We sought to determine if measurements using paired inspiratory and expiratory CT scans may be better able to separate gas trapping due to emphysema from gas trapping due to small airway disease. Methods Smokers with and without COPD from the COPDGene Study underwent inspiratory and expiratory chest CT scans. Emphysema was quantified by the percent of lung with attenuation < −950HU on inspiratory CT. Four gas trapping measures were defined: (1) Exp−856, the percent of lung < −856HU on expiratory imaging; (2) E/I MLA, the ratio of expiratory to inspiratory mean lung attenuation; (3) RVC856-950, the difference between expiratory and inspiratory lung volumes with attenuation between −856 and −950 HU; and (4) Residuals from the regression of Exp−856 on percent emphysema. Results In 8517 subjects with complete data, Exp−856 was highly correlated with emphysema. The measures based on paired inspiratory and expiratory CT scans were less strongly correlated with emphysema. Exp−856, E/I MLA and RVC856-950 were predictive of spirometry, exercise capacity and quality of life in all subjects and in subjects without emphysema. In subjects with severe emphysema, E/I MLA and RVC856-950 showed the highest correlations with clinical variables. Conclusions Quantitative measures based on paired inspiratory and expiratory chest CT scans can be used as markers of small airway disease in smokers with and without COPD, but this will require that future studies acquire both inspiratory and expiratory CT scans.http://deepblue.lib.umich.edu/bitstream/2027.42/134586/1/12931_2012_Article_1346.pd

Measurement of the multi-TeV neutrino cross section with IceCube using Earth absorption

Neutrinos interact only very weakly, so they are extremely penetrating. However, the theoretical neutrino-nucleon interaction cross section rises with energy such that, at energies above 40 TeV, neutrinos are expected to be absorbed as they pass through the Earth. Experimentally, the cross section has been measured only at the relatively low energies (below 400 GeV) available at neutrino beams from accelerators \cite{Agashe:2014kda, Formaggio:2013kya}. Here we report the first measurement of neutrino absorption in the Earth, using a sample of 10,784 energetic upward-going neutrino-induced muons observed with the IceCube Neutrino Observatory. The flux of high-energy neutrinos transiting long paths through the Earth is attenuated compared to a reference sample that follows shorter trajectories through the Earth. Using a fit to the two-dimensional distribution of muon energy and zenith angle, we determine the cross section for neutrino energies between 6.3 TeV and 980 TeV, more than an order of magnitude higher in energy than previous measurements. The measured cross section is $1.30^{+0.21}_{-0.19}$ (stat.) $^{+0.39}_{-0.43}$ (syst.) times the prediction of the Standard Model \cite{CooperSarkar:2011pa}, consistent with the expectation for charged and neutral current interactions. We do not observe a dramatic increase in the cross section, expected in some speculative models, including those invoking new compact dimensions \cite{AlvarezMuniz:2002ga} or the production of leptoquarks \cite{Romero:2009vu}.Comment: Preprint version of Nature paper 10.1038/nature2445