COPDGene® 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease

Background:Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods:Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results:Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics. Conclusions:A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop

Controlled intermittent shortening contractions of a muscle-tendon complex: muscle fibre damage and effects on force transmission from a single head of rat EDL

This study was performed to examine effects of prolonged (3 h) intermittent shortening (amplitude 2 mm) contractions (muscles were excited maximally) of head III of rat extensor digitorum longus muscle (EDL III) on indices of muscle damage and on force transmission within the intact anterior crural compartment. Three hours after the EDL III exercise, muscle fibre damage, as assessed by immunohistochemical staining of structural proteins (i.e. dystrophin, desmin, titin, laminin-2), was found in EDL, tibialis anterior (TA) and extensor hallucis longus (EHL) muscles. The damaged muscle fibres were not uniformly distributed throughout the muscle cross-sections, but were located predominantly near the interface of TA and EDL muscles as well as near intra- and extramuscular neurovascular tracts. In addition, changes were observed in desmin, muscle ankyrin repeat protein 1, and muscle LIM protein gene expression: significantly (P < 0.01) higher (1.3, 45.5 and 2.3-fold, respectively) transcript levels compared to the contralateral muscles. Post-EDL III exercise, length-distal force characteristics of EDL III were altered significantly (P < 0.05): at high EDL III lengths, active forces decreased and the length range between active slack length and optimum length increased. For all EDL III lengths tested, proximal passive and active force of EDL decreased. The slope of the EDL III length-TA + EHL force curve decreased, which indicates a decrease of the degree of intermuscular interaction between EDL III and TA + EHL. It is concluded that prolonged intermittent shortening contractions of a single head of multi-tendoned EDL muscle results in structural damage to muscle fibres as well as altered force transmission within the compartment. A possible role of myofascial force transmission is discussed. © Springer 2005

Autoclave cure simulation of composite structures applying implicit and explicit FE techniques

Simulation of the autoclave manufacturing technique of composites can yield a preliminary estimation of induced residual thermal stresses and deformations that affect component fatigue life, and required tolerances for assembly. In this paper, an approach is proposed to simulate the autoclave manufacturing technique for unidirectional composites. The proposed approach consists of three modules. The first module is a Thermo-chemical model to estimate the temperature and the degree of cure distributions in the composite part during the cure cycle. The second and third modules are a sequential stress analysis using FE-Implicit and FE-Explicit respectively. User-material subroutine is used to model the Viscoelastic properties of the material based on theory of micromechanics

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

Background: The small conducting airways are the major site of airflow obstruction in COPD and may precede emphysema development. We hypothesized a novel CT biomarker of small airways disease predicts FEV1 decline. Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/year) over 5 years. Separate models for non-obstructed and obstructed subjects were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by Parametric Response Mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRMemph) and functional small airways disease (PRMfSAD), a measure of non-emphysematous air trapping. Results: Mean (SD) rate of FEV1 decline in ml/year for GOLD 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8) respectively (trend test for grades 1-4, p<0.001). In multivariable linear regression, for non-obstructed participants, PRMfSAD but not PRMemph was associated with FEV1 decline, p<0.001. In GOLD 1-4 participants, both functional small airways disease (PRMfSAD) and emphysema (PRMemph) were associated with FEV1 decline (p<0.001 and p=0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% vs. 13% and 68% vs. 32% for PRMfSAD and PRMemph in GOLD 1/2 and 3/4, respectively. Conclusions: Both CT assessed functional small airways disease and emphysema are associated with FEV1 decline, but the association with functional small airways disease has greatest importance in mild-to-moderate stage COPD where the rate of FEV1 decline is the greatest