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Search Results: 1 - 10 of 288445 matches for " D. O'Donnell "
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Impacting patient-centred outcomes in COPD: breathlessness and exercise tolerance
D. E. O'Donnell
European Respiratory Review , 2006,
Abstract: The physiological hallmark of chronic obstructive pulmonary disease (COPD) is expiratory flow limitation. However, it is the resultant air trapping and associated increases in lung volume (hyperinflation) that provide a mechanistic link between the physiological impairment and the characteristic symptoms of COPD, such as dyspnoea (breathlessness), exercise intolerance and reduced health-related quality of life (HRQoL). During exercise, the negative consequences of hyperinflation are particularly apparent. Delayed lung emptying and increased end-expiratory lung volume are aggravated, and tidal volume cannot rise to meet the increased ventilatory demands. Dyspnoea intensity rises abruptly to intolerable levels, and further increases in ventilation can only be achieved by rapid breathing. This rebounds to cause greater hyperinflation in a vicious cycle. As a result, patients with COPD often prematurely stop or avoid activity, leading to deconditioning, increased dyspnoea, worsening of disease and, ultimately, reduced HRQoL. The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend long-acting bronchodilators as first-line maintenance treatment in COPD. Once-daily tiotropium 18 μg, a long-acting anticholinergic agent with 24-h efficacy, has been consistently shown to relieve dyspnoea and improve exercise tolerance and health status. These improvements may allow patients with chronic obstructive pulmonary disease to increase their daily activities, thereby reversing the cycle of chronic inactivity and muscle deconditioning.
An Open Access Database of Genome-wide Association Results
Andrew D Johnson, Christopher J O'Donnell
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-6
Abstract: We collected available results from 118 GWAS articles into a database of 56,411 significant SNP-phenotype associations and accompanying information, making this database freely available here. In doing so, we met and describe here a number of challenges to creating an open access database of GWAS results. Through preliminary analyses and characterization of available GWAS, we demonstrate the potential to gain new insights by querying a database across GWAS.Using a genomic bin-based density analysis to search for highly associated regions of the genome, positive control loci (e.g., MHC loci) were detected with high sensitivity. Likewise, an analysis of highly repeated SNPs across GWAS identified replicated loci (e.g., APOE, LPL). At the same time we identified novel, highly suggestive loci for a variety of traits that did not meet genome-wide significant thresholds in prior analyses, in some cases with strong support from the primary medical genetics literature (SLC16A7, CSMD1, OAS1), suggesting these genes merit further study. Additional adjustment for linkage disequilibrium within most regions with a high density of GWAS associations did not materially alter our findings. Having a centralized database with standardized gene annotation also allowed us to examine the representation of functional gene categories (gene ontologies) containing one or more associations among top GWAS results. Genes relating to cell adhesion functions were highly over-represented among significant associations (p < 4.6 × 10-14), a finding which was not perturbed by a sensitivity analysis.We provide access to a full gene-annotated GWAS database which could be used for further querying, analyses or integration with other genomic information. We make a number of general observations. Of reported associated SNPs, 40% lie within the boundaries of a RefSeq gene and 68% are within 60 kb of one, indicating a bias toward gene-centricity in the findings. We found considerable heterogeneity in inform
Estimating the direct and indirect effects of secondary organic aerosols using ECHAM5-HAM
D. O'Donnell,K. Tsigaridis,J. Feichter
Atmospheric Chemistry and Physics (ACP) & Discussions (ACPD) , 2011, DOI: 10.5194/acp-11-8635-2011
Abstract: Secondary organic aerosol (SOA) has been introduced into the global climate-aerosol model ECHAM5/HAM. The SOA module handles aerosols originating from both biogenic and anthropogenic sources. The model simulates the emission of precursor gases, their chemical conversion into condensable gases, the partitioning of semi-volatile condenable species into the gas and aerosol phases. As ECHAM5/HAM is a size-resolved model, a new method that permits the calculation of partitioning of semi-volatile species between different size classes is introduced. We compare results of modelled organic aerosol concentrations against measurements from extensive measurement networks in Europe and the United States, running the model with and without SOA. We also compare modelled aerosol optical depth against measurements from the AERONET network of grond stations. We find that SOA improves agreement between model and measurements in both organic aerosol mass and aerosol optical depth, but does not fully correct the low bias that is present in the model for both of these quantities. Although many models now include SOA, any overall estimate of the direct and indirect effects of these aerosols is still lacking. This paper makes a first step in that direction. The model is applied to estimate the direct and indirect effects of SOA under simulated year 2000 conditions. The modelled SOA spatial distribution indicates that SOA is likely to be an important source of free and upper tropospheric aerosol. We find a negative shortwave (SW) forcing from the direct effect, amounting to 0.31 Wm 2 on the global annual mean. In contrast, the model indicates a positive indirect effect of SOA of +0.23 Wm 2, arising from the enlargement of particles due to condensation of SOA, together with an enhanced coagulation sink of small particles. In the longwave, model results are a direct effect of +0.02 Wm 2 and an indirect effect of 0.03 Wm 2.
Physiology and consequences of lung hyperinflation in COPD
D. E. O'Donnell,P. Laveneziana
European Respiratory Review , 2006,
Abstract: Lung hyperinflation commonly accompanies expiratory flow limitation in patients with chronic obstructive pulmonary disease (COPD) and contributes importantly to morbidity and an impoverished quality of life. It is not surprising, therefore, that lung hyperinflation has become an important therapeutic target in symptomatic COPD patients. Acute dynamic increases in lung hyperinflation under conditions of worsening expiratory flow limitation and increased ventilatory demand (or both) can seriously stress cardiopulmonary reserves in patients with more advanced disease. The present understanding of the physiological mechanisms of dynamic hyperinflation during exacerbations of COPD and during physical activity continues to grow, together with an appreciation of its negative mechanical and sensory consequences. In this brief overview, definitions and measurement of lung hyperinflation during rest and exercise will be discussed and its potential clinical importance will be considered. The focus will mainly be on current concepts of the mechanisms of air trapping and its role in inducing respiratory discomfort and activity limitation in COPD.
Lung hyperinflation in COPD: the impact of pharmacotherapy
D. E. O'Donnell,P. Laveneziana
European Respiratory Review , 2006,
Abstract: Improvement in airway function in response to bronchodilator therapy is generally confirmed by simple spirometry. However, improvements in maximal expiratory flow rates have been shown to correlate poorly with important patient-centred outcomes, such as reduced exertional dyspnoea and improved exercise performance. Recent studies have suggested that attendant reductions in end-expiratory lung volume as a result of bronchodilator-induced improvements in lung emptying may be more closely associated with symptom relief and increased exercise capacity than traditional spirometric indices. To the extent that chronic lung hyperinflation and the superimposition of acute dynamic hyperinflation (in response to increased ventilation or expiratory flow limitation) result in excessive loading and weakening of the inspiratory muscles, then pharmacological lung volume reduction should have important mechanical and sensory benefits for the patient. The present article will examine the mechanisms of lung deflation following short-term bronchodilator therapy. The physiological links between reduced hyperinflation, improved dyspnoea and exercise endurance will be examined, and the emerging evidence for the additive effects of combining various modern pharmacological therapies will be reviewed.
Respiratory Consequences of Mild-to-Moderate Obesity: Impact on Exercise Performance in Health and in Chronic Obstructive Pulmonary Disease
Denis E. O'Donnell,Conor D. J. O'Donnell,Katherine A. Webb,Jordan A. Guenette
Pulmonary Medicine , 2012, DOI: 10.1155/2012/818925
Abstract: In many parts of the world, the prevalence of obesity is increasing at an alarming rate. The association between obesity, multiple comorbidities, and increased mortality is now firmly established in many epidemiological studies. However, the link between obesity and exercise intolerance is less well studied and is the focus of this paper. Although exercise limitation is likely to be multifactorial in obesity, it is widely believed that the respiratory mechanical constraints and the attendant dyspnea are important contributors. In this paper, we examined the evidence that critical ventilatory constraint is a proximate source of exercise limitation in individuals with mild-to-moderate obesity. We first reviewed existing information on exercise performance, including ventilatory and perceptual response patterns, in obese individuals who are otherwise healthy. We then considered the impact of obesity in patients with preexisting respiratory mechanical abnormalities due to chronic obstructive pulmonary disease (COPD), with particular reference to the effect on dyspnea and exercise performance. Our main conclusion, based on the existing and rather sparse literature on the subject, is that abnormalities of dynamic respiratory mechanics are not likely to be the dominant source of dyspnea and exercise intolerance in otherwise healthy individuals or in patients with COPD with mild-to-moderate obesity. 1. Introduction The prevalence of obesity is increasing at a remarkable rate in the Western world and this has major negative health and economic ramifications [1, 2]. Obesity is clearly linked to multiple comorbidities and is an independent risk factor for reduced survival [3, 4]. Obesity is also associated with reduced activity levels [5] and this, in turn, is associated with increased risk for comorbidities which include skeletal muscle deconditioning, insulin resistance, and cardiovascular disease [6, 7]. Of interest, obese individuals who remain active appear to have lower morbidity and mortality than normal weight individuals who are sedentary [8]. A better understanding of the nature and source of exercise intolerance in obesity is required if we are to offer more effective treatment for this increasingly common health problem. The mechanisms of activity restriction in obesity are likely to be multifactorial but the role of respiratory impairment and the associated respiratory discomfort is thought to be important. This paper will focus on the respiratory factors that may influence exercise capacity in individuals with mild-to-moderate obesity based on body
Long-lived selective spin echoes in dipolar solids under periodic and aperiodic pi-pulse trains
Clark D. Ridge,Lauren F. O'Donnell,Jamie D. Walls
Physics , 2013, DOI: 10.1103/PhysRevB.89.024404
Abstract: The application of Carr-Purcell-Meiboom-Gill (CPMG) $\pi-$trains for dynamically decoupling a system from its environment has been extensively studied in a variety of physical systems. When applied to dipolar solids, recent experiments have demonstrated that CPMG pulse trains can generate long-lived spin echoes. While there still remains some controversy as to the origins of these long-lived spin echoes under the CPMG sequence, there is a general agreement that pulse errors during the $\pi-$pulses are a necessary requirement. In this work, we develop a theory to describe the spin dynamics in dipolar coupled spin-1/2 system under a CPMG($\phi_{1},\phi_{2}$) pulse train, where $\phi_{1}$ and $\phi_{2}$ are the phases of the $\pi-$pulses. From our theoretical framework, the propagator for the CPMG($\phi_{1},\phi_{2}$) pulse train is equivalent to an effective ``pulsed'' spin-locking of single-quantum coherences with phase $\pm\frac{\phi_{2}-3\phi_{1}}{2}$, which generates a periodic quasiequilibrium that corresponds to the long-lived echoes. Numerical simulations, along with experiments on both magnetically dilute, random spin networks found in C$_{60}$ and C$_{70}$ and in non-dilute spin systems found in adamantane and ferrocene, were performed and confirm the predictions from the proposed theory.
Temporal Trends in Results Availability from Genome-Wide Association Studies
Andrew D. Johnson ,Richard Leslie,Christopher J. O'Donnell
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002269
Abstract:
The global aerosol-climate model ECHAM-HAM, version 2: sensitivity to improvements in process representations
K. Zhang,D. O'Donnell,J. Kazil,P. Stier
Atmospheric Chemistry and Physics (ACP) & Discussions (ACPD) , 2012, DOI: 10.5194/acp-12-8911-2012
Abstract: This paper introduces and evaluates the second version of the global aerosol-climate model ECHAM-HAM. Major changes have been brought into the model, including new parameterizations for aerosol nucleation and water uptake, an explicit treatment of secondary organic aerosols, modified emission calculations for sea salt and mineral dust, the coupling of aerosol microphysics to a two-moment stratiform cloud microphysics scheme, and alternative wet scavenging parameterizations. These revisions extend the model's capability to represent details of the aerosol lifecycle and its interaction with climate. Nudged simulations of the year 2000 are carried out to compare the aerosol properties and global distribution in HAM1 and HAM2, and to evaluate them against various observations. Sensitivity experiments are performed to help identify the impact of each individual update in model formulation. Results indicate that from HAM1 to HAM2 there is a marked weakening of aerosol water uptake in the lower troposphere, reducing the total aerosol water burden from 75 Tg to 51 Tg. The main reason is the newly introduced κ-K hler-theory-based water uptake scheme uses a lower value for the maximum relative humidity cutoff. Particulate organic matter loading in HAM2 is considerably higher in the upper troposphere, because the explicit treatment of secondary organic aerosols allows highly volatile oxidation products of the precursors to be vertically transported to regions of very low temperature and to form aerosols there. Sulfate, black carbon, particulate organic matter and mineral dust in HAM2 have longer lifetimes than in HAM1 because of weaker in-cloud scavenging, which is in turn related to lower autoconversion efficiency in the newly introduced two-moment cloud microphysics scheme. Modification in the sea salt emission scheme causes a significant increase in the ratio (from 1.6 to 7.7) between accumulation mode and coarse mode emission fluxes of aerosol number concentration. This leads to a general increase in the number concentration of smaller particles over the oceans in HAM2, as reflected by the higher ngstr m parameters. Evaluation against observation reveals that in terms of model performance, main improvements in HAM2 include a marked decrease of the systematic negative bias in the absorption aerosol optical depth, as well as smaller biases over the oceans in ngstr m parameter and in the accumulation mode number concentration. The simulated geographical distribution of aerosol optical depth (AOD) is better correlated with the MODIS data, while the surface aeros
Fooling functions of halfspaces under product distributions
P. Gopalan,R. O'Donnell,Y. Wu,D. Zuckerman
Computer Science , 2010,
Abstract: We construct pseudorandom generators that fool functions of halfspaces (threshold functions) under a very broad class of product distributions. This class includes not only familiar cases such as the uniform distribution on the discrete cube, the uniform distribution on the solid cube, and the multivariate Gaussian distribution, but also includes any product of discrete distributions with probabilities bounded away from 0. Our first main result shows that a recent pseudorandom generator construction of Meka and Zuckerman [MZ09], when suitably modifed, can fool arbitrary functions of d halfspaces under product distributions where each coordinate has bounded fourth moment. To eps-fool any size-s, depth-d decision tree of halfspaces, our pseudorandom generator uses seed length O((d log(ds/eps)+log n) log(ds/eps)). For monotone functions of d halfspaces, the seed length can be improved to O((d log(d/eps)+log n) log(d/eps)). We get better bounds for larger eps; for example, to 1/polylog(n)-fool all monotone functions of (log n)= log log n halfspaces, our generator requires a seed of length just O(log n). Our second main result generalizes the work of Diakonikolas et al. [DGJ+09] to show that bounded independence suffices to fool functions of halfspaces under product distributions. Assuming each coordinate satisfies a certain stronger moment condition, we show that any function computable by a size-s, depth-d decision tree of halfspaces is eps-fooled by O(d^4s^2/eps^2)-wise independence.
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