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Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.
Hancock DB, Soler Artigas M, Gharib SA, Henry A, Manichaikul A, Ramasamy A, Loth DW, Imboden M, Koch B, McArdle WL, Smith AV, Smolonska J, Sood A, Tang W, Wilk JB, Zhai G, Zhao JH, Aschard H, Burkart KM, Curjuric I, Eijgelsheim M, Elliott P, Gu X, Harris TB, Janson C, Homuth G, Hysi PG, Liu JZ, Loehr LR, Lohman K, Loos RJ, Manning AK, Marciante KD, Obeidat M, Postma DS, Aldrich MC, Brusselle GG, Chen TH, Eiriksdottir G, Franceschini N, Heinrich J, Rotter JI, Wijmenga C, Williams OD, Bentley AR, Hofman A, Laurie CC, Lumley T, Morrison AC, Joubert BR, Rivadeneira F, Couper DJ, Kritchevsky SB, Liu Y, Wjst M, Wain LV, Vonk JM, Uitterlinden AG, Rochat T, Rich SS, Psaty BM, O'Connor GT, North KE, Mirel DB, Meibohm B, Launer LJ, Khaw KT, Hartikainen AL, Hammond CJ, Gläser S, Marchini J, Kraft P, Wareham NJ, Völzke H, Stricker BH, Spector TD, Probst-Hensch NM, Jarvis D, Jarvelin MR, Heckbert SR, Gudnason V, Boezen HM, Barr RG, Cassano PA, Strachan DP, Fornage M, Hall IP, Dupuis J, Tobin MD, London SJ
(2012) PLoS Genet 8: e1003098
MeSH Terms: Forced Expiratory Volume, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Lung, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pulmonary Disease, Chronic Obstructive, Receptors, Cell Surface, SOX9 Transcription Factor, Smoking, Vital Capacity
Show Abstract · Added February 26, 2014
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
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16 MeSH Terms
Noninvasive testing of lung function and inflammation in pediatric patients with acute asthma exacerbations.
Arnold DH, Gebretsadik T, Abramo TJ, Hartert TV
(2012) J Asthma 49: 29-35
MeSH Terms: Academic Medical Centers, Adolescent, Age Factors, Airway Resistance, Asthma, Breath Tests, Bronchitis, Child, Child, Preschool, Cohort Studies, Disease Progression, Emergency Service, Hospital, Female, Follow-Up Studies, Forced Expiratory Volume, Humans, Male, Nitric Oxide, Predictive Value of Tests, Prospective Studies, Respiratory Function Tests, Risk Assessment, Severity of Illness Index, Sex Factors, Spirometry, Urban Population
Show Abstract · Added May 27, 2014
OBJECTIVE - There is limited information on performance rates for tests of lung function and inflammation in pediatric patients with acute asthma exacerbations. We sought to examine how frequently pediatric patients with acute asthma exacerbations could perform noninvasive lung function and exhaled nitric oxide (FE(NO)) testing and participant characteristics associated with successful performance.
METHODS - We studied a prospective convenience sample aged 5-17 years with acute asthma exacerbations in a pediatric emergency department. Participants attempted spirometry for percent predicted forced expiratory volume in 1 second (%FEV(1)), airway resistance (Rint), and FE(NO) testing before treatment. We examined overall performance rates and the associations of age, gender, race, and baseline acute asthma severity score with successful test performance.
RESULTS - Among 573 participants, age was (median [interquartile range]) 8.8 [6.8, 11.5] years, 60% were male, 57% were African-American, and 58% had Medicaid insurance. Tests were performed successfully by the following [n (%)]: full American Thoracic Society-European Respiratory Society criteria spirometry, 331 (58%); Rint, 561 (98%); and FE(NO), 354 (70% of 505 attempted test). Sixty percent with mild-moderate exacerbations performed spirometry compared to 17% with severe exacerbations (p = .0001). Participants aged 8-12 years (67%) were more likely to perform spirometry than those aged 5-7 years (48%) (OR = 2.23, 95% CI: 1.45-3.11) or 13-17 years (58%) (OR = 1.61, 95% CI: 1.00-2.59).
CONCLUSIONS - There is clinically important variability in performance of these tests during acute asthma exacerbations. The proportion of patients with severe exacerbations able to perform spirometry (17%) limits its utility. Almost all children with acute asthma can perform Rint testing, and further development and validation of this technology is warranted.
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The impact of adjuvant brachytherapy with sublobar resection on pulmonary function and dyspnea in high-risk patients with operable disease: preliminary results from the American College of Surgeons Oncology Group Z4032 trial.
Fernando HC, Landreneau RJ, Mandrekar SJ, Hillman SL, Nichols FC, Meyers B, DiPetrillo TA, Heron D, Jones DR, Daly BD, Starnes SL, Hatter JE, Putnam JB
(2011) J Thorac Cardiovasc Surg 142: 554-62
MeSH Terms: Aged, Aged, 80 and over, Brachytherapy, Carcinoma, Non-Small-Cell Lung, Dyspnea, Female, Forced Expiratory Volume, Humans, Lung Neoplasms, Male, Middle Aged, Prospective Studies, Pulmonary Diffusing Capacity, Radiotherapy, Adjuvant, Thoracic Surgery, Video-Assisted, Thoracotomy, Treatment Outcome
Show Abstract · Added March 27, 2014
BACKGROUND - Z4032 was a randomized study conducted by the American College of Surgeons Oncology Group comparing sublobar resection alone versus sublobar resection with brachytherapy for high-risk operable patients with non-small cell lung cancer (NSCLC). This evaluates early impact of adjuvant brachytherapy on pulmonary function tests, dyspnea, and perioperative (30-day) respiratory complications in this impaired patient population.
METHODS - Eligible patients with stage I NSCLC tumors 3 cm or smaller were randomly allocated to undergo sublobar resection with (SRB group) or without (SR group) brachytherapy. Outcomes measured included the percentage predicted forced expiratory volume in 1 second (FEV1%), percentage predicted carbon monoxide diffusion capacity (DLCO%), and dyspnea score per the University of California San Diego Shortness of Breath Questionnaire. Pulmonary morbidity was assessed per the Common Terminology Criteria for Adverse Events version 3.0. Outcomes were measured at baseline and 3 months. A 10% change in pulmonary function test or 10-point change in dyspnea score was deemed clinically meaningful.
RESULTS - Z4032 permanently closed to patient accrual in January 2010 at 224 patients. At 3-month follow-up, pulmonary function data are currently available for 148 (74 SR and 74 SRB) patients described in this report. There were no differences in baseline characteristics between arms. In the SR arm, 9 patients (12%) reported grade 3 respiratory adverse events, compared with 12 (16%) in the SRB arm (P = .49). There was no significant change in percentage change in DLCO% or dyspnea score from baseline to 3 months within either arm. In the case of FEV1%, percentage change from baseline to 3 months was significant within the SR arm (P = .03), with patients reporting improvement in FEV1% at month 3. Multivariable regression analysis (adjusted for baseline values) showed no significant impact of treatment arm, tumor location (upper vs other lobe), or surgical approach (video-assisted thoracoscopic surgery vs thoracotomy) on 3-month FEV1%, DLCO%, and dyspnea score. There was no significant difference in incidence of clinically meaningful (10% pulmonary function or 10-point dyspnea score change) change between arms. Twenty-two percent of patients with lower-lobe tumors and 9% with upper-lobe tumors demonstrated 10% decline in FEV1% (odds ratio, 2.79; 95 confidence interval, 1.07-7.25; P = .04).
CONCLUSIONS - Adjuvant intraoperative brachytherapy in conjunction with sublobar resection did not significantly worsen pulmonary function or dyspnea at 3 months in a high-risk population with NSCLC, nor was it associated with increased perioperative pulmonary adverse events. Lower-lobe resection was the only factor significantly associated with clinically meaningful decline in FEV1%.
Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
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17 MeSH Terms
Accessory muscle use in pediatric patients with acute asthma exacerbations.
Arnold DH, Gebretsadik T, Sheller JR, Abramo TJ, Hartert TV
(2011) Ann Allergy Asthma Immunol 106: 344-6
MeSH Terms: Adolescent, Asthma, Child, Child, Preschool, Cohort Studies, Female, Forced Expiratory Volume, Humans, Male, Muscle, Skeletal, Prospective Studies, Statistics, Nonparametric
Added May 27, 2014
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12 MeSH Terms
Socioeconomic status is positively associated with percent emphysema on CT scan: The MESA lung study.
Lovasi GS, Diez Roux AV, Hoffman EA, Smith LJ, Jiang R, Carr JJ, Barr RG
(2011) Acad Radiol 18: 199-204
MeSH Terms: Aged, Aged, 80 and over, Atherosclerosis, Forced Expiratory Volume, Humans, Male, Middle Aged, Pulmonary Emphysema, Smoking, Social Class, Socioeconomic Factors, Spirometry, Tomography, X-Ray Computed, Vital Capacity
Show Abstract · Added February 15, 2014
RATIONALE AND OBJECTIVES - Higher socioeconomic status (SES) has been associated with lower respiratory mortality and better lung function, but whether a similar gradient exists for computed tomography (CT) measures of subclinical emphysema is unknown.
MATERIALS AND METHODS - The Multi-Ethnic Study of Atherosclerosis (MESA) recruited African-American, Chinese, Hispanic, and white participants, ages 45 to 84 years, without clinical cardiovascular disease, from six US sites between 2000 and 2002. The MESA Lung Study assessed percent emphysema, defined based on the proportion of pixels below an attenuation threshold of 910 HU from lung windows of cardiac CT scans. Generalized linear models were adjusted for demographic characteristics, height, body mass index, history of respiratory illness, occupational and residential exposures, tobacco use, and CT scanner type.
RESULTS - Among 3706 participants with a mean age of 61 (±10), the median value for percent emphysema was 18 (interquartile range = 20). Compared with those who did not complete high school, participants with a graduate degree had a higher percent emphysema (difference of 4; P < .001). Income and wealth were also positively associated with percent emphysema. In contrast, higher SES was associated with better lung function. Descriptive and subgroup analyses were used to explore potential explanations for divergent results, including the possibility that suboptimal inspiration during CT scanning would decrease percent emphysema, making the lungs appear healthier when effort is relatively poor.
CONCLUSION - Although SES indicators were positively associated with subclinical emphysema detectable on CT scan, this unexpected association may highlight potential bias because of effort dependence of both CT measures and spirometry.
Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Genetic ancestry in lung-function predictions.
Kumar R, Seibold MA, Aldrich MC, Williams LK, Reiner AP, Colangelo L, Galanter J, Gignoux C, Hu D, Sen S, Choudhry S, Peterson EL, Rodriguez-Santana J, Rodriguez-Cintron W, Nalls MA, Leak TS, O'Meara E, Meibohm B, Kritchevsky SB, Li R, Harris TB, Nickerson DA, Fornage M, Enright P, Ziv E, Smith LJ, Liu K, Burchard EG
(2010) N Engl J Med 363: 321-30
MeSH Terms: Adolescent, Adult, African Americans, Aged, Aged, 80 and over, Female, Forced Expiratory Volume, Genetic Markers, Genotype, Humans, Linear Models, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Reference Values, Respiratory Function Tests, Vital Capacity, Young Adult
Show Abstract · Added February 26, 2014
BACKGROUND - Self-identified race or ethnic group is used to determine normal reference standards in the prediction of pulmonary function. We conducted a study to determine whether the genetically determined percentage of African ancestry is associated with lung function and whether its use could improve predictions of lung function among persons who identified themselves as African American.
METHODS - We assessed the ancestry of 777 participants self-identified as African American in the Coronary Artery Risk Development in Young Adults (CARDIA) study and evaluated the relation between pulmonary function and ancestry by means of linear regression. We performed similar analyses of data for two independent cohorts of subjects identifying themselves as African American: 813 participants in the Health, Aging, and Body Composition (HABC) study and 579 participants in the Cardiovascular Health Study (CHS). We compared the fit of two types of models to lung-function measurements: models based on the covariates used in standard prediction equations and models incorporating ancestry. We also evaluated the effect of the ancestry-based models on the classification of disease severity in two asthma-study populations.
RESULTS - African ancestry was inversely related to forced expiratory volume in 1 second (FEV(1)) and forced vital capacity in the CARDIA cohort. These relations were also seen in the HABC and CHS cohorts. In predicting lung function, the ancestry-based model fit the data better than standard models. Ancestry-based models resulted in the reclassification of asthma severity (based on the percentage of the predicted FEV(1)) in 4 to 5% of participants.
CONCLUSIONS - Current predictive equations, which rely on self-identified race alone, may misestimate lung function among subjects who identify themselves as African American. Incorporating ancestry into normative equations may improve lung-function estimates and more accurately categorize disease severity. (Funded by the National Institutes of Health and others.)
2010 Massachusetts Medical Society
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beta(2)-adrenergic receptor promoter haplotype influences spirometric response during an acute asthma exacerbation.
Moore PE, Williams SM, Gebretsadik T, Jiang L, Minton PL, Shintani A, Phillips Iii JA, Dawson EP, Hartert TV
(2008) Clin Transl Sci 1: 155-61
MeSH Terms: Acute Disease, Adolescent, Adult, Asthma, Cohort Studies, Demography, Forced Expiratory Volume, Gene Frequency, Haplotypes, Hospitalization, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Receptors, Adrenergic, beta-2, Spirometry
Show Abstract · Added May 27, 2014
Genetic variants in the beta(2)-adrenergic receptor (ADRB2) coding block have been associated with different parameters of asthma severity, but there is no consensus on which variants are most important. Our objective was to determine whether the genetic variants in the 5'- or 3'-flanking regions of ADRB2 impact the response to therapy. DNA was obtained initially from 72 adults hospitalized for an asthma exacerbation. We sequenced a 5,000 bp region of the ADRB2 gene that spanned the flanking regions and identified 31 single nucleotide polymorphisms (SNPs). Nonresponders to asthma therapy were defined as patients whose forced expiratory volume in 1 second (FEV(1)) worsened by >10% at 24 hours after admission. We then evaluated the relationship between the 19 common SNPs and response to asthma-specific therapy during acute disease exacerbations. Our results showed a significant association between nonresponders and a haplotype of five promoter SNPs in a nearly complete linkage disequilibrium. An analysis of the promoter and coding block polymorphisms in an extended cohort of 99 patients confirmed that promoter haplotype was the genetic component most strongly associated with asthmatic nonresponders, which was statistically significant among whites (p < 0.05). An identification of this promoter haplotype may provide an alternate explanation for the variation in the asthma responses observed with ADRB2 coding block polymorphisms.
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16 MeSH Terms
Noninvasive assessment of asthma severity using pulse oximeter plethysmograph estimate of pulsus paradoxus physiology.
Arnold DH, Jenkins CA, Hartert TV
(2010) BMC Pulm Med 10: 17
MeSH Terms: Adolescent, Adrenal Cortex Hormones, Airway Resistance, Asthma, Bronchodilator Agents, Child, Child, Preschool, Female, Forced Expiratory Volume, Humans, Logistic Models, Male, Models, Theoretical, Outcome Assessment, Health Care, Oximetry, Plethysmography, Prospective Studies, Reproducibility of Results, Respiratory Muscles, Severity of Illness Index, Time Factors
Show Abstract · Added May 27, 2014
BACKGROUND - Pulsus paradoxus estimated by dynamic change in area under the oximeter plethysmograph waveform (PEP) might provide a measure of acute asthma severity. Our primary objective was to determine how well PEP correlates with forced expiratory volume in 1-second (%FEV1) (criterion validity) and change of %FEV1 (responsiveness) during treatment in pediatric patients with acute asthma exacerbations.
METHODS - We prospectively studied subjects 5 to 17 years of age with asthma exacerbations. PEP, %FEV1, airway resistance and accessory muscle use were recorded at baseline and at 2 and 4 hours after initiation of corticosteroid and bronchodilator treatments. Statistical associations were tested with Pearson or Spearman rank correlations, logistic regression using generalized estimating equations, or Wilcoxon rank sum tests.
RESULTS - We studied 219 subjects (median age 9 years; male 62%; African-American 56%). Correlation of PEP with %FEV1 demonstrated criterion validity (r = - 0.44, 95% confidence interval [CI], - 0.56 to - 0.30) and responsiveness at 2 hours (r = - 0.31, 95% CI, - 0.50 to - 0.09) and 4 hours (r = - 0.38, 95% CI, - 0.62 to - 0.07). PEP also correlated with airway resistance at baseline (r = 0.28 for ages 5 to 10; r = 0.45 for ages 10 to 17), but not with change over time. PEP was associated with accessory muscle use (OR 1.16, 95% CI, 1.11 to 1.21, P < 0.0001).
CONCLUSIONS - PEP demonstrates criterion validity and responsiveness in correlations with %FEV1. PEP correlates with airway resistance at baseline and is associated with accessory muscle use at baseline and at 2 and 4 hours after initiation of treatment. Incorporation of this technology into contemporary pulse oximeters may provide clinicians improved parameters with which to make clinical assessments of asthma severity and response to treatment, particularly in patients who cannot perform spirometry because of young age or severity of illness. It might also allow for earlier recognition and improved management of other disorders leading to elevated pulsus paradoxus.
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21 MeSH Terms
Percent emphysema, airflow obstruction, and impaired left ventricular filling.
Barr RG, Bluemke DA, Ahmed FS, Carr JJ, Enright PL, Hoffman EA, Jiang R, Kawut SM, Kronmal RA, Lima JA, Shahar E, Smith LJ, Watson KE
(2010) N Engl J Med 362: 217-27
MeSH Terms: Aged, Aged, 80 and over, Airway Obstruction, Cardiac Output, Female, Forced Expiratory Volume, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multivariate Analysis, Pulmonary Emphysema, Smoking, Spirometry, Stroke Volume, Tomography, X-Ray Computed, Ventricular Dysfunction, Left, Vital Capacity
Show Abstract · Added February 28, 2014
BACKGROUND - Very severe chronic obstructive pulmonary disease causes cor pulmonale with elevated pulmonary vascular resistance and secondary reductions in left ventricular filling, stroke volume, and cardiac output. We hypothesized that emphysema, as detected on computed tomography (CT), and airflow obstruction are inversely related to left ventricular end-diastolic volume, stroke volume, and cardiac output among persons without very severe lung disease.
METHODS - We measured left ventricular structure and function with the use of magnetic resonance imaging in 2816 persons who were 45 to 84 years of age. The extent of emphysema (expressed as percent emphysema) was defined as the percentage of voxels below -910 Hounsfield units in the lung windows on cardiac computed tomographic scans. Spirometry was performed according to American Thoracic Society guidelines. Generalized additive models were used to test for threshold effects.
RESULTS - Of the study participants, 13% were current smokers, 38% were former smokers, and 49% had never smoked. A 10-point increase in percent emphysema was linearly related to reductions in left ventricular end-diastolic volume (-4.1 ml; 95% confidence interval [CI], -3.3 to -4.9; P<0.001), stroke volume (-2.7 ml; 95% CI, -2.2 to -3.3; P<0.001), and cardiac output (-0.19 liters per minute; 95% CI, -0.14 to -0.23; P<0.001). These associations were of greater magnitude among current smokers than among former smokers and those who had never smoked. The extent of airflow obstruction was similarly associated with left ventricular structure and function, and smoking status had similar modifying effects on these associations. Percent emphysema and airflow obstruction were not associated with the left ventricular ejection fraction.
CONCLUSIONS - In a population-based study, a greater extent of emphysema on CT scanning and more severe airflow obstruction were linearly related to impaired left ventricular filling, reduced stroke volume, and lower cardiac output without changes in the ejection fraction.
2010 Massachusetts Medical Society
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18 MeSH Terms
Circulating RNA transcripts identify therapeutic response in cystic fibrosis lung disease.
Saavedra MT, Hughes GJ, Sanders LA, Carr M, Rodman DM, Coldren CD, Geraci MW, Sagel SD, Accurso FJ, West J, Nick JA
(2008) Am J Respir Crit Care Med 178: 929-38
MeSH Terms: Acute Disease, Adult, Anti-Bacterial Agents, Biomarkers, Cohort Studies, Cystic Fibrosis, Cytokines, Female, Forced Expiratory Volume, Gene Expression Profiling, Humans, Leukocytes, Male, Oligonucleotide Array Sequence Analysis, Predictive Value of Tests, Prospective Studies, RNA Precursors, ROC Curve, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Spirometry, Young Adult
Show Abstract · Added November 17, 2011
RATIONALE - Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in cystic fibrosis (CF) lung disease. Although the standard assessment of pulmonary treatment response is FEV(1), a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits the testing of proposed therapeutics.
OBJECTIVES - We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation using a model by which RNA transcripts could increase the predictive value of spirometry.
METHODS - Peripheral blood mononuclear cells were isolated from 10 patients with CF and acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed that 10 genes significantly changed with treatment when compared with matched non-CF and control subjects with stable CF to establish baseline transcript abundance. Peripheral blood mononuclear cell RNA transcripts were prospectively validated, using real-time polymerase chain reaction amplification, in an independent cohort of acutely ill patients with CF (n = 14). Patients who responded to therapy were analyzed using general estimating equations and multiple logistic regression, such that changes in FEV(1)% predicted were regressed with transcript changes.
MEASUREMENTS AND MAIN RESULTS - Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of a therapeutic response beyond that of FEV(1) alone (P < 0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV(1).
CONCLUSIONS - Circulating mononuclear cell transcripts characterize a response to the treatment of pulmonary exacerbations. Even in small patient cohorts, changes in gene expression in conjunction with FEV(1) may enhance current outcomes measures for treatment response.
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22 MeSH Terms