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Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.

BACKGROUND: The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids.

METHODS: We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects.

RESULTS: We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P=0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P=0.0007 for pooled data). Overall, the mean (±SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2±1.6% vs. 9.4±1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.

CONCLUSIONS: A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma.

Identification of chronic obstructive pulmonary disease in lung cancer screening computed tomographic scans.

CONTEXT: Smoking is a major risk factor for both cancer and chronic obstructive pulmonary disease (COPD). Computed tomography (CT)-based lung cancer screening may provide an opportunity to detect additional individuals with COPD at an early stage.

OBJECTIVE: To determine whether low-dose lung cancer screening CT scans can be used to identify participants with COPD.

DESIGN, SETTING, AND PATIENTS: Single-center prospective cross-sectional study within an ongoing lung cancer screening trial. Prebronchodilator pulmonary function testing with inspiratory and expiratory CT on the same day was obtained from 1140 male participants between July 2007 and September 2008. Computed tomographic emphysema was defined as percentage of voxels less than -950 Hounsfield units (HU), and CT air trapping was defined as the expiratory:inspiratory ratio of mean lung density. Chronic obstructive pulmonary disease was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV(1)/FVC) of less than 70%. Logistic regression was used to develop a diagnostic prediction model for airflow limitation.

MAIN OUTCOME MEASURES: Diagnostic accuracy of COPD diagnosis using pulmonary function tests as the reference standard.

RESULTS: Four hundred thirty-seven participants (38%) had COPD according to lung function testing. A diagnostic model with CT emphysema, CT air trapping, body mass index, pack-years, and smoking status corrected for overoptimism (internal validation) yielded an area under the receiver operating characteristic curve of 0.83 (95% CI, 0.81-0.86). Using the point of optimal accuracy, the model identified 274 participants with COPD with 85 false-positives, a sensitivity of 63% (95% CI, 58%-67%), specificity of 88% (95% CI, 85%-90%), positive predictive value of 76% (95% CI, 72%-81%); and negative predictive value of 79% (95% CI, 76%-82%). The diagnostic model showed an area under the receiver operating characteristic curve of 0.87 (95% CI, 0.86-0.88) for participants with symptoms and 0.78 (95% CI, 0.76-0.80) for those without symptoms.

CONCLUSION: Among men who are current and former heavy smokers, low-dose inspiratory and expiratory CT scans obtained for lung cancer screening can identify participants with COPD, with a sensitivity of 63% and a specificity of 88%.

Screening by chest radiograph and lung cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized trial.

CONTEXT: The effect on mortality of screening for lung cancer with modern chest radiographs is unknown.

OBJECTIVE: To evaluate the effect on mortality of screening for lung cancer using radiographs in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial that involved 154,901 participants aged 55 through 74 years, 77,445 of whom were assigned to annual screenings and 77,456 to usual care at 1 of 10 screening centers across the United States between November 1993 and July 2001. The data from a subset of eligible participants for the National Lung Screening Trial (NLST), which compared chest radiograph with spiral computed tomographic (CT) screening, were analyzed.
INTERVENTION: Participants in the intervention group were offered annual posteroanterior view chest radiograph for 4 years. Diagnostic follow-up of positive screening results was determined by participants and their health care practitioners. Participants in the usual care group were offered no interventions and received their usual medical care. All diagnosed cancers, deaths, and causes of death were ascertained through the earlier of 13 years of follow-up or until December 31, 2009.
MAIN OUTCOME MEASURES: Mortality from lung cancer. Secondary outcomes included lung cancer incidence, complications associated with diagnostic procedures, and all-cause mortality.

RESULTS: Screening adherence was 86.6% at baseline and 79% to 84% at years 1 through 3; the rate of screening use in the usual care group was 11%. Cumulative lung cancer incidence rates through 13 years of follow-up were 20.1 per 10,000 person-years in the intervention group and 19.2 per 10,000 person-years in the usual care group (rate ratio [RR]; 1.05, 95% CI, 0.98-1.12). A total of 1213 lung cancer deaths were observed in the intervention group compared with 1230 in usual care group through 13 years (mortality RR, 0.99; 95% CI, 0.87-1.22). Stage and histology were similar between the 2 groups. The RR of mortality for the subset of participants eligible for the NLST, over the same 6-year follow-up period, was 0.94 (95% CI, 0.81-1.10).

CONCLUSION: Annual screening with chest radiograph did not reduce lung cancer mortality compared with usual care.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00002540.

Increasing pharmaceutical copayments: impact on asthma medication utilization and outcomes.

Increasing pharmaceutical copayments: impact on asthma medication utilization and outcomes.

Am J Manag Care. 2011 Oct;17(10):703-10

Authors: Campbell JD, Allen-Ramey F, Sajjan SG, Maiese EM, Sullivan SD

Abstract
OBJECTIVES: Unintended consequences may result from changes in pharmacy benefit design. The objective was to determine the impact of increasing patient prescription copayments for guideline recommended, long-term asthma controller (LTC) medications on asthma-related medication use and healthcare services.
STUDY DESIGN: We used 2005 MarketScan healthcare and pharmacy claims data to identify asthma (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis code 493.xx) patients aged 12 to 64 years who were continuously enrolled through 2006 with ≥ 1 claim for an asthma medication in 2005. LTCs included: inhaled corticosteroid (ICS) (n = 10,251), ICS plus long-acting beta agonist (COMBO) (n =27,407), and leukotriene receptor antagonist (LTRA) (n = 20,664).
METHODS: Using multivariable models, we estimated the associations between changes in LTC copayments and LTC consumption and asthma-related outpatient and emergency department (ED) visits.
RESULTS: Patients were dichotomized into ≥ $5 average increase in patient copayments per month of medication supplied (yes/no). The mean annual change (2005-2006) in copayments per month was $13.23 versus -$3.88 (ICS), $11.76 versus -$3.06 (COMBO), and $9.78 versus -$2.06 (LTRA). The ≥ $5 group experienced a significant decline in average annual days of medication supplied of -47.1 days of ICS (95% CI -43.5 to -50.8), -35.3 days of COMBO (-32.4 to -38.2), and -47.5 days of LTRA (-43.2 to -51.7). Among COMBO and LTRA medication users, the ≥ $5 copayment increase was associated with more asthma-related outpatient visits and ED visits compared with the < $5 group.
CONCLUSIONS: The findings suggest that even small changes in average copayment for asthma medications can result in significant reductions in medication use and unintended increases in healthcare services.

PMID: 22106463 [PubMed - in process]

Vitamin D levels not linked to acute exacerbations in COPD patients

Vitamin D levels are not associated with acute exacerbations in patients with chronic obstructive pulmonary disease, study results show.

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