Early childhood lung function is a stronger predictor of adolescent lung function in cystic fibrosis than early Pseudomonas aeruginosa infection

Pseudomonas aeruginosa has been suggested as a major determinant of poor pulmonary outcomes in cystic fibrosis (CF), although other factors play a role. Our objective was to investigate the association of early childhood Pseudomonas infection on differences in lung function in adolescence with CF

Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report

Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10−11), chr5p15.3 (SLC9A3; P=6.8 × 10−12), chr6p21.3 (HLA Class II; P=1.2 × 10−8) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10−9) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10−10), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF

Gene modifiers in cystic fibrosis

Studies of modifier genes in cystic fibrosis (CF) have often been performed in small or narrowly defined populations, leading to conflicting results. In this issue of the JCI, Dorfman et al. demonstrate in a large, population-based study that two previously studied modifier genes, coding for mannose-binding lectin 2 and TGF-β1, influence pulmonary outcome in pediatric CF patients (see the related article beginning on page 1040). They further show gene-gene interaction between the two, underscoring the complexity of CF lung disease. Their findings provide further impetus to study these molecules and associated signaling pathways in CF. In addition, these findings argue strongly for collecting genotypes of known modifiers prospectively in CF clinical trials as well as in longitudinal studies of infants identified through newborn screening, where the full impact of such modifiers can be defined more precisely

From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist

Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series

Population characteristics of GMS and NBS subjects.

<p>Population characteristics of GMS and NBS subjects.</p

Colorado NBS Population: Early childhood lung function by adolescent lung function quartile and early childhood <i>Pa</i> status.

<p>Early childhood lung function (mean FEV₁ at 6–8 years of age) by adolescent lung function quartile and early childhood <i>Pa</i> status (ever/never <i>Pa</i> positive before age 6). Subjects were first divided into even quartiles by adolescent lung function (n = 43 in each quartile), then further divided by <i>Pa</i> status in early childhood. Among <i>Pa</i> positive subjects, those in the lowest adolescent lung function quartile had significantly lower early childhood lung function compared to all other quartiles; differences in early childhood lung function among <i>Pa</i> negative subjects did not reach statistical significance. When comparing subjects within individual adolescent lung function quartiles, <i>Pa</i> positive subjects in the lowest adolescent lung function quartile had significantly lower early childhood lung function than <i>Pa</i> negative (p<0.001); otherwise there were no significant differences in early childhood lung function by <i>Pa</i> status within adolescent lung function quartiles.</p

Colorado NBS Population: Annual rate of change in FEV₁ percent predicted from childhood to adolescence by adolescent lung function quartile and <i>Pa</i> status before 6 years of age.

<p>Colorado NBS Population: Annual rate of change in FEV₁ percent predicted from childhood to adolescence by adolescent lung function quartile and <i>Pa</i> status before 6 years of age.</p