39 research outputs found

    Effect of Temperature on Cystic Fibrosis Lung Disease and Infections: A Replicated Cohort Study

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    Progressive lung disease accounts for the majority of morbidity and mortality observed in cystic fibrosis (CF). Beyond secondhand smoke exposure and socio-economic status, the effect of specific environmental factors on CF lung function is largely unknown.Multivariate regression was used to assess correlation between specific environmental factors, the presence of pulmonary pathogens, and variation in lung function using subjects enrolled in the U.S. CF Twin and Sibling Study (CFTSS: n = 1378). Significant associations were tested for replication in the U.S. CF Foundation Patient Registry (CFF: n = 16439), the Australian CF Data Registry (ACFDR: n = 1801), and prospectively ascertained subjects from Australia/New Zealand (ACFBAL: n = 167).In CFTSS subjects, the presence of Pseudomonas aeruginosa (OR = 1.06 per °F; p<0.001) was associated with warmer annual ambient temperatures. This finding was independently replicated in the CFF (1.02; p<0.001), ACFDR (1.05; p = 0.002), and ACFBAL (1.09; p = 0.003) subjects. Warmer temperatures (-0.34 points per °F; p = 0.005) and public insurance (-6.43 points; p<0.001) were associated with lower lung function in the CFTSS subjects. These findings were replicated in the CFF subjects (temperature: -0.31; p<0.001; insurance: -9.11; p<0.001) and similar in the ACFDR subjects (temperature: -0.23; p = 0.057). The association between temperature and lung function was minimally influenced by P. aeruginosa. Similarly, the association between temperature and P. aeruginosa was largely independent of lung function.Ambient temperature is associated with prevalence of P. aeruginosa and lung function in four independent samples of CF patients from two continents

    East Bay Coalition for the Homeless: Branding Study and Marketing Strategy

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    There are a number of potential positioning strategies. The two which make the most sense for the EBCH are to “position the EBCH away from others in the category” and to “position the EBCH as unique.” These strategies have the advantage of setting the EBCH apart from the other organizations that address homelessness. Occupying its own “position” in the minds of potential and current donors is not only an effective communications/marketing strategy but also a less costly one because it avoids head-to-head competition and comparisons

    Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis

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    Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10−5 to 1.08×10−6; Bonferroni P = 0.057 to 3.1×10−3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10−4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr−/− and Cftr−/−Msra−/− mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function

    A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis Genetic modifier studies

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    Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment

    Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

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    Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10−12 at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10−9 at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, P=0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis

    Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

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    A combined genome-wide association and linkage study was used to identify loci causing variation in CF lung disease severity. A significant association (P=3. 34 × 10-8) near EHF and APIP (chr11p13) was identified in F508del homozygotes (n=1,978). The association replicated in F508del homozygotes (P=0.006) from a separate family-based study (n=557), with P=1.49 × 10-9 for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family-based study identified a significant QTL on chromosome 20q13.2 (LOD=5.03). Our findings provide insight into the causes of variation in lung disease severity in CF and suggest new therapeutic targets for this life-limiting disorder

    Number Agreement in British and American English : Disagreeing to Agree Collectively

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    Contains fulltext : 55701.pdf (publisher's version ) (Open Access)British and American speakers exhibit different verb number agreement patterns when sentence subjects have collective head nouns. From linguistic and psycholinguistic accounts of how agreement is implemented, three alternative hypotheses can be derived to explain these differences. The hypotheses involve variations in the representation of notional number, disparities in how notional and grammatical number are used, and inequalities in the grammatical number specifications of collective nouns. We carried out a series of corpus analyses, production experiments, and norming studies to test these hypotheses. The results converge to suggest that British and American speakers are equally sensitive to variations in notional number and implement subject-verb agreement in much the same way, but are likely to differ in the lexical specifications of number for collectives. The findings support a psycholinguistic theory that explains verb and pronoun agreement within a parallel architecture of lexical and syntactic formulation.50 p

    Sea surface height variability in drake passage

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    Intercomparisons between altimeter sea surface height (SSH) and open-ocean in situ observations have been limited owing to sparse available datasets. Here, SSH anomaly (SSHA) determined from current and pressure recording inverted echo sounders (CPIES) from the cDrake experiment were compared with an up-to-date AVISO-mapped product. Meandering Antarctic Circumpolar Current (ACC) fronts in the passage interior elevated SSHA variance; south of the Shackleton Fracture Zone and along the northern continental slope, the variance decreased by factors between 6 and 10. In situ analysis focused on the two constituents of SSHA, SSHAref determined from bottom pressure and SSHAbcb calculated from geopotential height referenced to the bottom. The peak variance of both SSHAbcb and SSHAref occurred in the energetic region between the Subantarctic Front and the Polar Front. The contribution of SSHAbcb to total SSHA variance was greater than 40% at all sites and averaged over all sites it was 73%. For most sites, high-frequency (\u3e 1/20 cpd) SSHAbcb signals dominated total high-frequency variance. Aliasing of high-frequency signals resulting from 10-day altimeter sampling was assessed. The fraction of aliased energy at frequencies longer than 1/50 cpd for sites at and north of the Shackleton Fracture Zone approached 0.25 and approached 0.50 for southern sites. CPIES and mapped altimeter SSHA agreed well. The mean correlation coefficient was 0.82 and the mean RMS difference was 0.075 m. Correlations between CPIES and AVISO were notably poorer at the northern and southern boundaries. RMS differences increased as a function of CPIES high-frequency SSHA variance because the mapped altimetry product does not resolve these frequencies
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