Citations

AbstractBackgroundHeterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown.ObjectiveTo determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma‐enriched cohort.MethodsWe analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1‐3). Potentially pathogenic, rare CFTR variants (frequency < 0.05) were classified as CF‐causing or of varying clinical consequences (VVCC) (CFTR2. org). Regression‐based models tested for association between CFTR genotypes (0‐2 potentially pathogenic variants) and severity outcomes.ResultsOf 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non‐Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5 T; TG12[c.1210‐11 T > G] and one Arg1070Trp) and a homozygote for the VVCC, 5 T; TG12.ConclusionsWe found potentially pathogenic CFTR variants within a severe asthma‐enriched cohort, including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF‐related traits in individuals with severe asthma.

Background: Heterozygote carriers of potentially pathogenic variants in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene have increased asthma risk. However, the frequency and impact of CFTR variation among individuals with asthma is unknown. Objective: To determine whether potentially pathogenic CFTR variants associate with disease severity and whether individuals with two potentially pathogenic variants exist in a severe asthma-enriched cohort . Methods : We analyzed sequencing data spanning a 190.5Kb region of CFTR in participants from the Severe Asthma Research Program (SARP1-3). Potentially pathogenic, rare CFTR variants (frequency<0.05) were classified as CF-causing or of varying clinical consequences (VVCC) (CFTR2.org). Regression-based models tested for association between CFTR genotypes (0-2 potentially pathogenic variants) and severity outcomes. Results: Of 1401 participants, 9.5% (134) had one potentially pathogenic variant, occurring more frequently in non-Hispanic white (NHW, 10.1% [84 of 831]) compared to African American individuals (AA, 5.2% [22 of 426]). We found ≥2 potentially pathogenic CFTR variants in 1.4% (19); 0.5% (4) of NHW and 2.8% (12) of AA. Potentially pathogenic CFTR variant genotypes (≥1 or ≥2 variants) were not cumulatively associated with lung function or exacerbations. In NHW, we found three F508del compound heterozygotes with F508del and a VVCC (two 5T;TG12[c.1210-11T>G] and one Arg1070Trp) and a homozygote for the VVCC, 5T;TG12. Conclusions: We found potentially pathogenic CFTR variants within a severe asthma-enriched cohort , including three compound heterozygote genotypes variably associated with CF in NHW individuals. These findings provide the rationale for CFTR sequencing and phenotyping of CF-related traits in individuals with severe asthma.

SIGNIFICANCE A rigorously designed and calibrated symptom questionnaire for childhood intermittent exotropia would be useful for clinical care and for research. PURPOSE The aim of this study was to Rasch‐calibrate and evaluate the previously developed Child Intermittent Exotropia Symptom Questionnaire using data gathered as part of a randomized clinical trial. METHODS The questionnaire was administered to 386 children aged 3 to 10 years with intermittent exotropia who were enrolled in a randomized clinical trial comparing overminus with nonoverminus spectacles. Participants were followed at 6 and 12 months while on treatment and at 18 months off treatment. Factor analysis determined dimensionality, and Rasch analysis evaluated questionnaire performance. Logit values were converted to 0 (best) to 100 (worst). We evaluated differences in questionnaire scores between treatment groups and time points, and correlations with control scores. RESULTS The Child Intermittent Exotropia Symptom Questionnaire was unidimensional. Rasch analysis indicated that there was no notable local dependence and no significant differential item functioning for sex or age. There was suboptimal targeting (mean logit, −1.62), and person separation was somewhat poor (0.95). There were no significant differences in the Child Intermittent Exotropia Symptom score between overminus spectacles and nonoverminus spectacles at 6, 12, and 18 months. Combining data from both treatment groups, there was significant improvement from baseline at all follow‐up visits (e.g., mean change from baseline to 12 months, −6.6 points; 95% confidence interval, −8.6 to −4.6). Child Intermittent Exotropia Symptom scores were not correlated with distance or near control scores at 12 months. CONCLUSIONS The seven‐item Rasch‐scored Child Intermittent Exotropia Symptom Questionnaire is limited by suboptimal performance. Future study is needed to determine whether it may be useful for clinical practice and for research.

Abstract The Division of Lung Diseases of the NHLBI and the Cardiovascular Medical Education and Research Fund held a workshop to discuss how to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program to develop newer approaches to pulmonary vascular disease. PVDOMICS is a collaborative, protocol-driven network to analyze all patient populations with pulmonary hypertension to define novel pulmonary vascular disease (PVD) phenotypes. Stakeholders, including basic, translational, and clinical investigators; clinicians; patient advocacy organizations; regulatory agencies; and pharmaceutical industry experts, joined to discuss the application of precision medicine to PVD clinical trials. Recommendations were generated for discussion of research priorities in line with NHLBI Strategic Vision Goals that include: (1) A national effort, involving all the stakeholders, should seek to coordinate biosamples and biodata from all funded programs to a web-based repository so that information can be shared and correlated with other research projects. Example programs sponsored by NHLBI include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative, the National Biological Sample and Data Repository for PAH, and the National Precision Medicine Initiative. (2) A task force to develop a master clinical trials protocol for PVD to apply precision medicine principles to future clinical trials. Specific features include: (a) adoption of smaller clinical trials that incorporate biomarker-guided enrichment strategies, using adaptive and innovative statistical designs; and (b) development of newer endpoints that reflect well-defined and clinically meaningful changes. (3) Development of updated and systematic variables in imaging, hemodynamic, cellular, genomic, and metabolic tests that will help precisely identify individual and shared features of PVD and serve as the basis of novel phenotypes for therapeutic interventions.

Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2–derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I 2 analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH.