Progressive Early Interstitial Lung Abnormalities in Persons at Risk for Familial Pulmonary Fibrosis: A Prospective Cohort Study.

Relatives of patients with familial pulmonary fibrosis (FPF) are at increased risk to develop FPF. Interstitial lung abnormalities (ILAs) are a radiologic biomarker of subclinical disease, but the implications of very mild abnormalities remain unclear. To quantify the progression risk among FPF relatives with abnormalities below the threshold for ILAs as described by the Fleischner Society and to describe the characteristics of participants with new or progressive ILAs during observation.

Decoupling of catalysis and transition state analog binding from mutations throughout a phosphatase revealed by high-throughput enzymology.

Using high-throughput microfluidic enzyme kinetics (HT-MEK), we measured over 9,000 inhibition curves detailing impacts of 1,004 single-site mutations throughout the alkaline phosphatase PafA on binding affinity for two transition state analogs (TSAs), vanadate and tungstate. As predicted by catalytic models invoking transition state complementary, mutations to active site and active-site-contacting residues had highly similar impacts on catalysis and TSA binding. Unexpectedly, most mutations to more distal residues that reduced catalysis had little or no impact on TSA binding and many even increased tungstate affinity.

The Genetic Landscape of Familial Pulmonary Fibrosis.

Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction.

Incidence and Progression of Fibrotic Lung Disease in an At-Risk Cohort.

Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated.