To assess the contribution of the human kidney to gluconeogenesis (GN) and its role in conversion of glutamine and alanine to glucose, we used a combination of isotopic and organ balance techniques in nine normal postabsorptive volunteers and measured both overall and renal incorporation of these precursors into glucose before and after infusion of epinephrine. In the postabsorptive basal state, renal incorporation of glutamine (27 ± 2 μmol/min) and alanine (2.1 ± 0.5 μmol/min) into glucose accounted for 72.8 ± 3.3 and 3.9 ± 0.5% of their overall incorporation into glucose (37 ± 2 and 51 ± 6 μmol/min, respectively) and 19.0 ± 3.5 and 1.4 ± 0.2%, respectively, of overall renal glucose release. Infusion of epinephrine, which increased systemic and renal glucose release more than twofold ( P< 0.001), increased overall glutamine and alanine incorporation into glucose (both P < 0.001) and increased renal GN from glutamine ( P< 0.001) but not from alanine ( P = 0.15). Renal glutamine GN now accounted for 90.3 ± 4.0% of overall glutamine GN ( P = 0.01 vs. basal), whereas renal alanine GN still accounted for only 4.8 ± 1.7% of overall alanine GN ( P = 0.36 vs. basal). With the assumption that kidney and liver are the only gluconeogenic organs in humans, these results indicate that glutamine GN occurs primarily in kidney, whereas alanine GN occurs almost exclusively in liver. Isotopic studies of glutamine and alanine incorporation into plasma glucose may provide a selective, noninvasive method to assess hepatic and renal GN.

Ambient air pollution, as measured by average PM concentration, is associated with an increase in the rate of decline of FVC in IPF, suggesting a potential mechanistic role for air pollution in the progression of disease.

Idiopathic pulmonary fi brosis (IPF) is a fatal disease with a variable natural history. Pulmonary hypertension (PH) is frequently found in patients with IPF and is associated with an almost threefold increase in the risk of death. 1,2 In pulmonary arterial hypertension (PAH), outcome is directly related to the capacity of the right ventricle (RV) to adapt to elevated afterload. 3 However, the role of RV function is not clearly understood in pulmonary vascular disease related to IPF.Although right-sided heart catheterization (RHC) is the gold standard modality for hemodynamic assessment, Doppler echocardiogram is a complementary method of assessing RV function. While Doppler echocardiogram measurement of the right ventricular systolic pressure (RVSP) has limited accuracy in advanced lung disease, 4,5 several echocardiographic measurements of the RV have been associated with outcomes in PH. Such measurements include tricuspid annular plane systolic excursion (TAPSE) as a measure of RV ejection fraction, 6-8 RV outfl ow tract velocity-time integral (RVOT VTI) as a surrogate for stroke volume, and the presence of "notching" in the Doppler fl ow velocity envelope obtained from the RVOT, indicating elevated pulmonary vascular resistance (PVR). 9,10 We

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 3 10 2295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a variable clinical course and high mortality. We used data from a large national US registry of patients with IPF to investigate relationships between patient characteristics, including markers of disease severity, and mortality. Methods The analysis cohort comprised patients enrolled in the IPF-PRO Registry from its inception on 5 June 2014 to 26 October 2017. The primary criterion for inclusion in this registry is that patients must be diagnosed or confirmed with IPF at the enrolling centre within 6 months. Associations between patient characteristics and markers of disease severity at enrolment and mortality outcomes were investigated using univariable, multivariable and adjustment models. Results Among 662 patients enrolled, 111 patients died or had a lung transplant over a follow-up period of 30 months. The probability of being free of both events at month 30 was 50.6% (95% CI: 40.0, 60.2). When patient characteristics and markers of disease severity were jointly examined in a multivariable analysis, oxygen use at rest (hazard ratio [HR] 2.44 [95% CI: 1.45, 4.10]), lower forced vital capacity (FVC) % predicted (HR 1.28 [95% CI: 1.10, 1.49] per 10% decrease) and diffusion capacity for carbon monoxide (DLco) % predicted (HR 1.25 [95% CI: 1.04, 1.51] per 10% decrease) were significantly associated with increased risk of death or lung transplant. The risk of death or lung transplant increased with increasing age in patients ≥62 years old (HR 1.18 [95% CI: 0.99, 1.40] per 5-year increase), and decreased with increasing age in patients <62 years old (HR 0.60 [95% CI: 0.39, 0.92] per 5-year increase). Conclusions In an observational US registry of patients with IPF, oxygen use at rest, lower FVC % predicted, and lower DLco % predicted were associated with risk of death or lung transplant. An audio podcast of the lead author discussing these data can be downloaded from: http://www.usscicomms.com/respiratory/snyder/IPF-PROsurvival1/ . Trial registration ClinicalTrials.gov number: NCT01915511 . Electronic supplementary material The online version of this article (10.1186/s12931-019-1043-9) contains supplementary material, which is available to authorized users.