National Jewish Health is a Denver, Colorado academic hospital/clinic doing research and treatment in respiratory, cardiac, immune and related disorders. It is an internationally respected medical center that draws people from many countries to receive care. Founded in 1899 to treat tuberculosis, it is non-sectarian but had funding from B'nai B'rith until the 1950s.
Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants and phenotypes. Here, we examine 2157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2157 proteins follow a bimodal distribution (median r = 0.30). We evaluate protein measure associations with genetic variants, and find approximately 25-30
Background:Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex. Aim:To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery. Methods:We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes. Results:We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1, which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6, a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction. Conclusion:Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.
Circulating group 2 innate lymphoid cells (ILC2s) often serve as a first line of defense against infection prior to local expansion of lung-resident ILC2s. The fate of circulating ILC2s and their relationship with lung-resident ILC2s is not well understood. Using reporter mice in combination with single-cell RNA sequencing (scRNA-seq) and Cellular Indexing of Transcriptomes and Epitopes sequencing (CITE-seq), the fate of circulatory ILC2s was followed during the course of primary Nippostrongylus brasiliensis helminth infection. Circulating ILC2s rapidly acquire tissue-resident gene expression upon arrival to the lung. This transition occurs primarily as the cells enter the parenchyma from the vasculature. Despite acquiring a lung-resident phenotype by the peak of the immune response, these converted ILC2s retain some unique gene expression related to their intestinal origins which correlate with enhanced functionality. Findings provide insight into the tissue adaptation of circulatory ILC2s during recruitment to the lung and establish their contribution to the lung-resident ILC2 population.
Mycobacterium abscessus (Mab) is a highly drug-resistant non-tuberculous mycobacterium that presents major treatment challenges, particularly in individuals with structural lung disease. Although historically considered ineffective, β-lactam antibiotics have gained renewed attention due to advances in β-lactamase inhibition and cell wall biology. This review synthesizes more than a decade of work, including in vitro susceptibility studies, biochemical characterization of Mab's β-lactamase (BlaMab) and peptidoglycans synthesis, and published clinical cases supporting the potential role of β-lactam-based regimens. We detail the enzymatic pathways involved in peptidoglycan cross-linking and the dual inhibition of D,D- and L,D-transpeptidases by select β-lactams, as well as the functional impact of inhibiting BlaMab. Novel β-lactamase inhibitors such as durlobactam may further enhance β-lactam efficacy. By integrating laboratory insights with clinical experience, this review provides a comprehensive perspective and informs ongoing efforts to design clinical trials repurposing β-lactam/β-lactamase inhibitor combinations.
RATIONALE:Depemokimab is the first ultra-long-acting biologic with high IL-5 binding affinity, high potency, and an extended half-life enabling twice-yearly dosing. OBJECTIVES:Investigate the efficacy and safety of switching to depemokimab in participants with severe asthma already managed with and responsive to short-acting biologic therapies targeting IL-5 or its receptor. METHODS:NIMBLE (NCT04718389) was a multicenter, randomized, double-blind, double-dummy, parallel-group, phase 3A noninferiority study. Participants were ≥12 years old with asthma and documented clinical benefit on mepolizumab 100 mg subcutaneously every 4 weeks or benralizumab 30 mg subcutaneously every 8 weeks for ≥12 months. Participants were randomized 1:1 to depemokimab 100 mg subcutaneously every 26 weeks or maintained on their prior biologic (mepolizumab or benralizumab). The primary endpoint was annualized rate of clinically significant exacerbations over 52 weeks, with predefined noninferiority margin set at 1.28. Safety endpoints included adverse events. MEASUREMENTS AND MAIN RESULTS:Annualized rates (95% confidence intervals [CIs]) of clinically significant exacerbations over 52 weeks were 0.57 (0.50 to 0.64) with depemokimab (n = 848) and 0.49 (0.43 to 0.55) with active comparator (n = 839); the rate ratio (95% CI) was 1.16 (0.98 to 1.38). Since the upper bound of the 95% CI exceeded 1.28, noninferiority was not met. Most participants in both treatment arms experienced no clinically significant exacerbations. Health-related quality of life, asthma control, and lung function outcomes were stable throughout the study. Adverse events were comparable between treatment groups. CONCLUSIONS:While statistical noninferiority was not met, exacerbation rates were low and symptom control/lung function were maintained in both groups. This first randomized, controlled switch trial in severe asthma suggests that participants with severe asthma on mepolizumab or benralizumab may safely switch to twice-yearly depemokimab.
