Elevated risk of dyspnea in adults with obesity.

We investigated whether older adults (OA) with obesity are more likely to have dyspnea compared with OA without obesity, and whether OA with obesity are at a greater risk of having dyspnea compared with middle-aged (MA) and younger adults (YA) with obesity. We obtained de-identified data from the TriNetX UT Southwestern Medical Center database. We identified obesity and dyspnea using ICD-10-CM codes E66 and R06.0, respectively. Patients were separated into three age groups: OA, (65-75 y.o.), MA (45-55 y.o.), and YA (25-35 y.o). Within these groups, those with and without obesity or dyspnea were identified for analysis. The risk of dyspnea was greater in OA (risk ratio: 3.64), MA (risk ratio: 3.52), and YA (risk ratio: 2.76) with obesity compared with age-matched patients without obesity (all p < 0.01). The risk of dyspnea was greater in OA and MA with obesity compared with YA with obesity (both p < 0.001 vs. YA). These findings suggest that clinicians should consider obesity as an independent risk factor for dyspnea.

Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.

To address the problem of poor asthma control due to drug resistance, an antisense oligonucleotide complementary to mmu-miR-145a-5p (antimiR-145) was tested in a house dust mite mouse model of mild/moderate asthma. miR-145 was targeted to reduce inflammation, regulate epithelial-mesenchymal transitions, and promote differentiation of structural cells. In addition, several chemical variations of a nontargeting oligonucleotide were tested to define sequence-dependent effects of the miRNA antagonist. After intravenous administration, oligonucleotides complexed with a pegylated cationic lipid nanoparticle distributed to most cells in the lung parenchyma but were not present in smooth muscle or the mucosal epithelium of the upper airways. Treatment with antimiR-145 and a nontargeting oligonucleotide both reduced eosinophilia, reduced obstructive airway remodeling, reduced mucosal metaplasia, and reduced CD68 immunoreactivity. Poly(A) RNA-seq verified that antimiR-145 increased levels of many miR-145 target transcripts. Genes upregulated in human asthma and the mouse model of asthma were downregulated by oligonucleotide treatments. However, both oligonucleotides significantly upregulated many genes of interferon signaling pathways. These results establish effective lung delivery and efficacy of locked nucleic acid/DNA oligonucleotides administered intravenously, and suggest that some of the beneficial effects of oligonucleotide therapy of lung inflammation may be due to normalization of interferon response pathways.