Background Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma. Objective We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season. Methods The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2,128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma birth cohort study (COAST). Results A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study. Conclusions We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma.

Objective The aims of this study were to determine whether physical rehabilitation intervention for patients who required extracorporeal membrane oxygenation (ECMO) is associated with clinical outcomes and to assess whether the patient mobility response over initial rehabilitation sessions early in the intensive care unit (ICU) course predicts or is associated with survival, lengths of stay, discharge disposition, and 30-day readmissions. Methods This study was a 10-year retrospective practice analysis of adults who were critically ill and required ECMO for >72 hours in the cardiothoracic ICU at an academic medical center. Physical rehabilitation implemented during or following the initiation of ECMO was quantified on the basis of timing, frequency, and change in mobility level in response to the intervention over the first 4 consecutive sessions. The primary dependent outcome was in-hospital mortality. Secondary outcomes included 30-day readmission and discharge disposition ranked on an ordinal scale. Results Three hundred fifteen patients (mean age = 50 y [SD = 15 y]; 63% men; mean Sequential Organ Failure Assessment score = 11.6 [SD = 3.3]) met the inclusion criteria. Two hundred eighteen patients (69%) received at least 1 physical rehabilitation session while requiring ECMO, 70 (22%) received rehabilitation after ECMO was discontinued, and 27 (9%) never received rehabilitation. Patients discharged alive achieved higher mobility levels and had a steeper, more positive rate of change in mobility over the first 4 sessions than patients who died in the hospital (2.8 versus 0.38; t199 = 8.24). Those who received rehabilitation and achieved the milestones of sitting on the edge of the bed and walking for>45 m were more likely to survive (47% versus 13%; χ2 = 156) than those who did not (26% versus 3.5%; χ2 = 80). Conclusion A positive rate of change in mobility and the ability to achieve mobility milestones with rehabilitation were associated with improved clinical outcomes. Impact A patient’s mobility response to physical rehabilitation early in the ICU course is an important indicator of illness and should be used with clinical presentation to guide clinical decision making and predict outcomes.

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS.

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Several important recent advances in the development and evolution of in vivo Tooth Biodosimetry using Electron Paramagnetic Resonance (EPR) allow its performance to meet or exceed the U.S. targeted requirements for accuracy and ease of operation and throughput in a large-scale radiation event. Ergonomically based changes to the magnet, coupled with the development of rotation of the magnet and advanced software to automate collection of data, have made it easier and faster to make a measurement. From start to finish, measurements require a total elapsed time of 5 min, with data acquisition taking place in less than 3 min. At the same time, the accuracy of the data for triage of large populations has improved, as indicated using the metrics of sensitivity, specificity and area under the ROC curve. Applying these standards to the intended population, EPR in vivo Tooth Biodosimetry has approximately the same diagnostic accuracy as the purported 'gold standard' (dicentric chromosome assay). Other improvements include miniaturisation of the spectrometer, leading to the creation of a significantly lighter and more compact prototype that is suitable for transporting for Point of Care (POC) operation and that can be operated off a single standard power outlet. Additional advancements in the resonator, including use of a disposable sensing loop attached to the incisor tooth, have resulted in a biodosimetry method where measurements can be made quickly with a simple 5-step workflow and by people needing only a few minutes of training (which can be built into the instrument as a training video). In sum, recent advancements allow this prototype to meet or exceed the US Federal Government's recommended targets for POC biodosimetry in large-scale events.