A full Eulerian finite difference approach for solving fluid-structure coupling problems

A new simulation method for solving fluid-structure coupling problems has been developed. All the basic equations are numerically solved on a fixed Cartesian grid using a finite difference scheme. A volume-of-fluid formulation (Hirt and Nichols (1981, J. Comput. Phys., 39, 201)), which has been widely used for multiphase flow simulations, is applied to describing the multi-component geometry. The temporal change in the solid deformation is described in the Eulerian frame by updating a left Cauchy-Green deformation tensor, which is used to express constitutive equations for nonlinear Mooney-Rivlin materials. In this paper, various verifications and validations of the present full Eulerian method, which solves the fluid and solid motions on a fixed grid, are demonstrated, and the numerical accuracy involved in the fluid-structure coupling problems is examined.Comment: 38 pages, 27 figures, accepted for publication in J. Comput. Phy

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Superiority of Nebulized Corticosteroids over Dry Powder Inhalers in Certain Patients with Cough Variant Asthma or Cough-Predominant Asthma

Background: The particle distribution might differ between nebulizer therapy and metered-dose inhaler (MDI) or dry powder inhaler (DPI) therapy because the particles repeatedly enter/re-enter the airways with the nebulizer. Inhaled corticosteroids (ICS) were administered with a nebulizer to assess the benefit of changes in the distribution of particles in patients with cough variant asthma (CVA) and cough-predominant asthma (CPA). Methods: Patients whose symptoms were not controlled by their current therapy were enrolled. In patients receiving high-dose ICS by MDI or DPI (ICS-MDI/DPI), steroid therapy was switched to 1,320 μg/day of nebulized dexamethasone (1,600 μg as dexamethasone sodium phosphate) (chronic steroid-independent group). In patients receiving systemic steroids regardless of their ICS-MDI/DPI therapy, nebulized dexamethasone was added and any concurrent ICS-MDI/DPI therapy was halted to detect a steroid-sparing effect (chronic steroid-dependent group). In patients with acute exacerbation of CVA or CPA and persistent symptoms despite systemic corticosteroids, nebulized dexamethasone was added to assess its effect (acute group). Results: Superior symptom control was achieved in 10 out of 12 steroid-independent patients, 3 out of 6 steroid-dependent patients, and all 7 acute patients. Conclusions: Delivery of ICS via a nebulizer has advantages over ICS-MDI/DPI in some patients with CVA or CPA

Comparison of semiquantitative chest CT scoring systems to estimate severity in coronavirus disease 2019 (COVID-19) pneumonia.

Objectives:To compare the clinical usefulness among three different semiquantitative computed tomography (CT) severity scoring systems for coronavirus disease 2019 (COVID-19) pneumonia.Methods:Two radiologists independently reviewed chest CT images in 108 patients to rate three CT scoring systems (total CT score [TSS], chest CT score [CCTS], and CT severity score [CTSS]). We made a minor modification to CTSS. Quantitative dense area ratio (QDAR: the ratio of lung involvement to lung parenchyma) was calculated using the U-net model. Clinical severity at admission was classified as severe (n = 14) or mild (n = 94). Interobserver agreement, interpretation time, and degree of correlation with clinical severity as well as QDAR were evaluated.Results:Interobserver agreement was excellent (intraclass correlation coefficient: 0.952-0.970, p < 0.001). Mean interpretation time was significantly longer in CTSS (48.9-80.0 s) than in TSS (25.7-41.7 s, p < 0.001) and CCTS (27.7-39.5 s, p < 0.001). Area under the curve for differentiating clinical severity at admission was 0.855-0.842 in TSS, 0.853-0.850 in CCTS, and 0.853-0.836 in CTSS. All scoring systems correlated with QDAR in the order of CCTS (ρ = 0.443-0.448), TSS (ρ = 0.435-0.437), and CTSS (ρ = 0.415-0.426).Conclusions:All semiquantitative scoring systems demonstrated substantial diagnostic performance for clinical severity at admission with excellent interobserver agreement. Interpretation time was significantly shorter in TSS and CCTS than in CTSS. The correlation between the scoring system and QDAR was highest in CCTS, followed by TSS and CTSS. CCTS appeared to be the most appropriate CT scoring system for clinical practice.Key points: • Three semiquantitative scoring systems demonstrate substantial accuracy (area under the curve: 0.836-0.855) for diagnosing clinical severity at admission and (area under the curve: 0.786-0.802) for risk of developing critical illness. • Total CT score (TSS) and chest CT score (CCTS) were considered to be more appropriate in terms of clinical usefulness as compared with CT severity score (CTSS), given the shorter interpretation time in TSS and CCTS, and the lowest correlation with quantitative dense area ratio in CTSS. • CCTS is assumed to distinguish subtle from mild lung involvement better than TSS by adopting a 5% threshold in scoring the degree of severity

Comparison of semiquantitative chest CT scoring systems to estimate severity in coronavirus disease 2019 (COVID-19) pneumonia.

OBJECTIVES: To compare the clinical usefulness among three different semiquantitative computed tomography (CT) severity scoring systems for coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Two radiologists independently reviewed chest CT images in 108 patients to rate three CT scoring systems (total CT score [TSS], chest CT score [CCTS], and CT severity score [CTSS]). We made a minor modification to CTSS. Quantitative dense area ratio (QDAR: the ratio of lung involvement to lung parenchyma) was calculated using the U-net model. Clinical severity at admission was classified as severe (n = 14) or mild (n = 94). Interobserver agreement, interpretation time, and degree of correlation with clinical severity as well as QDAR were evaluated. RESULTS: Interobserver agreement was excellent (intraclass correlation coefficient: 0.952–0.970, p < 0.001). Mean interpretation time was significantly longer in CTSS (48.9–80.0 s) than in TSS (25.7–41.7 s, p < 0.001) and CCTS (27.7–39.5 s, p < 0.001). Area under the curve for differentiating clinical severity at admission was 0.855–0.842 in TSS, 0.853–0.850 in CCTS, and 0.853–0.836 in CTSS. All scoring systems correlated with QDAR in the order of CCTS (ρ = 0.443–0.448), TSS (ρ = 0.435–0.437), and CTSS (ρ = 0.415–0.426). CONCLUSIONS: All semiquantitative scoring systems demonstrated substantial diagnostic performance for clinical severity at admission with excellent interobserver agreement. Interpretation time was significantly shorter in TSS and CCTS than in CTSS. The correlation between the scoring system and QDAR was highest in CCTS, followed by TSS and CTSS. CCTS appeared to be the most appropriate CT scoring system for clinical practice. KEY POINTS: • Three semiquantitative scoring systems demonstrate substantial accuracy (area under the curve: 0.836–0.855) for diagnosing clinical severity at admission and (area under the curve: 0.786–0.802) for risk of developing critical illness. • Total CT score (TSS) and chest CT score (CCTS) were considered to be more appropriate in terms of clinical usefulness as compared with CT severity score (CTSS), given the shorter interpretation time in TSS and CCTS, and the lowest correlation with quantitative dense area ratio in CTSS. • CCTS is assumed to distinguish subtle from mild lung involvement better than TSS by adopting a 5% threshold in scoring the degree of severity