Pulmonary venous occlusion and death in pulmonary arterial hypertension: survival analyses using radiographic surrogates

BACKGROUND: Recent studies find that a considerable number of patients with pulmonary arterial hypertension (PAH) develop fibrous obstruction of the pulmonary veins. Such obstruction more commonly accompanies connective tissue disorder (CTD)-associated PAH than idiopathic PAH. However, few researchers have gauged the risk of death involving obstruction of the pulmonary veins. METHODS: Thirty-seven patients with PAH were enrolled (18 patients, idiopathic PAH; 19 patients, CTD-associated PAH). The patients were 49 ± 18 years and had a World Health Organization functional class of 3.2 ± 0.6. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were surrogates for obstruction of the pulmonary veins, and were detected by a 16-row multidetector computed tomography scanner. RESULTS: The follow-up period was 714 ± 552 days. Fifteen deaths occurred. Thickening of the interlobular septa, centrilobular ground-glass attenuation, and mediastinal adenopathy were found in 37.8%, 24.3%, and 16.2% of patients, respectively. Cox proportional hazard analysis revealed an increased risk of death with each radiographic surrogate (mediastinal adenopathy: p < 0.0001, hazard ratio = 13.9; thickening of interlobular septa: p < 0.001, hazard ratio = 12.0; ground-glass attenuation: p = 0.02, hazard ratio = 3.7). The statistical significance of these relationships was independent of the cause of PAH and plasma concentration of brain natriuretic peptide. CONCLUSIONS: The results of this study imply that obstruction of the pulmonary veins is associated with an increased risk of death in patients with PAH

高齢者への健康相談・保健指導を行う保健室による地元への貢献

　研究の目的は，地域において高齢者を対象にした先駆的な取り組みを行う看護職による健康相談・保健指導を行う窓口である保健室の特徴と，地元への貢献を明らかにすることである．高齢者を対象にした先駆的な取り組みを行う保健室8 か所の実施窓口担当者，保健室運営に関係が深い自治体の担当者1 名にインタビューを実施した．8 か所はその特徴から，経験豊かなプラチナナースが主体となり運営されている保健室，地域に開かれた事業所と共に運営されている保健室，そして震災復興の生活再建支援から継続する保健室という3 つに分類された．地元への貢献は，地元住民同士による生活・療養支援の自主活動の支援，地元の特性に融合した健康支援，地域包括ケアシステムの活用とならないはざまの支援，地元ボランティアから地元住民への効果の波及といったことがあった．3 つのタイプの保健室がもたらした地元への貢献の共通点として，地元住民の健康への意識を高める支援や地元住民との心理的な距離を縮める取り組みがあった

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

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

Autonomous Sequences in Myoglobin Emerging from X‑ray Structure of Holomyoglobin

The proposed continuous folding structure units are fundamental to analyze protein structure. Here, we could elucidate for the first time two types of hydrophobic core networks in apomyoglobin using continuous folding structure units. In myoglobin, two autonomous sequences emerged clearly. We could thus characterize the autonomous sequences using well-defined hydrophobic core networks within respective semifolds. A hydrophobic core is defined as a pair of topology-local hydrophobic amino acids in different folding structures. Hydrophobic core formation is indispensable to stabilize the different folding structures via an efficient hydrophobic interaction. Autonomous sequences in myoglobin encode tertiary structure information for semifolds. These sequences fold autonomously into small sets of continuous folding structure units to grow separate semifolds on each separate framework. The autonomous sequence can be defined as the local sequence assigned to the small set of continuous folding structure units. They create the discrete hydrophobic region in a semifold by assembly of their hydrophobic regions. Semifolds were characterized by discrete hydrophobic regions stabilized by respective type I hydrophobic core networks, which were present within each semifold. The discrete hydrophobic region of a semifold propagated itself with that of a different semifold by hydrophobic interactions in type II hydrophobic core network, which was present between different semifolds, as observed by the X-ray structures of semifolds. The most significant feature of semifolds in apomyoglobin was that they could be verified by the X-ray structure of holomyoglobin regardless of the instability of folds characteristic to autonomous sequence fragments. This work presents the first description of autonomous sequences