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

ハナス コト キク コト フレル コト カンジル コト フレラレル コト リンショウ ジッシュウ エ アンガジェ スル ホウホウ ノ ケントウ

理学療法学教育において臨床実習は重要な位置づけにある. しかし, その方法論は古くから変化しておらず, 現代の教育に必ずしも適当であるとはいえない. 今回, その課題について, 研究会を設立し検討した. その結果, 「関わること」の重要性が浮かび上がり, いかにして関われるのかを明確にする必要が示唆された. 研究会では人に関わる以前に自らに関わり, それを基盤に他者と関われると考えた. それは言語的コミュニケーションのみならず, 身体的コミュニケーションの重要性を前提としている. 関わりについてケア, クリティシズム, アンガージュマンなどのキーワードを使用し説明を加えた. 最終的に言語的・身体的コミュニケーションの経験を自らが解釈し, それを言語化できるような学習プロセスの経過(思考し表現すること)が必要であると結論づけた. 臨床実習は自己, 他者への関わりを理解し, 経験するプロセスなのである.Clinical training is the core of physical therapy education. However, its age-old methodology could be inappropriate for today\u27s education. We set up a study group and examined the issue. As a result, the importance of "participating with others" (i.e. interaction between instructors and students, and that between students and patients) came into focus and the necessity of exploring possible "participation" methods was indicated. We considered that one should be ready for participating with others by doing the same thing with oneself in advance. The idea was premised on the importance of physical communication as well as that of linguistic communication, and we discussed and tried to identify our concept of "participation" with keywords such as care, criticism or commitment (engagement). Finally we reached the conclusion that both instructors and students need a learning process, where they can interpret and verbalize (i.e. think and express) their experiences of linguistic and physical communication by themselves. Clinical training may be ultimately defined as a process of understanding what "participation" means and experiencing it

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease

AimsLimited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH.MethodsThis retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death.ResultsThe 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45–13.73; P = .009).ConclusionsThe IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered

Developmental Changes in Aortic Mechanical Properties in Normal Fetuses and Fetuses with Cardiovascular Disease

We hypothesized that fetal aortic mechanical properties assessed by aortic diameter (AoD) and flow show maturational changes during the gestational period, and that these properties are different in fetuses with congenital heart diseases and fetuses with normal development. Methods: Phasic changes in ascending AoD along with Doppler flow profile were measured in 84 consecutive normal fetuses (gestational age, 18–36 weeks) and in 30 consecutive fetuses with cardiovascular diseases (gestational age, 22–39 weeks). Results: AoD and cardiac output significantly increased with gestational age. Fetal aortic compliance (AC), assessed as (maximum AoD – minimum AoD)/stroke volume, significantly decreased with gestational age in normal fetuses, indicating maturational changes in aortic wall properties. Importantly, fetuses with Marfan syndrome and tetralogy of Fallot that exhibit “aortopathy” showed significantly lower AC than normal fetuses of the same gestational age, suggesting intrinsic abnormalities in aortic wall properties in these diseases. Fetuses with trisomy 18 and Noonan syndrome also had AC values below the normal ranges. Conclusion: Measurements of phasic changes in fetal AoD and flow measurements can provide useful information about aortic mechanical properties and may help clarify abnormal arterial hemodynamics in pathologic conditions