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

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

Effects of epinephrine administration in out-of-hospital cardiac arrest based on a propensity analysis

Background: Epinephrine administration has been advocated for cardiopulmonary resuscitation (CPR) for decades. Despite the fact that epinephrine administration during CPR is internationally accepted, the effects of the prehospital epinephrine administration still remain controversial. We investigated the effects of epinephrine administration on patients with out-of-hospital cardiac arrest based on a propensity analysis with regard to the ‘CPR time’. Methods: From April 1, 2007, to December 31, 2009, 633 out-of-hospital cardiac arrest patients with bystander witnesses were included in the present study. To rule out any survival bias, we used the propensity scores, which included CPR time. CPR time was defined as the time span from when the emergency medical technicians started CPR until either the return of spontaneous circulation or arrival at the hospital. After performing propensity score matching, the epinephrine and no-drug groups each included 141 patients. The primary study endpoint was a favorable neurological outcome at 30 days after cardiac arrest. Results: After propensity score matching, the frequency of the return of spontaneous circulation before arrival at the hospital in the matched epinephrine group was higher than that in the matched no-drug group (27% vs. 13%, P = 0.002). However, the frequency of a favorable neurological state did not differ between the two groups. With regard to the frequency of a favorable neurological state in the patients, the adjusted odds ratio of the time span from cardiac arrest to the first epinephrine administration was 0.917 (95% confidence interval 0.850–0.988, P = 0.023) per minute. Conclusions: In patients with witnessed out-of-hospital cardiac arrest, prehospital epinephrine administration was associated with increase of the return of spontaneous circulation before arrival at the hospital. Moreover, the early administration of epinephrine might improve the overall neurological outcome

Cardiopulmonary arrest caused by nafamostat mesylate during hemodialysis

Abstract Dialysis‐related adverse reactions can be serious and difficult to predict. In our case, nafamostat mesylate (NM) was thought to be the cause of cardiopulmonary arrest (CPA) due to NM‐induced anaphylaxis but was not reflected in the allergy tests. Rare but life‐threatening drawbacks occur immediately after hemodialysis initiation

『プロジェ初版』について

Projet de Code civil pour le(l'Empire du) Japon. accommpagné d'un commentaire. Premiére édDes biens : dispositions préliminaires, (Ire partie:) des droits réels, art. 1-31

Nasogastric tube syndrome: A case of vocal cord paralysis due to a nasogastric tube

Key Clinical Message Insertion of a nasogastric tube is one of the most common methods of administering nutrition, but can cause vocal cord paralysis

術後にメチシリン耐性黄色ブドウ球菌(MRSA)の創感染を来し死亡した1症例

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