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

Midwives’ respect and disrespect of women during facility-based childbirth in urban Tanzania: a qualitative study

Abstract Background Over the last two decades, facility-based childbirths in Tanzania have only minimally increased by 10% partly because of healthcare providers’ disrespect and abuse (D&A) of women during childbirth. Although numerous studies have substantiated women’s experience of D&A during childbirth by healthcare providers, few have focused on how D&A occurred during the midwives’ actual care. This study aimed to describe from actual observations the respectful and disrespectful care received by women from midwives during their labor period in two hospitals in urban Tanzania. Methods This descriptive qualitative study involved naturalistic observation of two health facilities in urban Tanzania. Fourteen midwives were purposively recruited for the one-on-one shadowing of their care of 24 women in labor from admission to the fourth stage of labor. Observations of their midwifery care were analyzed using content analysis. Results All the 14 midwives showed both respectful and disrespectful care and some practices that have not been explicated in previous reports of women’s experiences. For respectful care, five categories were identified: 1) positive interactions between midwives and women, 2) respect for women’s privacy, 3) provision of safe and timely midwifery care for delivery, 4) active engagement in women’s labor process, and 5) encouragement of the mother-baby relationship. For disrespectful care, five categories were recognized: 1) physical abuse, 2) psychological abuse, 3) non-confidential care, 4) non-consented care, and 5) abandonment of care. Two additional categories emerged from the unprioritized and disorganized nursing and midwifery management: 1) lack of accountability and 2) unethical clinical practices. Conclusions Both respectful care and disrespectful care of midwives were observed in the two health facilities in urban Tanzania. Several types of physical and psychological abuse that have not been reported were observed. Weak nursing and midwifery management was found to be a contributor to the D&A of women. To promote respectful care of women, pre-service and in-service trainings, improvement of working conditions and environment, empowering pregnant women, and strengthening health policies are crucial

A feasibility study of an educational program on obstetric danger signs among pregnant adolescents in Tanzania: A mixed-methods study

Background: In Tanzania, adolescents have a high lifetime risk of dying from pregnancy and childbirth complications. Objective: To determine the feasibility of an education program in improving knowledge of obstetric danger signs and promoting appropriate healthcare-seeking behavior, as well as encouraging the development of a peer network support group. Methods: An embedded mixed-methods design was used. This research was a pilot study conducted in a health facility in rural Tanzania. Quantitative data was collected before and after the education program using questionnaires. Focus group discussion was used to collect qualitative data. Results: 15 pregnant adolescents between 15 and 19 years of age participated. Their median age was 18.0 years (SD ± 1.19), and 66.7% were ≤18 years. There was a significant increase in the scores of knowledge of danger signs during pregnancy between the pre-test (M = 7.20, SD = 2.83) and the post-test (M = 9.07, SD = 1.67); t = 2.168, p = 0.048. There was a significant strong positive correlation between the healthcare-seeking behavior score and social support score variables [r = 0.654, p = 0.008]. The education program was feasible in terms of implementation, acceptability, and demand as indicated by its >84% score. Four categories were identified from the qualitative data: “supportive family”, “rejection and abortion”, “support from peers”, and “potential barriers to seek care”. Conclusion: The development of an education program particularly on obstetric danger signs was feasible and helpful for pregnant adolescents in Tanzania. Keywords: Pregnancy, Adolescent, Obstetric danger signs, Social support, Healthcare-seeking behavior, Antenatal car