エミシズマブは凝固第VIII因子と同様にフィブリン構造およびその安定性を向上させる

Introduction: Emicizumab is an antifactor (F)IXa/FX bispecific antibody, mimicking FVIIIa cofactor function. Emi prophylaxis effectively reduces bleeding events in patients with haemophilia A. The physical properties of emicizumab-induced fibrin clots remain to be investigated, however. Aim: We have investigated the stability and structure of emicizumab-induced fibrin clots. Methods: Coagulation was initiated by activated partial thromboplastin time (aPTT) trigger and prothrombin time (PT)/aPTT-mixed trigger in FVIII-deficient plasma with various concentrations of emicizumab or recombinant FVIII. The turbidity and stability of fibrin clots were assessed by clot waveform and clot-fibrinolysis waveform analyses, respectively. The resulting fibrin was analysed by scanning electron microscopy (SEM). Results: Using an aPTT trigger, the turbidity was decreased and the fibrinolysis times were prolonged in the presence of emicizumab dose-dependently. Scanning electron microscopy imaging demonstrated that emicizumab improved the structure of fibrin network with thinner fibres than in its absence. Although emicizumab shortened the aPTT dramatically, the nature of emicizumab-induced fibrin clots did not reflect the hypercoagulable state. Similarly, using a PT/aPTT-mixed trigger that could evaluate potential emicizumab activity, emicizumab improved the stability and structure of fibrin clot in a series of experiments. In this circumstance, fibrin clot properties with emicizumab at 50 and 100 µg/mL appeared to be comparable to those with FVIII at ~12 and ~24-32 IU/dL, respectively. Conclusion: Emicizumab effectively improved fibrin clot stability and structure in FVIII-deficient plasma, and the physical properties of emicizumab-induced fibrin clots were similar to those with FVIII.博士（医学）・甲第787号・令和3年3月15日© 2020 John Wiley & Sons Ltd.This is the peer reviewed version of the following article: https://onlinelibrary.wiley.com/doi/10.1111/hae.13961, which has been published in final form at https://doi.org/10.1111/hae.13961. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

Principles of the magnetic resonance imaging movie method for articulatory movement : a review

Magnetic resonance imaging (MRI) has become a critical tool for dental examination. MRI has many advantages over radiographic examination methods, including the lack of a requirement for patient exposure and the ability to capture high-contrast images of various tissue and organ types. However, MRI also has several limitations, including long examination times and the existence of metallic or motion artifacts. A cardiac imaging method using cine sequences was developed in the 1990s. This technique allows for analysis of heart movement and functional blood flow. Moreover, this method has been applied in dentistry. Recent research involving 3T MRI has led to the achievement of a temporal resolution of <10 ms, surpassing the frame rate of typical video recording. The current review introduces the history and principles of the cine sequence method and its application to the oral and maxillofacial regions

The Tokyo Oldest Old Survey on Total Health (TOOTH): A longitudinal cohort study of multidimensional components of health and well-being

<p>Abstract</p> <p>Background</p> <p>With the rapid worldwide increase in the oldest old population, considerable concern has arisen about the social and economic burden of diseases and disability in this age group. Understanding of multidimensional structure of health and its life-course trajectory is an essential prerequisite for effective health care delivery. Therefore, we organized an interdisciplinary research team consisting of geriatricians, dentists, psychologists, sociologists, and epidemiologists to conduct a longitudinal observational study.</p> <p>Methods/Design</p> <p>For the Tokyo Oldest Old Survey on Total Health (TOOTH) study, a random sample of inhabitants of the city of Tokyo, aged 85 years or older, was drawn from the basic city registry. The baseline comprehensive assessment consists of an in-home interview, a self-administered questionnaire, and a medical/dental examination. To perform a wide variety of biomedical measurements, including carotid ultrasonography and a detailed dental examination, participants were invited to our study center at Keio University Hospital. For those who were not able to visit the study center, we provided the option of a home-based examination, in which participants were simultaneously visited by a geriatrician and a dentist. Of 2875 eligible individuals, a total of 1152 people were recruited, of which 542 completed both the in-home interview and the medical/dental examination, with 442 completed the in-home interview only, and another 168 completed self or proxy-administered data collection only. Carotid ultrasonography was completed in 458 subjects, which was 99.6% of the clinic visitors (n = 460). Masticatory assessment using a colour-changeable chewing gum was completed in 421 subjects, a 91.5% of the clinic visitors.</p> <p>Discussion</p> <p>Our results demonstrated the feasibility of a new comprehensive study that incorporated non-invasive measurements of subclinical diseases and a detailed dental examination aiming at community-dwelling individuals aged 85 years or older. The bimodal recruitment strategy is critically important to capture a broad range of health profiles among the oldest old. Results form the TOOTH study will help develop new models of health promotion, which are expected to contribute to an improvement in lifelong health and well-being.</p> <p>Trial Registration</p> <p>This study has been registered in the UMIN-Clinical Trial Registry (CTR), ID: UMIN000001842.</p

Identification of cell cycle–arrested quiescent osteoclast precursors in vivo

Osteoclasts are multinucleated cells that resorb bone. Although osteoclasts originate from the monocyte/macrophage lineage, osteoclast precursors are not well characterized in vivo. The relationship between proliferation and differentiation of osteoclast precursors is examined in this study using murine macrophage cultures treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB (RANK) ligand (RANKL). Cell cycle–arrested quiescent osteoclast precursors (QuOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments show that QuOPs survive for several weeks and differentiate into osteoclasts in response to M-CSF and RANKL. Administration of 5-fluorouracil to mice induces myelosuppression, but QuOPs survive and differentiate into osteoclasts in response to an active vitamin D3 analogue given to those mice. Mononuclear cells expressing c-Fms and RANK but not Ki67 are detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. These results suggest that QuOPs preexist at the site of osteoclastogenesis and that osteoblasts are important for maintenance of QuOPs

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

臨地実習を通した看護学生の学びの評価とA病院における実習過程評価

本研究の目的は、B大学看護学部のA病院における臨地実習について学生を対象に実習を通した学びの到達度と授業過程評価スケール.看護学実習用.(以下、実習過程評価)を用いて調査し、さらに相互の関係について分析を行うことによって、教育内容とこれからのA病院における実習指導体制を検討する資料とすることである。質問紙により、在学4年間を通したA病院における全ての臨地実習について、B大学看護学部4年生78名に調査した。学びの評価の総合得点の平均は93.17点であり、「看護の難しさを実感できた」の得点が最も高く、一方「看護理論適用の重要性を理解できた」が最も低かった。また、実習過程評価の総合得点の平均は141.50点であった。実習過程評価の下位尺度【教員、看護師.学生相互行為】と【教員、看護師間の指導調整】および【目標・課題の設定】はいずれも相関関係があった。実習過程評価の下位尺度【カンファレンスと時間調整】以外は学びの評価と有意な正の相関がみられた。学生の学びを得点により低得点群・中得点群・高得点群に群分けし、実習過程評価スケールとの一元配置分散分析を行ったところ、学びの評価の低得点群と高得点群による実習過程評価の平均は下位尺度【カンファレンスと時間調整】以外の全てに有意な得点差がみられた。以上より、これらの視点を踏まえた教育を組み立てる必要性が示唆された

A病院でのB大学看護学臨地実習における実習指導役割実施状況に関する調査 : 実習指導者・看護学教員の自己評価と看護学生の満足度から

A病院におけるB大学看護学臨地実習について、次の2点を目的とした調査を実施した。1)実習指導役割で規定されている役割実施に対する実習指導者・教員の自己評価と、看護学生の実習指導者・教員に対する満足度を把握する、2)実習指導における課題を整理し、実習指導体制のあり方をよりよいものへと再構築をはかることである。調査対象はA病院の実習指導者9名、B大学のA病院での実習指導経験のある教員8名、B大学4年生の看護学生69名である。実習指導者、教員ともに実習指導における役割に対する自己評価は、学生満足度と比べ多くの項目で高かった。カンファレンスでの実習指導者・教員に対する学生満足度は、ともに約80%を超えていたことから、カンファレンスという実習指導、教員、学生の3者が集まる機会は有効に機能していることが示された。実習指導者の自己評価と学生満足度について乖離がみられたのは、「学生を暖かく受け入れる雰囲気づくり」、「学生への精神的サポート」であった。教員において乖離がみられたのは「学生の実習態度・様子の共有」であった。臨地実習にあたり、暖かい雰囲気づくりや精神的サポート、実習指導者と教員間の学生に関する情報共有を、学生が実習指導者と教員に求めていることが示された

Merging chemistry and biology in emerging countries

Chemical biology is not a new discipline, as research at the interface of chemistry and biology has been growing for decades. However, the field still needs regional and global support in emerging countries. The meeting organized by Asian Chemical Biology Initiative in Bangkok, Thailand in January 2013, brought together regional communities of young and established researchers to nurture chemical biology research programs and highlight some of the newer developments. Here, we report on the meeting and some of the key research topics discussed