Improved Survival With Higher-risk Donor Grafts in Liver Transplant With Acute-on-chronic Liver Failure

Use of higher-risk grafts in liver transplantation for patients with acute-on-chronic liver failure (ACLF) has been associated with poor outcomes. This study analyzes trends in liver transplantation outcomes for ACLF over time based on the donor risk index (DRI). Methods: Using the Organ Procurement and Transplantation Network and the United Network for Organ Sharing registry, 17 300 ACLF patients who underwent liver transplantation between 2002 and 2019 were evaluated. Based on DRI, adjusted hazard ratios for 1-y patient death were analyzed in 3 eras: Era 1 (2002-2007, n = 4032), Era 2 (2008-2013, n = 6130), and Era 3 (2014-2019, n = 7138). DRI groups were defined by DRI2.0. Results: ACLF patients had significantly lower risks of patient death within 1 y in Era 2 (adjusted hazard ratio, 0.69; 95% confidence interval, 0.61-0.78; P \u3c 0.001) and Era 3 (adjusted hazard ratio, 0.48; 95% confidence interval, 0.42-0.55; P \u3c 0.001) than in Era 1. All DRI groups showed lower hazards in Era 3 than in Era 1. Improvement of posttransplant outcomes were found both in ACLF-1/2 and ACLF-3 patients. In ACLF-1/2, DRI 1.2 to 1.6 and \u3e2.0 had lower adjusted risk in Era 3 than in Era 1. In ACLF-3, DRI 1.2 to 2.0 had lower risk in Era 3. In the overall ACLF cohort, the 2 categories with DRI \u3e1.6 had significantly higher adjusted risks of 1-y patient death than DRI \u3c1.2. When analyzing hazards in each era, DRI \u3e 2.0 carried significantly higher adjusted risks in Eras 1 and 3\u27 whereas DRI 1.2 to 2.0 had similar adjusted risks throughout eras. Similar tendency was found in ACLF-1/2. In the non-ACLF cohort, steady improvement of posttransplant outcomes was obtained in all DRI categories. Similar results were obtained when only hepatitis C virus-uninfected ACLF patients were evaluated. Conclusions: In ACLF patients, posttransplant outcomes have significantly improved, and outcomes with higher-risk organs have improved in all ACLF grades. These results might encourage the use of higher-risk donors in ACLF patients and provide improved access to transplant

Equivalent circuit model modified for free-standing bilayer lipid membranes beyond 1 TΩ

A cell is the basic functional unit of living organisms. Bilayer lipid membranes (BLMs), which form cell membranes can be assembled by using artificial methods. The electrochemical characteristics of BLMs are normally investigated using electrochemical impedance spectroscopy (EIS); however, the equivalent circuit need to be modified by the experimental conditions. In this study, we formed plain BLMs to determine the underlying equivalent circuit model of free-standing BLMs, and we measured the electrical characteristics using EIS. To analyze the results of EIS, we proposed equivalent circuit models including electrical double layer (EDL) effects on both sides of a BLM. We also extracted and evaluated the electrochemical parameters; the aperture-suspended BLMs using an Si chip having tapered edge recorded TΩ-order membrane resistances, which were one order higher than those reported in most previous studies. Regarding the capacitances of EDL, we compared the extracted values and the calculated results

Capacitance extraction method for a free-standing bilayer lipid membrane formed over an aperture in a nanofabricated silicon chip

A bilayer lipid membrane (BLM) is the main component of the cell membrane of living organisms, which can be formed artificially. Although the specific capacitance of a BLM is known to be in the range of 0.4–1.0 μF cm^–2, many previous works that formed free-standing BLMs over an aperture in silicon chips reported larger values beyond this typical range, which suggests that equivalent-circuit models are not adequate. In this work, we modified the equivalent-circuit model by adding a resistance element of silicon. To evaluate the validity of the modified model, we applied the model to the results of electrochemical impedance spectroscopy for free-standing BLMs formed over an aperture in nanofabricated silicon chips. The derived specific capacitance values were 0.57 ± 0.08 μF cm^–2, which settles in the typical range

Nationwide survey of radiation exposure during pediatric computed tomography examinations and proposal of age-based diagnostic reference levels for Japan

Background: Diagnostic reference levels (DRLs) have not been established in Japan. Objective: To propose DRLs for CT of the head, chest and abdomen for three pediatric age groups. Materials and methods: We sent a nationwide questionnaire by post to 339 facilities. Questions focused on pediatric CT technology, exposure parameters, CT protocols, and radiation doses for age groups <1 year, 1-5 years, and 6-10 years. Results: For the three age groups in the 196 facilities that responded, the 75th percentile values of volume CT dose index based on a 16-cm phantom (CTDIvol 16 [mGy]) for head, chest and abdominal CT were for infants 39.1, 11.1 and 12.0, respectively; for 1-to 5-year-olds 46.9, 14.3 and 16.7, respectively; and for 6-to 10-year-olds 67.7, 15.0 and 17.0, respectively. The corresponding dose–length products (DLP 16 [mGy・cm]) for head, chest and abdominal CT were for infants 526.1, 209.1 and 261.5, respectively; for 1-to 5-year-olds 665.5, 296.0 and 430.8, respectively; and for 6-to 10-year-olds 847.9, 413.0 and 532.2, respectively. Conclusion: The majority of CTDIvol 16 and DLP 16 values for the head were higher than DRLs reported from other countries. For risk reduction, it is necessary to establish DRLs for pediatric CT in Japan. © 2015 Springer-Verlag Berlin HeidelbergEmbargo Period 12 month

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