Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. 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.

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.

From December 26, 2020 to February 28, 2021, quantitative antigen test (Ag test) of SARS-CoV-2 was conducted by using a nasopharyngeal swab for 990 patients aged from 0 to 99 years old (average age; 63.1 +/-22.5 years old, male: 537, female: 463), who presented at least one of the following symptoms, such as fever, respiratory symptoms, and taste disorder. In 578 patients, Ag test and PCR test were conducted at the same time and these patients were analyzed. In 74 patients with Ag > = 1.0, 44 patients were PCR positive (positive ratio = 0.59). In 43 patients with Ag > = 10.0, 41 patients were PCR positive (positive ratio = 0.95), and all of 42 patients with Ag > = 100.0 were PCR positive. In 504 patients with Ag < 1.0, only five patients were PCR positive (positive ratio = 0.01). In 31 patients with 10 > Ag > = 1.0, three patients were PCR positive (positive ratio = 0.10). All eight patients presented a typical pneumonia, and five patients had a history of close contact with COVID-19 patients within 14 days. With an appropriate cut off value, Ag test is concluded to have enough sensitivity and specificity. Considering the advantage of handiness, rapidness, high-throughput and economy over PCR test, Ag test seems useful diagnostic method for COVID-19 in the pandemic situation.

BACKGROUND/AIM:The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19.METHODS:Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.RESULTS:During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively).CONCLUSION:COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.

The coronavirus disease 2019 (COVID‐19) has become a major health threat. To overcome COVID‐19, appropriate diagnosis methods are urgently needed. The aim of this study was to clinically evaluate the colloidal gold immunochromatography assay for SARS‐Cov‐2 IgM/IgG antibody (Ab).

Chronic fibrosing idiopathic interstitial pneumonia (IIP) can be divided into two main types: idiopathic pulmonary fibrosis (IPF), a steroid-resistant and progressive disease with a median survival of 2–3 years, and idiopathic non-specific interstitial pneumonia (INSIP), a steroid-sensitive and non-progressive autoimmune disease. Although the clinical courses of these two diseases differ, they may be difficult to distinguish at diagnosis. We performed a comprehensive analysis of serum autoantibodies from patients definitively diagnosed with IPF, INSIP, autoimmune pulmonary alveolar proteinosis, and sarcoidosis. We identified disease-specific autoantibodies and enriched KEGG pathways unique to each disease, and demonstrated that IPF and INSIP are serologically distinct. Furthermore, we discovered a new INSIP-specific autoantibody, anti–myxovirus resistance-1 (MX1) autoantibody. Patients positive for anti-MX1 autoantibody constituted 17.5% of all cases of chronic fibrosing IIPs. Notably, patients rarely simultaneously carried the anti-MX1 autoantibody and the anti–aminoacyl-transfer RNA synthetase autoantibody, which is common in chronic fibrosing IIPs. Because MX1 is one of the most important interferon-inducible anti-viral genes, we have not only identified a new diagnostic autoantibody of INSIP but also obtained new insight into the pathology of INSIP, which may be associated with viral infection and autoimmunity.

To assess image quality of filtered back-projection (FBP) and model-based iterative reconstruction (MBIR) with a conventional setting and a new lung-specific setting on submillisievert CT.

AimFor patients receiving endoscopic submucosal dissection (ESD), there is urgent need pertaining to the prevention of postoperative bleeding. We conducted a retrospective propensity score-matched study that evaluated whether pre-ESD gastric lavage prevents postoperative bleeding after ESD for gastric neoplasms.MethodsFrom September 2002 to October 2015, the 760 consecutive patients receiving ESD for gastric neoplasm were enrolled and data regarding them were retrospectively analyzed. All patients received conventional preventive treatment against delayed bleeding after ESD, including the administration of proton pump inhibitor and preventive coagulation of visible vessels, at the end of the ESD procedure.ResultsPre-ESD risk factors for postoperative bleeding included tumor size and no gastric lavage. Using multivariate analysis tumor size >2.0 cm (HR 2.90, 95% CI 1.65-5.10, p = 0.0002) and no gastric lavage (HR 3.20, 95% CI 1.13-9.11, p = 0.029) were found to be independent risk factors. Next, we evaluated the effect of gastric lavage on the prevention of post-ESD bleeding using a propensity score-matching method. A total of 284 subjects (142 per group) were selected. Adjusted odds ratio of gastric lavage for post-ESD bleeding was 0.25 (95% CI 0.071-0.886, p = 0.032).ConclusionPretreatment gastric lavage reduced postoperative bleeding in patients receiving ESD for gastric neoplasm.

Objectives: To compare iodine content (IC) of solitary lung cancer using dynamic measurements of CT attenuation (Hounsfield Units, HU) and to correlate their quantitative CT data with expressions of vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and hypoxia-inducible factor-1 alpha. (HIF-1 alpha) using immunostaining methods.Methods: This study included 18 patients with adenocarcinoma, who undergone dual energy dynamic multiphase CT to examine solitary lung nodules (6 part-solid and 12 solid nodules). Tumor size was 21.1 mm +/- 8.1 (9-39 mm) [Mean +/- SD (range)]. Contrast volume was determined by weight (2 ml/kg). Contrast volume and injection rate were 110.5 ml +/- 17.2 (80-144 ml) and 1.84 ml/s +/- 0.30 (1.3-2.4 ml/s), respectively. Enhancement values ([CT value at each delayed scan-CT value at unenhanced scan]) and net enhancement values ([peak CT value-CT value at unenhanced scan]) were calculated in HU from 65 keV monochromatic image. IC at each delayed scan was measured in mg/cm(3) from the iodine-water material decomposition pair on the advantage workstation VolumeShare4. Immunostaining using VEGF, EGFR, and HIF-1ce. was performed by two pathologists, who evaluated the expression level of them subjectively. Statistical analyses were performed with rank correlation tests and regression analysis.Results: IC at 2- and 3-minute delayed scan (x) and immunostaining score of HIF-1 alpha. (y) showed a significantly positive correlation (r = 0.64 and 0.52, p = 0.004 and 0.03): regression equation, y =1.34 +/- 0.58 x and y = 1.51 +/- 0.55x, respectively.Conclusions: Dual-energy dynamic multiphase CT can measure iodine content in lung adenocarcinoma. Iodine content at 2- and 3-minute delayed scan might correlate with the expression level of HIF-1 +/-. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Purpose To evaluate the prevalence rates and the correlations of thoracic computed tomography (CT) findings of neurofibromatosis 1 (NF1) in 88 patients. Materials and methods Chest CT images of 88 NF1 patients were independently reviewed by three observers, and the CT findings were evaluated. If abnormal findings were present, their number, size, and distribution were recorded. The prevalence rate of each CT finding was calculated, and the correlations between CT findings were analyzed. Results Of the 88 cases, 13 were positive for cysts, 16 for emphysema, 8 for nodules, 8 for GGNs (ground glass nodules), 13 for mediastinal masses, 20 for scoliosis, 44 for subcutaneous nodules, and 34 for skin nodules. Cysts showed upper and peripheral dominant distributions. Regarding 13 mediastinal masses, 2 were diagnosed as malignant peripheral nerve sheath tumors (MPNSTs), 1 was diagnosed as primary lung cancer, 2 were diagnosed as lateral meningocele, 3 were diagnosed as neurofibromas, and the remaining 7 were considered neurofibromas. There was a significant correlation between the prevalence of subcutaneous nodules and that of skin nodules. Significant positive correlations were also seen between size and number, size and rate of central distribution, and number and rate of central distribution of cysts. Conclusion Various CT findings were found in NF-1 patients, and the prevalence rates of subcutaneous and skin nodules were higher than other findings. Though the prevalence rates of subcutaneous nodules and skin nodules were significantly correlated, the other CT findings in NF-1 occurred independently. The number, size, and distribution of the cysts showed significant positive correlations with each other.

Objectives: Recent reports indicated that reduced SLC22A7 (a gene-encoding organic anion transporter 2) expression in noncancerous liver tissue predicts hepatocellular carcinoma (HCC) recurrence after curative resection. Our study aimed to elucidate the association between SLC22A7 expression and HCC development in chronic hepatitis C patients. Methods: HCC recurrence after local ablation therapy and SLC22A7 expression in noncancerous liver tissue were analyzed in 20 patients. Subsequently, the association between de novo HCC development and SLC22A7 expression was examined at baseline in 38 hepatitis C patients without HCC who subsequently developed HCC as well as in 76 hepatitis C patients who did not develop HCC and were matched for age, gender and stage of fibrosis. Results: In the patients whose HCC had been cured, reduced SLC22A7 expression in noncancerous liver tissue was significantly associated with a high incidence of multifocal HCC recurrence. In patients without HCC at baseline, cumulative incidence of de novo HCC development was significantly higher with a reduced SLC22A7 expression than with a normal expression (p = 0.01). This difference remained significant among patients without known risk factors for HCC like age and advanced fibrosis. Conclusion: Reduced SLC22A7 expression in the liver indicates a significant risk for HCC development in chronic hepatitis C, independently of other risk factors.

PURPOSE:To perform volumetric analysis of stage I lung adenocarcinomas by using an automated computer program and to determine value of volumetric computed tomographic (CT) measurements associated with prognostic factors and outcome.MATERIALS AND METHODS:Consecutive patients (n = 145) with stage I lung adenocarcinoma who underwent surgery after preoperative chest CT were enrolled. By using volumetric automated computer-assisted analytic program, nodules were classified into three subgroups: pure ground glass, part solid, or solid. Total tumor volume, solid tumor volume, and percentage of solid volume of each cancer were calculated after eliminating vessel components. One radiologist measured the longest diameter of the solid tumor component and of total tumor with their ratio, which was defined as solid proportion. The value of these quantitative data by examining associations with pathologic prognostic factors and outcome measures (disease-free survival and overall survival) were analyzed with logistic regression and Cox proportional hazards regression models, respectively. Significant parameters identified at univariate analysis were included in the multiple analyses.RESULTS:All 22 recurrences occurred in patients with nodules classified as part solid or solid. Multiple logistic regression analysis revealed that percentage of solid volume of 63% or greater was an independent indicator associated with pleural invasion (P = .01). Multiple Cox proportional hazards regression analysis revealed that percentage of solid volume of 63% or greater was a significant indicator of lower disease-free survival (hazard ratio, 18.45 [95% confidence interval: 4.34, 78.49]; P < .001). Both solid tumor volume of 1.5 cm(3) or greater and percentage of solid volume of 63% or greater were significant indicators of decreased overall survival (hazard ratio, 5.92 and 9.60, respectively [95% confidence interval: 1.17, 30.33 and 1.17, 78.91, respectively]; P = .034 and .036, respectively).CONCLUSION:Two volumetric measurements (solid volume, ≥1.5 cm(3); percentage of solid volume, ≥63%) were found to be independent indicators associated with increased likelihood of recurrence and/or death in patients with stage I adenocarcinoma.

The FIB-4 index is a simple formula to predict liver fibrosis. This study aimed to evaluate the utility of the FIB-4 index and associated time-course changes as a predictor of hepatocellular carcinoma (HCC) development.

Purpose: To evaluate the intracystic MRI (magnetic resonance imaging) signal intensity of mediastinal cystic masses on T2-weighted images.Materials and methods: A phantom study was performed to evaluate the signal intensity of a mediastinal cystic mass phantom (rubber balloon containing water) adjacent to a cardiac phantom pulsing at the rate of 601min. T2-weighted images (sequence, fast spin echo [FSE] and single shot fast spin echo [SSFSE]) were acquired for the mediastinal cystic mass phantom. Further, a clinical study was performed in 33 patients (16 men, 17 women; age range, 19-85 years; mean, 65years) with thymic cysts or pericardial cysts. In all patients, 12-weighted images (FSE and SSFSE) were acquired. The signal intensity of cystic lesion was evaluated and was compared with that of muscle. A region of interest (ROI) was positioned on the standard MR console, and signal intensity of the cystic mass (cSI), that of the muscle (mSI), and the rate of absolute value of cSI-mSI to standard deviation (SD) of background noise (vertical bar cSI-mSI vertical bar/SD = CNR [contrast-to-noise ratio]) were measured.Results: The phantom study demonstrated that the rate phantom-ROI/saline-ROI was higher in SSFSE (0.36) than in FSE (0.19). In clinical cases, the degree of the signal intensity was higher in SSFSE than in FSE. The CNR was significantly higher in SSFSE (mean +/- standard deviation, 111.0 +/- 47.6) than in FSE (72.8 +/- 36.6) (p < 0.001, Wilcoxon signed-rank test).Conclusions: Anterior media stinal cysts often show lower signal intensity than the original signal intensity of water on T2-weighted images. SSFSE sequence reduces this paradoxical signal pattern on T2-weighted images, which may otherwise cause misinterpretation when assessing cystic lesions. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Radiofrequency ablation (RFA) is an effective and safe noninvasive treatment for hepatocellular carcinoma (HCC) and may be useful as a bridging therapy in liver transplantation. The prognosis after liver transplantation for patients within the Milan criteria is excellent. This study was aimed at identifying risk factors associated with exceeding the Milan criteria after initial locally curative RFA therapy. Among 554 primary HCC patients, 323 with early-stage HCC after RFA were analyzed (mean age = 66 years). Two hundred forty-eight patients had hepatitis C virus, 33 patients had hepatitis B virus, and 41 patients had neither hepatitis B nor hepatitis C; 256, 67, and 0 patients were classified as Child-Pugh A, B, and C, respectively. The rates of cumulative overall survival and recurrence exceeding the Milan criteria were analyzed with Kaplan-Meier analysis, and factors associated with overall survival were determined with Cox proportional hazards analysis. The cumulative overall survival rates at 1, 3, 5, and 10 years were 96.2%, 84.4%, 69.9%, and 40.6% respectively, without liver transplantation. The cumulative rates of recurrence exceeding the Milan criteria at 1, 3, and 5 years were 15.1%, 46.0%, and 61.1% respectively. An alpha-fetoprotein (AFP) level > 100 ng/mL and recurrence within 1 year after initial ablation were independently associated with earlier recurrence exceeding the Milan criteria and overall survival. The 3- and 5-year survival rates for patients with both risk factors were 33.5% and 22.6%, respectively, despite an early stage at initial ablation. In conclusion, a higher AFP level and HCC recurrence within 1 year of RFA are risk factors for exceeding the Milan criteria and for overall survival. Early liver transplantation or adjuvant therapy should be considered for patients with both risk factors. Liver Transpl 20:291-297, 2014. © 2013 AASLD.