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A 70-year-old woman had been taking steroids for granulomatosis with polyangiitis since the age of 60 years and warfarin for deep vein thrombosis since the age of 63 years. She was admitted to the emergency unit of our hospital in a shock vital with complaints of sudden onset of epigastralgia, nausea, and melena. Laboratory data revealed anemia, hypoalbuminemia, and coagulation disorders. Enhanced computed tomography demonstrated extravasation in the middle part of the gastric body in an extensive submucosal hematoma extending from the upper esophagus to the entire gastric body. Emergency esophagogastroduodenoscopy depicted a large submucosal hematoma and a large amount of fresh blood in the stomach; however, active bleeding was not identified. Two sessions of interventional radiology treatment in the emergency department, followed by an intensive care, successfully treated the patient without any complications. We report a unique case of a sudden-onset esophagogastric submucosal hematoma with hemorrhagic shock requiring an intensive care and interventional radiology treatment. In this case, the extensive warfarization and the fragility in vascular and connective tissue components in the submucosa due to the long-term steroid therapy and the granulomatosis with polyangiitis-related alteration might comprehensively cause severe esophagogastric submucosal hematoma even without any apparent triggers., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Human and animal rights: This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent: Informed consent was obtained in this case report. Writing assistance: This manuscript has been checked by a native English speaker., (© 2024. Japanese Society of Gastroenterology.)

Background: Given the global shortage of child psychiatrists and barriers to specialized care, remote assessment is a promising alternative for diagnosing and managing attention-deficit/hyperactivity disorder (ADHD). However, only a few studies have validated the accuracy and acceptability of these remote methods., Objective: This study aimed to test the agreement between remote and face-to-face assessments., Methods: Patients aged between 6 and 17 years with confirmed Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnoses of ADHD or autism spectrum disorder (ASD) were recruited from multiple institutions. In a randomized order, participants underwent 2 evaluations, face-to-face and remotely, with distinct evaluators administering the ADHD Rating Scale-IV (ADHD-RS-IV). Intraclass correlation coefficient (ICC) was used to assess the reliability of face-to-face and remote assessments., Results: The participants included 74 Japanese children aged between 6 and 16 years who were primarily diagnosed with ADHD (43/74, 58%) or ASD (31/74, 42%). A total of 22 (30%) children were diagnosed with both conditions. The ADHD-RS-IV ICCs between face-to-face and remote assessments showed "substantial" agreement in the total ADHD-RS-IV score (ICC=0.769, 95% CI 0.654-0.849; P<.001) according to the Landis and Koch criteria. The ICC in patients with ADHD showed "almost perfect" agreement (ICC=0.816, 95% CI 0.683-0.897; P<.001), whereas in patients with ASD, it showed "substantial" agreement (ICC=0.674, 95% CI 0.420-0.831; P<.001), indicating the high reliability of both methods across both conditions., Conclusions: Our study validated the feasibility and reliability of remote ADHD testing, which has potential benefits such as reduced hospital visits and time-saving effects. Our results highlight the potential of telemedicine in resource-limited areas, clinical trials, and treatment evaluations, necessitating further studies to explore its broader application., Trial Registration: UMIN Clinical Trials Registry UMIN000039860; http://tinyurl.com/yp34x6kh., (©Shunya Kurokawa, Kensuke Nomura, Nana Hosogane, Takashi Nagasawa, Yuko Kawade, Yu Matsumoto, Shuichi Morinaga, Yuriko Kaise, Ayana Higuchi, Akiko Goto, Naoko Inada, Masaki Kodaira, Taishiro Kishimoto. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 19.02.2024.)

Objective: We aimed to develop a machine learning algorithm to screen for depression and assess severity based on data from wearable devices., Methods: We used a wearable device that calculates steps, energy expenditure, body movement, sleep time, heart rate, skin temperature, and ultraviolet light exposure. Depressed patients and healthy volunteers wore the device continuously for the study period. The modalities were compared hourly between patients and healthy volunteers. XGBoost was used to build machine learning models and 10-fold cross-validation was applied for the validation., Results: Forty-five depressed patients and 41 healthy controls participated, creating a combined 5,250 days' worth of data. Heart rate, steps, and sleep were significantly different between patients and healthy volunteers in some comparisons. Similar differences were also observed longitudinally when patients' symptoms improved. Based on seven days' data, the model identified symptomatic patients with 0.76 accuracy and predicted Hamilton Depression Rating Scale-17 scores with a 0.61 correlation coefficient. Skin temperature, sleep time-related features, and the correlation of those modalities were the most significant features in machine learning., Limitations: The small number of subjects who participated in this study may have weakened the statistical significance of the study. There are differences in the demographic data among groups although we performed a correction for multiple comparisons. Validation in independent datasets was not performed, although 10-fold cross validation with the internal data was conducted., Conclusion: The results indicated that utilizing wearable devices and machine learning may be useful in identifying depression as well as assessing severity., (© 2020 The Authors. Published by Elsevier Ltd.)

Aim: Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T-cell receptor (TCR) signaling is associated with inflammatory cytokine production through N-Ras upregulation. Although the CD4 + T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC-CD4 + T cell TCR repertoire using next generation sequencing (NGS)., Methods: Four PBC patients (one treatment-naïve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. NRAS expression in CD4 + T cells was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). N-Ras dynamics in CD4 + T cells were assessed by qRT-PCR and GTP-N-Ras activation assay. The TCR α- (TRA) and β-chain (TRB) repertoires on CD4 + T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC-specific TCRs., Results: NRAS was upregulated in PBC relative to control CD4 + T cells (P < 0.05), and N-Ras enhanced T cell activation in CD4 + T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls (P < 0.05, fold-change >2). Among them, TRAV29/J22, TRBV6-5/J2-6, and TRBV10-1/J2-1 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC-CD4 + T cells., Conclusions: N-Ras was upregulated in PBC-CD4 + T cells, and it enhanced TCR activation, indicating that PBC-CD4 + T cells were activated by N-Ras upregulation with differentially expressed TCR repertoires on their surfaces., (© 2019 The Japan Society of Hepatology.)

In our previous study on hepatocellular carcinoma (HCC) susceptibility genes in chronic hepatitis patients, we identified the MHC class I polypeptide-related sequence A (MICA). Natural killer cells eliminate various cancer cells, including HCC, by suppressing MICA shedding. Therefore, we investigated MICA sheddases and inhibitors for HCC immunotherapy. In this study, HepG2, PLC/PRF/5, and Hep3B were treated with the siRNA of a disintegrin and metalloproteases (ADAMs) and matrix metalloproteases to measure the concentration of soluble MICA (sMICA) by ELISA to detect the therapeutic target. Furthermore, an FDA-approved drug library was tested for the enzymatic inhibition of the targeted enzyme in an in vitro drug screening assay system. ADAM17 knockdown reduced sMICA levels and increased membrane-bound MICA (mMICA) expression in HCC cells. In an in vitro drug screen using an FDA-approved drug library, lomofungin, an antifungal drug, was found to strongly decrease ADAM17 activity. In HCC cells, mMICA expression was induced and sMICA production was inhibited in a dose-dependent manner. These effects were cancelled upon ADAM17 knockdown, suggesting that lomofungin targeted ADAM17. Analysis of lomofungin analogs revealed the responsible functional groups. In summary, we suggest lomofungin to be an attractive agent for the immunological control of HCC, via the suppression of ADAM17., (© 2018 UICC.)

Background and Aim: The multi-kinase inhibitor regorafenib (REG) was recently demonstrated to be effective in patients with sorafenib (SOR)-resistant hepatocellular carcinoma (HCC). Interestingly, SOR is known to enhance the accumulation of membrane-bound MHC class I polypeptide-related sequence A (mMICA) in HCC cells and to block the production of soluble MICA (sMICA), an immunological decoy. In addition, MICA is associated with HCC in patients with chronic hepatitis C. We have now compared the impact of REG and SOR on MICA in HCC cells, as well as the immunotherapeutic implications thereof., Methods: HepG2 and PLC/PRF/5 cells were exposed to REG and SOR, and levels of sMICA and mMICA were measured by ELISA and flow cytometry, respectively. The drugs were also tested in vitro for inhibitory activity against recombinant human A disintegrin and metalloprotease 9 (ADAM9), a sheddase that releases MICA from the membrane., Results: To a greater extent than SOR, but without marked difference in cytotoxicity, REG significantly suppressed mRNA and protein expression of ADAM9 and ADAM10, thereby decreasing production of sMICA and boosting accumulation of mMICA. Accumulation of mMICA in response to REG was reversed by siRNA against ADAM9. However, the drugs did not inhibit the enzymatic activity of ADAM9 in vitro., Conclusions: The clinical superiority of REG over SOR is partially attributable to reduced MICA shedding via transcriptional suppression of ADAM9 and ADAM10., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune liver disease of unknown pathogenesis. Consequently, therapeutic targets for PBC have yet to be identified. CD4 + T cells play a pivotal role in immunological dysfunction observed in PBC, and therefore, microRNA (miRNA) and mRNA expression were analysed in CD4 + T cells, to investigate PBC pathogenesis and identify novel therapeutic targets., Methods: Integral miRNA and mRNA analysis of 14 PBC patients and ten healthy controls was carried out using microarray and quantitative real-time polymerase chain reaction (qRT-PCR), with gene set enrichment analysis. The functional analyses of miRNA were then assessed using reporter and miRNA-overexpression assays., Results: The integral analysis of miRNA and mRNA identified four significantly downregulated miRNAs (miR-181a, -181b, -374b, and -425) related to the T cell receptor (TCR) signalling pathway in CD4 + T cells of PBC. N-Ras, a regulator of the TCR signalling pathway, was found to be targeted by all four identified miRNAs. In addition, in vitro assays confirmed that decreased miR-425 strongly induced inflammatory cytokines (interleukin [IL]-2 and interferon [IFN]-γ) via N-Ras upregulation in the TCR signalling pathway., Conclusion: The decreased expression of four miRNAs that dysregulate TCR signalling in PBC CD4 + T cells was identified. miR-425 was demonstrated as an inflammatory regulator of PBC via N-Ras upregulation. Therefore, the restoration of decreased miR-425 or the suppression of N-Ras may be a promising immunotherapeutic strategy against PBC., Lay Summary: Primary biliary cholangitis (PBC) is an autoimmune liver disease, but the causes are unknown. MicroRNAs are molecules known to regulate biological signals. In this study, four microRNAs were identified as being decreased in PBC patients, leading to activation of T cell receptor signalling pathways, involved in inflammation. One particular target, N-Ras, could be an attractive and novel immunotherapeutic option for PBC., Transcript Profiling: Microarray data are deposited in GEO (GEO accession: GSE93172)., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)