Search

Abstract We provide a quantitative estimate of the radiation dose during relativistic electron precipitation (REP) events at the International Space Station (ISS). To this goal, we take advantage of the data collected by the CALorimetric Electron Telescope, the Monitor of All‐sky X‐ray Image, and the Space Environment Data Acquisition equipment‐Attached Payload. The three ISS detectors offer complementary REP observations, including energy spectra and flux directional information, during a period of approximately 2.5 years, from November 2015 to March 2018. We have identified 762 REP events during this period from which we obtain the distribution of radiation dose, relevant to extravehicular activities outside the ISS.

The CALorimetric Electron Telescope, CALET, has been measuring high-energy cosmic rays on the International Space Station since October 13, 2015. The scientific objectives addressed by the mission are to search for possible nearby sources of high-energy electrons and potential signatures of dark matter, and to investigate the details of galactic cosmic-ray acceleration and propagation. The calorimetric instrument, which is 30 radiation lengths or 1.3 proton interaction lengths thick with fine imaging capability, is optimized to measure cosmic-ray electrons by achieving large proton rejection and excellent energy resolution well into the TeV region. In addition, very wide dynamic range of energy measurement and individual charge identification capability enable us to measure proton and nuclei spectra from a few tens GeV to a PeV scale. Nearly 20 million cosmic-ray shower events over 10 GeV per month are triggered and the continuous observation has been kept without any major interruption since the start of operation. Using the data obtained over 6.5 years of operation, we will present a brief summary of the CALET observation including electron spectrum, and proton and nuclei spectra as well as the performance study on orbit with MC simulations.

We present the results of searches for gamma-ray counterparts of the LIGO/Virgo gravitational wave events using CALorimetric Electron Telescope (CALET) observations. The main instrument of CALET, CALorimeter (CAL), observes gamma-rays from ∼1 GeV up to 10 TeV with a field of view (FOV) of nearly 2 sr. In addition, the CALET gamma-ray burst monitor views ∼3 sr and ∼2π sr of the sky in the 7 keV–1 MeV and the 40 keV–20 MeV bands, respectively, by using two different crystal scintillators. The CALET observations on the International Space Station started in 2015 October, and here we report analyses of events associated with the following gravitational wave events: GW151226, GW170104, GW170608, GW170814, and GW170817. Although only upper limits on gamma-ray emission are obtained, they correspond to a luminosity of 1049 ∼ 1053 erg s−1 in the GeV energy band depending on the distance and the assumed time duration of each event, which is approximately on the order of luminosity of typical short gamma-ray bursts. This implies that there will be a favorable opportunity to detect high-energy gamma-ray emission in further observations if additional gravitational wave events with favorable geometry will occur within our FOV. We also show the sensitivity of CALET for gamma-ray transient events, which is on the order of 10−7 erg cm−2 s−1 for an observation of 100 s in duration. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to introduce and evaluate a novel software-based system, BioTrace, designed for real-time monitoring of thermal ablation tissue damage during image-guided radiofrequency ablation for hepatocellular carcinoma (HCC)., Methods: BioTrace utilizes a proprietary algorithm to analyze the temporo-spatial behavior of thermal gas bubble activity during ablation, as seen in conventional B-mode ultrasound imaging. Its predictive accuracy was assessed by comparing the ablation zones it predicted with those annotated by radiologists using contrast-enhanced computed tomography (CECT) 24 hours post-treatment, considered the gold standard. The study included 20 liver tumors., Results: The median tumor measurement along the major axis was 1.2 cm. The median Dice coefficient, Sensitivity, and Precision between BioTrace and CECT were 0.90, 0.91, and 0.91, respectively. The intraclass correlation showed excellent agreement in volume size between BioTrace and CECT findings (0.98)., Conclusion: BioTrace effectively generates an ablation damage prediction map based on real-time ultrasound imaging, accurately predicting the ablation zone as confirmed by 24-hour post-procedural CECT. This system has the potential to enhance the safety and efficacy of ablation procedures in clinical settings., Competing Interests: This study was funded by TechsoMed Medical Technologies and designed in collaboration with the University of Tokyo and SCREEN Holdings Co., Ltd. RT has received lecture fee from TechsoMed Medical Technologies. RY is an employee of SCREEN Holdings Col, Ltd and a shareholder in the company. RY provided technical support for the BioTrace system. YZ is an employee of TechsoMed Medical Technologies. YZ involved in study design, data analysis, and drafting of the manuscript. NE is an employee of TechsoMed Medical Technologies. NE involved in drafting of the manuscript. IA is an employee of TechsoMed Medical Technologies. IA involved in data analysis. YA is an employee of TechsoMed Medical Technologies and a shareholder in the company. YA involved in study design and drafting of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2025 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aim: In recent years, the majority of patients eligible for endoscopic retrograde cholangiopancreatography (ERCP) have been aged ≥75 years. We investigated ERCP safety in very elderly patients (aged ≥90 years)., Methods: We included patients aged ≥75 years who underwent ERCP between January 2015 and December 2020. We compared background factors, comorbidities, ERCP indications, complications, and outcomes and identified risk factors for complications using binary logistic regression and inverse probability of treatment weighting with propensity scores., Results: The study included 1344 patients aged ≥75 years (137 and 1207 very elderly and elderly patients, respectively). The very elderly group had more women, less frequent diabetes, fewer antithrombotic medications, more frequent parapapillary diverticulum, less frequent post-cholecystectomy, and worse performance status. No significant differences were observed in the ERCP indications. Experienced endoscopists were likely to perform the procedure, and the procedure time was shorter for the very elderly. Complications occurred in 21 (15%) very elderly patients and 120 (10%) elderly patients, with no significant differences. The very elderly did not have an increased risk of complications but were less likely to be discharged home and had a significantly worse performance status at discharge., Conclusions: ERCP could be safely performed in the very elderly, and age did not increase the risk of complications. Geriatr Gerontol Int 2025; 25: 54-60., (© 2024 Japan Geriatrics Society.)

Background: Persons with dementia in nursing homes often experience cognitive decline (e.g., memory and visuospatial/construction problems), behavioural and psychological symptoms of dementia (BPSD), and impaired activities of daily living. Therefore, comprehensive interventions for this population are needed. We assessed whether a multimodal non-pharmacological intervention improved cognitive functions, BPSD, and activities of daily living in persons with dementia in nursing homes., Methods: This was a multicentre randomised controlled trial. Participants were 40 persons with dementia (38 women) living in four nursing homes (intervention group = 21; control group = 19). The intervention was conducted for 8 weeks, followed by an 8-week follow-up. Outcome measures were scores on the Japanese version of the Neurobehavioral Cognitive Status Examination Five and the ABC Dementia Scale. In the analysis, parameters were estimated using Bayesian statistics and a mixed-effects linear regression model for the change in each outcome measure., Results: There were significant between-group differences in changes in ABC Dementia Scale BPSD scores (8-week: posteriori median = 1.66, 95% Bayesian confidence interval 0.36-3.01; 16-week: median = 2.37, 95% Bayesian confidence interval 0.05-4.65). There was also a significant between-group difference in changes in Neurobehavioral Cognitive Status Examination Five constructional ability scores (16-week: median = 0.93, 95% Bayesian confidence interval 0.35-1.50)., Conclusion: This intervention may have a maintenance and improvement effect on BPSD in persons with dementia in nursing homes, and a sustained effect on constructional ability post-intervention. The intervention may be useful and easy to apply in practice., (© 2024 Japanese Psychogeriatric Society.)

Objectives: A relationship between endoscopic submucosal dissection (ESD) and deep vein thrombosis has been recognized. We previously reported that a high corrected midazolam dose (total midazolam dose/initial dose of midazolam used to induce sedation) is related to elevated D-dimer levels after ESD. In this study, the effect of compression stockings (CSs) in preventing thrombosis following ESD under sedation was evaluated by measuring D-dimer levels before and after ESD., Methods: The participants were patients who underwent ESD for upper gastrointestinal tumors during the period between April 2018 and October 2022. Patients with pre-ESD D-dimer levels ≥1.6 µg/m and patients with corrected midazolam doses ≤3.0 were excluded. A retrospective investigation of the relationship between CS use and high post-ESD D-dimer levels (difference in D-dimer levels ≥1.0 µg/mL between before and after ESD) was conducted., Results: There were 27 patients in the non-CS group (NCS) and 33 patients in the CS group. The number of patients with high post-ESD D-dimer levels was 13 (48.2%) in the non-CS group and six (18.2%) in the CS group; the number in the CS group was significantly lower ( p = 0.024). On logistic regression analysis, a relationship was seen between the wearing of CSs and a lower number of patients with high post-ESD D-dimer levels (odds ratio 0.24, 95% confidence interval 0.08-0.79, p = 0.019)., Conclusion: Wearing CSs was related to a lower risk of high post-ESD D-dimer levels. This result suggests that thrombus formation is a cause of elevated D-dimer levels after ESD., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Aim: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease., Methods: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected., Results: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination., Conclusion: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases., (© 2024 Japan Society of Hepatology.)

Duplicate testes lined in series were observed in the right scrotum of a 6-week-old Sprague-Dawley rat in a single-dose toxicity study. Of the two right testicles, one was spherical and less than half the size of a normal testis. The other was oval-shaped, slightly smaller than a normal testis, and possessed clear, tortuous blood vessels similar to those of a normal testis. Each right testis was grossly separated but faced the intertesticular adipose tissue and was sparsely joined by thin cord-like structures. Only one epididymis covered or encompassed the two right testes. The caput epididymis was attached to the smaller spherical testis, whereas the cauda epididymis was attached to the oval testis. Histopathological examination revealed that the smaller spherical testis on the right side and the testis on the left side were normal. The oval-shaped testis on the right exhibited markedly dilated degenerative seminiferous tubules with one to two layers of Sertoli or germ cells, and almost no spermatogenesis was observed. Multinucleated germ cells were observed in the lumen of the degenerated seminiferous tubules. The right epididymis was morphologically normal and contained few sperm in the epididymal duct of the tail. The cord-like structures between duplicate testes comprised fibrous and adipose tissues. Single efferent ductules, ectopic cartilage, and skeletal muscle tissues were buried in the adipose tissue. To our knowledge, this is the first report of spontaneous polyorchidism in a rodent., Competing Interests: The authors have no competing interests to disclose., (©2024 The Japanese Society of Toxicologic Pathology.)

Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases., (© 2024. The Author(s).)

Introduction: RRAS2, a member of the R-Ras subfamily of Ras-like low-molecular-weight GTPases, is considered to regulate cell proliferation and differentiation via the RAS/MAPK signaling pathway. Seven RRAS2 pathogenic variants have been reported in patients with Noonan syndrome; however, few functional analyses have been conducted. Herein, we report two patients who presented with a Noonan-like phenotype with recurrent and novel RRAS2 pathogenic variants (p.Gly23Val and p.Gly24Glu, respectively) and the results of their functional analysis. Materials and methods: Wild-type (WT) and mutant RRAS2 genes were transiently expressed in Human Embryonic Kidney293 cells. Expression of RRAS2 and phosphorylation of ERK1/2 were confirmed by Western blotting, and the RAS signaling pathway activity was measured using a reporter assay system with the serum response element-luciferase construct. WT and p.Gly23Val RRAS2 were expressed in Drosophila eye using the glass multiple reporter-Gal4 driver. Mutant mRNA microinjection into zebrafish embryos was performed, and the embryo jaws were observed. Results: No obvious differences in the expression of proteins WT, p.Gly23Val, and p.Gly24Glu were observed. The luciferase reporter assay showed that the activity of p.Gly23Val was 2.45 ± 0.95-fold higher than WT, and p.Gly24Glu was 3.06 ± 1.35-fold higher than WT. For transgenic flies, the p.Gly23Val expression resulted in no adults flies emerging, indicating lethality. For mutant mRNA-injected zebrafish embryos, an oval shape and delayed jaw development were observed compared with WT mRNA-injected embryos. These indicated hyperactivity of the RAS signaling pathway. Discussion: Recurrent and novel RRAS2 variants that we reported showed increased in vitro or in vivo RAS signaling pathway activity because of gain-of-function RRAS2 variants. Clinical features are similar to those previously reported, suggesting that RRAS2 gain-of-function variants cause this disease in patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Iida, Igarashi, Fukunaga, Aoki, Hidai, Yanagi, Yamamori, Satou, Go, Kosho, Maki, Suzuki, Nitta, Sugie, Asaoka, Furutani-Seiki, Kimura, Matsubara and Kaname.)

Detailed measurements of the spectral structure of cosmic-ray electrons and positrons from 10.6 GeV to 7.5 TeV are presented from over 7 years of observations with the CALorimetric Electron Telescope (CALET) on the International Space Station. The instrument, consisting of a charge detector, an imaging calorimeter, and a total absorption calorimeter with a total depth of 30 radiation lengths at normal incidence and a fine shower imaging capability, is optimized to measure the all-electron spectrum well into the TeV region. Because of the excellent energy resolution (a few percent above 10 GeV) and the outstanding e/p separation (10^{5}), CALET provides optimal performance for a detailed search of structures in the energy spectrum. The analysis uses data up to the end of 2022, and the statistics of observed electron candidates has increased more than 3 times since the last publication in 2018. By adopting an updated boosted decision tree analysis, a sufficient proton rejection power up to 7.5 TeV is achieved, with a residual proton contamination less than 10%. The observed energy spectrum becomes gradually harder in the lower energy region from around 30 GeV, consistently with AMS-02, but from 300 to 600 GeV it is considerably softer than the spectra measured by DAMPE and Fermi-LAT. At high energies, the spectrum presents a sharp break around 1 TeV, with a spectral index change from -3.15 to -3.91, and a broken power law fitting the data in the energy range from 30 GeV to 4.8 TeV better than a single power law with 6.9 sigma significance, which is compatible with the DAMPE results. The break is consistent with the expected effects of radiation loss during the propagation from distant sources (except the highest energy bin). We have fitted the spectrum with a model consistent with the positron flux measured by AMS-02 below 1 TeV and interpreted the electron+positron spectrum with possible contributions from pulsars and nearby sources. Above 4.8 TeV, a possible contribution from known nearby supernova remnants, including Vela, is addressed by an event-by-event analysis providing a higher proton-rejection power than a purely statistical analysis.

Background and Aims: For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF., Methods: We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models., Results: In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73-27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32-22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16-20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48-40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37-88.5, p = 0.004) were found significantly associated., Conclusion: In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages., (© 2023 Japan Society of Hepatology.)

Endoscopic submucosal dissection (ESD) is almost always performed with a sedative because of the longer procedure times involved. The risk of post-ESD deep vein thrombosis (DVT) has been reported as relatively high, and D-dimer levels are sometimes elevated after ESD. This retrospective study evaluated factors affecting changes in D-dimer levels from before to after ESD to identify causes of elevated D-dimer levels after ESD. This retrospective analysis included 117 patients with gastrointestinal tumors resected using ESD. After excluding eight patients with pre-ESD levels of D-dimer >1.5 μg/mL, factors correlating with changes in D-dimer from before to after ESD were analyzed using logistic regression analysis in 109 patients. Sedation was accomplished primarily using midazolam, but, because the sedative effect of midazolam shows marked inter-individual variability, a "corrected midazolam dose" was determined by dividing the total midazolam dose by the initial dose to correct for inter-individual differences in the sedative effect of midazolam. This value was used as one potential explanatory variable in the subgroup analysis of the 103 patients who received midazolam. In the subgroup analysis using the corrected midazolam dose as an explanatory variable, only the corrected midazolam dose correlated with a change in D-dimer ≥1.0 μg/mL in multivariate analysis (odds ratio (OR) = 1.5, 95% confidence interval (CI) 0.43-0.95; p = 0.030). The corrected midazolam dose correlated with increases in post-ESD D-dimer levels. This potential relationship indicates that patients undergoing ESD and requiring extended sedation may be at increased risk of DVT.

Background and Aims: Accurate risk stratification for hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) is necessary for optimal surveillance. We aimed to develop and validate a machine learning (ML) model to predict the risk of HCC after achieving an SVR in individual patients., Methods: In this multicenter cohort study, 1742 patients with chronic hepatitis C who achieved an SVR were enrolled. Five ML models were developed including DeepSurv, gradient boosting survival analysis, random survival forest (RSF), survival support vector machine, and a conventional Cox proportional hazard model. Model performance was evaluated using Harrel' c-index and was externally validated in an independent cohort (977 patients)., Results: During the mean observation period of 5.4 years, 122 patients developed HCC (83 in the derivation cohort and 39 in the external validation cohort). The RSF model showed the best discrimination ability using seven parameters at the achievement of an SVR with a c-index of 0.839 in the external validation cohort and a high discriminative ability when the patients were categorized into three risk groups (P <0.001). Furthermore, this RSF model enabled the generation of an individualized predictive curve for HCC occurrence for each patient with an app available online., Conclusions: We developed and externally validated an RSF model with good predictive performance for the risk of HCC after an SVR. The application of this novel model is available on the website. This model could provide the data to consider an effective surveillance method. Further studies are needed to make recommendations for surveillance policies tailored to the medical situation in each country., Impact and Implications: A novel prediction model for HCC occurrence in patients after hepatitis C virus eradication was developed using machine learning algorithms. This model, using seven commonly measured parameters, has been shown to have a good predictive ability for HCC development and could provide a personalized surveillance system., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Impulse control disorder has been suggested to meet the criteria of addiction and is often considered a behavioral addiction; however, few studies have examined whether the disorder involves altered responses to situational cues that are associated with symptoms. In this study, we examined behavioral and neural responses to situational cues among individuals with an impulse control disorder: kleptomania., Methods: Healthy adults and kleptomania patients whose symptoms were characterized by repetitive, uncontrolled shoplifting of sales goods in stores were recruited. Images with and without situational cues (e.g., a grocery store) were presented, and gazing patterns for the images were detected with the eye-tracker. Additionally, prefrontal cortical (PFC) responses were measured using functional near-infrared spectroscopy. PFC activities were further examined while participants were watching video clips in virtual reality with and without situational cues., Results: Among kleptomania patients, the gazing pattern for an image with situational cues was distinct from gazing patterns for other images; such differences were not observed in healthy individuals. Consistent with gazing patterns, PFC local network responses by hemoglobin changes to images and videos with situational cues were substantially different from other images and videos in kleptomania patients, whereas PFC responses were consistent across all image and video presentations in healthy individuals., Conclusions: These results suggest that kleptomania patients may perceive situational cues associated with their problematic behaviors differently from healthy individuals., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

We present the results of a direct measurement of the cosmic-ray helium spectrum with the CALET instrument in operation on the International Space Station since 2015. The observation period covered by this analysis spans from October 13, 2015, to April 30, 2022 (2392 days). The very wide dynamic range of CALET allowed for the collection of helium data over a large energy interval, from ∼40  GeV to ∼250  TeV, for the first time with a single instrument in low Earth orbit. The measured spectrum shows evidence of a deviation of the flux from a single power law by more than 8σ with a progressive spectral hardening from a few hundred GeV to a few tens of TeV. This result is consistent with the data reported by space instruments including PAMELA, AMS-02, and DAMPE and balloon instruments including CREAM. At higher energy we report the onset of a softening of the helium spectrum around 30 TeV (total kinetic energy). Though affected by large uncertainties in the highest energy bins, the observation of a flux reduction turns out to be consistent with the most recent results of DAMPE. A double broken power law is found to fit simultaneously both spectral features: the hardening (at lower energy) and the softening (at higher energy). A measurement of the proton to helium flux ratio in the energy range from 60  GeV/n to about 60  TeV/n is also presented, using the CALET proton flux recently updated with higher statistics.

Factors associated with serious colonic diverticular bleeding (CDB) are unclear, although the incidence of CDB has increased. We carried out this study to clarify factors associated with serious CDB and rebleeding. Subjects included 329 consecutive patients hospitalized for confirmed or suspected CDB between 2004 and 2021. Patients were surveyed regarding backgrounds, treatment, and clinical course. Of 152 with confirmed CDB, 112 showed bleeding from the right colon, and 40 did from the left colon. Patients received red blood cell transfusions in 157 (47.7%), interventional radiology in 13 (4.0%), and surgery in 6 (1.8%) cases. Early rebleeding within one month occurred in 75 (22.8%) patients, and late rebleeding within one year occurred in 62 (18.8%). Factors associated with red blood cell transfusion included confirmed CDB, anticoagulants, and high shock index. The only factor related to interventional radiology or surgery was confirmed CDB, which was also associated with early rebleeding. Late rebleeding was associated with hypertension, chronic kidney disease and past CDB. Right CDB showed higher rates of transfusion and invasive treatment than left CDB. Confirmed CDB had high frequencies of transfusion, invasive treatment, and early rebleeding. Right CDB seemed to be a risk for serious disease. Factors related to late rebleeding were different from those related to early rebleeding of CDB.

Background: Adjuvants are chemical or biological materials that enhance the efficacy of vaccines. A-910823 is a squalene-based emulsion adjuvant used for S-268019-b, a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is currently in clinical development. Published evidence has demonstrated that A-910823 can enhance the induction of neutralizing antibodies against SARS-CoV-2 in humans and animal models. However, the characteristics and mechanisms of the immune responses induced by A-910823 are not yet known., Methods and Results: To characterize A-910823, we compared the adaptive immune response profile enhanced by A-910823 with that of other adjuvants (AddaVax, QS21, aluminum salt-based adjuvants, and empty lipid nanoparticle [eLNP]) in a murine model. Compared with other adjuvants, A-910823 enhanced humoral immune responses to an equal or greater extent following potent T follicular helper (Tfh) and germinal center B (GCB) cell induction, without inducing a strong systemic inflammatory cytokine response. Furthermore, S-268019-b containing A-910823 adjuvant produced similar results even when given as a booster dose following primary administration of a lipid nanoparticle-encapsulated messenger RNA (mRNA-LNP) vaccine. Preparation of modified A-910823 adjuvants to identify which components of A-910823 play a role in driving the adjuvant effect and detailed evaluation of the immunological characteristics induced by each adjuvant showed that the induction of humoral immunity and Tfh and GCB cell induction in A-910823 were dependent on α-tocopherol. Finally, we revealed that the recruitment of inflammatory cells to the draining lymph nodes and induction of serum cytokines and chemokines by A-910823 were also dependent on the α-tocopherol component., Conclusions: This study demonstrates that the novel adjuvant A-910823 is capable of robust Tfh cell induction and humoral immune responses, even when given as a booster dose. The findings also emphasize that α-tocopherol drives the potent Tfh-inducing adjuvant function of A-910823. Overall, our data provide key information that may inform the future production of improved adjuvants., Competing Interests: YYo, MO, TN, MH, YYa, AN, JH, YA, MT, AH, SI, SO, and MN are employees of Shionogi & Co., Ltd. Shionogi & Co., Ltd. had the following involvement in the study; study design, data collection and analysis, decision to publish, and preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yoshioka, Kobiyama, Hayashi, Onishi, Yanagida, Nakagawa, Hashimoto, Nishinaka, Hirose, Asaoka, Tajiri, Hayata, Ishida, Omoto, Nagira and Ishii.)

Introduction: Balloon-occluded retrograde transvenous obliteration (BRTO) was developed as an effective treatment for gastric varices in patients with cirrhosis. Because liver fibrosis in these patients is assumed to be advanced, their prognosis is expected to be poor. In this study, we investigated the prognosis and characteristics of the patients., Methods: We enrolled 55 consecutive patients with liver cirrhosis treated with BRTO between 2009 and 2021 at our department. To evaluate factors related to variceal recurrence and long-term prognosis, survival analysis was performed on 45 patients, excluding those who died within 1 month, had an unknown prognosis, or whose treatments were converted to other treatments., Results: During a mean follow-up period of 2.3 years, esophageal varices recurred in 10 patients and could be treated endoscopically. Non-alcoholic steatohepatitis (NASH) was related to the variceal recurrence (hazard ratio [HR] = 4.27, 95% CI: 1.17-15.5, p = 0.028). The survival rate after the procedure at 1, 3, and 5 years was 94.2%, 74.0%, and 63.5%, respectively, and 10 patients died of hepatocellular carcinoma (n = 6), liver failure (n = 1), sepsis (n = 1), and unknown reasons (n = 2). The estimated glomerular filtration rate (eGFR) level was proved to be a significant poor prognostic factor (HR = 0.96, 95% CI: 0.93-0.99, p = 0.023). The comorbid hypertension (HTN) was the main cause of low eGFR, and HTN was also significantly related to survival (HR = 6.18, 95% CI: 1.57-24.3, p = 0.009). Most of the patients with HTN were treated with calcium channel blocker and/or angiotensin receptor blocker., Conclusion: The clinical course of patients with cirrhosis treated with BRTO was dependent on the metabolic factors including renal function, comorbid HTN, and NASH., (© 2023 S. Karger AG, Basel.)

We present the measurement of the energy dependence of the boron flux in cosmic rays and its ratio to the carbon flux in an energy interval from 8.4  GeV/n to 3.8  TeV/n based on the data collected by the Calorimetric Electron Telescope (CALET) during ∼6.4  yr of operation on the International Space Station. An update of the energy spectrum of carbon is also presented with an increase in statistics over our previous measurement. The observed boron flux shows a spectral hardening at the same transition energy E&#95;{0}∼200  GeV/n of the C spectrum, though B and C fluxes have different energy dependences. The spectral index of the B spectrum is found to be γ=-3.047±0.024 in the interval 25

Introduction: Proton beam therapy (PBT) is known to be an effective locoregional treatment for hepatocellular carcinoma (HCC). However, few comparative studies in treatment-naïve cases have been reported. The aim of this study was to compare the survival outcomes of PBT with those of radiofrequency ablation (RFA) in patients with treatment-naïve solitary HCC., Methods: Ninety-five consecutive patients with treatment-naïve HCC, a single nodule measuring ≤5 cm in diameter, and a Child-Pugh score of ≤8 who were treated with PBT at the University of Tsukuba Hospital between 2001 and 2013 were enrolled in the study. In addition, 836 patients with treatment-naïve HCC treated by RFA at the University of Tokyo Hospital during the same period were analyzed as controls. Recurrence-free survival (RFS) and overall survival (OS) were compared in 83 patient pairs after propensity score matching., Results: The 1-year, 3-year, and 5-year RFS rates were 86.6%, 49.5%, and 35.5%, respectively, in the PBT group and 59.5%, 34.0%, and 20.9% in the RFA group ( p = 0.058); the respective OS rates were 97.6%, 77.8%, and 57.1% in the PBT group and 95.1%, 81.7%, and 67.7% in the RFA group ( p = 0.16). Regarding adverse effects, no grade 3 or higher adverse events were noted in the PBT; however, two grade 3 adverse events occurred within 30 days of RFA in the RFA group: one hemoperitoneum and one hemothorax., Discussion: After propensity score matching, PBT showed no significant difference in RFS and OS compared to RFA. PBT can be an alternative for patients with solitary treatment-naïve HCC., Competing Interests: Ryosuke Tateishi has received lecture fees from STARmed Co., Ltd., Medtronic plc, Merk Sharp & Dohme, Chugai Pharmaceutical Co., Ltd., Bristol-Meyers Squibb, Giliad Sciences, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eisai Co., Ltd., and Bayer Co., Ltd. Hayato Nakagawa has received lecture fees from Bristol-Meyers Squibb, Giliad Sciences, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., and Sumitomo Dainippon Pharma Co., Ltd. Yoshinari Asaoka has received consultation fees from Eisai Co., Ltd. Shuichiro Shiina has received lecture fees from Starmed Co., Ltd., Medtronic plc, Japan Lifeline Co., Ltd., Canon Medical Co., Ltd., Shionogi Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Giliad Sciences, AbbVie GK, Eisai Co., Ltd., and Bayer Co., Ltd. Kazuhiko Koike has received lecture fees from Eisai, Bayer, MSD, Abbvie, Gilead, and Otsuka Pharmaceutical Co., Ltd., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Although concomitant medications have been raised as a factor affecting hemorrhage during direct oral anticoagulant (DOAC) therapy, details remain unelucidated. This study was conducted to clarify the relationship between concomitant medications with possible pharmacokinetic interactions and number of concomitant medications, and bleeding and embolism in patients with nonvalvular atrial fibrillation on DOACs. The subjects were 1010 patients prescribed DOACs from a single-center at the Teikyo University Hospital between April 2011 and June 2018. This study was an exploratory analysis and investigated their course between the first prescription and December 2018, including the presence or absence of clinically relevant bleeding, gastrointestinal bleeding, and major cardiovascular and cerebrovascular events. Impacts of medications were evaluated by the general linear model with inverse probability-weighted propensity score. The observation period was 2272 patient-years. The rate of bleeding was 4.7%/year, gastrointestinal bleeding was 2.8%/year, and major cardiovascular and cerebrovascular events were 2.0%/year. Taking 10 or more oral medications concurrently was a significant risk for gastrointestinal bleeding (hazard ratio, 2.046 [95%CI, 1.188-3.526]; P = .010). Nonsteroidal anti-inflammatory drugs were the only significant risk for gastrointestinal bleeding. Clinicians should be aware of gastrointestinal bleeding when using DOACs with patients taking more than 10 medications and/or nonsteroidal anti-inflammatory drugs., (© 2022, The American College of Clinical Pharmacology.)