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Uplifting fractured granitic rocks occur in substantial areas of countries such as Japan. Some of these areas might be considered when siting a deep geological repository for radioactive wastes. A repository site would be selected in such an area only if it is possible to make a safety case, accounting for the changing conditions during uplift. The safety case must include robust arguments that chemical processes in the rocks around the repository will contribute sufficiently to minimise radiological doses to biosphere receptors. Numerical modelling is an important aspect of making these arguments. To provide confidence in the safety arguments, numerical models need to be sufficiently realistic, but also parameterised conservatively (pessimistically). However, model development is challenging because uplift involves many complex couplings between groundwater flow, chemical reactions between water and rock, and changing rock properties. The couplings would affect radionuclide mobilisation and retardation, by influencing diffusive radionuclide fluxes between groundwater flowing in fractures and effectively immobile porewater in the rock matrix (rock matrix diffusion, RMD) and radionuclide partitioning between water and solid phases, via: (i) mineral precipitation/dissolution; (ii) mineral alteration; and (iii) sorption/desorption. It is difficult to represent all this complexity in numerical models while showing that they are parameterised conservatively. Here we present a modelling approach, illustrated by simulation cases for some exemplar radioelements, to identify realistically conservative process conceptualisations and model parameterisations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support was provided by Japan Ministry of Economy Trade and Industry, as part of “The project for validating near-field system assessment methodology in geological disposal (FY2019-2022, JPJ007597)”., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A safety case for an underground radioactive waste repository must show that groundwater will not in future transport radionuclides from the repository to the near-surface environment (the biosphere) in harmful quantities. Safety cases are developed step-wise throughout a programme to site and develop a repository. At early stages, before a site is selected, safety cases are generic and based on simplified safety assessment models of the disposal system that have conservative parameter values. Later, when site-specific conditions are known, more realistic models are needed for the long-term geo-environmental evolution and their impacts on radionuclide migration/retention. Uplift is one such environmental change, which may be particularly important in countries near active tectonic plate boundaries, such as Japan. Here we review the state of knowledge about how the properties of fractured granitic rocks evolve during uplift, based on studies in Japan. Hence, we present conceptual models and a generic scenario for mass transport and retardation processes in uplifting granitic rocks as a basis for realistic numerical models to underpin safety assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest of personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Adipose-derived stem cells (ADSCs) are widely used in the field of regenerative medicine because of their various functions, including anti-inflammatory effects. ADSCs are considered to exert their anti-inflammatory effects by secreting anti-inflammatory cytokines and extracellular vesicles. Although recent studies have reported that metabolites have a variety of physiological activities, whether those secreted by ADSCs have anti-inflammatory properties remains unclear. Here, we performed multiomics analyses to examine the effect of ADSC-derived metabolites on M1-like macrophages, which play an important role in inflammatory responses., Methods: The concentration of metabolites in the culture supernatant of ADSCs was quantified using capillary electrophoresis time-of-flight mass spectrometry. To evaluate their effects on inflammatory responses, M1-like macrophages were exposed to the conditioned ADSC medium or their metabolites, and RNA sequencing was used to detect gene expression changes. Immunoblotting was performed to examine how the metabolite suppresses inflammatory processes. To clarify the contribution of the metabolite in the conditioned medium to its anti-inflammatory effects, metabolite uptake was pharmacologically inhibited, and gene expression and the tumor necrosis factor-α concentration were measured by quantitative PCR and enzyme-linked immunosorbent assay, respectively., Results: Metabolomic analysis showed large amounts of lactate in the culture supernatant. The conditioned medium and lactate significantly suppressed or increased the pro-inflammatory and anti-inflammatory gene expressions. However, sequencing and immunoblotting analysis revealed that lactate did not induce polarization from M1- to M2-like macrophages. Based on a recent report that the immunosuppressive effect of lactate depends on epigenetic reprogramming, histone acetylation was investigated, and H3K27ac expression was upregulated. In addition, 7ACC2, which specifically inhibits the monocarboxylate transporter 1, significantly inhibited the anti-inflammatory effect of the conditioned ADSC medium on M1-like macrophages., Conclusions: Our results showed that ADSCs suppress pro-inflammatory effects of M1-like macrophages by secreting lactate. This study adds to our understanding of the importance of metabolites and is also expected to elucidate new mechanisms of ADSC treatments., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted in accordance with the Declaration of Helsinki and approved by the Kanazawa Medical University Specified Certified Regenerative Medicine Committee, the Institutional Review Board for Genetic Analysis Research according to the following two protocols: (1) Investigation of the regenerative effects of adipose-derived stem cells on various organ failures and gene expression (approval number: G129, date of approval: April 17, 2017); (2) Omics analysis of autologous adipose-derived stem cells for treatment of knee osteoarthritis (approval number: G173, date of approval: June 25, 2021). Informed consent was obtained from all subjects involved in this study. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background/Objectives : Knee osteoarthritis (KOA) is a degenerative joint disease typically managed with conservative treatments, such as anti-inflammatory medications and intra-articular hyaluronic acid injections; however, advanced cases may eventually require surgical intervention. Recently, cooled radiofrequency ablation (CRFA) has emerged as a novel treatment option for alleviating KOA-related pain by temporarily disabling pain-transmitting nerves. This study evaluated the short-term effects of CRFA on pain relief and walking ability in KOA patients, with a specific focus on functional improvements in walking capacity. Methods : This study included 58 patients (71 knees) with KOA who underwent CRFA after experiencing inadequate pain control with conservative treatments. The cohort consisted of 28 men and 30 women, with a mean age of 75.2 years (55-90). Under ultrasound guidance, CRFA was performed on the superior lateral geniculate nerve, superior medial geniculate nerve, and inferior medial geniculate nerve, with each targeted nerve ablated. Pre- and post-procedural evaluations (one month after CRFA) included assessments of visual analog scale (VAS) scores for pain at rest and during walking, range of motion (ROM), knee extensor strength, walking speed, and gait stability. Results : Significant improvements in the mean VAS (rest/walking) and mean walking speed (comfortable/maximum) were observed following CRFA. However, no significant changes were noted in ROM, knee extensor strength, or walking stability. Conclusions : These findings suggest that rehabilitation may be essential to further enhance walking stability. Overall, CRFA appears to be a promising short-term treatment option for reducing VAS pain scores and enhancing walking speed in patients with KOA.

Aim: To investigate the characteristics and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Atz/Bev) who achieved a complete response (CR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST)., Methods: A total of 120 patients with Eastern Cooperative Oncology Group performance status (PS) 0 or 1 and Child-Pugh A at the start of Atz/Bev treatment were included. Barcelona Clinic Liver Cancer stage C was recorded in 59 patients., Results: The CR rate with Atz/Bev alone was 15.0%. The median time to CR was 3.4 months, and the median duration of CR was 15.6 months. A significant factor associated with achieving CR with Atz/Bev alone was an AFP ratio of 0.34 or less at 3 weeks. Adding transarterial chemoembolization (TACE) in the six patients who achieved a partial response increased the overall CR rate to 20%. Among the 24 patients who achieved CR, the median progression-free survival was 19.3 months, the median overall survival was not reached, and 14 patients (58.3%) were able to discontinue Atz/Bev and achieve a drug-free status. Twelve of these patients developed progressive disease (PD), but eleven successfully received post-PD treatments and responded well., Conclusions: Achieving CR by mRECIST using Atz/Bev alone or with additional TACE can be expected to offer an extremely favorable prognosis.

Background: Adenosquamous carcinoma of the pancreas (ASCP) accounts for only 1-4% of all pancreatic exocrine cancers and has a particularly poor prognosis. The efficacy of chemotherapy for ASCP remains unknown because of the small number of cases, and few studies have evaluated conversion-intended chemotherapy., Case Presentation: A 76-year-old woman was referred to our hospital because of epigastric pain and nausea. A preoperative contrast-enhanced multidetector row computed tomography (MDCT) scan revealed a 17 × 17 mm low-density tumor with an ill-defined margin at the arterial phase in the pancreatic head. The tumor involved the common hepatic artery, left hepatic artery bifurcated from the common hepatic artery, and gastroduodenal artery, and was in contact with the portal vein. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed an uptake in the pancreatic head but no evidence of distant metastasis. The tumor was diagnosed as an adenocarcinoma of the pancreatic head and staged unresectable because the common and left hepatic arteries were involved. Hence, the patient underwent seven courses of conversion-intended chemotherapy using gemcitabine and nab-paclitaxel for pancreatic ductal adenocarcinoma over 7 months. After chemotherapy, the tumor shrank to 10 × 10 mm on contrast-enhanced MDCT. Consequently, the boundary between the tumor and major vessels of the common and left hepatic arteries and the portal vein became clear, and the involvement of the arteries with the tumor was evaluated to be released. The contact of the tumor to the portal vein also reduced to less than half the circumference of the portal vein. FDG-PET showed decreased accumulation in the tumor. Hence, the tumor was judged resectable, and pancreaticoduodenectomy was performed. The tumor and major blood vessels were easily dissected and R0 resection was achieved. The patient experienced no major complications and was discharged on postoperative day 28. The tumor was revealed as ASCP via pathological examination. The patient is alive and recurrence-free seven months after surgery. This is the first report of successful R0 resection for an initially unresectable ASCP following conversion-intended chemotherapy using gemcitabine and nab-paclitaxel regimen., Conclusions: Conversion-intended chemotherapy using gemcitabine and nab-paclitaxel regimen may be effective for ASCP., (© 2024. The Author(s).)

Introduction: Administration of adipose-derived stem cells (ADSCs) into the joint cavity has been shown to alleviate the symptoms of knee osteoarthritis (OA) by releasing exosomes and anti-inflammatory cytokines. However, the therapeutic effect of these cells is limited by their rapid disappearance after administration. Thus, it is necessary to prolong cell survival in the joint cavity. This study aimed to investigate the potential application of ADSCs adhered to atelocollagen microspheres (AMSs) for cell therapy of knee OA., Methods: ADSCs were cultured for 2, 4, and 7 days in AMS suspension or adherent culture dishes. The supernatants were analyzed for IL-10 and exosome secretion via enzyme-linked immunosorbent assay and Nanosight. The effect of AMS was compared with that of adherent-cultured ADSCs (2D-cultured ADSCs) using transcriptome analysis. Moreover, the solubility of AMS and viability of ADSCs were evaluated using synovial fluid (SF) from patients with knee OA., Results: Compared with 2D-cultured ADSCs, AMS-cultured ADSCs exhibited a significant increase in secretion of exosomes and IL-10, and the expression of several genes involved in extracellular matrix and immune regulation were altered. Furthermore, when AMS-cultured ADSCs were cultured in SF from knee OA patients to mimic the intra-articular environment, the SF dissolved the AMSs and released viable ADSCs. In addition, AMS-cultured ADSCs showed significantly higher long-term cell viability than 2D-cultured ADSCs., Conclusion: Increased survival of AMS-adhered ADSCs was observed in the intra-articular environment, and AMSs were found to gradually dissipate. These results suggest that AMS-adhered ADSCs are promising source for cell therapy of knee OA., Competing Interests: The authors declared that there is no conflict of interest regarding the publication of this paper., (© 2024 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Objectives: We set out to predict whether nonsurgical treatment is likely to succeed in removing pancreatic stones in a given patient and also to determine an optimal maximal number of extracorporeal shock wave lithotripsy (ESWL) sessions for treatment of pancreatolithiasis in that patient., Materials and Methods: We ascertained the number of ESWL sessions for each of 164 patients undergoing that treatment for pancreatolithiasis between 1992 and 2020. Median follow-up duration was 31 months (range, 0-239), median age was 58 years (22-83), and the male to female ratio was 5.1:1.0. Patients were divided into 2 groups based upon an optimal maximal number of ESWL sessions determined by receiver operating characteristic analysis., Results: Total stone clearance was achieved in 130 of 164 patients (79%). The median number of ESWL sessions was 3 (1-61). Receiver operating characteristic analysis determined 7 to be the optimal maximal number of sessions. Complete clearance was more frequent (87%) among the 131 patients requiring 7 or fewer ESWL sessions than among the 33 undergoing more (48%, P < 0.001). Seventeen patients (52%) undergoing 8 or more sessions still had residual stones., Conclusions: If any pancreatic stones persist after 7 ESWL sessions, we recommend transition to medical or surgical treatments., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Canine induced pluripotent stem cells (ciPSCs) can provide useful insights into novel therapies in both veterinary and medical fields. However, limited accessibility to the present culture medium and requirement of considerable time, effort, and cost for routine ciPSC maintenance restrict advancement in ciPSC research. In addition, it is unknown whether ciPSC culture conditions influence differentiation propensity. We investigated the availability of the common human pluripotent stem cells (hPSCs) culture systems for ciPSC maintenance and the differentiation propensities of the ciPSCs maintained in these culture systems. StemFlex and mTeSR Plus supported PSC-like colony formation and pluripotency markers expression in ciPSCs even after five passages. Additionally, ciPSCs were maintained under weekend-free culture conditions with a stable growth rate, pluripotency marker expression, and differentiation abilities using vitronectin (VTN-N) and Geltrex. Following maintenance of spontaneously differentiated ciPSCs under various conditions by embryoid body formation, there were few differences in the differentiation propensities of ciPSCs among the tested culture conditions. Thus, ciPSCs were successfully cultured under weekend-free conditions for ciPSC maintenance using StemFlex or mTeSR Plus with VTN-N or Geltrex. The present study offers simpler and more effort-, time-, and cost-saving options for ciPSC culture systems, which may lead to further development in research using ciPSCs.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor composed of myofibroblasts with inflammatory blood cell infiltration. It commonly occurs in the lungs and rarely in the esophagus. We herein report a valuable case of IMT originating in the esophagus. A 60-year-old Japanese woman with dysphagia had a large subepithelial lesion in the cervical esophagus, which was 15 cm in length. Surgical resection was performed to confirm the pathological diagnosis and improve the symptoms. The postoperative diagnosis was IMT composed of multiple nodules. There was no recurrence or metastasis within one year after surgery.

Competing Interests: None declared.

Cemented polished tapered femoral stems (PTS) made of cobalt-chrome alloy (CoCr) are a known risk factor for periprosthetic fracture (PPF). The mechanical differences between CoCr-PTS and stainless-steel (SUS) PTS were investigated. CoCr stems having the same shape and surface roughness as the SUS Exeter ® stem were manufactured and dynamic loading tests were performed on three each. Stem subsidence and the compressive force at the bone-cement interface were recorded. Tantalum balls were injected into the cement, and their movement was tracked to indicate cement movement. Stem motions in the cement were greater for the CoCr stems than for the SUS stems. In addition, although we found a significant positive correlation between stem subsidence and compressive force in all stems, CoCr stems generated a compressive force over three times higher than SUS stems at the bone-cement interface with the same stem subsidence ( p < 0.01). The final stem subsidence amount and final force were greater in the CoCr group ( p < 0.01), and the ratio of tantalum ball vertical distance to stem subsidence was significantly smaller for CoCr than for SUS ( p < 0.01). CoCr stems appear to move more easily in cement than SUS stems, which might contribute to the increased occurrence of PPF with the use of CoCr-PTS.

Objectives: We aimed to determine when a coexisting pseudocyst was likely to complicate the nonsurgical treatment of pancreatolithiasis., Methods: We treated 165 patients with pancreatolithiasis nonsurgically between 1992 and 2020, including 21 with pseudocysts. Twelve patients had a single pseudocyst less than 60 mm in diameter. Pseudocysts in the other nine patients had diameters of at least 60 mm or were multiple. The locations of pseudocysts along the length of the pancreas varied from the area with stone involvement to the pancreatic tail. We compared the outcomes in these groups., Results: We found no significant differences in pain relief, stone clearance, stone recurrence, or the likelihood of adverse events between pseudocyst groups or between patients with vs without pseudocysts. However, 4 of 9 patients with large or multiple pseudocysts required transition to surgical treatment (44%) compared with 13 of 144 patients with pancreatolithiasis and no pseudocyst (9.0%) ( P =0.006)., Conclusions: Patients with smaller pseudocysts typically underwent nonsurgical stone clearance successfully with few adverse events, similar to findings in patients with pancreatolithiasis and no pseudocysts. Pancreatolithiasis complicated by large or multiple pseudocysts did not cause more adverse events but was more likely to require transition to surgery compared with pancreatolithiasis without pseudocysts. In patients with large or multiple pseudocysts, early transition to surgery should be considered when nonsurgical treatment is ineffective., Competing Interests: All authors have no conflicts of interest regarding this manuscript.

Mycobacterium tuberculosis (M. tuberculosis) is a rare cause of prosthetic joint infection (PJI). Previous studies have reported that many cases of PJI caused by M. tuberculosis have no medical history of active tuberculosis (TB) or other localization, which contributes to diagnostic difficulties. Furthermore, owing to the limited number of studies on treatment, appropriate treatment strategies, such as the duration of anti-tuberculosis (anti-TB) drugs and surgical indications, remain unclear. We report a case of PJI caused by M. tuberculosis and secondary pyogenic arthritis caused by Staphylococcus aureus and Streptococcus dysgalactiae in a 67-year-old man after knee joint replacement surgery in Japan, which was a moderately endemic country until 2020 and a low endemic country since 2021. Although he had no past medical history or close contact with TB, he was diagnosed with PJI caused by M. tuberculosis, following the culture of a synovectomy specimen. He underwent two-stage surgery and was treated with anti-TB drugs for a total of 12 months and recovered without recurrence. Based on our case and previous studies, there are three points of clinical significance for PJI caused by M. tuberculosis. First, about one year of anti-TB drugs with two staged joint revision resulted in a good course of treatment. Second, surgical treatment might be considered in cases complicated by secondary bacterial infection. Third, because the diagnosis of PJI caused by M. tuberculosis is difficult, TB should be considered in the differential diagnosis of routine bacterial culture-negative PJI, especially in endemic areas., Competing Interests: Declaration of competing interest The authors state that they have no conflict of interest., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Structural determination of adsorbed atoms on layered structures such as clay minerals is a complex subject. Radioactive cesium (Cs) is an important element for environmental conservation, so it is vital to understand its adsorption structure on clay. The nuclear magnetic resonance (NMR) parameters of 133 Cs, which can be determined from solid-state NMR experiments, are sensitive to the local neighboring structures of adsorbed Cs. However, determining the Cs positions from NMR data alone is difficult. This paper describes an approach for identifying the expected atomic positions on clay minerals by combining machine learning (ML) with experimentally observed chemical shifts. A linear ridge regression model for ML is constructed from the smooth overlap of atomic position descriptor and gauge-including projector augmented wave (GIPAW) ab initio data. The constructed ML model predicts the GIPAW data to within a 3 ppm root-mean-squared error. At this stage, the 133 Cs chemical shifts can be instantaneously calculated from the Cs positions on any clay layers using ML. The inverse analysis, which derives the atomic positions from experimentally observed chemical shifts, is developed from the ML model. The input data for the inverse analysis are the layer structure and the experimentally observed chemical shifts. The Cs positions for the targeted chemical shifts are then output. Inverse analysis is applied to montmorillonite, and the resultant Cs positions are found to be consistent with previous results (Ohkubo, T.; et al. J. Phys. Chem. A 2018 , 122 , 9326-9337). The Cs positions on saponite clay are also clarified from experimentally observed chemical shifts and inverse analysis.

Objective: The dual mobility cup (DMC) is designed to extend the longevity of the prosthesis by improving stability, enhancing the range of motion, and decreasing impingement without increasing wear. We hypothesized that DMC would reduce the risk of dislocation in elderly patients. This study aimed to investigate the clinical and radiographic outcomes of DMC-total hip arthroplasty (THA) in elderly patients at high risk of dislocation., Methods: From June 2016 to March 2020, 94 patients with a mean age of 77.7 years (97 hips) who underwent a posterolateral approach for DMC-THA in our department were followed up for at least one year. Preoperative and postoperative pelvic tilt angles (PTA) and DMC orientation were prospectively collected for all patients. Intraoperative and postoperative complications were recorded. A parametric test was used for normal distribution, and a non-parametric test was used for non-normal distribution., Results: Abduction and anteversion angles of the cup were 42.4 and 18.0° in the supine position immediately postoperative. The average PTA for patients in the supine and standing positions were 26.5 and 34.5°, respectively. When moving from the supine to the standing position, patients experienced a mean posterior pelvic tilt of 9°. No intraoperative acetabular-related complications were recorded. Postoperative complications included early infection in one patient (1.0%) and dislocation in one patient (1.0%)., Conclusion: Our study demonstrates that DMC-THA provides satisfactory short-term outcomes in elderly patients at a high risk of dislocation, regardless of the change in PTA resulting from postural transition., (© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Knee osteoarthritis (Knee OA) is an irreversible condition that causes bone deformity and degeneration of the articular cartilage that comprises the joints, resulting in chronic pain and movement disorders. The administration of cultured adipose-derived stem cells (ADSCs) into the knee joint cavity improves the clinical symptoms of Knee OA; however, the effect of synovial fluid (SF) filling the joint cavity on the injected ADSCs remains unclear. In this study, we investigated the effect of adding SF from Knee OA patients to cultured ADSCs prepared for therapeutic use in an environment that mimics the joint cavity. An increase in the viability of ADSCs was observed following the addition of SF. Gene expression profiling of SF-treated ADSCs using DNA microarrays revealed changes in several genes involved in cell survival. Of these genes, we focused on FOSL1, which is involved in the therapeutic effect of ADSCs and the survival and proliferation of cancer stem cells. We confirmed the upregulation of FOSL1 mRNA and protein expression using RT-PCR and western blot analysis, respectively. Next, we knocked down FOSL1 in ADSCs using siRNA and observed a decrease in cell viability, indicating the involvement of FOSL1 in the survival of ADSCs. Interestingly, in the knockdown cells, ADSC viability was also decreased by SF exposure. These results suggest that SF enhances cell viability by upregulating FOSL1 expression in ADSCs. For therapy using cultured ADSCs, the therapeutic effect of ADSCs may be further enhanced if an environment more conducive to the upregulation of FOSL1 expression in ADSCs can be established.

This paper backtests a nowcast of Japan's real GDP growth. It has three contributions: (i) use of genuine real-time data, (ii) implementation of a new method for the revision analysis that relates the revision of the nowcast to not only new observations but also data revisions, and (iii) a benchmarking of the nowcast to a market consensus forecast at monthly forecasting horizons. Our nowcast's forecast accuracy is comparable to that of the consensus at most, but not all, monthly horizons. Our revision analysis of the March 2011 earthquake finds the nowcast reacting to a steep post-quake decline in car production. In contrast, the consensus hardly budged, most likely because the decline was correctly viewed as temporary. The onset of COVID-19 triggers the consensus to take a precipitous descent. The nowcast, despite timely red flags from "soft" (i.e., survey-based) indicators, does not respond immediately in full, because it took a month or more for "hard" (i.e., non-survey-based) indicators to register sharply reduced economic activities., Competing Interests: Conflict of interestThe authors have no conflict of interest to report., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Diphenhydramine is an antihistamine drug widely used to alleviate symptoms caused by allergies and the common cold. Diphenhydramine-involved fatalities have been reported in the past but usually involving overdose by ingestion. We report a peculiar case of fatal hypothermia during non-winter season involving topical diphenhydramine., Methods: A 23-year-old male with no known preexisting medical conditions was found dead in the bathroom of his apartment with a small amount of running water on his back. Postmortem examinations and toxicological analysis on blood and urine were performed., Results: Color difference was apparent between the right and left cardiac blood. Wischnewski spots were observed in the gastric mucosa. Histological examination revealed no obvious findings that could attribute to serious cardiovascular events. Drug screening by gas chromatograph-tandem mass spectrometry (GC/MS/MS) detected diphenhydramine in blood and urine. Further quantification revealed the postmortem concentrations to be 0.44 μg/mL in blood and 2500 μg/mL in urine., Conclusions: The cause of death was determined to be hypothermia. Diphenhydramine-induced drowsiness and possible intrinsic cardiac factor may have led to prolonged impaired consciousness, preventing his ability to escape from the running cold water leading to hypothermia and death., (© 2022. The Author(s), under exclusive licence to Japanese Association of Forensic Toxicology.)

Background: Many guidelines for nonsurgical treatment of pancreatolithiasis suggest little guidance for patients with pancreatolithiasis who do not have abdominal pain. Some patients with pancreatolithiasis whom we have treated nonsurgically with extracorporeal shock-wave lithotripsy did not have abdominal pain, and we describe one of them here., Methods and Results: A 42-year-old man complaining of an 8-kg weight loss over 6 months was admitted to a nearby hospital, where fasting blood sugar and hemoglobin A1c values were 500 mg/dL and 11.8%. Computed tomography showed stones in the head of the pancreas and dilation of the main pancreatic duct. He was referred to our hospital to be considered for nonsurgical treatment of pancreatolithiasis. His height and weight were 160 cm and 52 kg (body mass index, 20.31). No tenderness or other abdominal findings were evident. After obtaining informed consent for nonsurgical treatment despite absence of abdominal pain, we performed extracorporeal shock wave lithotripsy. Computed tomography showed disappearance of stones from the pancreatic head. At discharge, his weight had increased to 62 kg and hemoglobin A1c was 6.8%, though antidiabetic medication has since become necessary., Conclusion: We believe that nonsurgical treatment of pancreatolithiasis was helpful for this patient, and could improve exocrine and endocrine function in other patients without abdominal pain., Competing Interests: The authors declare no conflict of interest or funding., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Adipose-derived stem cell (ADSC) sheets have potential to be effective in various therapies. In this study, we first demonstrated that a cell sheet composed of human ADSCs could be created using a new temperature-responsive culture dish from the DIC Corporation. The dish can cause detachment of adherent cells due to temperature changes, but a few morphological analyses have evaluated the presence or absence of damage on the detached surface of cell sheet. To characterize our ADSC sheet, we tried to observe the surface of ADSC sheets with scanning electron microscope (SEM) using the ionic liquid, which enables the rapid preparation of samples. No damage was found on the surface of the ADSC sheets on the side that had been in contact with the surface of the culture dishes. In addition, when the transcriptomes of the harvested cell sheets were compared with those of monolayer cultures, no up-regulation of cell death related genes were detected. These results propose that the detachment from temperature-responsive culture dish causes no serious damage on the prepared ADSC sheet. It is also suggested that the SEM with ionic liquids is a useful and rapid method for the analysis of ADSC sheets for therapy., (© 2022. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

A small fused polycyclic molecule containing a phenothiazine and diazapyrene skeleton as the donor and acceptor, respectively, has a redox potential similar to those of the corresponding donor and acceptor molecules, indicating that the inherent electronic properties of the donor and acceptor were retained due to weak orbital interactions.

The oxidation of alkanes with m -chloroperbenzoic acid ( m CPBA) catalyzed by the B 12 derivative, heptamethyl cobyrinate, was investigated under several conditions. During the oxidation of cyclohexane, heptamethyl cobyrinate works as a catalyst to form cyclohexanol and cyclohexanone at a 0.67 alcohol to ketone ratio under aerobic conditions in 1 h. The reaction rate shows a first-order dependence on the [catalyst] and [ m CPBA] while being independent of [cyclohexane]; V obs = k 2 [catalyst][ m CPBA]. The kinetic deuterium isotope effect was determined to be 1.86, suggesting that substrate hydrogen atom abstraction is not dominantly involved in the rate-determining step. By the reaction of m CPBA and heptamethyl cobyrinate at low temperature, the corresponding cobalt(III)acylperoxido complex was formed which was identified by UV-vis, IR, ESR, and ESI-MS studies. A theoretical study suggested the homolysis of the O-O bond in the acylperoxido complex to form Co(III)-oxyl (Co-O • ) and the m -chlorobenzoyloxyl radical. Radical trapping experiments using N - tert -butyl-α-phenylnitrone and CCl 3 Br, product analysis of various alkane oxidations, and computer analysis of the free energy for radical abstraction from cyclohexane by Co(III)-oxyl suggested that both Co(III)-oxyl and the m -chlorobenzoyloxyl radical could act as hydrogen-atom transfer reactants for the cyclohexane oxidation.

Objective: Clinical guidelines consider abdominal pain an indication for nonsurgical treatment of pancreatolithiasis. We examined benefit from nonsurgically treating asymptomatic pancreatolithiasis., Methods: We retrospectively reviewed 165 patients with pancreatolithiasis who underwent nonsurgical treatment between 1992 and 2020. Symptoms were absent in 41, while 124 had abdominal pain. In the asymptomatic group, the median follow-up duration was 8 months (range, 0-166 months), and the median age was 61 years (range, 32-80 years). In patients with pain, the median follow-up duration was 43 months (range, 0-293 months), while the median age was 57 years (range, 22-80 years). The male:female ratio was 3.6:1 for asymptomatic patients and 5.9:1 for those with pain. We compared treatment outcome, stone recurrence rate, and changes in pancreatic exocrine function (bentiromide- p -aminobenzoic acid test results) between groups., Results: Nonsurgical treatment for patients with asymptomatic pancreatolithiasis had a 63% stone clearance rate, lower than 84% for symptomatic pancreatolithiasis but comparable to outcomes at other institutions. Pancreatic exocrine function values during the year after treatment were mean, 52% (standard deviation, 16%) in the asymptomatic group, similar to mean, 57% (standard deviation, 17%) in the symptomatic group., Conclusions: Nonsurgical treatment in asymptomatic pancreatolithiasis may preserve pancreatic exocrine function as well as in symptomatic pancreatolithiasis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Alzheimer's disease is thought to be caused by the aggregation of amyloid-β (Aβ) peptides. Their aggregation is accelerated at hydrophilic/hydrophobic interfaces such as the air-water interface and the surface of monosialotetrahexosylganglioside (GM1) clusters on neuronal cell membranes. In this review, we present recent studies of full-length Aβ (Aβ40) peptides and Aβ(16-22) fragments in such heterogeneous environments by molecular dynamics (MD) simulations. These peptides have both hydrophilic and hydrophobic amino-acid residues and tend to exist at the hydrophilic/hydrophobic interface. Therefore, the peptide concentration increases at the interface, which is one of the factors that promote aggregation. Furthermore, it was found that Aβ40 forms an α-helix structure and then a β-hairpin structure at the interface. The β-hairpin promotes the formation of oligomers with intermolecular β-sheets. It means that not only the high concentration of Aβ40 at the interface but also the structure of Aβ40 itself promotes aggregation. In addition, MD simulations of Aβ40 on recently-developed GM1-glycan clusters showed that the HHQ (13-15) segment of Aβ40 is important for the recognition of GM1-glycan clusters. It was also elucidated that Aβ40 forms a helix structure in the C-terminal region on the GM1-glycan cluster. This result suggests that the helix formation, which is the first step in the conformational changes toward pathological aggregation, is initiated at the GM1-glycan moieties rather than at the lipid-ceramide moieties. These studies will enhance the physicochemical understanding of the structural changes of Aβ at the heterogeneous interfaces and the mechanism of Alzheimer's disease pathogenesis., (2022 THE BIOPHYSICAL SOCIETY OF JAPAN.)

The radionuclide selenium-79 (Se-79) is predicted to be a key contributor to the long-term radiologic hazards associated with geological high-level waste (HLW) repositories; hence its release is of pertinent concern in the safety assessment of repositories. However, interactions of reduced Se species with aqueous Fe(II) species and solid phases arising from the corrosion of a steel overpack could play a role in mitigating its migration to the surrounding environment. In this study, we examined the immobilization mechanisms of Se(-II) during its interaction with aqueous Fe(II) and freshly precipitated Fe(OH) 2 at circumneutral and alkaline conditions, respectively, its response to changes in pH, and its behavior during aging at 90 °C. Using microscopic and spectroscopic techniques, we observed β-FeSe precipitation, regardless of whether Se(-II) reacts with aqueous species or solid phases, and that modifying the pH following initial immobilization did not remobilize Se(-II). These observations indicate that Se(-II) migration beyond the overpack can be effectively and rapidly retarded via interactions with Fe(II) species arising from overpack corrosion. Thermodynamic calculations, however, showed that iron selenides became metastable at alkaline conditions and will dissolve in the long term. Aging experiments at 90 °C showed that Se(-II) can be completely retained via the crystallization of ferroselite at circumneutral conditions, while it will be largely remobilized at alkaline conditions. Our results show that Se(-II) mobility can be significantly influenced by its interactions with the corrosion products of the steel overpack and that these behaviors will have to be considered in repository safety assessments.

Aim: Direct-acting antivirals (DAAs) are currently available even for patients with decompensated cirrhosis. Reportedly, hepatic functional reserve improved in the short term after achievement of sustained virologic response (SVR). We aimed to clarify the outcomes after achievement of SVR in patients with decompensated cirrhosis who were treated by DAAs in real-world clinical practice., Methods: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted in 86 patients with decompensated cirrhosis, who were evaluated for 48 weeks post-treatment., Results: The cohort included 8 patients with Child-Pugh class A, 56 with B, and 22 with C. The proportion of Child-Pugh class A patients increased from 9.1% at baseline to 44.1% at 48 weeks post-treatment, while that of class B and C patients decreased from 66.2% to 35.1% and from 24.7% to 14.3%, respectively. Among the patients with Child-Pugh class B and C, univariate analysis identified low total bilirubin, Child-Pugh score, Child-Pugh class B, ALBI score, and high serum albumin as factors associated with improvement to Child-Pugh class A. The optimal cut-off value of the factors for predicting improvement to Child-Pugh class A were 1.4 mg/dl for total bilirubin, 2.9 g/dl for serum albumin, 8 points for Child-Pugh score, and -1.88 for ALBI score., Conclusion: Achievement of SVR with sofosbuvir/velpatasvir improved the liver functional reserve at 12 weeks post-treatment and maintained the stable effects until 48 weeks post-treatment in patients with decompensated cirrhosis. Specifically, the patients with less advanced conditions had the likelihood of improving to Child-Pugh class A at 48 weeks post-treatment., (© 2021 Japan Society of Hepatology.)

Objectives: While chronic pancreatitis associated with pancreatolithiasis presents with pain, exocrine and endocrine pancreatic functions worsen with time. We examined outcomes of nonsurgical treatment., Methods: Between 1992 and 2020, we treated pancreatolithiasis nonsurgically in 165 patients with chronic pancreatitis using extracorporeal shock wave lithotripsy alone or followed by endoscopic procedures. The mean follow-up duration was 49 months (standard deviation, 56 months) and the age was 56 years (standard deviation, 13 years). The male:female ratio was 5.1:1 (138 men, 27 women). We followed treatment results including relief of abdominal pain, stone clearance and recurrence, and pancreatic exocrine function (bentiromide-p-aminobenzoic acid testing)., Results: Treatment relieved pain in 117 of 124 patients (94%). The overall stone clearance was achieved in 130 of 165 patients (79%). Stones recurred during follow-up in 50 of 130 patients (38%). One fifth of recurrences were early, often involving stricture of the main pancreatic duct. After 1 year, 65% of the patients had improved or stable exocrine function., Conclusions: Nonsurgical stone removal usually improved symptoms and preserved pancreatic exocrine function. Nonsurgical treatment with extracorporeal shock wave lithotripsy followed by endoscopic treatment if needed is useful as initial management for pancreatolithiasis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Osteoarthritis (OA) is an irreversible degenerative condition causing bone deformation in the joints and articular cartilage degeneration with chronic pain and impaired movement. Adipose-derived stem cell (ADSC) or crushed adipose tissue injection into the joint cavity reportedly improve knee function and symptoms, including pain. Stem cell spheroids may be promising treatment options due to their anti-inflammatory and enhanced tissue regeneration/repair effects. Herein, to form human ADSC spheroids, we used first SphereRing ® (Fukoku Co., Ltd., Ageo, Japan), a newly developed rotating donut-shaped tube and determined their characteristics by DNA microarray of mRNA analysis. The variable gene expression cluster was then identified and validated by RT-PCR. Gene expression fluctuations were observed, such as COL15A1 and ANGPTL2, related to vascular endothelial cells and angiogenesis, and TNC, involved in tissue formation. In addition, multiplex cytokine analysis in the medium revealed significant cytokines and growth factors production increase of IL-6, IL-10, etc. However, ADSC administration into the joint cavity involves their contact with the synovial fluid (SF). Therefore, we examined how SF collected from OA patient joint cavities affect 2D-culture ADSCs and ADSC spheroids and observed SF induced cell death. ADSC spheroids could become promising OA treatment options, although studying the administration methods and consider their interaction with SF is essential.

Diseases associated with gallbladder wall thickening include benign entities such as adenomyomatosis of the gallbladder, acute and chronic cholecystitis, and hyperplasia associated with pancreaticobiliary maljunction, and also cancer. Unique conditions such as sclerosing cholecystitis and cholecystitis associated with immune checkpoint inhibitor treatment can also manifest as wall thickening, as in some systemic inflammatory conditions. Gallbladder cancer, the most serious disease that can show wall thickening, can be difficult to diagnose early and to distinguish from benign causes of wall thickening, contributing to a poor prognosis. Differentiating between xanthogranulomatous cholecystitis and gallbladder cancer with wall thickening can be particularly problematic. Cancers that thicken the wall while coexisting with benign lesions that cause wall thickening represent another potential pitfall. In contrast, some benign gallbladder lesions that can cause wall thickening, such as adenomyomatosis and acute cholecystitis, typically show characteristic ultrasonographic features that, together with clinical findings, permit easier diagnosis. In this review of the literature, we describe B-mode abdominal ultrasonographic diagnosis of gallbladder lesions showing wall thickening.

Background: The high prevalence of low bone mass in young women in Japan has emerged as a serious health issue in recent years. Therefore, the aim of the present study was to reevaluate the relationship between genetic and dietary factors, as well as its influence on bone mass in young Japanese women, with particular emphasis on vitamin D receptor (VDR) gene polymorphisms and calcium intake., Methods: A total of 499 Japanese women aged 20-24 years were enrolled in the study. The bone mass of the calcaneus was assessed using the quantitative ultrasound method and expressed as the osteo sono-assessment index (OSI). VDR gene polymorphisms (BsmI, TaqI, ApaI, and FokI) were analyzed using DNA extracted from saliva. Calcium intake was assessed using the Food Frequency Questionnaire based on food groups (FFQg) and adjusted with the energy intake. Participants were divided into two groups based on the median calcium intake (250 mg/1000 kcal)., Results: Consequently, bone mass was significantly different among the BsmI and TaqI genotypes after adjusting for body mass index (BMI) (p = 0.030 and 0.019, respectively). In addition, the BsmI AA and ApaI GT genotypes showed significant differences in bone mass between the calcium-intake groups, with low OSI in the low-calcium intake group and high OSI in the high-calcium intake group, respectively, even after adjusting for BMI (p = 0.020 and 0.038, respectively)., Conclusions: These findings may prove instrumental in developing a logical approach towards preventing bone loss in young Japanese women.

Although atelocollagen gel is used as a scaffold for culturing human articular cartilage-derived chondrocytes, little is known about cell-gel interactions. In this study, we investigated the mechanism via which atelocollagen gel affects human articular cartilage-derived chondrocytes. Two types of three-dimensional cultures of human articular cartilage-derived chondrocytes (i.e., with and without atelocollagen gel) were compared. While the amount of atelocollagen gel in culture gradually decreased with time, it promoted the expression of matrix metalloproteinases (MMPs) during the early stages of culture. Genome-wide differential gene expression analysis revealed that cell membrane- and extracellular matrix-related genes were highly ranked among up- and down-regulated groups in cells cultured in the presence of atelocollagen gel. Among the integrin family of genes, the expression of integrin subunit alpha 2 and integrin subunit alpha 10 was significantly increased in the presence of atelocollagen gel. Blocking α2β1 integrin with the specific inhibitor BTT 3033 had a significant effect on cell proliferation, MMP expression, and cell shape, as well as on the response to mechanical stimulation. Taken together, our findings indicate that the α2β1 integrin pathway plays an important role in the interaction of atelocollagen gel with human articular cartilage-derived chondrocytes and may be a potential therapeutic target for articular cartilage disorders.

Introduction: Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice., Methods: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions., Results: The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child-Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5-13). The albumin-bilirubin (ALBI) score ranged from - 3.01 to - 0.45 (median - 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child-Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10 -4 and 2.42 × 10 -4 , respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively., Conclusion: Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications., Trial Registration: UMIN registration no, 000038587.

In patients with a reconstructed gastric tube, the right gastroepiploic artery is a very important feeding artery of the tube, which must be preserved when performing a pancreaticoduodenectomy. A 76-year-old man with a reconstructed gastric tube underwent pancreaticoduodenectomy for distal bile duct carcinoma. On postoperative day 8, he had an arterial hemorrhage from a drain, apparently from a ligation of the anterior superior duodenal artery. He, therefore, underwent stent-graft placement in the gastroduodenal artery. The stent-grafts were temporarily occluded, and the gastric tube was necrotizing. However, thrombolytic therapy allowed the stent-grafts to reopen and prevented gastric tube necrosis. We believe our case of stent-graft implantation in the gastroduodenal artery is the first of this kind to successfully prevent lethal necrosis of the gastric tube., (© 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Amyloid-β (Aβ) aggregates are believed to be one of the main causes of Alzheimer's disease. Aβ peptides form fibrils having cross β-sheet structures mainly through primary nucleation, secondary nucleation, and elongation. In particular, self-catalyzed secondary nucleation is of great interest. Here, we investigate the adsorption of Aβ42 peptides to the Aβ42 fibril to reveal a role of adsorption as a part of secondary nucleation. We performed extensive molecular dynamics simulations based on replica exchange with solute tempering 2 (REST2) to two systems: a monomeric Aβ42 in solution and a complex of an Aβ42 peptide and Aβ42 fibril. Results of our simulations show that the Aβ42 monomer is extended on the fibril. Furthermore, we find that the hairpin structure of the Aβ42 monomer decreases but the helix structure increases by adsorption to the fibril surface. These structural changes are preferable for forming fibril-like aggregates, suggesting that the fibril surface serves as a catalyst in the secondary nucleation process. In addition, the stabilization of the helix structure of the Aβ42 monomer on the fibril indicates that the strategy of a secondary nucleation inhibitor design for Aβ40 can also be used for Aβ42.

A condensed phenoxazine dimer was synthesized and characterized. X-ray crystallographic analysis of the dimer shows a double-butterfly structure, in which the nitrogen atoms are located above and below the molecular plane. A radical cation salt of the dimer was obtained using tris(4-bromophenyl)aminium hexafluoroantimonate as the oxidant. The salt is air-stable in solid and solution states. The cation structure was evaluated by X-ray crystallographic analysis, showing that the phenoxazine units were converted to a planar structure upon oxidation.

Background and Aim: The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12 weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent., Methods: In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen., Results: Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching., Conclusion: Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

We systematically investigated the sorption and fixation behaviors of radiocesium ( 137 Cs) for sediments taken from the rivers of Ukedo and Odaka around the Fukushima Daiichi Nuclear Power Plant. By comparing the Cs sorption and sequential desorption results at various Cs concentrations, across a range of sediment properties, we were able to understand the different contributions at frayed edge sites (FESs) and regular exchange sites (RESs) of the clay minerals, and their relationships with the Cs concentrations and the contents of organic matter (OM). The Cs sorption and fixation were dominated by FESs at trace Cs concentrations, and by ion exchange at RES and the collapse of interlayers at higher Cs concentrations. The Cs sorption at lower Cs concentration was strongly related to radiocesium interception potential (RIP); however, Cs fixation was more related to clay mineralogy (i.e. contents of mica, vermiculite and hydroxy-interlayered vermiculite) rather than the RIP. The first-order kinetic constants for time-dependent Cs sorption at low Cs concentrations were correlated negatively to the ratio between the total organic carbon and RIP values. This implies that Cs access to FESs requires a relatively long duration that is dependent on the contents of the OM. From these results, the sorption and fixation mechanisms were confirmed to be significantly different at different Cs concentrations. Then, the prediction of Cs transport should be based on the key mechanisms that are dominant at the actual trace levels of Cs. A significant difference between the Cs fixation behaviors at the Ukedo River and Odaka River may be understood by considering the differences in their clay mineralogy, due to the different geological settings and weathering stages of both catchments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In order to elucidate the radiocesium transport behaviors in natural environment, we systematically investigated sediments from the highly contaminated rivers of Ukedo and Odaka around the Fukushima Daiichi Nuclear Power Plant. We focused on determining the key factors controlling the radiocesium sorption and fixation, such as variations in the particle size, clay mineralogy, and organic matter (OM). The distribution patterns of the 137 Cs concentration and particle size fractions were found to be similar for the two rivers, indicating that both clay and silt fractions contributed almost equally to the Cs sorption. The clay mineralogical composition evaluated using X-ray diffraction analysis showed that the relative contents of micaceous minerals were higher in the Ukedo River samples, whereas the relative contents of smectite and kaolinite were higher in the Odaka River samples. This implies that the sediments in both rivers were likely at different weathering stages due to the different geological settings in both catchments. The effects of OM on the sediment properties were also investigated by comparing the cation exchange capacity (CEC) and the radiocesium interception potential (RIP) of the two samples both with and without OM present. The CEC values were controlled by both the clay minerals and OM, and the RIP values increased significantly in the absence of OM. Such trends were correlated to the total organic carbon values, which may be used to understand the direct and indirect roles of OM in the sorption and fixation of Cs. These key differences in river sediment were attributed to the differences in the geological settings and weathering stages. These properties may contribute to the different sorption and fixation behaviors of radiocesium. In the second part paper, we further examined these behaviors and identified key factors by investigating their relationship to the sediment properties of both rivers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan., Methods: In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen., Results: Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period., Conclusion: The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naïve, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aims: Real-time tissue elastography is a non-invasive method for measuring liver elasticity. However, there are no reports evaluating the value of real-time tissue elastography for liver fibrosis in hepatitis C virus-infected patients with sustained virological response. The aim of this study is to clarify the diagnostic performance of real-time tissue elastography in patients with sustained virological response., Methods: In this prospective study, we enrolled 425 chronic hepatitis C patients who underwent liver biopsy: 118 patients with sustained virological response (45.8% women) and 307 patients with hepatitis C virus (51.1% women). The post-sustained virological response biopsy was performed 5.9 ± 1.8 years after the therapy. Liver fibrosis index measurements as assessed using real-time tissue elastography were performed on the same day of biopsy., Results: The respective mean liver fibrosis index values for fibrosis stages F0, F1, F2, F3, and F4 were 2.82 ± 0.33, 2.90 ± 0.51, 3.06 ± 0.58, 3.65 ± 0.24, and 3.83 ± 0.65, respectively, in patients with sustained virological response. The diagnostic accuracies expressed as areas under the receiver operating characteristic curves in patients with sustained virological response were 0.776 for the diagnosis of significant fibrosis (≥F2), 0.885 for severe fibrosis (≥F3), and 0.860 for cirrhosis (F4), respectively. The optimum cut-off values liver fibrosis index were 3.14 for ≥F2, 3.24 for ≥F3, and 3.30 for F4 in patients with sustained virological response., Conclusion: Real-time tissue elastography is an acceptable method for predicting the severity of fibrosis in hepatitis C virus patients with sustained virological response.

A stimulus-responsive receptor 1 was designed and prepared to control the ligand-binding ability of three active sites, two zinc tetraphenylporphyrin units (P1) and one zinc diethynyldiphenylporphyrin unit (P2), with one effector molecule 2. Bulky hexarylbenzene units were incorporated as shielding panels in the middle of the flexible side arms of 1. Spectroscopic titrations indicated that a stable supramolecular complex 1⋅2 (K 1⋅2 =6.7×10 6  m -1 ) was produced by the cooperative formation of multiple hydrogen and coordination bonds. As a result, the binding of a ligand to P1 was inhibited by 2 in a competitive manner. Additionally, the formation of 1⋅2 brought about conformational restriction of the side arms to cover both faces of P2 with the shielding panels. The binding constant of 4-phenylpyridine with P2 in 1⋅2 decreased to 8.9 % of that in 1. Namely, the ligand-binding ability of P2 was inhibited according to an allosteric mechanism., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment., Methods: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed., Results: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10 -5 ; genotype 2 vs. 3, p = 3.28 × 10 -5 ) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10 -5 )] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10 -5 ). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10 -18 ) patients., Conclusions: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

Studies investigating the effect of the caudal-type homeobox protein 2 (Cdx2) polymorphism in the vitamin D receptor gene and calcium intake on bone mass have shown inconsistent results. This study investigated whether the effect of calcium intake on peak bone mass is affected by Cdx2 polymorphism in young Japanese women. A cross-sectional study of 500 young women was conducted. Dietary intake was assessed by the Food Frequency Questionnaire. The osteo sono-assessment index (OSI), assessed by the qualitative ultrasound method, was used as a bone mass index. The subjects were divided into two groups by the median calcium intake. The OSI was not different among Cdx2 genotypes and between calcium groups ( p = 0.960, p = 0.191, respectively). The interaction between calcium and Cdx2 genotypes on the OSI approached significance (GG versus GA and AA genotypes, p = 0.092). The difference in the OSI between calcium groups was significant in the GG genotype ( p = 0.028), but not in the GA or AA genotypes ( p = 0.501, p = 0.306, respectively). Adjustment for covariates (body mass index and physical activity) did not change the results. In conclusion, the relationship between dietary calcium intake and peak bone mass may vary according to Cdx2 polymorphism.

The purpose of this study is to clarify the method to achieve high transmutation rates of four long-lived fission products ( 79 Se, 99 Tc, 107 Pd, and 129 I) using a fast reactor. New LLFP target assemblies were invented in consideration of the suppression of thermal spikes in adjacent fuel assemblies by combining YD 2 and YH 2 moderators or using a thermal neutron filter material. It was clarified that the high transmutation rate of about 8%/year was achieved, if the new LLFP target assemblies of 4 nuclides were loaded in the blanket region of the sodium cooled, MOX fueled fast reactor. The feasibility of the LLFP transmutation target was clarified through experiments on material properties and fabrication of the LLFP target, YH 2 and YD 2 moderators.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan., (© 2019 John Wiley & Sons Ltd.)

Background: The virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings., Methods: In a Japanese nationwide multicenter study, the rate of sustained virologic response (SVR) and safety were analyzed in 91 patients who started the DCV/ASV/BCV regimen between November 2016 and July 2017. SVR rates were compared based on baseline patient characteristics., Results: More than 60% of patients had a history of failure to achieve SVR with interferon (IFN)-free DAA therapy. Overall, 50 of 91 patients (54.9%) achieved SVR. Multivariate analysis identified a history of failure with IFN-free DAA therapy and pretreatment HCV RNA levels as factors significantly associated with treatment failure. Whereas the SVR rate in patients without a history of IFN-free DAA therapy was 91.7% (33 of 36 patients), it was only 30.9% (17 of 55 patients) among patients with a history of IFN-free DAA therapy. The rate of discontinuation due to an adverse event was 4.4%., Conclusions: Many patients treated with the DCV/ASV/BCV regimen have a history of a failure to achieve SVR with previous IFN-free DAA therapy. SVR rate was not as high as that in pre-approval clinical trial of this regimen in IFN-free DAA-naïve patients. In addition, most patients with a history of failure with IFN-free DAA therapy, particularly the DCV/ASV regimen, showed resistance to this regimen.

Aggregates of amyloid-β (Aβ) peptide are well known to be the causative substance of Alzheimer's disease (AD). Recent studies showed that monosialotetrahexosylganglioside (GM1) clusters induce the pathological aggregation of Aβ peptide responsible for the onset and development of AD. However, the effect of GM1-glycan cluster on Aβ conformations has yet to be clarified. Interactions between Aβ peptide and GM1-glycan cluster is important for the earliest stage of the toxic aggregation on GM1 cluster. Here, we performed all-atom molecular dynamics (MD) simulations of Aβ40 on a recently developed artificial GM1-glycan cluster. The artificial GM1-glycan cluster facilitates the characterization of interactions between Aβ40 and multiple GM1-glycans. We succeeded in observing the binding of Aβ40 to the GM1-glycan cluster in all of our MD simulations. Results obtained from these MD simulations indicate the importance of HHQ (13-15) segment of Aβ40 for the GM1-glycan cluster recognition. This result is consistent with previous experimental studies regarding the glycan recognition of Aβ peptide. The recognition mechanism of HHQ (13-15) segment is mainly explained by non-specific stacking interactions between side-chains of histidine and rings of sugar residues, in which the HHQ regime forms coil and bend structures. Moreover, we found that Aβ40 exhibits helix structures at C-terminal side on the GM1-glycan cluster. The helix formation is the initial stage of the pathological aggregation at ceramide moieties of GM1 cluster. The binding of Lys28 to Neu triggers the helix formation at C-terminus side because the formation of a salt bridge between Lys28 and Neu leads to change of intrachain interactions of Aβ40. Our findings suggest that the pathological helix formation of Aβ40 is initiated at GM1-glycan moieties rather than lipid ceramide moieties.

Background: Patients with chronic hepatitis C are often complicated by chronic kidney disease (CKD)., Aim: To evaluate the efficacy, safety and pharmacokinetics of glecaprevir/pibrentasvir in patients with severe renal impairment., Methods: In a prospective, multicentre study involving 35 medical institutions, 832 genotype 1-3 patients were treated with glecaprevir/pibrentasvir. The efficacy and safety of glecaprevir/pibrentasvir were analysed for patients with CKD stage 4 or 5. Multivariate analysis was performed to identify the factors associated with the most frequently observed adverse event. In patients undergoing haemodialysis, a pharmacokinetic study was conducted to investigate the dialysability of the drugs: plasma samples were obtained from the arterial and venous sides of a dialyser to serially measure drug concentrations., Results: The subjects comprised 141 patients (32 with CKD stage 4 and 109 with CKD stage 5), of whom 100 were undergoing haemodialysis. All but one stage 5 CKD patients undergoing haemodialysis achieved sustained virologic response (99.3%). Adverse events were observed in 39.7% of subjects: pruritus was the most frequent (30.5%), and was significantly associated with haemodialysis. In the pharmacokinetic study, no arterial-venous differences in the plasma concentrations of glecaprevir/pibrentasvir were detected during the haemodialysis sessions., Conclusions: Glecaprevir/pibrentasvir was highly effective and safe in chronic hepatitis C patients with severe renal impairment. Haemodialysis was associated with increased incidence of pruritus, which was the most frequent adverse event, but had little or no influence on the drug concentrations, which indicated that their dialysability is very low and that no dose modification is required in patients undergoing haemodialysis. (UMIN registration no. 000032073)., (© 2019 John Wiley & Sons Ltd.)