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In Japan, about 40 million tonnes of slag is generated annually during the iron and steelmaking process. This large amount of byproduct warrants investigation on its disposal. In this study, the production, chemical characteristics, and use of iron and steel slag in Japan, especially converter slag, have been reviewed. Then, the necessity for sodium removal and nutrient supply for the recovery of the paddy fields damaged by the Tsunami, which resulted from the great east Japan earthquake, has been explained. Since converter slag can serve the above two requirements simultaneously, owing to its chemical properties, investigations on efficient utilisation of converter slag have been carried out. With the perspective of both agriculture and engineering science, the positive effects of converter slag on desalting, pH improvement, and supply of nutrients such as silicon have been found. [ABSTRACT FROM AUTHOR]

Winter climate change is an important environmental driver that alters the biogeochemical processes of forest soils. The decrease in snowpack amplifies soil freeze–thaw cycles and decreases the snowmelt water supply to soil. This study examined how snow decrease affects nitrogen (N) mineralization and nitrification in forest soil in northern Japan by conducting an in situ experimental snowpack manipulation experiment and a laboratory incubation of soil with different moisture, temperature and freeze–thaw magnitudes. For the incubation studies, surface mineral soil (0–10 cm) was collected from a cool-temperate natural mixed forest and incubated using the resin core method during the winter. In the field, there were two treatments: 50 and 100 % snow removal and control plots. The increase in the soil freeze–thaw cycle increased net N mineralization and marginally decreased the net nitrification in soil. The dissolved organic carbon (DOC) and DOC/DON ratio in soil increased with the decrease in snowpack especially during the snow melt period. These results suggested that the change in substrate quality by the increase in freeze–thaw cycles caused the significant enhancement of microbial ammonium production in soil. The lower soil moisture and higher gross immobilization of inorganic N by soil microbes may be maintaining the slow net nitrification and low nitrate leaching in freeze–thaw cycles with less snowpack. The results indicate that winter climate change would strongly impact N biogeochemistry through the increase in ammonium availability in soil for plants and microbes, whereas it would be unlikely that nitrate loss from surface soil would be enhanced. [ABSTRACT FROM AUTHOR]

Background The Japanese Red Cross (JRC) conducted a prospective study to evaluate the frequency of transfusion-transmitted HBV, HCV and HIV infections to assess the risk of transfusion of blood components routinely supplied to hospitals. Study Design and Methods Post-transfusion specimens from patients at eight medical institutes were examined for evidence of infection with HBV (2139 cases), HCV (2091) and HIV (2040) using individual nucleic acid amplification testing (NAT). If these specimens were reactive, pre-transfusion specimens were also examined for the virus concerned by individual NAT. In the event that the pre-transfusion specimen was non-reactive, then all repository specimens from implicated donors were tested for the viruses by individual donation NAT. In addition, a further study was carried out to evaluate the risk of transfusion of components from donors with low anti-HBc titres or high anti-HBc with high anti-HBs titres. Results Transfusion-transmitted HCV and HIV infections were not observed. One case of post-transfusion HBV infection was identified (rate, 0·0004675; 95% CI for the risk of transmission, 1 in 451-41 841). The background rates of HBV, HCV and HIV infections in patients prior to transfusion were 3·4% (72/2139), 7·2% (150/2091) and 0% (0/2040), respectively. Sixty-four anti-HBc- and/or anti-HBs-reactive blood components were transfused to 52 patients non-reactive for anti-HBc or anti-HBs before and after transfusion (rate, 0; 95% CI for the risk of transmission, <1 in 22). Conclusion This study demonstrated that the current criteria employed by JRC have a low risk, but the background rates of HBV and HCV infections in Japanese patients are significant. [ABSTRACT FROM AUTHOR]

Abstract: Dwarf bamboos (mainly Sasa species) form dense undergrowth in many forests in Japan and compete with overstory vegetation for soil resources. For a better understanding of the interaction between tree and undergrowth root for soil nutrients, we compared soil N availability, root biomass and its substrate quality in two Betula ermanii stands. In one stand, the aboveground part of undergrowth (Sasa kurilensis) had been removed for 5 years (SR) and in the other, the undergrowth was present (SP). The SR stand had significantly higher NO3-N levels in soil (1.7–5.5mgkg−1 at different soil depths) than the SP stand (1.2–1.7mgkg−1), which may affect the amount and substrate quality of fine root. Although the total (live+dead) of the root and rhizome (root–rh) mass did not differ between the two stands, the total production by these categories was about half in the SR stand than the SP stand. Further, the proportion of dead root–rh mass was about two times in the SR stand than the SP stand. In the investigated depth (to 30cm), the contribution of the C and N inputs to the total in the uppermost layer (0–10cm deep) was greater in the SR stand (56–59%) than the SP stand (38–42%). Total root–rh of S. kurilensis in the SP stand contributed to about 38–40% of the total C and N input, and in the SR stand the contribution was still about half that of the SP stand. Further, the acid-insoluble C:N ratio in very fine root and live fine root of B. ermanii was significantly less in the SR stand. The contribution of N content in very fine root to the total root–rh was much greater in the SR (45%) stand than the SP stand (36%). These results suggest that the remaining S. kurilensis detritus and the decreased N use by this species after its removal resulted in increased N availability for B. ermanii. Natural regeneration of tree species after simultaneous death of Sasa species, which is very common in Sasa-dominant forests in Japan, may in part, be facilitated by the presence of residues of the root–rh of Sasa species. [Copyright &y& Elsevier]

Annual biogeochemical fluxes (bulk precipitation, throughfall, stem flow, soil solution and vegetation uptake) of inorganic elements were observed in eight cool temperature forested ecosystems in Hokkaido, northern Japan, in order to determine the mechanisms of acid neutralization in Japanese forest ecosystems. We compared our results with the other biogeochemical studies in Japan, north Europe and US from the literature. In many Japanese forests, the internal proton production (IPS) by base cation accumulation into the vegetation was a major proton source, rather than external acidic deposition, and the IPS also affected the base cation fluxes from the mineral. IPS in Japanese forest tended to be larger than that in north Europe and US. Our results suggested that the high acid neutralizing ability of Japanese forests could be attributed to the strong relationship between the base cation buffering of the soil and the larger contribution of IPS as a proton source. acidic deposition|biogeochemical cycling|forest ecosystem|Japan|proton budget [ABSTRACT FROM AUTHOR]

Biogeochemical proton and base cation fluxes in a 30-year old white birch forest composed of Dystric Cambisols in northern Hokkaido, Japan were estimated using data on atmospheric deposition (AD), throughfall (TF), stemflow (SF), and discharge from soils (DS) and plant uptake (UP) from early June to November 1999. In the monitoring period, proton flux was 0.20kmolcha-1 for AD, 0.07 for TF+SF, and 0.03 for DS, indicating that atmospheric acid input was neutralized through plant and soil. Base cation flux was 1.29 for AD, 1.23 for TF+SF, and 0.99 for DS and plant base cation uptake was 2.14, indicating that the soil was the major source of base cation for plant. However, these seasonal fluxes showed various trends. Cumulative base cation flux in TF+SF showed constant increase trend during the whole period, which was similar to AD. Proton flux in AD jumped once just after a heavy rain of 255mm for 8 days at the end of July. Trends for the proton and base cation fluxes in TF plus SF were similar to that of AD. Although proton and base cation fluxes of DS were not found until middle July because of vegetation uptake and no flow, both fluxes increased suddenly after the heavy rain in July. After August, the base cation and proton fluxes in the DS increased continuously, due to the lack of plant uptake and intermittent rainfall. In this study, it is clear that plant activity and water flow are very important driving force for seasonal dynamics of biogeochemical cycling. [ABSTRACT FROM AUTHOR]

The proton budgets of deciduous and coniferous forest ecosystems on volcanogenous regosols in Hokkaido, northern Japan, were studied by measuring the biogeochemical fluxes (atmospheric deposition, canopy leaching, vegetation uptake and leaching from soil) at each site duringa three year period. The proton budgets were developed for individual compartments of the ecosystem: vegetation canopy, organic and mineral soil layers. At both sites, atmospheric S deposition was the dominant proton source in the vegetation canopy. In organic horizons, dissociation of weak acids (bicarbonate and/or organic acids) and vegetation uptake of base cations were the dominant proton sources, and the net mineralization of base cations was the dominant proton sink. Atmospheric acid deposition was almost neutralized in the forest canopy and organic horizon. At both sites, weathering and/or ion exchange of base cations and protonation of weak acids (mainly bicarbonate) were the dominant proton sinks in the mineral soil. In both organic and mineral soil, internal proton sources (mainly vegetation uptake of basecations and dissociation of weak acids) exceeded external proton sources, indicating that acid deposition was not the main driving force of soil acidification in the studied forest ecosystems. [ABSTRACT FROM AUTHOR]

As a candidate accident tolerant fuel cladding material, the high temperature oxidation behaviour of an Oxygen Dispersion Strengthened (ODS) Fe–12Cr–6Al alloy has been examined in isothermal air and steam environments. While the oxidation behaviour of FeCrAl has been extensively studied, very little has been reported in the literature on FeCrAl-ODS, which is the focus of this manuscript. By conducting Thermogravimetric Analysis (TGA), oxidation experiments were performed on specimens of Fe–12Cr–6Al-ODS at temperatures up to 1400 °C in air and up to 1215 °C in high purity steam. Oxidation kinetics were evaluated by calculating reaction rate constants and activation energies. The formation of an alumina scale was correlated to kinetics results from TGA by coupling Scanning Electron Microscopy (SEM) with Energy Dispersive X-ray Spectroscopy (EDS) line scans to investigate the chemical composition of the primary oxide layer, local oxidation effects, as well as the bulk alloy material. Electron Probe Micro-Analysis (EPMA) point scans were applied to the heavily oxidized specimen to achieve an accurate composition profiling of areas of interest. Finally, thermodynamic calculations were performed to interpret the formation of the complex oxide layer. These experiments support research efforts for the development of accident tolerant fuel technologies at Nippon Nuclear Fuel Development Co., Ltd. [ABSTRACT FROM AUTHOR]

The long-term impact of the coronavirus disease 2019 (COVID-19) pandemic on the disruption of gastrointestinal cancer diagnoses remains unclear. This study investigated the actual impact on esophagogastric cancer (EGC) and colorectal cancer (CRC) diagnoses up to the third year of the pandemic in Akita Prefecture, Japan, using population-based registry data. We collected data on the annual number of EGC and CRC diagnoses using a database from the collaborative Akita Prefecture hospital-based registration. The net number of cancers diagnosed in the first three years of the pandemic (2020-2022) were compared with those diagnosed in the three years before the pandemic (2017-2019). Changes in the proportion of cancer stage and initial treatment for diagnosed EGC and CRC after the pandemic were then compared. The total number of EGCs was 9.3% lower in the first three years of the pandemic than in the three years before, probably due to its long-term declining trend. The total number of CRCs in the first three years of the pandemic exceeded that in the three years before, suggesting successful recovery of the diagnostic procedure. The proportion of cancer stages and initial treatment for EGCs and CRCs remained largely unchanged after the onset of the pandemic. Based on the population-based registry data from the first three years of the pandemic, the disruption of gastrointestinal cancer diagnoses caused by the pandemic is settling down without any substantial disease progression, even in Akita Prefecture, the area with the highest incidence of cancer in all of Japan.

The aim of the present study was to determine whether the trough plasma concentrations (C 0 ) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C 0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C 0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C 0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C 0 of regorafenib is not maintained. Monitoring the C 0 of regorafenib regularly is necessary to guide dose adjustment., (© 2024. The Author(s).)

Introduction: There is limited information regarding multidimensional relationships between asthma control and health-related quality of life (HRQoL), work productivity, and asthma symptom burden in Japan. Furthermore, systematic qualitative investigations about asthma burden have not been performed., Methods: This cross-sectional, mixed-methods study included Japanese patients (≥ 20 years) with asthma adherent to inhaled corticosteroids/long-acting β 2 -agonists (ICS/LABA). The primary endpoint was impact of asthma on HRQoL, measured using the Asthma Health Questionnaire-33 (AHQ-33). Secondary endpoints were cough burden (Japanese-adapted Leicester Cough Questionnaire [J-LCQ]) and impact of asthma on work/activities (asthma-specific Work Productivity and Activity Impairment Questionnaire [WPAI:Asthma]). Quantitative data were assessed for the overall population and for well-controlled (WC) and not well-controlled (NWC) asthma subgroups. Qualitative verbal interviews further assessed the impact of NWC asthma on patients' HRQoL; emergent themes were extracted using thematic analyses., Results: Of 454 patients, 45.2% (n = 205) had NWC asthma. Patients with NWC asthma had significantly worse asthma- and cough-related HRQoL across all AHQ-33 and J-LCQ domains and significantly greater work and activity impairment versus patients with WC asthma, across all assessed WPAI:Asthma domains. AHQ-33 total score was highly correlated with J-LCQ total and domain scores (r = - 0.8132 to r = - 0.7407). Nine themes emerged from qualitative interviews and confirmed that patients with NWC asthma had considerable HRQoL impairment due to asthma symptoms., Conclusions: Patients with NWC asthma had higher symptom burden and worse HRQoL than patients with WC asthma, despite ICS/LABA adherence. Cough burden correlated with HRQoL, suggesting cough may be one of the key markers to inform treatment strategy for patients with asthma., (© 2023. The Author(s).)

In Japan an original pathological classification of IgA nephropathy was used, while Oxford classification of IgA nephropathy was used globally. The Oxford classification requires ≥ 8 glomeruli while the Japanese classification requires ≥ 10. Ninety-nine patients diagnosed with IgA nephropathy were included. To determine the accuracy of histological staging, we calculated the posterior probability using Bayes' theorem and adopted three model of prior distribution. First, the actual staging distribution was reclassified using the beta distribution (reclassified distribution). Second a model with the same distribution (actual distribution) as the actual staging was used. Third, a model assuming that all cases are equally distributed (equal distribution) was used. The median number of collected glomeruli was 12 (8-19). There were 33 cases (33%) wherein the glomerular count was ≤ 9. When only cases with ≥ 10 glomeruli were included, the median posterior probability was 91% (74-99) (actual distribution, 90% [74-98]; equal distribution, 85% [73-96]). Even among the 33 cases with ≤ 9 glomeruli, there were approximately 7 cases in which the posterior probability was ≥ 90% for each model. Using Bayesian probabilistic analysis, it was possible to evaluate the histologic classification of IgA nephropathy, even when the number of obtained glomeruli was ≤ 9., (© 2023. The Author(s).)

As interest in natural capital grows and society increasingly recognizes the value of biodiversity, we must discuss how ecosystem observations to detect changes in biodiversity can be sustained through collaboration across regions and sectors. However, there are many barriers to establishing and sustaining large-scale, fine-resolution ecosystem observations. First, comprehensive monitoring data on both biodiversity and possible anthropogenic factors are lacking. Second, some in situ ecosystem observations cannot be systematically established and maintained across locations. Third, equitable solutions across sectors and countries are needed to build a global network. Here, by examining individual cases and emerging frameworks, mainly from (but not limited to) Japan, we illustrate how ecological science relies on long-term data and how neglecting basic monitoring of our home planet further reduces our chances of overcoming the environmental crisis. We also discuss emerging techniques and opportunities, such as environmental DNA and citizen science as well as using the existing and forgotten sites of monitoring, that can help overcome some of the difficulties in establishing and sustaining ecosystem observations at a large scale with fine resolution. Overall, this paper presents a call to action for joint monitoring of biodiversity and anthropogenic factors, the systematic establishment and maintenance of in situ observations, and equitable solutions across sectors and countries to build a global network, beyond cultures, languages, and economic status. We hope that our proposed framework and the examples from Japan can serve as a starting point for further discussions and collaborations among stakeholders across multiple sectors of society. It is time to take the next step in detecting changes in socio-ecological systems, and if monitoring and observation can be made more equitable and feasible, they will play an even more important role in ensuring global sustainability for future generations. This article is part of the theme issue 'Detecting and attributing the causes of biodiversity change: needs, gaps and solutions'.

We recently reported the decrease in the number of gastrointestinal (GI) cancer diagnoses in 2020 due to disturbance of the healthcare system by the coronavirus disease 2019 (COVID-19) pandemic, using a hospital-based cancer registration system in Akita prefecture, Japan. In this study, we extended the research by showing the latest data (2021) on the number of cancers and examinations. Information on the occurrence and stage of esophageal, gastric, and colorectal cancers was collected from the same database. The number of GI examinations (cancer screening procedures and endoscopic examinations) was also investigated. Following the immediate decrease in the numbers of both GI examinations and GI cancer diagnoses in 2020, a rebound increase in the numbers of GI cancer diagnoses-especially colorectal cancers-was observed in 2021, resulting from an increased number of GI examinations i.e., the total number of colorectal cancers in 2021 increased by 9.0% and 6.8% in comparison to 2020 and pre-pandemic era, respectively. However, the rebound increase in 2021 was largely due to an increase in early-stage cancers, and there was no apparent trend toward the increased predominance of more advanced cancers. It therefore seems that we managed to escape from the worst-case scenario of disturbance of the healthcare system due to pandemic (i.e., an increase in the number of more advanced cancers due to delayed diagnoses). We need to continue to watch the trends in Akita prefecture, which has the highest rate of mortality from the 3 major GI cancers in Japan.

Background: A paradigm shift has occurred in cancer chemotherapy from tumor-specific treatment with cytotoxic agents to personalized medicine with molecular-targeted drugs. Thus, it is essential to identify genomic alterations and molecular features to recommend effective targeted molecular medicines regardless of the tumor site. Nevertheless, it takes considerable expertise to identify treatment targets from primary-sequencing data in order to provide drug recommendations. The Molecular Tumor Board (MTB) denotes a platform that integrates clinical and molecular features for clinical decisions., Methods: This study retrospectively analyses all the cases of discussion and decision at the MTB in Tohoku University Hospital and summarizes genetic alterations and treatment recommendations., Results: The MTB discussed 1003 comprehensive genomic profiling (CGP) tests conducted in patients with solid cancer, and the resulting rate of assessing treatment recommendations was approximately 19%. Among hundreds of genes in the CGP test, only 30 genetic alterations or biomarkers were used to make treatment recommendations. The leading biomarkers that led to treatment recommendations were tumor mutational burden-high (TMB-H) (n = 32), ERBB2 amplification (n = 24), BRAF V600E (n = 16), and BRCA1/2 alterations (n = 32). Thyroid cancer accounted for most cancer cases for which treatment recommendation was provided (81.3%), followed by non-small cell lung cancer (42.4%) and urologic cancer (31.3%). The number of tests performed for gastrointestinal cancers was high (n = 359); however, the treatment recommendations for the same were below average (13%)., Conclusion: The results of this study may be used to simplify treatment recommendations from the CGP reports and help select patients for testing, thereby increasing the accuracy of personalized medicine., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aims: This retrospective study compared the survival between elderly and non-elderly patients., Methods: A total of 5545 treatment-naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively., Results: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non-elderly patients, the median albumin-bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non-elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non-elderly patients did (p = 0.017). Non-liver-related death in elderly patients significantly differed among periods (p = 0.023), while liver-related death did not (p = 0.050). Liver- and non-liver-related death in non-elderly patients significantly differed among periods (p < 0.001, p = 0.005)., Conclusions: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Genes encoding snake venom toxins have been studied extensively. However, genes involved in the modification and functioning of venom proteins are little known. Protobothrops is a genus of pit vipers, which are venomous and inhabit the Nansei (Southwest) islands of Japan, Taiwan China, Vietnam, Thailand, Myanmar, Nepal, Bhutan, and India. Our previous study decoded the genome of Protobothrops flavoviridis , a species endemic to the Nansei Islands, Japan, and revealed unique evolutionary processes of some venom genes. In this study, we analyzed genes that are highly expressed in venom glands to survey genes for candidate enzymes or chaperone proteins involved in toxin folding and modification. We found that, in addition to genes that encode venom proteins and ribosomal proteins, genes that encode protein disulfide isomerase (PDI) family members (orthologs of human P4HB and PDIA3 ), Selenoprotein M ( SELENOM ), and Calreticulin ( CALR ) are highly expressed in venom glands. Since these enzymes or chaperones are involved in protein modification and potentially possess protein folding functions, we propose that P4HB , SELENOM , CALR , and PDIA3 encode candidate enzymes or chaperones to confer toxic functions upon the venom transcriptome.

Background: With the spread of COVID-19, anti-SARS-CoV-2 antibody tests have been utilized. Herein we evaluated the analytical performance of anti-SARS-CoV-2 antibody test kits using a new reference standard prepared from COVID-19 patient sera. Methods: Fifty-seven kits in total (16 immunochromatography types, 11 ELISA types and 30 types for automated analyzers) were examined. By measuring serially diluted reference standards, the maximum dilution factor showing a positive result and its precision were investigated. Results: The measured cut-off titers varied largely depending on the antibody kit; however, the variability was small, with the titers obtained by each kit being within twofold in most cases. Conclusion: The current results suggest that a suitable kit should be selected depending on the intended purpose.

Background/aim: With the development of systemic treatment methods for unresectable hepatocellular carcinoma (uHCC), the concept of unsuitable for transcatheter arterial chemoembolization (TACE) has become important. This study aimed to establish a simple predictive scoring system for determining TACE unsuitable status., Materials/methods: From 1998 to 2015, 196 patients with intermediate-stage uHCC with Child-Pugh A (score 5:6 = 108:88) and given TACE as the initial treatment were enrolled. At the baseline, tumor burden (Milan criteria-out, up-to-7 in/out, and up-to-11 in/out: 0-2 points) and modified albumin-bilirubin grade 1/2a or 2b (0-1 point) were added to determine the score for TACE unsuitable (CITRUS-MICAN score; low <2 and high ≥2). In addition, a previously reported tumor marker (TM) score, in which alpha-fetoprotein (AFP) was ≥100 ng/mL, fucosylated AFP ≥10%, and des-gamma-carboxy prothrombin ≥100 mAU/mL (each 1 point) (total 0, 1, or ≥2 points), was used for additionally evaluating tumor malignancy potential. Prognosis was retrospectively evaluated based on those scores., Results: Median survival time (MST) was better for low compared to high CITRUS-MICAN score (42.0 vs. 26.4 months) (p = 0.002). A 2-step evaluation using the combination of CITRUS-MICAN and TM scores showed an MST of 43.2 months for low CITRUS-MICAN/TM score 0/1 (rank-A) and 39.6 months for low CITRUS-MICAN/TM score ≥2 (rank-B2), while it was 46.8 months for high CITRUS-MICAN/TM score 0 (rank-B1), 28.8 months for high CITRUS-MICAN/TM score 1 (rank-B2), and 22.8 months for high CITRUS-MICAN/TM score ≥2 (rank-C). For rank-A cases (n = 51), MST was 43.2 months, while it was 46.8 months for rank-B1 (n = 12), 31.2 months for rank-B2 (n = 82), and 22.8 months for rank-C (n = 51) (p = 0.001)., Conclusion: The results showed that rank-C indicates absolute TACE unsuitable status. For rank-A patients, good prognosis with TACE can be expected, while TACE refractoriness status during the clinical course should be carefully evaluated so as to anticipate the appropriate timing for switching to systemic treatment in rank-B1 and -B2 patients., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Particular batches of Moderna mRNA Coronavirus Disease 2019 (COVID-19) vaccine were recalled after foreign particles were found in some vaccine vials at the vaccination site in Japan in August 2021. We investigated the foreign particles at the request of the Ministry of Health, Labour and Welfare. Energy dispersive X-ray spectroscopy analysis suggested that the foreign particles found in the vials recalled from the vaccination sites were from stainless steel SUS 316L, which was in line with the findings of the root cause investigation by the manufacturer. The sizes of the observed particles ranged from <50 μm to 548 μm in the major axis. Similar foreign particles were also detected in 2 of the 5 vaccine vials of the same lot stored by the manufacturer, indicating that the foreign particles have already been administered to some people via vaccine. Observation of the vials of the same lot by digital microscope found smaller particles those were not detected by visual inspection, suggesting that more vials were affected. Contrarily, visual inspection and subvisible particulate matter test indicated no foreign particles in the vials of normal lots. Possible root cause and strategies to prevent such a deviation were discussed from technical and regulatory aspects.

Nitrogen (N) is an essential nutrient but may become a pollution source in the environment when the N concentration exceeds a certain threshold for humans and nature. Nitrate is a major N species in river water with notable spatial and temporal variations under the influences of natural factors and anthropogenic N inputs. We analyzed the relationship between riverine N (focusing on nitrate) concentration and various factors (land use, climate, basin topography, atmospheric N deposition, agricultural N sources and human-derived N) in 104 rivers located throughout the Japanese Archipelago except small remote islands. We aimed to better understand processes and mechanisms to explain the spatial and temporal changes in riverine nitrate concentration. A publicly available river water quality database observed in the 1980s (1980-1989) and 2000s (2000-2009) was used. This study is the first to evaluate the long-term scale of 20 years in the latter half of Japan's economic growth period at the national level. A geographic information system (GIS) was employed to determine average values of each variable collected from multiple sources of statistical data. We then performed regression analysis and structural equation modeling (SEM) for each period. The forestland area influenced by the basin topography, climate (i.e., air temperature) and other land uses (i.e., farmland and urban area) played a major role in decreasing nitrate concentrations in both the 1980s and 2000s. Atmospheric N deposition (especially N oxides) and agricultural N sources (fertilizer and manure) were also significant variables regarding the spatial variations in riverine nitrate concentrations. The SEM results suggested that human-derived N (via food consumption) intensified by demographic shifts during the 2000s increased riverine nitrate concentrations over other variables within the context of spatial variation. These findings facilitate better decision making regarding land use, agricultural practices, pollution control and individual behaviors toward a sustainable society., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The benefits of the artificial fixation of reactive nitrogen (Nr, nitrogen [N] compounds other than dinitrogen), in the form of N fertilizers and materials are huge, while at the same time posing substantial threats to human and ecosystem health by the release of Nr to the environment. To achieve sustainable N use, Nr loss to the environment must be reduced. An N-budget approach at the national level would allow us to fully grasp the whole picture of Nr loss to the environment through the quantification of important N flows in the country. In this study, the N budgets in Japan were estimated from 2000 to 2015 using available statistics, datasets, and literature. The net N inflow to Japanese human sectors in 2010 was 6180 Gg N yr -1 in total. With 420 Gg N yr -1 accumulating in human settlements, 5760 Gg N yr -1 was released from the human sector, of which 1960 Gg N yr -1 was lost to the environment as Nr (64% to air and 36% to waters), and the remainder assumed as dinitrogen. Nr loss decreased in both atmospheric emissions and loss to terrestrial water over time. The distinct reduction in the atmospheric emissions of nitrogen oxides from transportation, at -4.3% yr -1 , was attributed to both emission controls and a decrease in energy consumption. Reductions in runoff and leaching from land as well as the discharge of treated water were found, at -1.0% yr -1 for both. The aging of Japan's population coincided with the reductions in the per capita supply and consumption of food and energy. Future challenges for Japan lie in further reducing N waste and adapting its N flows in international trade to adopt more sustainable options considering the reduced demand due to the aging population., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate peripapillary choroidal thickness (PPCT) in normal Japanese subjects by using spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) technique and evaluate its association with ocular and systemic factors., Study Design: Cross-sectional study., Methods: This study included 85 eyes of 85 normal Japanese subjects. Normal subjects were defined as those without retinal and optic nerve disorders of any kind. The PPCT was measured at the location of 3.4 mm diameter peripapillary circle centered on the optic nerve head. It was measured as the distance between the retinal pigment epithelium and scleral-choroidal interface at the following six sectors; temporal, supra-temporal, supra-nasal, nasal, infero-nasal, and infero-temporal. Global PPCT was calculated based on these sectorial data. In addition, association between the PPCT and ocular and systemic factors were evaluated., Results: Among the included subjects, 39 (45.9%) were men and mean age was 51.4 ± 17.6 years. The mean global PPCT was 135.8 ± 40.6 µm. The infero-nasal and infero-temporal sectors were significantly thinner than other sectors (all, P < 0.05). In multiple regression analysis, thinner global PPCT was significantly associated with older age (P < 0.0001) and female sex (P = 0.0330) after considering effects of other confounders., Conclusions: This study provided global PPCT and its profile in normal Japanese subjects by using EDI SD-OCT. These results may be used as a reference in the assessment of normal status of the PPCT. The age and sex of the subjects should be considered in interpreting the PPCT data., (© 2021. Japanese Ophthalmological Society.)

Background: There is a growing interest in the significance of adopting a variety of lifestyle habits for maintaining cognitive function among older adults. A lifestyle that is easy to modify, simple, and less burdensome for older people is ideal. We investigated the longitudinal association between global cognitive decline and cognitive leisure activities (CLAs) combined with long-chain polyunsaturated fatty acids (LCPUFAs) intake., Methods: The National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) enrolled community-dwelling middle-aged and older men and women who were randomly selected from Obu-City and Higashiura Town, Aichi, Japan. Baseline data (2006-2008), including CLAs and dietary intake, were obtained from 517 participants (aged 60-84 years) with normal cognition. Global cognitive decline, defined as the Mini-Mental State Examination (MMSE) score ≤ 27, was assessed at baseline and four years later. Interaction between CLAs and LCPUFAs on cognitive decline was investigated using a multiple logistic analysis with adjustment for confounders. CLA engagement and LCPUFA intake were divided into high and low groups according to the frequency at which each participant engaged in the activity and the median intake level according to sex, respectively., Results: A significant interaction was detected for the combination of CLA engagement and LCPUFA intake. Logistic regression coefficients revealed significant interactions when participants engaged in more than five CLA varieties. One of the CLAs, art appreciation, produced a significant main effect against cognitive decline and a significant interaction in combination with LCPUFA intake. The major LCPUFAs-docosahexaenoic acid and arachidonic acid-also exhibited a significant interaction. The combination of high LCPUFA intake and high art appreciation frequency yielded a lower adjusted odds ratio for cognitive decline than the combination of low LCPUFA and low art appreciation [0.25 (95 % confidence intervals, 0.11-0.56)]., Conclusions: Preserving cognitive function might be associated with a combination of varied and high-frequency engagement in CLAs combined with high LCPUFA intake., (© 2021. The Author(s).)

Dietary habits are of considerable interest as a modifiable factor for the maintenance of muscle health, especially sarcopenia. The present study aimed to investigate the association between dietary intake and sarcopenia prevalence in community-dwelling Japanese subjects. This cross-sectional study was conducted using data from the fifth survey of the Research on Osteoarthritis/Osteoporosis against Disability (ROAD) study, and 1345 participants (437 men and 908 women) aged ≥60 years were included in the analysis. Sarcopenia was determined by the definition of the Asian Working Group for Sarcopenia established in 2014, and dietary intake was assessed with the brief-type self-administered diet history questionnaire. Overall, 77 subjects (5.7%) were identified as having sarcopenia, 5.0% of men and 6.1% of women. Multiple logistic regression analysis showed that the odds ratios of sarcopenia for the dietary intake of vitamin E (α-tocopherol, 0.14 (CI 0.04-0.49), β-tocopherol (0.24, CI 0.07-0.78), γ-tocopherol (0.28, CI 0.09-0.87), and fats (fat 0.27, CI 0.08-0.96; monounsaturated fatty acids, 0.22, CI 0.07-0.72, polyunsaturated fatty acids, 0.28, CI 0.09-0.89) at the highest quantile were significantly lower compared with those at the lowest quantile. Therefore, higher dietary intakes of vitamin E and fats would be associated with a lower prevalence of sarcopenia.

To investigate the effect of reduced snow cover on fine root dynamics in a cool-temperate forest in northern Japan because of decreases in snowfall at high latitudes due to global warming, we monitored root length, production, and mortality before and after snow removal with an in-ground root scanner. We measured root dynamics of both overstory deciduous oak (Quercus crispula) and understory evergreen dwarf bamboo (Sasa nipponica), the two major species in the forest. Snow removal advanced the timing of peak root production by a month both in total and in Sasa, but not in oak. There was a significant interaction between snow removal and plant form on root production; this indicates that enhanced Sasa root production following snow removal might increase its ability to compete with oak. In contrast, snow removal did not enhance root mortality, suggesting that the roots of these species tolerate soil freezing. The earlier snow disappearance in the snow removal plot expanded the growing season in Sasa. We speculate that this change in the understory environment would advance the timing of root production by Sasa by extending the photosynthetic period in spring. We propose that different responses of root production to reduced snow cover between the two species would change the competitive interactions of overstory and understory vegetation, influencing net primary production and biogeochemistry (e.g., carbon and nitrogen cycles) in the forest ecosystem.

Black carbon (BC) is a pyrolyzed product derived from incomplete combustion. A major fraction of BC produced by landscape fires is initially deposited onto onsite soils. Atmospheric deposition of soot is known to be an important source of soil BC, especially in watersheds that are not affected by landscape fires. The transport of the dissolved fraction of oxidized BC in soil, defined as dissolved black carbon (DBC), to streams is considered one of the important loss pathways of BC in soil, but the mechanism is not well documented. We measured the quantity and quality of DBC, determined by a benzenepolycarboxylic acid method, and the quantitative and qualitative parameters of bulk dissolved organic matter (DOM) in streams in Hokkaido, northern Japan, whose catchments were not affected by landscape fire for at least 110 years. DBC with relatively low polycondensed signatures occurred in the streams, irrespective of differences in watershed characteristics and seasons, suggesting that atmospheric deposition of soot into the catchment is probably a major source of stream DBC. The DBC concentration was linearly related to the dissolved organic carbon (DOC) concentration, irrespective of the differences in watershed characteristics and seasons. Furthermore, the polycondensation degree of DBC was observed to correlate with the qualitative parameters of bulk DOM. Such quantitative and qualitative relationships between DBC and bulk DOM imply that the transfer mechanism from soils to streams of soot-derived polycondensed DBC is linked with that of higher plant-derived, high-molecular-weight aromatic DOM., 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 © 2021 Elsevier Ltd. All rights reserved.)

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca 2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] -17.7 [-20.6, -14.7] and -9.5 [-11.7, -7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K + increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

Background/aim: To evaluate complications and risk factors associated with transumbilical incision as an organ removal site in laparoscopic pancreatectomy (LP)., Patients and Methods: In total, 52 patients who underwent LP between 2009 and 2017 were included in this study. The development of superficial surgical site infection (SSI) and transumbilical port-site incisional hernia was recorded., Results: None of the patients had SSI. However, three (5.77%) presented with transumbilical incisional hernia. No variables were significantly associated with the risk of transumbilical incisional hernia., Conclusion: No evident risk factors correlated with hernia formation. Hence, incisional hernia might have occurred at a certain probability. In some cases, it was caused by technical problems. However, the use of transumbilical incision as an organ removal site was feasible, and a new incision for organ removal alone was not required., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The abundance and composition of anthropogenic marine debris from 2012 to 2014 was assessed according to three bottom trawl surveys conducted on the upper continental slope between 198 m and 501 m off the Pacific coast of northeastern Japan. The surveys quantitated marine debris as follows: 33.52-164.62 items km -2 (January to July 2012), 91.68-215.11 items km -2 (November 2012 to May 2013), and 160.13-178.19 items km -2 (November 2013 to May 2014). Plastic bags or household materials mainly dominated terrestrial sources of debris. Principal component analysis latitudinally divided the study area according to debris abundance caused by geographical and hydrodynamic features. The long-term effect of tsunami-associated debris on the seafloor environment was recognized, because terrestrial sources such as heavy household materials were most abundant throughout the study period, with the additional accumulation of fishing gear and plastic bags., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim/background: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria., Materials/methods: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis., Results: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035)., Conclusions: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria., (© 2021 S. Karger AG, Basel.)

As reported in the previous commentary (Ishii-Watabe et al., J Pharm Sci 2017), the Japanese biopharmaceutical research group is promoting collaborative multilaboratory studies to evaluate and standardize new methodologies for biopharmaceutical characterization and quality control. We have conducted the studies and held 2 annual meetings in 2018 and 2019. At the 2018 meeting, Dr. Rukman DeSilva of the U.S. Food and Drug Administration and Dr. Srivalli Telikepalli of the National Institute of Standards and Technology participated as guest speakers. At the 2019 meeting, we invited Prof. John Carpenter of the University of Colorado, Prof. Gerhard Winter and Prof. Wolfgang Friess of Ludwig Maximilian University of Munich, and Dr. Tim Menzen of Coriolis Pharma Research, as guest commentators. In both meetings, the main research topic was strategies for the characterization and control of protein aggregates/subvisible particles in drug products. Specifically, the use of the light obscuration method for insoluble particulate matter testing with reduced injection volumes, and a comparison of analytical performance between flow imaging and light obscuration were discussed. Other topics addressed included host cell protein analysis, bioassay, and quality control strategies. In this commentary, the recent achievements of the research group, meeting discussions, and future perspectives are summarized., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Omega-3 fatty acid ethyl esters (omega-3), an eicosapentaenoic acid and docosahexaenoic acid preparation (Lotriga ® , Takeda Pharmaceutical Company Limited), are approved in Japan to treat triglyceridemia. We investigated the effects of omega-3 on vascular endothelial function, measured by flow-mediated dilation (FMD)., Methods: Patients with dyslipidemia receiving 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors were randomized 1:1 to receive omega-3 at 2 g (QD) or 4 g (2 g BID) for 8 weeks. The primary end point was the change from baseline of fasting  %FMD in each treatment group. Secondary end points included the 4-h postprandial  %FMD and 4-h postprandial triglyceride (TG) level., Results: Thirty-seven patients were randomized to receive omega-3 at 2 g (n = 18) or 4 g (n = 19). Mean fasting %FMD did not increase from baseline to week 8 in the 2-g group (- 1.2%) or 4-g group (- 1.3%). Mean 4-h postprandial %FMD did not change from baseline to week 8 in the 2-g group (0.0%), but increased in the 4-g group (1.0%). Mean 4-h postprandial TG level decreased by 34.7 mg/dl from baseline over week 8 in the 2-g group, with a significantly larger decrease in the 4-g group of 75.9 mg/dl (p < 0.001). No new safety concerns were identified., Conclusions: Fasting %FMD did not improve after 8 weeks of omega-3 treatment at 2 g or 4 g. After 8 weeks, 4-h postprandial TG levels showed improvement at both doses, with a greater reduction in the 4-g group., Trial Registration: ClinicalTrials.gov, ID: NCT02824432.

We report the identification of a mutation in the solute carrier family 5 member 2 (SLC5A2) gene, which encodes sodium-glucose cotransporter 2, in a family with familial renal glucosuria. The proband was a 26-year-old Japanese man referred to the diabetes division with repeated glucosuria without hyperglycemia. His mother, uncle and grandfather also had a history of glucosuria. A heterozygous missense mutation (c.303T>A:p.N101K) in SLC5A2 was identified in the patient and his mother, but not in 200 chromosomes from 100 healthy and unrelated individuals, or in 3,408 Japanese individuals in the Tohoku Medical Megabank. Furthermore, bioinformatics software predicted that this lesion would be pathogenic. We infer that the mutation led to clinically relevant sodium-glucose cotransporter 2 dysfunction. The patient showed no symptoms of hypoglycemia, but continuous glucose monitoring confirmed asymptomatic hypoglycemia., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Primary aldosteronism (PA) is a common curable cause of hypertension. Adrenal venous sampling (AVS) is recommended for subtype diagnosis but is a difficult procedure. Recently, an increased prevalence of PA was reported, creating a greater demand for treatment of the condition in clinical facilities. The aim of the present study was to identify the historical changes over time and the differences between facilities in the success rate and subtype diagnosis of PA. The database of the PA registry developed by the Japan PA Study (JPAS) was used. A total of 2599 patients with PA who underwent AVS were evaluated. The overall success rate of AVS was 88%. The bilateral subtype was the dominant subtype, comprising 69% of cases. During the period 2004-2011 to 2011-2017, there were significant changes in the total number of AVS procedures (from 562 to 1732), ratio of ACTH administration with AVS (75 to 97%), success rate (79 to 90%), and proportion with bilateral subtype diagnosis (53 to 72%). There were also significant inter-facility differences in the number of AVS procedures (6 to 322), success rate (59 to 97%), and proportion with the bilateral subtype (44 to 86%). The principal enrolled department was Endocrinology (86%), and the ratio of unilateral PA was significantly higher in this department than in others (32% vs. 25%). In conclusion, the number of AVS procedures performed, the success rate, and the proportion with the bilateral subtype increased over time after normalizing the centre difference. Significant differences were observed between the centres.

The present study aimed to propose local diagnostic reference levels (DRLs) formulated by calculating entrance surface doses for general radiography at 20 facilities of Aichi prefecture in Japan, by comparing these values with DRLs established in Japan in 2015 (DRLs 2015) and assessing radiation dose differences among facilities. X-ray outputs (half-value layer and air kerma) of each facility were measured with a non-invasive type of detector. The results were employed to formulate local DRLs based on the 75th percentiles of dose distributions. These local DRLs were lower than the DRLs 2015 for all examinations. If proposed local DRLs from other 46 prefectures can be collected, this paper can be used to benefit the next effort to draft better DRL for Japan., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

With the use of an in situ and static method for gamma-ray measurements, levels of radioactive cesium 137 on shallow rugged reefs which lie between 37.3° N and 37.4° N, from the coastline of Fukushima to 141.06° E, at a depth of around 10 m were surveyed for the first time from May 2016 to December 2017. To confirm the contact between the detector and a surface of rock, we used a fact that potassium containing minerals are abundant and uniformly distributed in the area, and thus the strength of the photoelectric peak of natural radioactive potassium 40 is nearly constant over the area. We have found that the levels of radioactive cesium 137 varied from point to point within a range from 1 × 10 4  Bq/m 2 to 6 × 10 4  Bq/m 2 ., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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.

In this study, we investigated the relationships between body weight (BW), computed tomography (CT)-assessed abdominal adipose tissue, and the glycemic metabolic profile in obese Japanese patients following laparoscopic sleeve gastrectomy (LSG). This study analyzed adipose tissue compartments using CT methods before and 1 year after LSG. Thirty obese patients were studied, and variables measured included visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), density of VAT (VAT-D), and density of SAT (SAT-D). We also examined the parameters in patients according to whether they had type-2 diabetes (T2DM). LSG induced significant losses in BW, SAT, and VAT after LSG. Additionally, SAT-D and VAT-D both increased and fasting plasma glucose (FPG) and HbA1c, but not C-peptide, decreased after surgery. ΔSAT and ΔVAT were positively related, and ΔSAT-D and ΔVAT-D were negatively related to ΔBW and/or FPG. Furthermore, a multivariate regression model showed that total BW loss (TBWL) was closely related to ΔSAT (β = 0.84; p < 0.001) and ΔVAT-D (β = -0.45; p < 0.05) and improvement of FPG was related to ΔVAT (β = 0.61; p < 0.05) after LSG. Finally, ΔFPG was correlated with ΔVAT in 16 T2DM patients (r = 0.58; p < 0.05) but not in non-T2DM patients. TBWL was related to ΔSAT and ΔVAT-D, and improvement of FPG was related to ΔVAT in obese Japanese patients after LSG.

Objectives: Because of the influence on the renin-angiotensin-aldosterone system, it is recommended to avoid, if possible, the use of angiotensin-converting-enzyme inhibitors, angiotensin II type 1 receptor blockers, diuretics, β-blockers, and mineralocorticoid receptor antagonists during the diagnostic period of primary aldosteronism. A laterality index more than 4 in adrenocorticotropic hormone (ACTH)-stimulated adrenal venous sampling (ACTH-AVS) is a widely used classification of the unilateral subtype that can benefit from adrenalectomy. Here, we revealed clinical features of patients taking drugs that could affect the primary aldosteronism diagnosis (DAPD) and investigated whether the classification with laterality index more than 4 in ACTH-AVS is applicable to these patients., Patients and Methods: Using a large database of primary aldosteronism patients in Japan, we analyzed 2122 patients with successful ACTH-AVS., Results: Patients who received any DAPD (n = 209) showed higher prevalence of comorbidity burdens and took more antihypertensive drugs compared with patients without DAPD. In patients taking DAPD, those with laterality index more than 4 had a higher prevalence of hypokalemia, a higher aldosterone-to-renin ratio and a higher prevalence of adrenal mass than those with laterality index of 4 or less. Adrenalectomy was performed in 76% patients with laterality index more than 4 and 20% with laterality index of 4 or less. Patients who underwent adrenalectomy showed biochemical cure in 89% with laterality index more than 4 and 50% with laterality index of 4 or less (P = 0.001). Multivariate regression analysis showed that laterality index more than 4 was an independent predictor of a biochemical cure. Biochemical cure rate in patients with laterality index more than 4 was consistently high, irrespective of the potential effect of individual DAPD on laterality index., Conclusion: Our findings suggest that in primary aldosteronism patients to whom DAPD were administrated due to severe clinical features, laterality index more than 4 in ACTH-AVS could accurately predict a biochemical cure after adrenalectomy.

Objectives: Current clinical guidelines of primary aldosteronism recommend adrenalectomy (AdX) for unilateral primary aldosteronism based on the studies showing the potential superiority of AdX over the medical treatment. However, since most medically treated cases consisted of bilateral primary aldosteronism and all surgically treated cases consisted of unilateral primary aldosteronism, the different subtype of primary aldosteronism could be a bias for their effects. This study compared the effects of AdX and medical therapy in patients with unilateral primary aldosteronism confirmed by adrenal vein sampling., Methods: Of the 339 patients with unilateral primary aldosteronism in the Japan Primary Pldosteronism Study data base, unilateral AdX and treatment with mineral corticoid receptor antagonists (MRAs) was done in 276 patients (AdX group) and in 63 patients (MRAs group), respectively. The effects were compared by the clinical (improvement of blood pressure) and biochemical outcomes (improvement of hypokalemia)., Results: At baseline, use of potassium replacement, plasma aldosterone concentration, aldosterone-to-renin ratio, estimated glomerular filtration rate, and prevalence of adrenal mass on imaging were higher in the AdX group than in the MRAs group. At 6 months after commencement of specific treatment for primary aldosteronism, clinical outcome and biochemical outcome in the AdX group were superior than those in the MRAs group. The difference of the outcome between the two groups were the case even after adjusting for the different clinical backgrounds in the two groups before the specific treatment., Conclusion: Our study provides evidence that AdX is the first choice of treatment in the patients with unilateral primary aldosteronism in terms of clinical and biochemical outcome.

Objective: To investigate the prevalence and causes of diabetes in patients with primary aldosteronism (PA) in a multi-institutional cohort study in Japan., Research Design and Methods: The prevalence of diabetes was determined in 2,210 patients with PA (diagnosed or glycated hemoglobin [HbA 1c ] ≥6.5% [≥48 mmol/mol]; NGSP) and compared with that of the Japanese general population according to age and sex. In 1,386 patients with PA and clear laterality (unilateral or bilateral), the effects of plasma aldosterone concentration (PAC), hypokalemia (<3.5 mEq/L), suspected subclinical hypercortisolism (SH; serum cortisol ≥1.8 µg/dL after 1-mg dexamethasone suppression test), and PA laterality on the prevalence of diabetes or prediabetes (5.7% ≤ HbA 1c <6.5% [39 mmol/mol ≤ HbA 1c <48 mmol/mol]) were examined., Results: Of the 2,210 patients with PA, 477 (21.6%) had diabetes. This prevalence is higher than that in the general population (12.1%) or in 10-year cohorts aged 30-69 years. Logistic regression or χ 2 test revealed a significant contribution of suspected SH to diabetes. Despite more active PA profiles (e.g., higher PAC and lower potassium concentrations) in unilateral than bilateral PA, BMI and HbA 1c values were significantly higher in bilateral PA. PA laterality had no effect on the prevalence of diabetes; however, the prevalence of prediabetes was significantly higher in bilateral than unilateral PA., Conclusions: Individuals with PA have a high prevalence of diabetes, which is associated mainly with SH. The prevalence of prediabetes is greater for bilateral than unilateral PA, suggesting a unique metabolic cause of bilateral PA., (© 2019 by the American Diabetes Association.)

The evaluation of subvisible particles, including protein aggregates, in therapeutic protein products has been of great interest for both pharmaceutical manufacturers and regulatory agencies. To date, the flow imaging (FI) method has emerged as a powerful tool instead of light obscuration (LO) due to the fact that (1) protein aggregates contain highly transparent particles and thereby escape detection by LO and (2) FI provides detailed morphological characteristics of subvisible particles. However, the FI method has not yet been standardized nor listed in any compendium. In an attempt to assess the applicability of the standardization of the FI method, we conducted a collaborative study using FI and LO instruments in a Japanese biopharmaceutical consortium. Three types of subvisible particle preparations were shared across 12 laboratories and analyzed for their sizes and counts. The results were compared between the methods (FI and LO), inter-laboratories, and inter-instruments (Micro Flow Imaging and FlowCam). We clarified the marked difference between the detectability of FI and LO when counting highly transparent protein aggregates in the preparations. Although FlowCam provided a relatively higher number of particles compared with MFI, consistent results were obtained using the instrument from the same manufacturer in all 3 samples., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10 -9 ). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10 -8 ). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.

Context: Recently, the relationship between primary aldosteronism (PA) and various metabolic disorders, including obesity, diabetes mellitus, and dyslipidemia, has been discussed. However, in PA, aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) have different etiologies., Objective: Our objectives were to clarify differences in obesity and metabolic disorders between APA and IHA and to gain insight in the pathogenesis of IHA., Design, Setting, and Participants: This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan Primary Aldosteronism Study. For comparative analysis, data were also collected from 274 patients with essential hypertension (EHT)., Main Outcome Measures: We compared prevalences of obesity and metabolic disorders between patients with APA and patients with IHA. Comparisons with sex-, age-, and blood pressure-matched patients with EHT were also performed. Correlations between metabolic parameters and plasma aldosterone concentrations (PACs) in each subtype were analyzed., Results: Analysis of 516 patients with APA and 1015 patients with IHA revealed PACs were significantly higher in patients with APA than patients with IHA. By contrast, after we adjusted for clinical backgrounds, the prevalence of obesity was significantly higher in patients with IHA than in patients with APA or EHT. Although the prevalences of diabetes mellitus and dyslipidemia did not significantly differ between patients with IHA and patients with APA, triglyceride and HbA1c were significantly higher in patients with IHA than in patients with APA. There was no significant correlation between metabolic parameters and PACs in either subtype., Conclusions: Patients with IHA tend to be obese despite lower PACs than in patients with APA. The present results suggest that obesity-related factors contribute to the pathogenesis of IHA.

It remains unclear whether n -3 long-chain polyunsaturated fatty acids (LCPUFA) have a preventive effect on depression in the general population. This study investigated the longitudinal association between n -3 LCPUFA intake and depressive symptoms in community-dwelling Japanese participants. The participants were aged 40⁻79 years at baseline in the cohort study; wherein examinations; including the assessment of depressive symptoms and nutritional status; were biennially conducted from 1997 to 2012. The subjects ( n = 2335) who had a Center for Epidemiologic Studies Depression Scale (CES-D) score < 16 at the first examination and who participated in the follow-up study at least once were included in the analysis. The follow-up end point was the first onset (CES-D ≥ 16) or the last examination participation. Hazard ratios (95% CIs) for CES-D ≥ 16 were estimated using the adjusted Cox proportional hazards model. Overall; 22.1% participants showed depressive symptoms during follow-up (average; 8.1 years). Compared with the lowest tertile; the highest HR for EPA was 0.74 (0.60⁻0.93), and highest and middle HRs for DHA were 0.79 (0.63⁻0.98) and 0.80 (0.65⁻0.99) ( P for trend = 0.009 and 0.032), respectively. Among populations with high fish consumption; higher n -3 LCPUFA intake may be associated with a low risk of depressive symptoms.