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A 63-year-old man underwent transcatheter arterial embolization (TAE) using a mixture of N -butyl-2-cyanoacrylate (NBCA) and iodized oil to treat acute gastrointestinal (GI) bleeding. The procedure was initially successful; however, the patient developed ileus >1 month later and subsequently underwent several surgeries to treat the multiple metachronous ileal stenoses. The flux of a small amount of off-target glue was the primary cause of these complications. As the patient had few symptoms in the first month post-TAE, however, affirming the diagnosis took time. A detailed review of plain CT scans was a decisive factor in achieving the final diagnosis. This case demonstrates that TAE using an NBCA-iodized oil mixture effectively treats acute GI bleeding. However, a complication such as off-target embolization is likelier to occur because of a combination of certain factors such as vascular anatomy, complexity of the procedure, and NBCA dilution. Close observation using plain CT should be performed for the identification of off-target embolization occurrence even in cases of successful TAE., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology.)

Primary cilia are thin hair-like organelles that protrude from the surface of most mammalian cells. They act as specialized cell antennas that can vary widely in response to specific stimuli. However, the effect of changes in cilia length on cellular signaling and behavior remains unclear. Therefore, we aimed to characterize the elongated primary cilia induced by different chemical agents, lithium chloride (LiCl), cobalt chloride (CoCl2) and rotenone, using human retinal pigmented epithelial 1 (hRPE1) cells expressing ciliary G protein-coupled receptor (GPCR), melanin-concentrating hormone (MCH) receptor 1 (MCHR1). MCH induces cilia shortening mainly via MCHR1-mediated Akt phosphorylation. Therefore, we verified the proper functioning of the MCH-MCHR1 axis in elongated cilia. Although MCH shortened cilia that were elongated by LiCl and rotenone, it did not shorten CoCl2-induced elongated cilia, which exhibited lesser Akt phosphorylation. Furthermore, serum readdition was found to delay cilia shortening in CoCl2-induced elongated cilia. In contrast, rotenone-induced elongated cilia rapidly shortened via a chopping mechanism at the tip of the cilia. Conclusively, we found that each chemical exerted different effects on ciliary GPCR signaling and serum-mediated ciliary structure dynamics in cells with elongated cilia. These results provide a basis for understanding the functional consequences of changes in ciliary length., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this study, we report the synthesis of 2'-formamidonucleoside phosphoramidite derivatives and their incorporation into siRNA strands to reduce seed-based off-target effects of small interfering RNAs (siRNAs). Formamido derivatives of all four nucleosides (A, G, C and U) were synthesized in 5-11 steps from commercial compounds. Introducing these derivatives into double-stranded RNA slightly reduced its thermodynamic stability, but X-ray crystallography and CD spectrum analysis confirmed that the RNA maintained its natural A-form structure. Although the introduction of the 2'-formamidonucleoside derivative at the 2nd position in the guide strand of the siRNA led to a slight decrease in the on-target RNAi activity, the siRNAs with different sequences incorporating 2'-formamidonucleoside with four kinds of nucleobases into any position other than 2nd position in the seed region revealed a significant suppression of off-target activity while maintaining on-target RNAi activity. This indicates that 2'-formamidonucleosides represent a promising approach for mitigating off-target effects in siRNA therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The increasing incidence and prevalence of breast cancer alongside diagnostic and treatment technology advances have produced a debate about the financial burden cancer places on the healthcare system and concerns about access., Methods: This study was conducted at 51 hospitals belonging to the Breast Cancer Study Group of the Japan Clinical Oncology Group using a web-based survey. The survey period conducted from July 2021 to June 2022. The study population included patients with metastatic breast cancer who received the related treatment as their first-line therapy. The proportion of patients who selected that regimen as their first-line treatment was tabulated. The total cost increase for each current standard therapy in comparison to conventional treatments was calculated., Results: A total of 702 patients (pts) were surveyed. Of those enrolled, 342 (48.7%) received high-cost treatment [estimated monthly drug costs exceeding ~500 000 Japanese Yen (JPY)]. Of these, 16 pts (4.7%) were receiving very high-cost treatment, amounting to more than 1 000 000 JPY per month. Fifty three (15.5%) of the patients who received high-cost treatment were 75 years of age or older. Of these, 1 pt (0.3%) were receiving very high-cost treatment. Analyses of incremental costs by current drugs showed that abemaciclib was costly with total additional cost of 6 365 670 JPY per patient. The total additional cost of the regimen per patient that included palbociclib was the second highest at 4011248 JPY, followed by atezolizumab at 3209033 JPY., Conclusions: The findings indicate that evaluating the financial implications of high-cost treatments requires considering not only drug prices but also analysis of total cost increase., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The present study aimed to summarize and report data on errors related to treatment planning, which were collected by medical physicists. The following analyses were performed based on the 10-year error report data: (1) listing of high-risk errors that occurred and (2) the relationship between the number of treatments and error rates, (3) usefulness of the Automated Plan Checking System (APCS) with the Eclipse Scripting Application Programming Interface and (4) the relationship between human factors and error rates. Differences in error rates were observed before and after the use of APCS. APCS reduced the error rate by ~1% for high-risk errors and 3% for low-risk errors. The number of treatments was negatively correlated with error rates. Therefore, we examined the relationship between the workload of medical physicists and error occurrence and revealed that a very large workload may contribute to overlooking errors. Meanwhile, an increase in the number of medical physicists may lead to the detection of more errors. The number of errors was correlated with the number of physicians with less clinical experience; the error rates were higher when there were more physicians with less experience. This is likely due to the lack of training among clinically inexperienced physicians. An environment to provide adequate training is important, as inexperience in clinical practice can easily and directly lead to the occurrence of errors. In any environment, the need for additional plan checkers is an essential factor for eliminating errors., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Prognostic predictors of immunotherapy in patients with advanced endometrial cancer remain unclear. The potential role of inflammatory predictors, including pretreatment neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and hemoglobin, albumin, lymphocyte and platelet scores, was investigated., Methods: Between August 2018 and December 2023, 35 patients were retrospectively analyzed. Prognostic predictors were compared, and optimal cut-off values that exhibited the greatest discrimination for overall response, disease control, progression-free survival and overall survival were determined. Multivariate analysis was used to assess the prognostic significance of the predictors., Results: The greatest discrimination for overall response, progression-free survival and overall survival included platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and hemoglobin, albumin, lymphocyte and platelet; the areas under the curve were 0.638, 0.649 and 0.641, respectively. The precise cut-off values of neutrophil-to-lymphocyte ratio for progression-free survival and overall survival were 4.92 and 5.40, respectively. The lower neutrophil-to-lymphocyte ratio group had a significantly longer progression-free survival (P = 0.001, median survival; 4.0 months vs. 19 months) and longer overall survival (P = 0.002, median survival; 5.0 months vs. 21 months). Of the risk factors assessed, neutrophil-to-lymphocyte ratio (hazard ratio = 4.409; 95% CI = 1.10-17.64; P = 0.036) and regimen (hazard ratio = 5.559; 95% CI = 1.26-24.49; P = 0.023) were independently correlated with overall survival., Conclusion: In patients with advanced endometrial cancer, pretreatment neutrophil-to-lymphocyte ratio may be a prognostic predictor of those who would benefit from immunotherapy., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Immunoglobulin A vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Due to a lack of evidence, treatment recommendations are based on expert opinion, resulting in variation. The aim of this study was to describe the clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy-proven IgAVN in order to identify prognostic risk factors and signals of treatment efficacy., Methods: Retrospective data were collected on 1148 children with biopsy-proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analysed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow-up., Results: The median follow-up was 3.7 years (interquartile range 2-6.2). At last follow-up, 29% of patients had an eGFR <90 mL/min/1.73 m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second-line immunosuppressive regimen being superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow-up., Conclusion: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly, there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma that primarily affects the genital and axillary areas in older individuals. A limited number of paired patients with familial EMPD (i.e. parent-offspring, siblings) have been reported but the genetics have not yet been adequately studied. We report, to the best of our knowledge, the first familial cases of patients with EMPD involving three affected siblings. The tumour-only multigene panel testing using surgical specimens revealed a heterozygous c.2997A>C (p.Glu999Asp) nonsynonymous variant in the proto-oncogene MET (NM&#95;000245.4) in the three affected siblings. The germline multigene panel testing using peripheral blood lymphocytes revealed the same missense MET variant in all five family members who were tested, including two asymptomatic offspring (51 and 37 years of age). The MET variant we identified could be involved in EMPD carcinogenesis. Further genomic analyses of patients with familial EMPD are warranted to validate the pathogenic relevance of MET variants in EMPD development., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide., Methods: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients., Results: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70., Conclusions: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility., (© The Author(s) 2024. Published by Oxford University Press.)

The study investigated radiation dose, vascular computed tomography (CT) enhancement and image quality of cardiac computed tomography angiography (CCTA) with and without bolus tracking (BT) methods in infants with congenital heart disease (CHD). The volume CT dose index (CTDIvol) and dose length product (DLP) were recorded for all CT scans, and the effective dose was obtained using a conversion factors. The CT number for the ascending aorta (AO) and pulmonary artery (PA), image noise of muscle tissue and contrast-to-noise ratio (CNR) were measured and calculated. The median values in the groups with and without BT were 2.20 mGy versus 0.44 mGy for CTDIvol, 8.10 mGy·cm versus 6.20 mGy·cm for DLP, and 0.66 mSv versus 0.51 mSv for effective dose (p < 0.001). There were no statistical differences in vascular CT enhancement, image noise, and CNR. CCTA without BT methods can reduce the radiation dose while maintaining vascular CT enhancement and image quality compared to CCTA with BT methods., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Due to the lack of a national mortality inequality monitoring framework, the overall picture in Japan remains unclear. Here, we investigated educational inequalities in mortality and their cause-specific contribution in Japan., Method: Data were obtained by linking the 2010 Japanese population census and death records between 1 October 2010 and 30 September 2015. We included 7 984 451 Japanese people aged 30-79 years who had a unique 'matching key' generated by sex, birth year/month, address (municipality), marital status and age of spouse (9.9% of the total census population). We computed population-weighted all-cause and cause-specific age-standardized mortality rates (ASMRs) by education level. In addition, we calculated the slope index of inequality (SII), relative index inequality (RII) by education level, and population attributable fraction (PAF) referenced with the highest education (e.g. university graduation)., Results: Individuals with less education had higher all-cause and cause-specific ASMRs than highly educated individuals. All-cause SII (per 100 000 person-years) values were 433 (95% CI: 410-457) for men and 235 (95% CI: 217-252) for women. RII values were 1.48 (95% CI: 1.45-1.51) for men and 1.47 (95% CI: 1.43-1.51) for women. Estimated PAFs, excess premature deaths caused by educational inequalities, were 11.6% for men and 16.3% for women, respectively. Cerebrovascular diseases, ischaemic heart diseases and lung cancer were the major contributors to mortality inequalities for both sexes., Conclusions: This first census-based comprehensive report on cause-specific educational mortality inequalities suggested that differences in unfavourable health risk factors by educational background might be associated with these inequalities in Japan., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

In association with an update of the Japan Society of Gynecologic Oncology clinical practice guidelines for endometrial cancer in 2023, a systematic review was conducted about the therapeutic benefit of adjuvant therapy on patients with early-stage endometrial carcinoma, who presented positive peritoneal cytology (PPC) without the risk factors for recurrence. The systematic review only included two eligible retrospective studies. Both studies included patients with risk factors for recurrence. A nationwide study in the United States reported that adjuvant chemotherapy was associated with the reduced risk of death among patients with stages I-II endometrial cancer with PPC by multivariate, propensity score-adjusted analysis. Another single-center study in Japan reported no association between adjuvant chemotherapy and relapse-free survival among patients with stage IA endometrial cancer by univariate analysis. This systematic review identified that evidence was limited with conflicting results. Continuous evaluation is warranted to address this clinical question., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objectives: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM., Methods: Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed., Results: A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03)., Conclusions: Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The N-terminal tails of histones protrude from the nucleosome core and are target sites for histone modifications, such as acetylation and methylation. Histone acetylation is considered to enhance transcription in chromatin. However, the contribution of the histone N-terminal tail to the nucleosome transcription by RNA polymerase II (RNAPII) has not been clarified. In the present study, we reconstituted nucleosomes lacking the N-terminal tail of each histone, H2A, H2B, H3 or H4, and performed RNAPII transcription assays. We found that the N-terminal tail of H3, but not H2A, H2B and H4, functions in RNAPII pausing at the SHL(-5) position of the nucleosome. Consistently, the RNAPII transcription assay also revealed that the nucleosome containing N-terminally acetylated H3 drastically alleviates RNAPII pausing at the SHL(-5) position. In addition, the H3 acetylated nucleosome produced increased amounts of the run-off transcript. These results provide important evidence that the H3 N-terminal tail plays a role in RNAPII pausing at the SHL(-5) position of the nucleosome, and its acetylation directly alleviates this nucleosome barrier., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We investigated the radiation-quality-dependent bystander cellular effects using heavy-ion microbeams with different ion species. The heavy-ion microbeams were produced in Takasaki Ion Accelerators for Advanced Radiation Application, National Institutes for Quantum Science and Technology. Carbon (12C5+, 220 MeV), neon (20Ne7+, 260 MeV) and argon (40Ar13+, 460 MeV) ions were used as the microbeams, collimating the beam size with a diameter of 20 μm. After 0.5 and 3 h of irradiation, the surviving fractions (SFs) are significantly lower in cells irradiated with carbon ions without a gap-junction inhibitor than those irradiated with the inhibitor. However, the same SFs with no cell killing were found with and without the inhibitor at 24 h. Conversely, no cell-killing effect was observed in argon-ion-irradiated cells at 0.5 and 3 h; however, significantly low SFs were found at 24 h with and without the inhibitor, and the effect was suppressed using vitamin C and not dimethyl sulfoxide. The mutation frequency (MF) in cells irradiated with carbon ions was 8- to 6-fold higher than that in the unirradiated control at 0.5 and 3 h; however, no mutation was observed in cells treated with the gap-junction inhibitor. At 24 h, the MFs induced by each ion source were 3- to 5-fold higher and the same with and without the inhibitor. These findings suggest that the bystander cellular effects depend on the biological endpoints, ion species and time after microbeam irradiations with different pathways., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

To understand the growth of lactic acid bacteria (LAB), Limosilactobacillus fermentum, in response to medium compositions, a deep neural network (DNN) was designed using amino acids (AAs) as explanatory variables and LAB growth as the objective variable. Sixty-four different patterns of free AAs were set using an orthogonal array. The best DNN model had high accuracy with low mean square errors and predicted that Asp would affect LAB growth. Bayesian optimization (BO) using this model recommended an optimal growth media comprising maximum amounts of Asn, Asp, Lys, Thr, and Tyr and minimum amounts of Gln, Pro, and Ser. Furthermore, this proposed media was empirically validated to promote LAB growth. The absence of Gln, Ser, and Pro indicates that the different growth trends among the DNN-BO-optimized media were likely caused by the interactions among the AAs and the other components., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background/objectives: Hypoxia during orthodontic tooth movement (OTM) induces reactive oxygen species (ROS) production in periodontal tissues. Superoxide dismutase 3 (SOD3) is an anti-inflammatory enzyme that protects cells from ROS. This study investigated the expression and function of SOD3 during rat OTM and in hypoxia-exposed rat periodontal ligament (PDL) cells., Materials/methods: OTM of right maxillary first molars were performed in 8-week-old male Sprague-Dawley rats using closed-coil spring for 1 and 14 days (n = 6 per group). SOD3 and hypoxia-inducible factor 1-alpha (HIF-1α) protein expression was evaluated by immunohistochemistry. The effects of SOD3 on cell viability and proliferation, ROS production, and mRNA expression of Hif1-α, receptor activator of nuclear factor kappa-Β ligand (Rankl), and osteoprotegerin (Opg) in PDL cells and osteoclast differentiation were investigated under normal and hypoxic conditions., Results: SOD3 expression in PDL tissues significantly decreased on the compression side on day 1 and on both sides on day 14 of OTM. HIF-1α levels significantly increased on the compression side on day 14. Cell viability, cell proliferation, and Opg mRNA expression decreased, whereas ROS production and Hif1-α and Rankl mRNA expression increased in the PDL cells upon SOD3 silencing. Hypoxia reduced Sod3 and Opg mRNA expression and increased ROS, Rankl mRNA expression, and osteoclast formation; SOD3 treatment attenuated these effects., Conclusion/implications: SOD3 plays a role in periodontal tissue remodelling during OTM and in hypoxia-exposed PDL cells through ROS, HIF-1α, and RANKL/OPG pathways. Moreover, SOD3 treatment could attenuate the negative effects of hypoxia on the PDL cells., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Hypothesis: Dynamics of the distributed sets of functionally synchronized brain regions, known as large-scale networks, are essential for the emotional state and cognitive processes. However, few studies were performed to elucidate the aberrant dynamics across the large-scale networks across multiple psychiatric disorders. In this paper, we aimed to investigate dynamic aspects of the aberrancy of the causal connections among the large-scale networks of the multiple psychiatric disorders., Study Design: We applied dynamic causal modeling (DCM) to the large-sample multi-site dataset with 739 participants from 4 imaging sites including 4 different groups, healthy controls, schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), to compare the causal relationships among the large-scale networks, including visual network, somatomotor network (SMN), dorsal attention network (DAN), salience network (SAN), limbic network (LIN), frontoparietal network, and default mode network., Study Results: DCM showed that the decreased self-inhibitory connection of LIN was the common aberrant connection pattern across psychiatry disorders. Furthermore, increased causal connections from LIN to multiple networks, aberrant self-inhibitory connections of DAN and SMN, and increased self-inhibitory connection of SAN were disorder-specific patterns for SCZ, MDD, and BD, respectively., Conclusions: DCM revealed that LIN was the core abnormal network common to psychiatric disorders. Furthermore, DCM showed disorder-specific abnormal patterns of causal connections across the 7 networks. Our findings suggested that aberrant dynamics among the large-scale networks could be a key biomarker for these transdiagnostic psychiatric disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objective: We occasionally observed internal mammary lymph node metastases of breast cancer in a clinical setting. However, unlike a standard treatment in axillary metastasis, surgical resection for internal mammary lymph node metastasis is not prevalent because of unclear safety and benefits. Thus, we aimed to evaluate the diagnostic ability and clinical outcomes of positron emission tomography/computed tomography and video-assisted thoracoscopic surgery., Methods: We retrospectively investigated 34 patients with breast cancer with abnormal 18F-fluorodeoxyglucose uptake in internal mammary lymph nodes, at a single centre, between January 2015 and June 2022 and identified 11 female patients (mean age ± SD, 51.5 ± 12.9 years) who underwent video-assisted thoracoscopic surgery resection. Positron emission tomography/computed tomography was used to determine the clinical stage. We reviewed the surgical pathology of eleven and two patients who underwent direct-view internal mammary lymph node resection to calculate the positive predictive value of positron emission tomography/computed tomography., Results: Ipsilateral fluorodeoxyglucose accumulation was observed, with an average maximum standardized uptake value of 8.9 (range, 3.1-24.0). No perioperative complications occurred, and all patients who underwent video-assisted thoracoscopic surgery alone were discharged from the hospital on post-operative day 2 or 3. The estimated positive predictive value was 80%. All patients were alive, and seven of nine patients with metastasis were relapse-free, at a mean follow-up period of 17.9 months (range, 1-51). However, two patients had recurrence at 16 and 14 months after surgery for internal mammary lymph node relapse., Conclusions: Radiotherapy is the standard treatment for suspected internal mammary lymph node metastasis detected using positron emission tomography/computed tomography; however, we could safely perform minimally invasive video-assisted thoracoscopic surgery resection, leading to a definite pathological diagnosis., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

12(S)-hydroxyheptadecatrienoic acid (12-HHT) is a bioactive fatty acid synthesized from arachidonic acid via the cyclooxygenase pathway and serves as an endogenous ligand for the low-affinity leukotriene B4 receptor 2 (BLT2). Although the 12-HHT/BLT2 axis contributes to the maintenance of epithelial homeostasis, 12-HHT metabolism under physiological conditions is unclear. In this study, 12-keto-heptadecatrienoic acid (12-KHT) and 10,11-dihydro-12-KHT (10,11dh-12-KHT) were detected as 12-HHT metabolites in the human megakaryocytic cell line MEG01s. We found that 12-KHT and 10,11dh-12-KHT are produced from 12-HHT by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and prostaglandin reductase 1 (PTGR1), key enzymes in the degradation of prostaglandins, respectively. The 15-PGDH inhibitor SW033291 completely suppressed the production of 12-KHT and 10,11dh-12-KHT in MEG01s cells, resulting in a 9-fold accumulation of 12-HHT. 12-KHT and 10,11dh-12-KHT were produced in mouse skin wounds, and the levels were significantly suppressed by SW033291. Surprisingly, the agonistic activities of 12-KHT and 10,11dh-12-KHT on BLT2 were comparable to that of 12-HHT. Taken together, 12-HHT is metabolized into 12-KHT by 15-PGDH, and then 10,11dh-12-KHT by PTGR1 without losing the agonistic activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Mycorrhizae are one of the most fundamental symbioses between plants and fungi, with ectomycorrhizae being the most widespread in boreal forest ecosystems. Ectomycorrhizal fungi are hypothesized to have evolved convergently from saprotrophic ancestors in several fungal clades, especially members of the subdivision Agaricomycotina. Studies on fungal genomes have identified several typical characteristics of mycorrhizal fungi, such as genome size expansion and decreases in plant cell-wall degrading enzymes (PCWDEs). However, genomic changes concerning the evolutionary transition to the ectomycorrhizal lifestyle are largely unknown. In this study, we sequenced the genome of Lyophyllum shimeji, an ectomycorrhizal fungus that is phylogenetically related to saprotrophic species and retains some saprotroph-like traits. We found that the genome of Ly. shimeji strain AT787 lacks both incremental increases in genome size and reduced numbers of PCWDEs. Our findings suggest that the previously reported common genomic traits of mycorrhizal fungi are not essential for the ectomycorrhizal lifestyle, but are a result of abolishing saprotrophic activity. Since Ly. shimeji is commercially consumed as an edible mushroom, the newly available genomic information may also impact research designed to enhance the cultivation of this mushroom., (© The Author(s) 2023. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

The olfactory epithelium can regenerate after damage; however, the regeneration process is affected by various factors, such as viral infections, head trauma, and medications. Zinc is an essential trace element that has important roles in organ development, growth, and maturation. Zinc also helps regulate neurotransmission in the brain; nevertheless, its relationship with olfactory epithelium regeneration remains unclear. Therefore, we used a severe zinc deficiency mouse model to investigate the effects of zinc deficiency on olfactory epithelium regeneration. Male wild-type C57BL/6 mice were divided into zinc-deficient and control diet groups at the age of 4 weeks, and methimazole was administered at the age of 8 weeks to induce severe olfactory epithelium damage. We evaluated the olfactory epithelium before and 7, 14, and 28 days after methimazole administration by histologically analyzing paraffin sections. RNA sequencing was also performed at the age of 8 weeks before methimazole administration to examine changes in gene expression caused by zinc deficiency. In the zinc-deficient group, the regenerated olfactory epithelium thickness was decreased at all time points, and the numbers of Ki-67-positive, GAP43-positive, and olfactory marker protein-positive cells (i.e. proliferating cells, immature olfactory neurons, and mature olfactory neurons, respectively) failed to increase at some time points. Additionally, RNA sequencing revealed several changes in gene expression, such as a decrease in the expression of extracellular matrix-related genes and an increase in that of inflammatory response-related genes, in the zinc-deficient group. Therefore, zinc deficiency delays olfactory epithelium regeneration after damage in mice., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Physical inactivity due to prolonged sedentary behavior induces obesity. Therefore, we investigated whether housing mice in small cages to mimic sedentary behavior induced obesity and whether dietary oleamide (cis-9,10-octadeceneamide) suppressed the induced obesity. A single oral administration of oleamide (50 mg/kg) to mice resulted in the accumulation of the exogenous oleamide in abdominal visceral fat. Next, mice were housed in small cages and oleamide (50 mg/kg/d) was orally administered for 12 weeks. Housing mice in small cages impaired glucose tolerance and increased food efficiency. It also increased body weight and abdominal fat mass. Dietary oleamide improved the impairment and inhibited their increase in mice housed in small cages. Furthermore, dietary oleamide suppressed the mRNA expression of inflammation-related factors in the abdominal fat of mice housed in small cages. Hence, these results indicate that although housing mice in small cages induces obesity and increases abdominal fat mass, dietary oleamide suppresses the obesity., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Objective: Recent studies suggest that the knee is frequently involved in PMR. In this study, we aimed to determine whether the US assessment of the shoulder and knee discriminates between PMR and other differential diagnoses and improves the accuracy of the 2012 EULAR/ACR provisional classification criteria for PMR., Methods: We consecutively enrolled 81 untreated patients who received a diagnosis of PMR. These patients were divided into two groups based on the final diagnosis made at 1-year follow-up: PMR-definite group (n = 60) and PMR-mimic group (n = 21). We also enrolled age/sex-matched untreated RA patients with shoulder pain from an independent cohort (RA group, n = 60). All patients underwent comprehensive US assessment of the shoulder and knee for synovitis, bursitis, tenosynovitis, tendinitis and ligament inflammation at baseline., Results: US scores for tenosynovitis, tendinitis and ligament inflammation better discriminated the PMR-definite group from the PMR-mimic and RA groups than do those for synovitis or bursitis. Among logistic regression models to identify US variables that were associated with the PMR-definite group, the best fitted model included two US variables: the bilateral involvement of the shoulder (long head of biceps, supraspinatus or subscapularis tendon) and the bilateral involvement of the knee (popliteus tendon or medial or lateral collateral ligament). Incorporating these two items into the 2012 EULAR/ACR provisional classification criteria numerically increased the accuracy to classify the PMR-definite group., Conclusion: US assessment of the tendon/ligament-related lesions in the shoulder and knee may improve the accuracy of the 2012 EULAR/ACR provisional classification criteria for PMR., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

In Nepal, the number of diarrhoea hospitalizations in all ages is seriously high. According to the World Health Organization, diarrheal diseases can be substantially prevented through safe drinking water sources. In the Kathmandu Valley, because of the shortage of piped water, local residents use alternative water sources, such as groundwater, jars and tanker water. However, these alternative water sources can be contaminated. This study aimed to clarify the relationship between diarrhoea risk and the combinations of drinking water sources. A survey using multiple questionnaires on diarrhoea occurrence, water sources and water treatment was conducted three time between 2015 and 2016. The odds ratios (ORs) of developing diarrhoea were significantly high for drinking jar (OR 6.1) and tanker water (OR 8.4) compared with not drinking. The combined drinking of jar and tanker water obtained the 1 log higher OR compared with drinking only piped water. Conversely, drinking groundwater had a low OR, implying that the residents refrained from drinking polluted groundwater. In conclusion, diarrhoea occurrence was related not only to the level of water contamination, but also to a behavioural factor, i.e. people's careful management of the choice of multiple water sources., (© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Coronavirus disease 2019 (COVID-19) continues to be a major global health burden. This study aims to estimate the all-cause excess mortality occurring in the COVID-19 outbreak in Japan, 2020, by sex and age group., Methods: Daily time series of mortality for the period January 2015-December 2020 in all 47 prefectures of Japan were obtained from the Ministry of Health, Labour and Welfare, Japan. A two-stage interrupted time-series design was used to calculate excess mortality. In the first stage, we estimated excess mortality by prefecture using quasi-Poisson regression models in combination with distributed lag non-linear models, adjusting for seasonal and long-term variations, weather conditions and influenza activity. In the second stage, we used a random-effects multivariate meta-analysis to synthesize prefecture-specific estimates at the nationwide level., Results: In 2020, we estimated an all-cause excess mortality of -20 982 deaths [95% empirical confidence intervals (eCI): -38 367 to -5472] in Japan, which corresponded to a percentage excess of -1.7% (95% eCI: -3.1 to -0.5) relative to the expected value. Reduced deaths were observed for both sexes and in all age groups except those aged <60 and 70-79 years., Conclusions: All-cause mortality during the COVID-19 outbreak in Japan in 2020 was decreased compared with a historical baseline. Further evaluation of cause-specific excess mortality is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Aims: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated., Methods and Results: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected., Conclusion: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Microsatellite instability-high is a known biomarker for anti-PD-1/PD-L1 immune checkpoint therapy. It is also a known tumour feature of Lynch syndrome, detected most frequently in endometrial cancer. However, it remains unclear how microsatellite instability testing is carried out in the clinical field., Methods: Ninety-nine patients with gynaecological malignant tumours who underwent microsatellite instability testing as a companion diagnosis for pembrolizumab and 16 patients who previously underwent microsatellite instability testing as a screening for Lynch syndrome were recruited. Clinical information, microsatellite instability status, outcomes, genetic assessments and information about cancer tissue were retrospectively analysed., Results: Ninety-nine patients had 101 gynaecologic malignant tumours including 26 endometrial, 38 ovarian and 28 cervical cancers, 9 with other tumours including 2 synchronous endometrial and ovarian cancers. All tissue samples were successfully tested, even though some were ≥10-year-old samples. Three cases (3.0%, 3/99) showed microsatellite instability-high; all cases were endometrial cancers with one case of synchronous endometrial and ovarian cancer [11.5% (3/26) in endometrial cancer, 2.6% (1/38) in ovarian cancer], and there was no microsatellite instability-high in cervical and other cancers. One of the endometrial cancer patients received pembrolizumab treatment, but finally died of cancer. Two other cases underwent genetic testing; both were diagnosed as Lynch syndrome. Six cases (37.5%) showed microsatellite instability-high in screening for Lynch syndrome., Conclusions: Microsatellite instability-high was less commonly detected as a companion diagnosis for pembrolizumab in unselected gynaecologic patients. Genetic counselling should be always provided along with treatment selection., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The lipopolysaccharide (LPS)-triggered coagulation cascade in horseshoe crabs is composed of three zymogens belonging to the trypsinogen family: prochelicerase C, prochelicerase B (proB) and the proclotting enzyme (proCE). Trypsinogen-family members contain three conserved disulphides located around the active site. While it is known that proB evolutionarily lost one of the disulphides, the His-loop disulphide, the roles of the missing His-loop disulphide in proB remain unknown. Here, we prepared a proB mutant, named proB-murasame, equipped with a regenerated His-loop disulphide. The activation rate by upstream α-chelicerase C for proB-murasame was indistinguishable from that for wild-type (WT) proB. The resulting protease chelicerase B-murasame exhibited an 8-fold higher kcat value for downstream proCE than WT chelicerase B, whereas the Km value of chelicerase B-murasame was equivalent to that of WT chelicerase B. WT serpins-1, -2 and -3, identified as scavengers for the cascade, had no reactivity against WT chelicerase B, whereas chelicerase B-murasame was inhibited by WT serpin-2, suggesting that WT chelicerae B may trigger as-yet-unsolved phenomena after performing its duty in the cascade. The reconstituted LPS-triggered cascade containing proB-murasame exhibited ∼5-fold higher CE production than that containing WT proB. ProB-murasame might be used as a high value-adding reagent for LPS detection., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Objectives: This study aimed to evaluate whether recoarctation of the aorta (reCoA) after the Norwood procedure for hypoplastic left heart syndrome correlates with pre- and postoperative anatomic factors., Methods: This retrospective study included 48 patients who underwent Norwood procedure with right ventricle-to-pulmonary artery conduit between 2009 and 2017. Anatomical factors such as preoperative length, diameter of the main pulmonary artery (MPA), and postoperative neoaortic arch angle stratified by arch reconstruction technique were analysed using the receiver operating characteristic analysis., Results: Eleven patients needed surgical intervention for reCoA at stage 2. Out of the 30 patients who underwent direct anastomosis during arch reconstruction, 7 developed reCoA. Seven patients received the full patch augmentation (patch augmentation for both lesser and greater curvatures) and were all spared from reCoA. Among the patients who had direct anastomosis, the preoperative MPA length was correlated with the postoperative arch angle (P = 0.021) and was associated with the occurrence of reCoA (P = 0.002) and the best cutoff value for MPA length was 10 mm. The postoperative arch angle was also correlated with the incidence of reCoA (P < 0.001) and was larger in patients who underwent the full patch augmentation than in patients who had direct anastomosis (126° vs 112°, P = 0.005) despite comparable MPA length., Conclusions: ReCoA after the Norwood procedure correlates with MPA length when a direct anastomosis was used. Direct anastomosis can be considered in patients with a longer preoperative MPA. In other cases, the full patch augmentation should be considered for obtaining a large and smooth neoaortic arch., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Lessons Learned: Because S-1 is orally administered, OX-IRIS does not necessitate the continuous infusion of 5-FU and is more convenient. The recommended dose of OX-IRIS was determined to be level -1 (oxaliplatin, 65 mg/m 2 ; irinotecan, 100 mg/m 2 ; S-1, 80 mg/m 2 ), which has manageable safety and promising anticancer activities., Background: OX-IRIS is a new combination therapy of oxaliplatin, irinotecan, and S-1 for unresectable pancreatic ductal adenocarcinoma (PDAC), which may be beneficial because S-1 is administered orally and continuous infusion of 5-fluorouracil (5-FU) is not needed., Methods: Patients who had not received prior therapy for unresectable PDAC were enrolled. Adenocarcinoma or adenosquamous histology was required. Oxaliplatin and irinotecan were administered on days 1 and 15; S-1 was administered orally twice a day on days 1-14, followed by 14 days of rest (one cycle). Primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). Secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: In level 0 (oxaliplatin, 85 mg/m 2 ; irinotecan, 100 mg/m 2 ; S-1, 80 mg/m 2 ), two of five patients experienced DLT. In level -1 (oxaliplatin, 65 mg/m 2 ; irinotecan, 100 mg/m 2 ; S-1, 80 mg/m 2 ), DLT could not be evaluated in two of eight patients because one cycle was not completed; one of the remaining six patients experienced DLT. Anemia, thrombocytopenia, fatigue, nausea, anorexia, diarrhea, and peripheral sensory neuropathy were seen frequently in levels 0 and -1. ORR was 30% in levels 0 and -1. Median progression-free survival and median overall survival were 4.1 months (95% confidence interval [CI], 0.0-8.9 months) and 13.7 months (95% CI, 4.8-22.6 months), respectively., Conclusion: MTD of OX-IRIS therapy was estimated to be level 0, and the recommended dose (RD) for future trial was level -1., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Hydrogenophilus thermoluteolus, Thermochromatium tepidum, and Allochromatium vinosum, which grow optimally at 52, 49, and 25 °C, respectively, have homologous cytochromes c' (PHCP, TTCP, and AVCP, respectively) exhibiting at least 50% amino acid sequence identity. Here, the thermal stability of the recombinant TTCP protein was first confirmed to be between those of PHCP and AVCP. Structure comparison of the 3 proteins and a mutagenesis study on TTCP revealed that hydrogen bonds and hydrophobic interactions between the heme and amino acid residues were responsible for their stability differences. In addition, PHCP, TTCP, and AVCP and their variants with altered stability similarly bound nitric oxide and carbon oxide, but not oxygen. Therefore, the thermal stability of TTCP together with PHCP and AVCP can be tuned through specific interactions around the heme without affecting their gas-binding function. These cytochromes c' will be useful as specific gas sensor proteins exhibiting a wide thermal stability range., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Dietary fatty acids can affect chronic intestinal inflammation and have been reported to be associated with the development of ulcerative colitis (UC), mainly in Europe and the United States. The association of dietary intake of fatty acids and the risk for UC was investigated in Japan, where dietary habits lead to lower meat and higher fish consumption than in Western countries., Methods: A multicenter case-control study of 83 newly diagnosed patients with UC and 128 age- and sex-matched control patients in the hospital was conducted from 2008 to 2014. Dietary fatty acid intake in the preceding 1 month and 1 year were examined using a self-administered diet history questionnaire that was developed for Japanese people., Results: About 92% of patients had experienced the first symptoms of UC within the preceding 11 months. Regarding dietary habits in the preceding year, the risk for UC was significantly decreased in patients who consumed n-6/n-3 polyunsaturated fatty acids at a ratio of ≥5.2 (odds ratio [OR] = 0.26; 95% confidence interval [CI], 0.10-0.68). Conversely, an increased risk for UC was observed in the highest tertiles of consumption of docosahexaenoic acid (OR = 7.22; 95% CI, 2.09-24.95), eicosapentaenoic acid (OR = 6.91; 95% CI, 1.88-25.44), and docosapentaenoic acid (OR = 4.83; 95% CI, 1.56-14.95)., Conclusions: The ratio of n-6/n-3 polyunsaturated fatty acid intake was associated with a decreased risk for UC development. However, high intakes of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid may increase the risk for UC development., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Malate efflux from roots, which is regulated by the transcription factor STOP1 (SENSITIVE-TO-PROTON-RHIZOTOXICITY1) and mediates aluminum-induced expression of ALUMINUM-ACTIVATED-MALATE-TRANSPORTER1 (AtALMT1), is critical for aluminum resistance in Arabidopsis thaliana. Several studies showed that AtALMT1 expression in roots is rapidly observed in response to aluminum; this early induction is an important mechanism to immediately protect roots from aluminum toxicity. Identifying the molecular mechanisms that underlie rapid aluminum resistance responses should lead to a better understanding of plant aluminum sensing and signal transduction mechanisms. In this study, we observed that GFP-tagged STOP1 proteins accumulated in the nucleus soon after aluminum treatment. The rapid aluminum-induced STOP1-nuclear localization and AtALMT1 induction were detected in the presence of a protein synthesis inhibitor, suggesting that post-translational regulation is involved in these events. STOP1 also regulated rapid aluminum-induced expression for other genes that carry a functional/high-affinity STOP1-binding site in their promoter, including STOP2, GLUTAMATE-DEHYDROGENASE1 and 2 (GDH1 and 2). However STOP1 did not regulate Al resistance genes which have no functional STOP1-binding site such as ALUMINUM-SENSITIVE3, suggesting that the binding of STOP1 in the promoter is essential for early induction. Finally, we report that GDH1 and 2 which are targets of STOP1, are novel aluminum-resistance genes in Arabidopsis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Population studies investigating the contribution of immunometabolic disturbances to heart dysfunction remain scarce. We combined high-throughput biomarker profiling, multidimensional network analyses, and regression statistics to identify immunometabolic markers associated with subclinical heart dysfunction in the community., Methods: In 1,236 individuals (mean age, 51.0 years; 51.5% women), we measured 39 immunometabolic markers and assessed echocardiographic indexes of left ventricular diastolic dysfunction (LVDD) and left atrial (LA) reservoir dysfunction. We used partial least squares (PLS) to filter the most relevant biomarkers related to the echocardiographic characteristics. Subsequently, we assessed the associations between the echocardiographic features and biomarkers selected in PLS while accounting for clinical confounders., Results: Influential biomarkers in PLS of echocardiographic characteristics included blood sugar, γ-glutamyl transferase, d-dimer, ferritin, hemoglobin, interleukin (IL)-4, IL-6, and serum insulin and uric acid. In stepwise regression incorporating clinical confounders, higher d-dimer was independently associated with higher E/e' ratio and LA volume index (P ≤ 0.05 for all). In multivariable-adjusted analyses, the risk for LVDD increased with higher blood sugar and d-dimer (P ≤ 0.048). After full adjustment, higher serum insulin and serum uric acid were independently related to worse LA reservoir strain and higher risk for LA reservoir dysfunction (P ≤ 0.039 for all). The biomarker panels detected LVDD and LA reservoir dysfunction with 87% and 79% accuracy, respectively (P < 0.0001)., Conclusions: Biomarkers of insulin resistance, hyperuricemia, and chronic low-grade inflammation were associated with cardiac dysfunction. These biomarkers might help to unravel cardiac pathology and improve the detection and management of cardiac dysfunction in clinical practice., (© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Risk-reducing salpingo-oophorectomy is performed for the primary prevention of ovarian cancer in patients with hereditary breast-ovarian cancer syndrome. We performed risk-reducing salpingo-oophorectomy for the first time in Japan in 2008, and we experienced 20 cases of risk-reducing salpingo-oophorectomy through 2019. In the past, the use of risk-reducing salpingo-oophorectomy in Japan was restricted because it was not covered by a Japanese National Health Insurance. Since April 2020, risk-reducing salpingo-oophorectomy has been covered by insurance for patients with breast-ovarian cancer syndrome and pre-existing breast cancer, and this surgery is expected to become more widely implemented in Japan., Methods: To contribute to the widespread use of risk-reducing salpingo-oophorectomy in the future, we retrospectively reviewed 20 cases of risk-reducing salpingo-oophorectomy at our hospital cohort study to clarify the issues in its implementation., Results: The variant genes for which risk-reducing salpingo-oophorectomy was indicated were BRCA1 and BRCA2 in 13 (65%) and 7 patients (35%), respectively. The median age at which risk-reducing salpingo-oophorectomy was performed was 49 years (range, 38-58), 13 patients (65%) had gone through menopause, and 16 patients (80%) had a history of breast cancer. Of the five patients (25%) with vasomotor symptoms, four received Chinese medicine, and only one received hormone replacement therapy. Occult cancer was detected in the removed ovaries in two patients (10%), although no postoperative peritoneal carcinogenesis has been observed to date., Conclusions: Women who paid for risk-reducing salpingo-oophorectomy out of pocket were older than the recommended age at which the procedure should be performed, and this may explain the higher rate of occult cancers than previously reported. We need to perform risk-reducing salpingo-oophorectomy at the recommended age to ensure that the procedure is effective for primary prevention., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The carbon (C) ratios, namely the atomic ratios of C/(C + M), in nano-sized coherent MC precipitates (M = Ti, Nb) with the NaCl-type (B1) structure in ferritic steels, which had been isothermally aged at 580 °C, were investigated using atom probe tomography (APT). Considering the influences of the trajectory aberration, detection loss, and peak overlap, we determined the C ratios to be ~0.40 and ~0.45 for an equivalent volume diameter of 1.5–5 nm and 1–5 nm for the TiC and NbC precipitates, respectively, suggesting that there is a considerable fraction of C vacancies in both nano-sized precipitates. The apparent C ratios show significant scatter with decreasing particle size, while the apparent mean C ratios of very fine TiC particles, smaller than 1.5 nm, decreased with decreasing particle size. With the use of one of the latest APT instruments with a high detection efficiency, the scattering in the apparent C ratios was reduced because the counting statistics were improved; however, the artificial enrichment of C atoms to particular crystallographic directions of ferrite hindered the determination of the C ratio for very fine TiC particles smaller than 1.5 nm.

Background and Objectives: Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene are responsible for both Apert syndrome (AS) and Crouzon syndrome (CS). These diseases share phenotypic characteristics, including midfacial hypoplasia and premature fusion of the calvarial suture(s). Given the extensive range of craniofacial growth and developmental abnormalities, management of these patients requires a multidisciplinary approach. This study aimed to compare craniofacial, oral, and cervical morphological characteristics in Japanese orthodontic patients with AS or CS., Subjects and Methods: Lateral cephalograms, orthopantomograms, dental casts, medical interview records, facial photographs, and intraoral photographs of 7 AS patients and 12 CS patients on initial visits were used in this study. Cephalometric analyses were performed, and standard scores were calculated based on age- and sex-matched Japanese standard values., Results: Cephalometric analysis revealed that AS patients had significantly more severe maxillary hypoplasia in two dimensions and increased clockwise mandibular rotation. Additionally, cleft of the soft palate, anterior open bite, severe crowding in the maxillary dental arch, and congenitally missing teeth occurred more frequently among AS patients. Multiple fusions between cervical vertebrae C2, C3, C5, and C6 were observed in the AS patients., Limitations: Small sample size., Conclusions/implications: Our study shows that AS patients have more severe craniofacial and maxillofacial deformities than CS patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Long-term survival outcomes of patients who undergo endoscopic management of non-invasive upper tract urothelial carcinoma remain uncertain. The longest mean follow-up period in previous studies was 6.1 years. This study reports the long-term outcomes of patients with upper tract urothelial carcinoma who underwent ureteroscopic ablation at a single institution over a 28-year period., Methods: We identified all patients who underwent ureteroscopic management of upper tract urothelial carcinoma as their primary treatment at our institution between January 1991 and April 2011. Survival outcomes, including overall survival, cancer-specific survival, upper-tract recurrence-free survival and renal unit survival, were estimated using Kaplan-Meier methodology., Results: A total of 15 patients underwent endoscopic management, with a mean age at diagnosis of 66 years. All patients underwent ureteroscopy, and biopsy-confirmed pathology was obtained. Median (range; mean) follow-up was 11.7 (2.3-20.9, 11.9) years. Upper tract recurrence occurred in 87% (n = 13) of patients. Twenty percent (n = 3) of patients proceeded to nephroureterectomy. The estimated cancer-specific survival rate was 93% at 5, 10, 15 and 20 years. Estimated overall survival rates were 86, 80, 54 and 20% at 5, 10, 15 and 20 years. Only one patient experienced cancer-specific mortality. The estimated mean and median overall survival times were 14.5 and 16.6 years, respectively. The estimated mean cancer-specific survival time was not reached., Conclusions: Although upper tract recurrence is common, endoscopic management of non-invasive upper tract urothelial carcinoma provides a 90% cancer-specific survival rate at 20 years in selected patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Our aims were to assess whether arterial stiffness is associated with a higher risk for kidney dysfunction among persons without chronic kidney disease (CKD)., Methods: We analyzed data from the national health checkup system in Japan; for our analyses, we selected records of individuals who completed assessments of cardio-ankle vascular index (CAVI) and kidney function from 2005 to 2016. We excluded participants who had CKD at baseline, defined as the presence of proteinuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. We compared 2 groups of CAVI measurements-the highest quartile (≧8.1) and the combined lower 3 quartiles (<8.1). We used Cox proportional hazards models to assess associations between these 2 groups and subsequent CKD events, proteinuria, eGFR <60 ml/min/1.73 m2, and rapid eGFR decline (greater than or equal to -3 ml/min/1.73 m2 per year)., Results: The mean age of the 24,297 included participants was 46.2 years, and 60% were female. Over a mean follow-up of 3.1 years, 1,435 CKD events occurred. In a multivariable analysis, the hazard ratios with 95% confidence intervals (CIs) for the highest vs. combined lower quartiles of CAVI measurements were 1.3 (1.1, 1.5) for CKD events, 1.3 (0.96, 1.62) for proteinuria, 1.4 (1.1, 1.7) for eGFR <60 ml/min/1.73 m2, and the odds ratio with 95% CI was 1.3 (1.1, 1.4) for rapid eGFR decline., Conclusions: Persons with CAVI measurements ≧8.1 had a higher risk for CKD events compared with their counterparts with CAVI measurements <8.1. Greater arterial stiffness among adults without CKD may be associated with kidney dysfunction., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)